Exertional ventilation/carbon dioxide output relationship in COPD: from physiological mechanisms to clinical applications

J. Alberto Neder, Danilo C. Berton, Devin B. Phillips, Denis E. O'Donnell
European Respiratory Review 2021 30: 200190; DOI: 10.1183/16000617.0190-2020

Abstract

There is well established evidence that the minute ventilation (V′E)/carbon dioxide output (V′CO2) relationship is relevant to a number of patient-related outcomes in COPD. In most circumstances, an increased V′E/V′CO2 reflects an enlarged physiological dead space (“wasted” ventilation), although alveolar hyperventilation (largely due to increased chemosensitivity) may play an adjunct role, particularly in patients with coexistent cardiovascular disease. The V′E/V′CO2 nadir, in particular, has been found to be an important predictor of dyspnoea and poor exercise tolerance, even in patients with largely preserved forced expiratory volume in 1 s. As the disease progresses, a high nadir might help to unravel the cause of disproportionate breathlessness. When analysed in association with measurements of dynamic inspiratory constraints, a high V′E/V′CO2 is valuable to ascertain a role for the “lungs” in limiting dyspnoeic patients. Regardless of disease severity, cardiocirculatory (heart failure and pulmonary hypertension) and respiratory (lung fibrosis) comorbidities can further increase V′E/V′CO2. A high V′E/V′CO2 is a predictor of poor outcome in lung resection surgery, adding value to resting lung hyperinflation in predicting all-cause and respiratory mortality across the spectrum of disease severity. Considering its potential usefulness, the V′E/V′CO2 should be valued in the clinical management of patients with COPD.

Abstract

The minute ventilation/carbon dioxide production relationship is relevant to a number of patient-related outcomes in COPD. Minute ventilation/carbon dioxide production, therefore, should be valued in the clinical management of these patients. https://bit.ly/3df2upH

Introduction

It has been well established that changes in minute ventilation (V′E) are tightly coupled to the rate at which metabolically produced carbon dioxide (CO2) is released by the lungs during exercise (V′CO2, i.e. venous return × mixed-venous CO2 content) [1, 2]. The submaximal ventilatory demands are particularly relevant to set the limits of exercise tolerance in patients with reduced ventilatory capacity, e.g. those suffering from COPD [3, 4]. In fact, relatively minor increases in the V′E/V′CO2 relationship are expected to have a large impact on the rate at which V′E reaches a relatively-fixed “ceiling” (as roughly estimated by the maximal breathing capacity, for example (supplementary figure S1) [5].

As discussed elsewhere in this series, the V′E required to wash out a given rate of V′CO2 is inversely related to the arterial partial pressure for CO2 (PaCO2) (since more alveolar ventilation is needed to maintain the PaCO2 at a low compared to a high value), and positive related to the fraction of tidal volume (VT) “wasted” in the dead space (VD), i.e. the higher the physiological (phys) VD/VT [1]. Since the PaCO2 is maintained relatively constant as V′CO2 increases (at least during moderate exercise) (supplementary figure S2c) [1], the hyperbolic decrease in VD/VTphys (supplementary figure S2a) is accompanied by a similar decrease in the V′E/V′CO2 ratio towards a minimum value (“nadir”) (supplementary figure S2b) [6]. Thus, when V′E is plotted as a function of V′CO2 during an incremental cardiopulmonary exercise test, a linear relationship with a positive y-intercept emerges (supplementary figure S2d). In this context, increases in the intercept and/or in the slope can lead to a high V′E/V′CO2 nadir [7]. From a physiological standpoint, the higher the VD/VTphys and the lower the PaCO2 set-point, the higher the V′E/V′CO2 nadir [2]. The VD/VTphys is the lowest at the V′E/V′CO2 nadir (supplementary figure S2a and b), allowing a more accurate estimation of the wasted ventilation. Moreover, the V′E/V′CO2 nadir has been found to be highly reproducible in normal subjects [8] and in patients with COPD [9].

