Physiological and clinical relevance of exercise ventilatory efficiency in COPD

J. Alberto Neder, Danilo C. Berton, Flavio F. Arbex, Maria Clara Alencar, Alcides Rocha, Priscila A. Sperandio, Paolo Palange, Denis E. O'Donnell
European Respiratory Journal 2017 49: 1602036; DOI: 10.1183/13993003.02036-2016

Abstract

Exercise ventilation (V′E) relative to carbon dioxide output (V′CO2) is particularly relevant to patients limited by the respiratory system, e.g. those with chronic obstructive pulmonary disease (COPD). High V′E−V′CO2 (poor ventilatory efficiency) has been found to be a key physiological abnormality in symptomatic patients with largely preserved forced expiratory volume in 1 s (FEV1). Establishing an association between high V′E−V′CO2 and exertional dyspnoea in mild COPD provides evidence that exercise intolerance is not a mere consequence of detraining. As the disease evolves, poor ventilatory efficiency might help explaining “out-of-proportion” breathlessness (to FEV1 impairment). Regardless, disease severity, cardiocirculatory co-morbidities such as heart failure and pulmonary hypertension have been found to increase V′E−V′CO2. In fact, a high V′E−V′CO2 has been found to be a powerful predictor of poor outcome in lung resection surgery. Moreover, a high V′E−V′CO2 has added value to resting lung hyperinflation in predicting all-cause and respiratory mortality across the spectrum of COPD severity. Documenting improved ventilatory efficiency after lung transplantation and lung volume reduction surgery provides objective evidence of treatment efficacy. Considering the usefulness of exercise ventilatory efficiency in different clinical scenarios, the V′E−V′CO2 relationship should be valued in the interpretation of cardiopulmonary exercise tests in patients with mild-to-end-stage COPD.

Abstract

Ventilatory efficiency is a key measurement for the interpretation of cardiopulmonary exercise testing in COPD http://ow.ly/1nsY307pbz8

To me it does not seem all movements are exercise, but only when it is vigorous. Since vigor is relative, the same movement might be exercise for one and not for another. The criterion of vigorousness is change of respiration; those movements which do not alter the respiration are not exercise. Galen, Exercise and Massage, in On Hygiene, circa 200 AD

Introduction

Dynamic exercise, as recognised by Galen, is characteristically associated with changes in frequency and depth of breathing, i.e. hyperpnoea. Moreover, he cogently observed that those respiratory changes are somehow linked to exercise intensity (“movement vigorousness”). Eighteen centuries later we now know that changes in exercise pulmonary ventilation (V′E), at least before the development of metabolic acidosis (or hypoxaemia in disease), are exquisitely commensurate to the rate at which metabolically produced carbon dioxide is released by the lungs (V′CO2, i.e. venous return × mixed-venous CO2 content) [1, 2]. Thus, the response of V′E relative to V′CO2 (the V′E−V′CO2 relationship) has been named “ventilatory efficiency” [3], an implicit recognition that meeting metabolic demand to maintain arterial blood gas and pH is the overriding goal of ventilation [2]. Although increased (or even decreased) V′E relative to V′CO2 may not always inform us how efficient V′E is relative to arterial blood gas homeostasis (see section Physiological bases), the term “ventilatory efficiency” has gained popularity to describe the exercise V′E−V′CO2 relationship [4–7].

It is rather axiomatic that the issue of exercise ventilatory efficiency is particularly relevant to patients primarily limited by ventilation, e.g. those with chronic obstructive pulmonary disease (COPD) [8, 9]. Surprisingly, however, its clinical importance has been mostly recognised in diseases for which mechanical–ventilatory constraints are not the dominant feature, e.g. heart failure [4–7, 10] and pulmonary arterial hypertension (PAH) [11, 12]. More recently, however, a substantial body of evidence has accumulated showing that abnormalities in the V′E−V′CO2 relationship during incremental cardiopulmonary exercise testing (CPET) are present across the spectrum of COPD severity. Thus, V′E−V′CO2 measurement has advanced our understanding of mechanisms of exercise intolerance and, particularly in milder COPD, exertional breathlessness. Moreover, this measurement has allowed us to better judge the functional impact of co-morbidities, to assess future risk and prognosis and to determine the complex effects of therapeutic interventions on exercise tolerance in COPD (table 1). The present manuscript will discuss these emerging findings from a clinically applied perspective with emphasis on the extant gaps in current knowledge.

