Inspiratory Constraints and Ventilatory Inefficiency Are Superior to Breathing Reserve in the Assessment of Exertional Dyspnea in COPD

Figures & data

Table 1. Contingency table showing the level of agreement between low or preserved breathing reserve (maximal voluntary ventilation estimated as FEV₁ × 40) versus the presence of not of critical inspiratory constraints (end-inspiratory lung volume (EILV)/total lung capacity (TLC) ratio) or excess ventilation (ventilation (V̇E)/CO₂ output (V̇CO₂) ratio) in patients with COPD.

	Breathing reserve (BR), ≤20%	Breathing reserve (BR), >20%
EILV/TLC ≥ 0.9	91 (72.8 % within BR) (53.8 % within EILV/TLC)	78 (47.9 % within BR) (46.2% within EILV/TLC)	169 (58.7%)
EILV/TLC < 0.9	34 (27.2 % within BR) (28.6 % within EILV/TLC)	85 (52.1 % within BR) (71.4 % within EILV/TLC)	119 (41.3%)
V̇E/V̇CO2 nadir > 34	64 (51.2 % within BR) (45.4 % within V̇E/V̇CO2)	77 (47.2 % within BR) (54.6 % within V̇E/V̇CO2)	141 (49.0 %)
V̇E/V̇CO2 nadir ≤ 34	61 (48.8 % within BR) (41.5 % within V̇E/V̇CO2)	86 (52.8 % within BR) (58.5% within V̇E/V̇CO2)	147 (51.0 %)
	125 (43.4 %)	163 (56.6 %)	288

Note: Breathing reserve versus EILV/TLC: overall % agreement = 61.1%; positive % agreement = 72.8%; negative % agreement = 52.1%; κ = 0.240. Breathing reserve versus V̇E/V̇CO₂ nadir: overall % agreement = 52.0%; positive % agreement = 51.2%; negative % agreement = 52.8%; κ = 0.034.

Table 2. Resting and exercise characteristics of COPD patients separated according to preserved or low breathing reserve (BR > or ≤20%, respectively) versus absence or presence of critical inspiratory constraints (end-inspiratory lung volume (EILV)/total lung capacity (TLC) ratio < or ≥0.9, respectively) at the peak of incremental cardiopulmonary exercise testing (CPET).