In the present review we update and expand a previous review on the V′E/V′CO2 relationship published in 2017 in the European Respiratory Journal [10]. Although a high V′E/V′CO2 has been widely termed “ventilatory inefficiency” or “excess ventilation” [11–14], we avoid this terminology herein, because, as discussed below, substantial inefficiency (i.e. increased wasted V′E) may coexist with a relatively preserved, or even reduced, V′E/V′CO2 in patients with COPD. After a concise overview on the structural and functional determinants of V′E/V′CO2 in COPD, we focus on its relevance to exertional dyspnoea and exercise tolerance, exploring the clinical scenarios in which the measurement may add to resting clinical assessment. Additionally, we provide evidence on how V′E/V′CO2 may allow us to better judge the functional impact of comorbidities, assess future risk and prognosis, and determine the effects of selected therapeutic interventions on patients’ exercise tolerance (table 1). Finally, we outline some key gaps in knowledge that might benefit from additional research (table 2).

View this table:
TABLE 1

Overview of cardiopulmonary exercise testing-based studies on the minute ventilation (V′E)/carbon dioxide output (V′CO2) relationship in different clinical scenarios in COPD

View this table:
TABLE 2

Key unanswered questions on the mechanisms and consequences of minute ventilation (V′E)/carbon dioxide output (V′CO2) abnormalities in COPD

Structural and functional determinants of V′E/V′CO2 in COPD

Several studies have shown that an increased VD/VTphys, partially due to emphysema [21, 23, 25, 28, 96, 97], constitutes an important correlate of a high V′E/V′CO2. As discussed later, this is particularly true in patients who are not severely compromised from the mechanical standpoint, i.e. those who are able to increase V′E in an attempt to overcome an increased alveolar VD. There is some limited evidence that the increased VD/VTphys is more closely related to an enlarged alveolar VD per se rather than a small VT [20]. Additionally, external (series) VD predictably increased V′E/V′CO2 [18]. As in many chronic pulmonary diseases, increased regional [98], and, in some patients, “mean” alveolar ventilation/perfusion (V′/Q′) ratio heterogeneity and diffusion limitation [99] are probably related to a high VD/VTphys in COPD [100].

Impaired pulmonary perfusion of non-emphysematous areas [101] may also contribute to high VD/VTphys and V′E/V′CO2 in a highly variable combination in subjects with similar forced expiratory volume in 1 s (FEV1) [19, 97]. It is noteworthy that a low transfer factor of the lung for carbon monoxide (TLCO), which is notoriously influenced by V′/Q′ abnormalities [102], has been inversely related to V′E/V′CO2 in recent studies [22, 27]. Patients unable to expand gas exchange surface area (as assessed with TLCO during exercise) relative to pulmonary blood flow showed a higher V′E/V′CO2 and a lower exercise capacity [24]. In addition, patients with mild COPD and high V′E/V′CO2 (≥34) had lower TLCO and pulmonary capillary blood volume response to exercise [26]. It is conceivable that the cross-relationships among V′E/V′CO2, VD/VTphys and TLCO represent, in addition to emphysema, a complex combination of the effects of accelerated pulmonary vascular ageing in smokers [103], destruction/dysfunction of the alveolar–capillary bed [101], and, in some patients, hypoxic pulmonary vasoconstriction [104]. In any case, the pulmonary vascular abnormalities may progress to overt pulmonary hypertension in selected patients, an important cause of a high V′E/V′CO2 (see the section on Impact of COPD comorbidities on V′E/V′CO2).

Alveolar hyperventilation is another potential cause of a high V′E/V′CO2 in COPD [1, 2]. A chronically low PaCO2 (likely due to heightened chemostimulation) [105] may shift the level at which it is centrally regulated (“set-point”) downward [106], in a vicious circle. The relative contribution of a low PaCO2 to a high V′E/V′CO2 remains elusive, being probably more relevant in those with cardiocirculatory comorbidities (see the section on Impact of COPD comorbidities on V′E/V′CO2). For instance, Elbehairy et al. [20] found that PaCO2 was inversely related to V′E/V′CO2, though to a lesser extent than VD/VTphys, in a group of patients with preserved FEV1. Heightened stimulation of mechano- and metaboreceptors in the peripheral muscles (“ergoreceptors”) [83] may also contribute to alveolar hyperventilation in selected patients.

