Exercise Ventilatory Inefficiency Adds to Lung Function in Predicting Mortality in COPD

Figures & data

Table 1. Clinical, resting functional, and CPET responses for the whole sample and for patients separated by mortality status.

	All patients (N = 288)	Survivors (N = 211)	Nonsurvivors (N = 77)
Age, years	65.5 ± 9.1	64.8 ± 8.9	67.4 ± 9.1^*
Males, N (%)	160 (55.6)	110 (52.1)	50 (64.9)^*
BMI, kg/m^2	27.7 ± 6.1	28.7 ± 6.1	25.5 ± 5.2^*
Current smoking, N (%)	84 (29.2)	67 (31.8)	17 (22.1)
Cumulative smoking, pack-years	50.0 ± 21.1	50.3 ± 20.1	48.1 ± 23.1
BDI, total score	7.1 ± 2.1	7.4 ± 2.3	6.1 ± 1.8^*
Charlson Index (total score)	4 [3.5]	3 [3.5]	5.5 [4.0]^*
Coronary artery disease, N	51	32	19
Chronic heart failure, N	34	13	21^*
Cerebrovascular disease, N	22	12	10
Diabetes mellitus, N	39	28	11
COPD-related medications
Short-acting bronchodilators, N	288 (100)	211 (100)	77 (100)
Long-acting bronchodilators, N	243 (84.4)	171 (81.0)	72 (93.5)^*
Inhaled corticosteroids, N	216 (75.0)	149 (70.6)	67 (87.0)^*
Roflumilast, N	24 (8.3)	10 (4.7)	14 (18.2)^*
Lung function
FEV1/FVC	0.49 ± 0.11	0.51 ± 0.11	0.44 ± 0.10^*
FEV1, % pred	61.2 ± 25.0	65.6 ± 25.2	49.1 ± 21.1^*
GOLD stages
I	75 (26.0)	67 (31.8)	8 (10.4)^*
II	103 (35.8)	82 (38.9)	21(27.3)
III/IV	110 (38.2)	62 (29.4)	48 (62.3)^*
TLC, % pred	113.9 ± 16.9	111.1 ± 15.7	121.7 ± 17.8^*
RV, % pred	158.5 ± 61.1	145.5 ± 57.2	193.4 ± 58.0^*
TLCO, % pred	68.6 ± 22.1	70.8 ± 21.1	62.5 ± 23.6^*
TLCO/VA, % pred	85.1 ± 19.5	85.1 ± 19.5	72.9 ± 23.5^*
IC, % pred	85.8 ± 24.1	91.5 ± 23.9	70.2 ± 16.9^*
IC/TLC	0.35 ± 0.11	0.38 ± 0.10	0.27 ± 0.07^*
Cardiopulmonary exercise test^a
Metabolic and cardiovascular responses
VO2, mL/min/kg	16.2 ± 6.0	17.1 ± 6.4	13.9 ± 4.0^*
VO2, % pred	73.5 ± 27.4	77.8 ± 28.3	61.6 ± 20.8^*
HR, bpm	123 ± 20	126 ± 22	117 ± 18^*
HR, % pred	74.5 ± 12.6	75.7 ± 13.0	71.1 ± 10.8^*
O2 pulse, mL/beat	9.9 ± 3.	10.8 ± 4.0	8.6 ± 3.4^*
Ventilatory and gas exchange responses
VE/VCO2 rest	40.2 ± 8.5	38.1 ± 7.3	43.3 ± 10.1^*
VE/VCO2 nadir	34.5 ± 7.1	32.6 ± 6.7	38.7 ± 9.2^*
VE/VCO2 peak	35.0 ± 6.8	33.4 ± 6.1	39.0 ± 9.4^*
PETCO2 nadir, kPa	5.13 ± 0.87	5.37 ± 0.78	5.30 ± 0.94^*
SpO2, %	92.9 ± 5.1	93.3 ± 4.1	91.8 ± 2.7^*
Δ Peak-rest IC, L	−0.42 ± 0.44	−0.40 ± 0.49	−0.46 ± 0.38
IC, L	1.98 ± 0.70	2.08 ± 0.79	1.59 ± 0.52^*
IRV, L	0.58 ± 0.38	0.63 ± 0.41	0.42 ± 0.28^*
VT, L	1.40 ± 0.30	1.46 ± 0.32	1.18 ± 0.20^*
VT/IC	0.71 ± 0.13	0.70 ± 0.13	0.74 ± 0.11^*
Sensorial responses
Dyspnea score	5 [3]	5 [3.5]	5 [2.5]
Leg effort score	5 [3]	5 [3.3]	5 [1.8]^*
Dyspnea ≥ leg effort, N (%)	161 (55.9)	112 (48.3)	59 (76.6)^*
Dyspnea–leg effort	0 [2.5]	0 [3]	0 [1.5]^*