	Breathing reserve > 20% (N = 163)		Breathing reserve ≤ 20% (N = 125)
	EILV/TLC < 0.9 (N = 85)	EILV/TLC ≥ 0.9 (N = 78)	EILV/TLC < 0.9 (N = 34)	EILV/TLC ≥ 0.9 (N = 91)
Demographic/Anthropometric
Males, N (%)	49 (57.6)	33 (42.3)	20 (58.8)	54 (59.3)
Age, years	65.3 ± 9.1	67.3 ± 9.6	65.5 ± 9.8	64.7 ± 8.2
Body mass index, kg/m^2	28.8 ± 6.8	25.5 ± 5.3	29.8 ± 6.4	26.3 ± 4.7
Lung function
FVC, L (% predicted)	3.23 ± 0.65 (95 ± 17)	3.06 ± 1.01 (84 ± 22)	3.10 ± 1.10 (85 ± 21)	2.50 ± 0.78 (67 ± 16)*
FEV1, L (% predicted)	1.62 ± 0.94 (69 ± 20)	1.59 ± 0.56 (60 ± 22)	1.57 ± 0.69 (62 ± 22)	1.01 ± 0.32 (39 ± 11)*
FEV1/FVC	0.54 ± 0.08	0.49 ± 0.10	0.50 ± 0.09	0.39 ± 0.08*
IC, L (% predicted)	2.55 ± 0.82 (96 ± 23)	2.20 ± 0.75 (80 ± 24)*	2.48 ± 0.89 (89 ± 23)	1.93 ± 0.63 (69 ± 18)*
TLC, L (% predicted)	6.13 ± 1.21 (107 ± 13)	7.41 ± 1.43 (123 ± 16)*	6.24 ± 1.42 (105 ± 14)	7.51 ± 1.32 (125 ± 14)*
IC/TLC	0.41 ± 0.09	0.31 ± 0.09*	0.39 ± 0.09	0.26 ± 0.07*
TLCO, mL/minutes/mmHg (% predicted)	14.1 ± 5.6 (69 ± 17)	10.8 ± 3.9 (55 ± 19)*	13.8 ± 4.9 (67 ± 18)	8.9 ± 4.6 (43 ± 21)*
Estimated (est) MVV
estMVV35, L/minutes	56.7 ± 22.6	55.2 ± 19.5	53.0 ± 24.1	35.9 ± 11.1*
estMVV40, L/minutes	64.8 ± 20.8	63.1 ± 22.1	62.9 ± 27.6	40.2 ± 12.7*
CPET
Power/metabolic/cardiovascular
Peak work rate, W	70.9 ± 25.0^†	58.1 ± 26.2	92.7 ± 32.1*	56.2 ± 24.7
Peak V˙O2, L/minutes (% predicted)	1.38 ± 0.39^†	1.27 ± 0.32	1.64 ± 0.30*	1.20 ± 0.29
Peak heart rate, bpm (% predicted)	90.9 ± 12.7*	78.6 ± 13.4	90.4 ± 15.3*	77.4 ± 13.1
Ventilatory
Peak breathing reserve (BR)
BR35, %	31.5 ± 9.6*	26.4 ± 6.9*	8.4 ± 9.0	−3.6 ± 10.1
BR40, %	37.7 ± 8.1*	31.7 ± 7.6*	13.1 ± 7.8	2.3 ± 9.1
Peak EILV/TLC	0.80 ± 0.05	0.94 ± 0.04*	0.81 ± 0.04	0.95 ± 0.04*
Peak EELV/TLC	0.56 ± 0.06	0.82 ± 0.06*	0.53 ± 0.07	0.81 ± 0.07*
Peak VT, L/minutes	1.52 ± 0.52	1.29 ± 0.39*	1.59 ± 0.60	1.22 ± 0.32*
Peak ICdyn (L)	2.37 ± 0.44	1.69 ± 0.33*	2.41 ± 0.47	1.52 ± 0.46*
Δ Peak-rest ICdyn (L)	−0.15 ± 0.28	−0.49 ± 0.31*	−0.07 ± 0.17	−0.39 ± 0.32*
Peak VT/ICdyn	0.64 ± 0.06	0.76 ± 0.05*	0.66 ± 0.07	0.80 ± 0.05*
ΔV˙E-ΔV˙CO2 slope	28.0 ± 3.3	30.1 ± 3.9*	27.8 ± 3.0	28.1 ± 5.2
ΔV˙E-ΔV˙CO2 intercept	4.3 ± 2.7	5.6 ± 3.8	3.9 ± 2.1	8.8 ± 3.7*
V˙E/V˙CO2 nadir	32.6 ± 6.1	35.7 ± 8.2*	31.1 ± 4.4	36.2 ± 8.2*
Gas exchange responses
SpO2
Peak, %	93 ± 5	91 ± 5.9*	94 ± 5	89 ± 5*
Peak-rest	−2 ± 4	−4 ± 7*	−1 ± 5	−6 ± 8*
Sensory responses
Peak dyspnea scores	4.5 [4.0]	6.5 [2.0]*	4.5 [3.0]	6.5 [3.0]*
Peak dyspnea > median, % group	37.2	52.9*	29.8	56.3*
Dyspnea/work rate	0.06 [0.06]	0.11 [0.06]*	0.06 [0.05]	0.14 [0.09]*
Leg effort scores	5.3 [3.4]	5.0 [3.0]	5.0 [4.0]	4.5 [3.3]
Leg effort/work	0.08 [0.05]	0.09 [0.07]	0.06 [0.06]	0.08 [0.08]
Dyspnea ≥ leg effort, % group	33.4	48.7*	32.1	59.2*

Note: p < 0.05: *compared to the other groups; ^†compared to the group showing breathing reserve >20% and EILV/TLC ≥ 0.9. Values are mean ± SD, median [interquartile range] or frequency (N). FVC: forced vital capacity; FEV₁: forced expiratory volume in one second; IC: inspiratory capacity; TLC: total lung capacity; T_LCO: lung transfer factor for carbon monoxide; MVV₃₅: maximal voluntary ventilation calculated as FEV₁ × 35; MVV₄₀: maximal voluntary ventilation as calculated as FEV₁ × 40;V˙O₂: oxygen uptake; EILV: end-inspiratory lung volume; EELV: end-expiratory lung volumes; TLC: total lung capacity; VT: tidal volume; IC_dyn: dynamic (exercise) inspiratory capacity;V˙E: ventilation;V˙CO₂: carbon dioxide output; SpO₂: oxygen saturation by pulse oximetry.

Figure 1. Metabolic (panel A), cardiovascular (panel B), ventilatory (panels C–E) and sensory (panel F) responses to symptom-limited incremental CPET in COPD patients presenting or not with a low breathing reserve (BR ≤ or >20%, respectively) and/or high inspiratory constraints (end-inspiratory lung volume (EILV)/total lung capacity (TLC) ≥ or <0.9, respectively). Commonly used ranges for severe physiological and sensory impairment are highlighted (shadow areas in panels C–F). The arrows in panels C, D and F emphasize the exercise intensity associated with a disproportionate increase in dyspnea relative to metabolic and ventilatory demand.