It should be noted that the contribution of alveolar hyperventilation to a high V′E/V′CO2 in COPD is likely to be overestimated if one considers the end-tidal partial pressure for CO2 (PETCO2) rather than the PaCO2 [107]. This is the case because V′/Q′ abnormalities, specifically, alveolar VD, are known to decrease PETCO2 at a given PaCO2 [108] (as the former is diluted in the VD/VTphys); an effect that increases as exercise intensifies [20]. The topic is further complicated by the fact that VD/VTphys and PaCO2 are not independent variables. For instance, the extent to which the mean alveolar CO2 tension decreases in response to hyperventilation (high overall ratio alveolar V′/Q′) is underestimated by PaCO2, thereby artificially increasing VD/VTphys as measured by the Bohr–Enghoff method [109, 110]. Moreover, larger fluctuations in end-capillary CO2 pressure due to a high VD/VTphys may overstimulate the peripheral and central chemoreceptors, leading to a low PaCO2 [111].

It remains unclear whether the V′E–V′CO2 slope and the V′E intercept have specific structural and physiological determinants in COPD. The addition of external VD had a more discernible effect on the V′E intercept than the V′E–V′CO2 slope both in health [110, 112, 113] and mild COPD [18]. However, a high intercept may merely reflect the expected effect of shallow slope (secondary to worsening mechanical constraints; figure 1), independent of the VD [39, 114]. In individual cases, there is some disconnection between the directional changes of slope and intercept, suggesting that they may provide additive information [39, 54]. As outlined in table 2, relating V′E–V′CO2 slope and V′E intercept to structural abnormalities (emphysema burden, microvascular abnormalities, small airways disease) and CO2 chemosensitivity might shed new light on this topic.

FIGURE 1
FIGURE 1

Effects of COPD severity on different parameters of the minute ventilation (V′E)/carbon dioxide output (V′CO2) relationship. a) V′E/V′CO2 intercept increased and b) V′E/V′CO2 slope diminished as the disease progressed from Global Lung Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric stages 1 to 4. c) As the V′E/V′CO2 nadir depends on both slope and intercept, it remained elevated (compared to controls (C)) across disease stages. d) Increasing nadir-slope differences from GOLD stages 1 to 4 reflects the impact of a progressively higher intercept. Data are presented as mean±sd. *: p<0.05 different from controls. Reproduced with permission [39].

Influence of V′E/V′CO2 on the physiological and sensory responses to exercise in COPD

A substantial body of evidence has been accumulated pointing out abnormalities in the V′E/V′CO2 relationship across the spectrum of COPD severity (table 1). In particular, a high V′E/V′CO2 has been consistently found in dyspnoeic patients with preserved or only mildly reduced FEV1 (supplementary figure S3) [18, 20, 35, 37–39, 115]. A high V′E/V′CO2 nadir in flow-limited patients accelerates the rate of dynamic lung hyperinflation and earlier attainment of critical dynamic inspiratory constraints [116]. In fact, the rate of decline of the dynamic inspiratory reserve volume to its minimal value is superior to conventional “breathing reserve” at peak exercise in the assessment of exertional dyspnoea in mild to advanced COPD [44] (figure 2). Patients showing a high V′E/V′CO2 also showed a low tolerance to short bursts of high-intensity interval exercise, an exercise modality which is associated with more preserved breathing reserve [43]. Interestingly, a recent study found that even a high resting V′E/V′CO2, if associated with a low inspiratory capacity, predicts the burden of exertional dyspnoea in patients with COPD [46]. Therefore, a high V′E/V′CO2 and the dynamic inspiratory constraints, are jointly relevant to explain increased exertional dyspnoea and poor exercise capacity in COPD compared with age-matched healthy controls [18, 20, 35, 37–39, 117, 118]. Interestingly, V′E/V′CO2 nadir was increased in dyspnoeic [30], but not in asymptomatic [41], smokers. These findings are consistent with the notion that a high V′E/V′CO2 is linked to exertional dyspnoea since the early stages of the disease [117].