Values are mean ± SD or median [interquartile range]. ^*p < 0.05.

^aPeak exercise responses (unless stated otherwise).

Abbreviations: BMI = body mass index; BDI = baseline dyspnea index; COPD = chronic obstructive pulmonary disease; FEV₁ = forced expiratory volume in one second; FVC = forced vital capacity; GOLD= Global Initiative for Chronic Obstructive Lung Disease; TLC = total lung capacity; RV = residual volume; TL_CO = transfer factor; VA= alveolar volume; IC = inspiratory capacity; IRV = inspiratory reserve volume; VO₂ = oxygen uptake; HR = heart rate; VE = minute ventilation; VCO₂ = carbon dioxide output; PETCO2= end-tidal partial pressure for CO2; SpO₂ = oxy-hemoglobin saturation by pulse oximetry; VT= tidal volume.

Figure 1. Receiver operating characteristics curve analyses contrasting lung function and exercise variables performance in predicting all-cause and respiratory mortality in patients with COPD. Best cut-offs for individual variables are marked by circles and shown in Tables 2 and 3, respectively. p < 0.05: ^* vs. FEV₁, TLC, and TL_CO/VA (lung function) and vs. O₂ pulse, HR, and SpO₂ (exercise). Abbreviations: COPD = chronic obstructive pulmonary disease; AUC = area under the curve; CI = confidence interval; IC = inspiratory capacity; TLC = total lung capacity; RV = residual volume; FEV₁ = forced expiratory volume in one second; TL_CO = transfer factor; VO₂ = oxygen uptake; VE = minute ventilation; VCO₂ = carbon dioxide output; HR = heart rate; SpO₂ = oxy-hemoglobin saturation by pulse oximetry.

Table 2. All-cause mortality prediction: performance of optimal thresholds for individual lung function and exercise variables.

	Criterion	Youden Index	Sensitivity (95% CI)	Specificity (95% CI)	PPV (95% CI)	NPV (95% CI)
Lung function
FEV1, % pred	≤55	0.37	0.75 (0.64–0.84)	0.62 (0.55–0.69)	2.01 (1.62–2.54)	0.39 (0.30–0.60)
TLC, % pred	>115	0.32	0.67 (0.55–0.77)	0.64 (0.58–0.71)	1.93 (1.54–2.43)	0.50 (0.42–0.71)
RV, % pred	>150	0.43	0.79 (0.68–0.87)	0.54 (0.57–0.70)	2.23 (1.81–2.84)	0.32 (0.21–0.51)
TLCO, % pred	≤63	0.26	0.64 (0.53–0.75)	0.61 (0.54–0.68)	1.69 (1.33–2.16)	0.57 (0.42–0.84)
IC/TLC	≤0.34	0.48	0.83 (0.72–0.90)	0.65 (0.58–0.72)	2.40 (1.91–3.08)	0.26 (0.24–0.42)
Cardiopulmonary exercise test^a
VO2, % pred	≤75	0.32	0.81 (0.71–0.89)	0.50 (0.43–0.57)	1.64 (1.43–2.09)	0.36 (0.24–0.51)
HR, % pred	≤72	0.24	0.64 (0.53–0.75)	0.59 (0.52–0.65)	1.59 (1.32–2.07)	0.59 (0.43–0.83)
O2 pulse, mL/beat	≤8.5	0.23	0.59 (0.47–0.70)	0.63 (0.56–0.70)	1.64 (1.34–2.16)	0.63 (0.52–0.84)
VE/VCO2nadir	>34	0.31	0.67 (0.54–0.76)	0.65 (0.58–0.72)	1.91 (1.51–2.47)	0.52 (0.43–0.72)
SpO2, %	≤91	0.17	0.37 (0.26–0.49)	0.79 (0.73–0.84)	1.85 (1.24–2.76)	0.78 (0.62–0.92)

^a Peak exercise responses (unless stated otherwise).