Note: p < 0.05. *versus the other groups; ^†versus the remaining groups. Data are mean ± SEM. O₂= oxygen uptake, HR: heart rate, EELV: end-expiratory lung volume; VT: tidal volume, TLC: total lung capacity, V˙E: minute ventilation,V˙CO₂: carbon dioxide output.

Figure 2. Distribution of COPD patients presenting or not with a higher dyspnea burden (peak dyspnea/work rate ratio > sample’s median (0.09 Borg unit/W) and peak dyspnea ≥ peak leg effort) relative to the breathing reserve (maximal voluntary ventilation = FEV₁ × 40) and inspiratory constraints. Patients were separated by the presence or not of excess ventilation (high ventilation (V̇E)/CO₂ output (V̇CO₂) nadir). The dotted lines are the cut-offs for ventilatory limitation according to a low breathing reserve or critically high inspiratory constraints. The upper right shaded quadrant represents the patients with preserved breathing but critically high inspiratory constraints: the lower left shaded quadrant depicts the opposite.

Note: EILV: end-inspiratory lung volume; TLC: total lung capacity.

Figure 3. Distribution of COPD patients presenting or not with a lower exercise tolerance (peak O₂ uptake < sample’s median (1.04 L/minutes) and <50% predicted) relative to the breathing reserve (maximal voluntary ventilation = FEV₁ × 40) and inspiratory constraints. Patients were separated by the presence or not of excess ventilation (high ventilation (V̇E)/CO₂ output (V̇CO₂) nadir). The dotted lines are the cut-offs for ventilatory limitation according to a low breathing reserve or critically high inspiratory constraints. The upper right shaded quadrant represents the patients with preserved breathing but critically high inspiratory constraints: the lower left shaded quadrant depicts the opposite.

Note: EILV: end-inspiratory lung volume, TLC: total lung capacity.

Table 3. Association between CPET-based negative outcomes (“higher” dyspnea burden = peak dyspnea/work rate ratio > sample’s median and peak dyspnea ≥ peak leg effort and/or “lower” exercise tolerance (peakV˙O₂ < sample’s median and <50% predicted) with abnormal or preserved breathing reserve (maximal voluntary ventilation estimated as FEV₁ × 40), end-inspiratory lung volume (EILV)/total lung capacity (TLC) and the nadir of ventilation (V̇E)/CO₂ output (V̇CO₂) ratio in patients with COPD.

		Higher dyspnea burden and lower exercise tolerance (N = 84)	Higher dyspnea burden or lower exercise tolerance (N = 99)	Lower dyspnea burden and higher exercise tolerance (N = 105)
Breathing reserve	≤20% (N = 125)	48 (37.8%)	38 (28.3%)	43 (33.9%)
	>20% (N = 163)	36 (42.9%)	63 (63.6%)	62 (59.0%)
Likelihood ratio = 8.6; χ^2 = 8.5; p = 0.01
EILV/TLC	≥0.9 (N = 169)	71 (42.0%)	65 (38.4%)	33 (19.5%)
	<0.9 (N = 119)	10 (8.4%)	37 (31.1%)	72 (60.5%)
Likelihood ratio= 42.3; χ^2= 39.7; p < 0.001
V̇E/V̇CO2 nadir	>34 (141)	64 (45.3)	54 (38.5%)	23 (16.2%)
	≤34 (147)	20 (13.6%)	45 (30.6%)	82 (55.8%)
Likelihood ratio = 47.7; χ^2 = 44.7; p < 0.001

Table 4. Final outcome of a multiple logistic regression analysis to predict the association of a high dyspnea burden (dyspnea/work rate ratio > study population’s median value and peak dyspnea ≥ leg effort scores) with a low peak O₂ uptake (peakV˙O₂ < sample’s median and <50% predicted) (26).

Variables	β	Standard error	Odds ratio (95% confidence interval)	p
EILV/TLC ≥ 0.9	2.106	0.363	8.21 (4.03–16.7)	.0001
V˙E/V˙CO2 nadir > 34	1.834	0.314	6.25 (3.37–11.59)	.0001
Constant	−3.313	0.398	0.036

Note: Other variables initially considered in the regression analysis were: gender (male: 1, female: 0), age (≥70 years= 1, <70 years = 0); body mass index (≥30 kg/m² = 1, <30 kg/m² = 0), breathing reserve (≤20% = 1, >20% = 0 or ≤ 15% = 1, >15% = 0 or ≤ 30% = 1, >30 = 0 using both estimated maximal voluntary ventilation = FEV₁ × 40 or × 35), end-inspiratory lung volume (EILV)/total lung capacity (TLC)-ventilation (V˙E)- carbon dioxide output (V˙CO₂) interaction term and exercise-induced hypoxemia (Δ O₂ saturation by pulse oximetry peak-rest < −4% = 1; ≥ −4% = 0). FEV₁ was coded as a “dummy” variable with categories coded according to the GOLD criteria for functional impairment

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