FIGURE 2
FIGURE 2

a) Metabolic, b) cardiovascular, c–e) ventilatory and f) sensory responses to symptom-limited incremental cardiopulmonary exercise testing in COPD patients presenting or not with a low breathing reserve ((BR) ≤20% or >20%, respectively) and/or high inspiratory constraints (end-inspiratory lung volume (EILV)/total lung capacity (TLC) ≥0.9 or <0.9, respectively). Commonly used ranges for severe physiological and sensory impairment are highlighted (shaded areas in panels c–f). The arrows in panels c), d) and f) emphasise the exercise intensity associated with a disproportionate increase in dyspnoea relative to metabolic and ventilatory demand. Note that patients who were particularly limited due to f) exertional dyspnoea (closed symbols) presented with d) high inspiratory constraints and e) high ventilation (V′E)/carbon dioxide output (V′CO2) ratio, regardless of c) the breathing reserve. *: p<0.05 versus the other groups; #: p<0.05 versus the remaining groups; : p<0.05 versus BR ≤20% or EILV/TLC <0.9 and BR >20% or EILV/TLC ≥0.9. Data are presented as mean±sem. V′O2: oxygen uptake; HR: heart rate; EELV: end-expiratory lung volume; VT: tidal volume. Reproduced from [44] with permission.

There is sound evidence that VD/VTphys worsens as heart failure [119–121] and COPD (as reviewed by O’Donnell et al. [118]) progress. However, it is interesting to note that while the V′E–V′CO2 slope is higher (and the V′E intercept is lower) in patients with more severe heart failure [11–14, 122], the former decreases (and the latter increases) in severe to very severe COPD. Consequently, the V′E/V′CO2 nadir may remain stable (albeit higher compared to a healthy subject) if the effects of a low V′E–V′CO2 slope is cancelled out by a high V′E intercept in severe to very severe COPD (figure 1) [39, 123]. In a large cross-sectional study, worsening dynamic hyperinflation, greater exertional dyspnoea and poorer exercise tolerance were associated with lower V′E–V′CO2 slope and higher V′E intercept [39]. Thus, a lower V′E–V′CO2 slope in advanced COPD is largely explained by worsening mechanical constraints [45, 118] and, in end-stage disease, by a high PaCO2 [15, 114]. Of note, obesity in COPD also decreased V′E/V′CO2 nadir, probably due to greater ventilatory constraints [31] and, conceivably, a higher PaCO2 set-point in severely obese patients. Teasing out the relative contribution of severe mechanical constraints versus a blunted CO2 chemosensitivity to decrease the V′E–V′CO2 slope constitutes a formidable challenge, since these abnormalities are intrinsically linked as COPD evolves [118].

Impact of COPD comorbidities on V′E/V′CO2

Pulmonary arterial hypertension (PAH) [124, 125], systolic heart failure [11–14, 122] and, to a lesser extent, coronary artery disease [126] are well known causes of a high V′E/V′CO2. The underlying mechanisms are multiple, probably involving heightened ventilatory drive from chemo-, baro- and ergoreceptors and a high VD/VTphys [127]. Accordingly, patients with COPD and comorbid PAH do present with a high V′E/V′CO2 [47, 48] with the steepest V′E–V′CO2 slope found in severe, out-of-proportion pulmonary hypertension [49]. In keeping with the concept that the mechanical constraints typical of advanced COPD may blunt the ventilatory response to exertion, the V′E–V′CO2 slope did not differ in patients with severe versus very severe COPD who presented with coexistent PAH [51].

There is mounting evidence that patients with comorbid COPD–heart failure with reduced left ventricular ejection fraction present with higher V′E–V′CO2 slope but lower V′E intercept than patients with COPD in isolation [52, 54, 55, 60]. However, if the former patients are compared with those with heart failure alone, they show higher V′E intercept [54, 60]. In other words, patients with COPD–heart failure typically show intermediate V′E–V′CO2 slope and V′E intercept compared to those with each disease alone. These findings are likely explained by the increased ventilatory stimuli brought by heart failure being partially counterbalanced by the mechanical constraints (and increased PaCO2 in more advanced disease) induced by COPD [128, 129]. Of note, Arbex et al. [55] found that exertional dyspnoea and exercise intolerance were significantly related to the overall ventilatory response to exertion in COPD–heart failure. The study by Rocha et al. [57] highlighted the importance of alveolar hyperventilation to increase V′E/V′CO2 and dyspnoea at a given VD/VTphys in COPD–heart failure (supplementary figure S4). In another investigation, these authors found that COPD–heart failure patients showing impaired aerobic function (as indicated by a blunted increase in oxygen uptake (V′O2) as a function of work rate, suggesting impaired oxygen delivery) had a higher V′E/V′CO2 than their counterparts with more preserved aerobic metabolism [130]. These findings provide indirect support for a link between increased ergoreceptor activation and a high V′E/V′CO2 [83] caused (or worsened) by a cardiovascular comorbidity [115]. Periodic breathing, specifically ventilatory oscillations, induced by heart failure, a phenomenon associated with increased VD/VTphys and V′E/V′CO2 [127], is associated with increased dyspnoea and reduced exercise tolerance in the presence of underlying COPD [56]. Interestingly, the oscillatory breathing ceased at high operating lung volumes when critically high inspiratory constraints prevented further increases in VT. As expected, this subgroup of patients with COPD–heart failure was particularly dyspnoeic, since the heightened ventilatory drive compounded the mechanical abnormalities [56].