CI = confidence interval; PPV = positive predictive value; NPV = negative predictive value; FEV₁ = forced expiratory volume in one second; TLC = total lung capacity; RV = residual volume; TL_CO = transfer factor; IC = inspiratory capacity; VO₂ = oxygen uptake; HR = heart rate; VE = minute ventilation; VCO₂ = carbon dioxide output; SpO₂ = oxy-hemoglobin saturation by pulse oximetry.

Table 3. Respiratory mortality prediction: performance of optimal thresholds for individual lung function and exercise variables.

	Criterion	Youden Index	Sensitivity (95%CI)	Specificity (95% CI)	PPV (95% CI)	NPV (95% CI)
Lung function
FEV1, % pred	≤50	0.39	0.79 (0.66–0.88)	0.60 (0.53–0.66)	2.00 (1.64–2.51)	0.34 (0.24–0.66)
TLC, % pred	>120	0.35	0.70 (0.57–0.82)	0.64 (0.57–0.70)	1.98 (1.60–2.50)	0.46 (0.31–0.72)
RV, % pred	>160	0.42	0.79 (0.66–0.88)	0.63 (0.56–0.69)	2.17 (1.81–2.73)	0.33 (0.24–0.55)
TLCO, % pred	≤63	0.29	0,68 (0.55–0.80)	0.43 (0.53–0.66)	1.74 (1.46–2.28)	0.51 (0.32–0.82)
IC/TLC	≤0.31	0.48	0.75 (0.62–0.86)	0.70 (0.63–0.75)	2.53 (2.08–3.22)	0.34 (0.22–0.51)
Cardiopulmonary exercise test^a
VO2, % pred	≤66	0.37	0.74 (0.61–0.84)	0.63 (0.56–0.69)	2.03 (1.62–2.60)	0.41 (0.34–0.62)
HR, % pred	<70	0.18	0.62 (0.48–0.74)	0.56 (0.49–0.63)	1.43 (1.14–1.82)	0.67 (0.51–1.00)
O2 pulse, mL/beat	≤10	0.30	0.93 (0.83–0.98)	0.37 (0.31–0.44)	1.49 (1.32–1.72)	0.18 (0.07–0.54)
VE/VCO2 nadir	≥34	0.45	0.79 (0.66–0.88)	0.66 (0.59–0.72)	2.34 (1.92–2.92)	0.31 (0.20–0.54)
SpO2, %	≤92	0.24	0.53 (0.39–0.66)	0.70 (0.64–0.76)	1.83 (1.31–2.53)	0.66 (0.54–0.96)

^a Peak exercise responses (unless stated otherwise).

CI = confidence interval; PPV = positive predictive value; NPV = negative predictive value; FEV₁ = forced expiratory volume in one second; TLC = total lung capacity; RV = residual volume; TL_CO = transfer factor; IC = inspiratory capacity; VO₂ = oxygen uptake; HR = heart rate; VE = minute ventilation; VCO₂ = carbon dioxide output; SpO₂ = oxy-hemoglobin saturation by pulse oximetry.

Table 4. All-cause mortality prediction: univariate and multivariate logistic regression modeling.

	Univariate analysis		Multivariate analysis^a
	Relative risk (95% CI)	p	Relative risk (95% CI)	p
Clinical
Age, per 1 year increase	1.032 (1.002–1.064)	0.042	1.047 (1.007–1.087)	0.019
Males	0.998 (0.990–1.096)	0.321
BMI, per 1 kg/m^2 less	0.881 (0.832–0.934)	<0.001	0.905 (0.844–0.970)	0.005
BDI, per 1 unit less	0.923 (0.813–1.023)	0.282
Charlson Index, per 1 unit increase	1.101 (1.065–1.142)	<0.001	1.095 (1.058–1.137)	0.001
Lung function
FEV1 ≤ 55% pred	5.100 (2.832–9.186)	<0.001
TLC > 115% pred	3.544 (2.031–6.182)	<0.001
RV > 150% pred	6.772 (3.649–12.565)	<0.001
TLCO ≤ 63% pred	2.913 (1.691–5.018)	0.001	-	-
IC/TLC ≤ 0.34	7.326 (4.423–15.673)	<0.001	2.659 (1.208–5.852)	0.015
Cardiopulmonary exercise test^b
VO2 ≤ 75% pred	3.922 (2.124–7.241)	<0.001	−	−
HR ≤ 72% pred	2.603 (1.520–4.458)	0.004	−	−
O2 pulse ≤ 8.7 mL/beat	2.447 (1.436–4.169)	0.001	−	−
VE/VCO2 nadir > 34	3.708 (2.137–6.433)	<0.001	2.081 (1.170–3.766)	0.010
SpO2 ≤ 91%	2.360 (1.154–4.198)	0.003	−	−

