Beyond Spirometry: Linking Wasted Ventilation to Exertional Dyspnea in the Initial Stages of COPD

Figures & data

Figure 1. Selected ventilatory and gas exchange responses to incremental cardiopulmonary exercise testing. Proportional decreases in dead space (VD)/tidal volume (VT) ratio (i.e. the physiological dead space) (a) and ventilation (V̇E)/carbon dioxide output (V̇CO₂) (b) ratios maintain arterial carbon dioxide partial pressure (PaCO₂) close to resting value during mild-to-moderate exercise (c). The V̇E/V̇CO₂ response contour is established by both the slope and the intercept of the linear V̇E-V̇CO₂ relationship (d). V̇E increases out of proportion to V̇CO₂ after the respiratory compensation point (RCP) (b–d) leading to respiratory alkalosis (c) to compensate for progressive lactic acidemia. Note the increases in the lowest V̇E/V̇CO₂ when the lactate threshold is reached at a low exercise intensity, i.e. before the stabilization of V̇E/V̇CO₂ at the “true” nadir. Given eucapnia during exercise in most dyspneic patients with mild COPD, their high V̇E-V̇CO₂ largely reflects a high physiological dead space, i.e. wasted ventilation. Reproduced, with permission of the publisher, from: Neder et al. [34].

Figure 2. Putative mechanisms by which the structural abnormalities associated with COPD development may increase alveolar ventilation (V̇a)/capillary perfusion (Q̇c) relationship, increasing the wasted ventilation in the physiological dead space. The relative contribution of these abnormalities vary substantially amongst patients with similar spirometric findings justifying the use of more elaborated pulmonary function tests in addition to imaging to improve disease phenotyping. Reproduced, with permission of the American Thoracic Society. Copyright © 2023 American Thoracic Society. All rights reserved. Neder [43]. Annals of the American Thoracic Society is an official journal of the American Thoracic Society.

Figure 3. A putative explanation by which increased physiological dead space (wasted ventilation) and alveolar hyperventilation may trigger exertional dyspnea. The combination of pulmonary fibrosis and emphysema (CPFE) is depicted for illustrative purposes. In the presence of increased (⇑) airspace (alveolar ventilation (V̇a)) relative to capillary perfusion (Q̇c)) (wasted ventilation), less CO₂ from the mixed venous blood is unloaded into the right alveolus. Consequently, the alveolar carbon dioxide tension (PACO₂) diminishes (⇓) markedly but PCO₂ at the end of the capillary (c’) may rise transitorily, subsequently enriching the PCO₂ of the arterial blood sensed by the central and/or peripheral chemoreceptors. This may add to the other sources of afferent stimuli to the pontine–medullary respiratory centers (red circle). The inspiratory neural drive (IND) is heightened; accordingly. Of note, IND is also modulated by cortical (black circle) and limbic (blue circle) influences. Excessive ventilation of the left alveolus with preserved V̇a/Q̇c relationship, triggered by increased chemostimulation or other source(s) of additional ventilatory stimuli, leads to alveolar hyperventilation and hypocapnia. A low arterial Pco₂ may downward shift the CO₂ set-point, impair the cerebrovascular reactivity (CVR) to CO₂, and increase the central and peripheral chemoreceptor gains. Hypoxemia (arterial partial pressure for O₂ (PaO₂)), if present, sums up with these excitatory inputs to further increase the IND in a vicious circle that fuels breathlessness. In mild COPD, the evidence accrued to date does not support a major contribution of hyperventilation and/or low PaO₂ to the patient high IND, suggesting a dominant role for the wasted ventilation.

Figure 4. Schematic representation of the key mechanisms by which alveolar ventilation (V̇a)/capillary perfusion (Q̇c) mismatching may conspire to increase the inspiratory neural drive (IND), eventually leading to exertional dyspnea and exercise intolerance in patients with mild COPD. The putative mechanisms that have been ruled out in previous studies are highlighted (reviewed in refs. [9,28]). Emphasis is given to the unknown contribution of impaired perfusion of non-emphysematous lung tissue (in addition to emphysema) to increased (↑) wasted ventilation in the physiological dead space (high dead space (VD)/tidal volume (VT) ratio), heightened dyspnea at given work rate (WR) in these patients was largely commensurate to preserved dyspnea-ventilation (V̇_E) relationship, in keeping with the pattern of “excessive breathing” (Figure 5). See text for further elaboration. Definition of abbreviations: HPV: hypoxic pulmonary vasoconstriction; PAP = pulmonary arterial pressure. Modified, with permission of the publisher, from: Neder et al. [111].