Little is currently known on the potential modulating effects of emphysema extent, heart failure aetiology and heart failure with preserved ejection fraction [131, 60] on the V′E/V′CO2 in individual COPD–heart failure patients [128]. More subtle abnormalities in left ventricular function may increase V′E/V′CO2 in susceptible patients with COPD; in fact, coronary artery disease, even without overt heart failure, increased V′E/V′CO2 in these patients [53]. Owing to the fact that only a minority of hypoxaemic patients with COPD–heart failure have been assessed in previous studies [52, 54, 55, 60], it remains possible that a heightened hypoxic drive further increases V′E/V′CO2 in some patients. Selected interventions aimed at decreasing the ventilatory drive (such as β-blockers) have not decreased V′E/V′CO2 in patients with COPD [50], but this approach has not yet been tested in COPD–heart failure. There is conflicting evidence concerning a putative relationship between diastolic dysfunction and V′E/V′CO2 [58, 59], an issue that requires further investigation (table 2) [49].

The relevance of considering the additive effects of a high VD/VTphys and a low PaCO2 to increase V′E/V′CO2 and exertional dyspnoea has been shown by Costa et al. [62] in combined pulmonary fibrosis and emphysema (supplementary figure S5). Interestingly, VD/VTphys was associated with the burden of emphysema (including admixed emphysema in areas of pulmonary fibrosis) and traction bronchiectasis, another potential source of wasted ventilation. In addition, it is conceivable that heightened peripheral chemostimulation [111] potentiated ventilatory stimulation in hypoxaemic patients, leading to a particularly deleterious combination of enlarged wasted ventilation, hypoxic stimulation and alveolar hyperventilation (supplementary figure S5).

V′E/V′CO2 for risk assessment and prognosis in COPD

Resting lung function parameters (particularly FEV1 and TLCO) have long been used to estimate the risk of peri-operative complications in patients submitted to lung resection surgery due to lung cancer [132]. Among the exercise-based measurements, more experience has been accumulated with V′O2 peak [133]. More recently, some groups reported that a high V′E–V′CO2 slope may also predict a negative outcome [64–66]. For instance, Torchio et al. [69] reported that a high V′E–V′CO2 slope was the strongest predictor of mortality after pneumonectomies, a finding extended by Miyazaki et al. [70] to less extensive anatomical lung resections. Ellenberger et al. [71] found that a particularly high V′E/V′CO2 (>40) predicted poor survival after radical surgery for lung cancer. It remains unclear why a high V′E/V′CO2 predicts a negative surgical outcome in this context, but the reasons are probably multiple, including more severe emphysema, higher pulmonary vascular pressures, poorer cardiac performance, heightened sympathetic drive, exertional hypoxaemia and increased ergoreceptor stimulation due to severe deconditioning [134]. However, it should be recognised that the reduction in V′E/V′CO2 in severe to very severe COPD (figure 1) may decrease its predictive power in these patients, an issue that needs further investigation (table 2).

Similar to heart failure [11–14, 122], a high V′E/V′CO2 (V′E/V′CO2 nadir ≥34) predicts poor survival in patients with COPD. Of note, lung hyperinflation added to V′E/V′CO2 to predict mortality due to respiratory and nonrespiratory causes (figure 3) [67]. Increased sympathetic stimulation, as inferred by a slow decrease in post-exercise heart rate, was observed in COPD patients with higher and worsening mechanical constraints [42], providing a potential clue for the mechanisms underlying the association between these variables and the risk of a future negative event. Furthermore, a high V′E/V′CO2 nadir compound impaired right ventricular systolic function to predict poor outcome in COPD–heart failure [68]. A high V′E–V′CO2 slope has been associated with increasing risk of hospitalisation in this specific subpopulation [61]. Pending experimental confirmation in larger studies, V′E/V′CO2 might become a relevant effort-independent prognostic parameter in patients with COPD (table 2).