^a Backward stepwise method with Wald's criteria adjusted at nine iterations. Variables presenting multicollinearity with IC/TLC were not considered in the initial model (FEV₁, RV, and TLC). Only variables with statistically significant relative risks are shown.

^b Peak exercise responses (unless stated otherwise).

CI = confidence interval; BMI = body mass index; BDI = baseline dyspnea index; FEV₁ = forced expiratory volume in one second; TLC = total lung capacity; RV = residual volume; TL_CO = transfer factor; IC = inspiratory capacity; VO₂ = oxygen uptake; HR = heart rate; VE = minute ventilation; VCO₂ = carbon dioxide output; SpO₂ = oxy-hemoglobin saturation by pulse oximetry.

Table 5. Respiratory mortality prediction: univariate and multivariate logistic regression modeling.

	Univariate analysis		Multivariate analysis^a
	Relative risk (95% CI)	p	Relative risk (95% CI)	p
Clinical
Age, per 1 year increase	1.036 (1.006–1.070)	0.021	1.046 (1.007–1.087)	0.02
Males	0.998 (0.990–1.096)	0.321
BMI, per 1 kg/m^2 less	0.893 (0.840–0.950)	0.010	0.910 (0.849–0.974)	0.04
BDI, per 1 unit less	0.923 (0.813–1.023)	0.282
Charlson Index, per 1 unit increase	1.081 (1.045–1.122)	0.014	1.035 (1.010–1.121)	0.04
Lung function
FEV1 ≤ 50% pred	6.214 (2.715–10.124)	<0.001
TLC > 120% pred	2.724 (1.984–7.321)	<0.001
RV > 160% pred	6.487 (3.631–12.624)	<0.001
TLCO ≤ 63% pred	2.874 (1.641–5.128)	0.001	−	−
IC/TLC ≤ 0.31	8.154 (4.125–16.081)	<0.001	4.486 (2.156–9.337)	<0.001
Cardiopulmonary exercise test^b
VO2 ≤ 66% pred	3.628 (2.091–7.187)	<0.001	−	−
HR ≤ 70% pred	2.124 (1.314–4.474)	0.002	−	−
O2 pulse ≤ 10.0 mL/beat	2.084 (1.321–4.312)	0.001	−	−
VE/VCO2 nadir > 34	3.999 (2.148–7.021)	<0.001	1.998 (1.432–2.803)	0.010
SpO2 ≤ 92%	2.184 (1.335–4.198)	0.003	−	−

^a Backward stepwise method with Wald's criteria adjusted at nine iterations. Variables presenting multicollinearity with IC/TLC were not considered (FEV₁, RV, and TLC). Only variables with statistically significant relative risks are shown.

^b Peak exercise responses (unless stated otherwise).

CI = confidence interval; BMI = body mass index; BDI = baseline dyspnea index; FEV₁ = forced expiratory volume in one second; TLC = total lung capacity; RV = residual volume; TL_CO = transfer factor; IC = inspiratory capacity; VO₂ = oxygen uptake; HR = heart rate; VE = minute ventilation; VCO₂ = carbon dioxide output; SpO₂ = oxy-hemoglobin saturation by pulse oximetry.

Figure 2. Kaplan–Meyer survival curves for resting IC/TLC and VE/VCO₂ nadir optimal thresholds as defined by receiver operating characteristics curve analyses. Abbreviations: IC = inspiratory capacity; TLC = total lung capacity; VE = exercise ventilation; VCO₂ = CO₂ output.