Figure 5. A simplified framework to expose the major “pulmonary” determinants of exertional dyspnea during incremental cardiopulmonary exercise testing as related to the pathophysiology of COPD. The key physiological abnormalities are highlighted: excess ventilation (high ventilation (V̇E)-(carbon dioxide output (V̇CO₂) relationship) and the attainment of critical inspiratory constraints (CIC). In most dyspneic patients with mild COPD, increased wasted ventilation in the physiological dead space (VD_phys) prompts a high, V̇E/V̇CO₂ ratio leading to a pattern of “excessive breathing” rather than “restrained” (or “constrained”) breathing, i.e. increased dyspnea at given work rate (WR) but within the expected range when expressed relative to the heightened V̇E. Definition of abbreviations and symbols: ⇑: high; ⇓: low’; V̇A: alveolar ventilation; Q̇c: capillary perfusion; Pa: arterial partial pressure; PET: end-tidal partial pressure; Hypervent: alveolar hyperventilation; CIC: end-inspiratory lung volume/total lung capacity≥ 0.9, tidal volume (VT)/inspiratory capacity ≥ 0.7, VT plateau, all reached at an abnormally-low work rate. Ranges of dyspnea severity based on percentiles distribution of scores at a given ventilation as a function of age and sex: 5th–25th: “mild”; 25th–50th: “moderate”; 50th 75th: “severe”; 75th 95th: “very severe” [14]. Reproduced, with permission of the publisher, from: Neder [66].

Figure 6. An illustrative example of how respiratory functional imaging (phase-resolved functional lung (PREFUL) ¹H magnetic resonance imaging for ventilation and perfusion [109–113] can be combined with computed tomography-based emphysema extension and distribution (parametric response mapping) to provide relevant insights into the genesis of out-of-proportion dyspnea in patients with mild COPD. This 54 years old woman with preserved FEV₁ and out-of-proportion decrease in lung diffusing capacity for carbon monoxide showed high ventilation-CO₂ output and an increased physiological dead space (VD_phys) on cardiopulmonary exercise testing. Despite trivial emphysema (red and pink), note extensive areas of perfusion deficit percent (QDP) in non-emphysematous regions of the lung which were well ventilated (low ventilation deficit percent (VDP)) at rest and during exercise (light green). These findings are in keeping with the notion that impaired pulmonary perfusion beyond expected by emphysema, may increase the wasted ventilation in these patients, contributing to exertional dyspnea.

Table 1. A simplified overview of main invasive and noninvasive physiologic measurements potentially sensitive to disturbances in pulmonary gas exchange efficiency in patients with mild COPD.