FIGURE 3
FIGURE 3

Value of high ventilation (V′E)/carbon dioxide output (V′CO2) nadir in isolation and associated with resting lung hyperinflation (low inspiratory capacity (IC)/total lung capacity (TLC) ratio) to predict a) all-cause and b) respiratory mortality in patients with mild to severe COPD. Reproduced from [67] with permission.

Effects of interventions on V′E/V′CO2 in COPD

The effects of interventions on V′E/V′CO2 are highly variable, depending on the main mechanism of action. Thus, interventions which may lessen the mechanical constraints (heliox [76, 80, 81, 86], lobectomy [79] and bronchodilators [75, 77, 85]) typically increased V′E at a given V′CO2. In other circumstances where the main mechanism of action was probably related to a lower VD and/or a higher VT (single [72] and double lung [82] transplantation and lung volume reduction surgery [84, 87]), V′E decreased at a given V′CO2. Similarly, interventions aimed at lowering the respiratory neural drive (supplemental oxygen [82, 95], spinal anaesthesia [83]) also decreased V′E/V′CO2. At least theoretically, exercise training may lessen V′E/V′CO2 in some patients due to high VT leading to a low VD/VTphys as well as delaying metabolic acidosis, thereby reducing afferent stimuli from the active peripheral muscles [135]. These mechanistic considerations raise the question of why inhaled bronchodilators have not been reported to change the V′E/V′CO2 in COPD [136]. In fact, Elbehairy et al. [92] found that despite appreciable lung deflation after acute bronchodilation, VD/VTphys and V′E/V′CO2 both remained unaltered. These findings highlight the importance of wasted ventilation in regulating V′E/V′CO2 in COPD while suggesting that the higher VT and regional alveolar ventilation after bronchodilation occurs preferentially directed in areas which were already better ventilated. Nevertheless, this topic merits more detailed analysis in longer trials (table 2).

Applying V′E/V′CO2 to clinical management of COPD

The data summarised in table 1 provide some clues on the specific scenarios in which measuring V′E/V′CO2 may have practical implications for the management of patients with COPD. Exertional dyspnoea is a ubiquitous symptom across the range of COPD severity. However, in some circumstances, it is chiefly related to unfitness, obesity, hyperventilation or comorbidities. Establishing a link between a high V′E/V′CO2 and dyspnoea in patients with only mildly to moderately reduced FEV1 might prompt a more proactive approach to bronchodilator treatment. A similar line of reasoning applies to patients with disproportionate dyspnoea relative to resting lung function impairment. In both circumstances, it is important to jointly analyse V′E/V′CO2 and noninvasive measurements of lung mechanics as they provide complementary information (figure 2). A high V′E/V′CO2 coupled with severely increased operating lung volumes might also suggest that the patient is poorly prepared to face the challenges brought by an acute exacerbation; thus, regardless of FEV1, the patient might benefit from closer follow-up and optimisation of anti-exacerbation measures. Marked increases in V′E/V′CO2 might raise concerns regarding associated pulmonary vascular disease or, if appropriate, heart failure. This is particularly true when there is only a trivial burden of emphysema on high-resolution computed tomography to otherwise explain a high V′E/V′CO2. Conversely, a lower-than-expected V′E/V′CO2 might be related to morbid obesity or another potential cause of blunted ventilatory response, including severe sleep disordered breathing, neuromuscular disease and hypercapnic respiratory failure of other aetiology. In fact, Paoletti et al. [17] showed that V′E/V′CO2 may decrease in more advanced emphysema as the severe mechanical constraints preclude appropriate ventilatory response to metabolic demand, despite an enlarged dead space. It follows that a low V′E/V′CO2 in patients with substantial emphysema signals for the dominance of mechanical abnormalities over the gas exchange disturbances. Therefore, in the right clinical context, this piece of information might be useful to select patients more likely to derive benefit from interventions aimed to release the mechanical constraints, e.g. volume reduction surgery. A high V′E/V′CO2 in COPD patients referred for resection surgery due to lung cancer should raise concerns about the increased risk of peri-operative complications. If feasible, a more limited resection might be advisable in these patients. Finally, documenting a lower V′E/V′CO2 after lung transplantation or lung volume reduction surgery might provide objective evidence attesting the efficacy of these expensive treatment approaches.

Conclusions

The relevance of abnormalities in V′E/V′CO2 during exercise has only recently become a target for systematic assessment in COPD (table 1). Whereas the V′E–V′CO2 slope and the V′E/V′CO2 nadir are frequently increased in mild to moderate COPD, increasing ventilatory constraints may lead to a “preserved” V′E–V′CO2 slope in more advanced COPD. A higher V′E intercept may partially counterbalance the latter effect; thus, the V′E/V′CO2 nadir may still be elevated in these patients. However, in end-stage COPD, the mechanical constraints (and the associated hypercapnia) may eventually prevail, leading to a “normal” or low V′E/V′CO2 nadir. Overall, a high V′E/V′CO2 frequently exposes clinically significant V′/Q′ distribution though alveolar hyperventilation may also contribute, particularly in the presence of cardiovascular comorbidities or lung fibrosis. Published evidence (table 1) indicates that the V′E/V′CO2 nadir is a particularly useful index of abnormal uncoupling between ventilation and metabolic demand in COPD, being linked to important clinical outcomes such as dyspnoea, reduced exercise capacity and even mortality. In daily practice, V′E/V′CO2 measurements are particularly useful in the individualised assessment of exercise intolerance in mild to moderate COPD, notably in individuals with disproportionate exertional dyspnoea. Providing evidence-based answers to the questions posed in table 2 may prove valuable to extend the clinical applications of V′E/V′CO2 in this patient population.

Supplementary material

Supplementary Material

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Supplementary_figures ERR-0190-2020_Supplementary_figures

Footnotes

  • Number 8 in the Series “Ventilatory efficiency and its clinical prognostic value in cardiorespiratory disorders” Edited by Pierantonio Laveneziana and Paolo Palange

  • Provenance: Commissioned article, peer reviewed.

  • Previous articles in this series: No. 1: Laveneziana P, Di Paolo M, Palange P. The clinical value of cardiopulmonary exercise testing in the modern era. Eur Respir Rev 2021; 30: 200187. No. 2: Agnostoni P, Sciomer S, Palermo P, et al. Minute ventilation/carbon dioxide production in chronic heart failure. Eur Respir Rev 2021; 30: 200141. No. 3: Watson M, Ionescu MF, Sylvester K, et al. Minute ventilation/carbon dioxide production in patients with dysfunctional breathing. Eur Respir Rev 2021; 30: 200182. No. 4: Ward SA. Ventilation/carbon dioxide output relationships during exercise in health. Eur Respir Rev 2021; 30: 200160. No. 5: Collins SÉ, Phillips DB, Brotto AR, et al. Ventilatory efficiency in athletes, asthma and obesity. Eur Respir Rev 2021; 30: 200206. No. 6: Schaegger MR, Guenette JA, Jensen D. Impact of ageing and pregnancy on the minute ventilation/carbon dioxide production response to exercise. Eur Respir Rev 2021; 30: 200225. No. 7: Weatherald J, Philipenko B, Montani D, et al., Ventilatory efficiency in pulmonary vascular diseases. Eur Respir Rev 2021; 30: 200214.

  • This article has supplementary material available from err.ersjournals.com

  • Conflict of interest: J.A. Neder has nothing to disclose.

  • Conflict of interest: D.C. Berton has nothing to disclose.

  • Conflict of interest: D.B. Philips has nothing to disclose.

  • Conflict of interest: D.E. O'Donnell has nothing to disclose.

  • Support statement: J. Alberto Neder has been funded by a New Clinician Scientist Program from the Southeastern Ontario Academic Medical Association (SEAMO), Canada. The funder had no role in the study design, data collection and analysis, or preparation of the manuscript.

  • Received June 18, 2020.
  • Accepted September 30, 2020.
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Exertional ventilation/carbon dioxide output relationship in COPD: from physiological mechanisms to clinical applications
J. Alberto Neder, Danilo C. Berton, Devin B. Phillips, Denis E. O'Donnell
European Respiratory Review Sep 2021, 30 (161) 200190; DOI: 10.1183/16000617.0190-2020
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