Measurement	Rationale/Advantages	Main Limitations
Noninvasive
O2 deficit [45]	• ⇑ values indicate a low arterial PO2 (estimated from the O2 dissociation curve) at a given alveolar PO2, providing a noninvasive approximate of P(A-a)O2, i.e. poor efficiency in O2 transfer.[46]	• Inaccuracies in PaO2 estimation due to under/overestimation of PaCO2 based on PETCO2 • The estimation of PaO2 becomes unreliable at a SpO2 > 94%
PETCO2	• ⇓ values might indicate lower mean mixed expired “alveolar” PCO2 due to the diluting effects of areas of wasted ventilation which, be definition, have lower PCO2	• Whereas a superficial and fast breathing pattern may reduce PETCO2, areas of hypoventilation may increase PETCO at a given PaCO2 (“normalizing” PETCO2)
Volumetric capnography [47]	• Slower kinetics/lower amplitude of expired PCO2 increase toward PaCO2 (or a close estimate) signals high VDphys • Once Fowler dead space (∼ anatomical) is taken into consideration, VA can be estimated	• Influenced by acute hypo or hyperventilation • Changes in cardiac output increase variability • Airflow obstruction prolongs the time to complete tidal exhalation, overestimating VDphys
DLCO [48]	• ⇓ values indicate reduced rate of CO transfer which is influenced by inhomogeneities in V̇A/Q̇c matching (amongst others) • Using different FIO2, the contribution of “membrane” and “blood” components to DLCO can be portioned out [49]	• Sensitive to total ventilation, mixed venous CO, diffusion limitation, [hemoglobin} and blood volume (including in units with normal V̇A/Q̇c) • Sensitive, but not specific
KCO [50]	• ⇓ values indicate reduced gas transfer related to its distribution volume (VA) • Increases curvilinearly as VA decreases	• Impaired ventilation distribution may decrease VA at a given TLC, leading to KCO normalization despite extensive abnormalities in gas exchange efficiency • Complex KCO-VA relationship [51] • See DLCO limitations
DLNO [52]	• ⇓ values relative to DLCO biased to indicate a higher contribution of the “membrane” diffusing capacity compared with the “blood” component of pulmonary gas transfer	• Might be also influenced by the membrane component; unclear clinical advantage over DLCO • See DLCO limitations
Exercise V̇E:V̇CO2	• ⇑ wasted ventilation and/or venous admixture (if associated with low PaO2) requires a higher V̇E to control PaCO2 at a given metabolic demand	• Might reflect alveolar hyperventilation (rather than a high VDphys), requiring concomitant measurements (or a close estimate) of PaCO2
Invasive
PaO2	• ⇓ age-corrected values secondary to ⇓ V̇A/Q̇c and “true” shunt	• It should be related to PAO2 to provide an index of gas exchange inefficiency
P(A-a)O2 [46]	• ⇑ age-corrected values indicate that less O2 has been added to arterial blood at a given mixed expired alveolar O2 pressure	• In isolation, it cannot differentiate diffusion limitation, ⇓ V̇A/Q̇c, and shunt as cause of hypoxemia • ⇑ FIO2 variably increases P(A-a)O2
P(a-ET)CO2 (and P(a-ET)CO2/ PaCO2)	• ⇑ values indicate that the arterial blood contains more CO2 than expected for a given mixed expired alveolar CO2 pressure, excluding the effect of anatomical and apparatus dead space on wasted ventilation	• Negative values may occur on exercise since VT and mixed venous PCO2 increases, and lung volume decreases as expiration progresses [53] • See PETCO2 limitations
Bohr dead space [54]	• ⇑ values indicate a lower mean mixed exhaled CO2 pressure at given mean alveolar CO2 pressure, signaling an increased volume of air within the conducting airways, i.e. it is biased to reflect anatomical dead space	• A gas sample captured late within a single exhalation. do not necessarily reflect the true mean alveolar gas composition • Ignores P(A-a)CO2, leading to lower dead space compared with Bohr-Enghoff VDphys
Bohr-Enghoff dead space (VDphys) [55]	• ⇑ values indicate a lower mean mixed exhaled CO2 pressure at a given PaCO2 signaling increased contribution of air which was not exposed to gas exchanging units (wasted ventilation) • Since mean PaCO2 might be higher than mean PACO2 in disease, VDphys is sensitive to intrapulmonary shunt and diffusion impairment, being strongly influenced by V̇A/Q̇c heterogeneity	• ⇑ values might result from any mechanism that increases P(A-a)CO2, being an index of overall gas exchange inefficiency • ⇑ ventilation of areas of ⇑ V̇A/Q̇c reduces PACO2 at given PaCO2 leading to higher dead space compared to Bohr formulation
Shunt by the 100% O2 test [56]	• As any ventilated alveoli which receives 100% O2 would contribute to PaO2, ⇑ values indicate that a higher fraction of cardiac output has not been exposed to 100% O2 (either intra- or extra-pulmonary, i.e. “anatomical” shunt)	• Alveolar collapse induced by 100% O2 may increase the estimated shunt • Hemodynamic effects of 100% O2 may reduce anatomical shunting, particularly during exercise
Shunt fraction (Q̇s/Q̇t)	• ⇑ values indicate that a higher fraction of cardiac output has the same (low) O2 content of mixed venous blood • Conceivably, the best estimation of venous admixture	• Requires central catheterization • Unpredictable increases with higher cardiac output on exercise

Symbols and Abbreviations: ⇑: high; ⇓:low; []: concentration; CO: carbon monoxide; CO₂: carbon dioxide; FI_: inspired fraction; K: transfer coefficient; MIGET: multiple inert gas exchange technique; NO: nitric oxide; O₂: oxygen; Pa: arterial partial pressure; PA: alveolar partial pressure; PET: end tidal partial pressure; RER: respiratory exchange ratio; Sp: hemoglobin saturation by pulse oximetry; Q̇c: capillary blood flow; Q̇s: shunted blood; Q̇t: cardiac output; TL: lung transfer factor; TLC: total lung capacity; VA: alveolar volume; V̇A: alveolar ventilation; VD_phys; physiologic dead space; V̇CO₂: pulmonary carbon dioxide output; V̇_E: minute ventilation.

Reproduced, with permission of the publisher, from: Neder et al. [57] (On-Line Supplement).

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