View this table:
TABLE 1

Overview of cardiopulmonary exercise testing-based studies on ventilatory efficiency in different clinical scenarios in chronic obstructive pulmonary disease (COPD)

Physiological bases

It is well established that the V′E required to washout a given rate of CO2 production is higher the lower the arterial partial pressure for CO2 (PaCO2) (as more V′E is needed to keep PaCO2 low compared with a high value) and the larger the ventilation “wasted” in the dead space (VD), i.e. Embedded Image(1)where V′E/V′CO2 ratio is the ventilatory equivalent for CO2 and VD/VT is the physiological (anatomical plus alveolar) dead space fraction of tidal volume [2]. Of note, VD/VT decreases in a curvilinear manner as exercise progresses, i.e. more alveoli are recruited as VT and V′E increase (figure 1a) [67]. Thus, a major contribution to the decreasing VD/VT is the greater compliance of the alveoli over that of the airways, allowing greater alveoli expansion relative to the airways ([67] and reviewed in [68]). Moreover, VT increases owing to a large increase in end-inspiratory lung volume and a small, but important, decrease in end-expiratory lung volume; thus, VT remains positioned on the most compliant (linear) portion of the respiratory system S-shaped pressure–volume relationship (as reviewed in [69]).

FIGURE 1
FIGURE 1

Selected ventilatory and gas exchange responses to incremental CPET in a young healthy male. Proportional decreases in dead space (VD)/tidal volume (VT) (a) and ventilation (V′E)/carbon dioxide output (V′CO2) (b) ratios maintain arterial carbon dioxide partial pressure (PaCO2) close to resting value during mild-to-moderate exercise (c). The V′E/V′CO2 response contour is established by both slope and intercept of the linear V′E−V′CO2 relationship (d). Thus, the lowest (nadir) V′E/V′CO2 closely approximates slope plus intercept. V′E−V′CO2 increases out of proportion to V′CO2 after the respiratory compensation point (RCP) (b–d) leading to respiratory alkalosis (c) to compensate for progressive lactacidaemia. Note the increases in nadir when the lactate threshold is reached earlier (dashed line in b).

In this context, if V′E/V′CO2 did not decrease in tandem with VD/VT the resulting alveolar hyperventilation would lower PaCO2 leading to progressive respiratory alkalosis [2, 70]. Although the exact mechanisms remain controversial (see [71] and [72] for a recent debate on the topic), V′E/V′CO2 decreases in direct proportion to VD/VT (figure 1b). Thus, PaCO2 is kept constant (↔) during mild-to-moderate exercise in healthy humans (figure 1c) [1, 2, 67, 73]: Embedded Image(2)These considerations provide the physiological basis for the assertion that the V′E/V′CO2 profile provides useful information about the VD/VT trajectory, particularly if PaCO2 is concomitantly measured [2, 67, 70, 74]. The major assumptions, however, are the absence of mechanical constraints to V′E increase [75], i.e. the “output” (V′E) can appropriately adjust to its determinants (V′CO2, VD/VT and PaCO2) and there is neither exercise-induced hypercapnia nor increased additional chemo-stimulation of ventilation, e.g. hypoxaemia [1, 2, 4, 73].

Equation 1 also helps us to understand why increases in V′E relative to V′CO2 do not necessarily imply poor ventilatory efficiency. For instance, the system is arguably not “inefficient” if a high V′E/V′CO2 is needed to keep PaCO2 at a low level as determined by the respiratory controller (e.g. chronic respiratory alkalosis or chronic metabolic acidosis) or there is an extra source of afferent stimuli to increase ventilation (e.g. hypoxaemia) [10]. For the sake of simplicity, the subsequent discussion assumes that an increased slope of the V′E−V′CO2 relationship and/or an increased V′E/V′CO2 ratio equals “poor efficiency” unless otherwise specified.

Methodological considerations

In response to rapidly incremental CPET, the V′E−V′CO2 relationship has been analysed in the V′E/V′CO2 ratio versus V′CO2 plot (figure 1b) or in the V′E versus V′CO2 plot (figure 1d) [4]. The lowest (nadir) V′E/V′CO2 is typically reached just before V′E starts to increase in compensation for lactic acidosis at the respiratory compensation point (RCP) (figure 1b–d). Provided the subject can tolerate high levels of exercise (i.e. high V′CO2), V′E/V′CO2 virtually equals (i.e. “asymptotes”) to the slope of the V′E−V′CO2 relationship (refer to the supplementary material for further elaboration) [76]. Thus, the V′E/V′CO2 nadir and V′E/V′CO2 at the lactate threshold are almost indistinguishable in normal subjects [74]. As the lactate threshold may not always be identified, particularly in clinical populations with low exercise capacity [77, 78], the V′E/V′CO2 nadir seems a more accurate indication of ventilatory efficiency than the V′E/V′CO2 at the lactate threshold. The V′E/V′CO2 nadir has been found to be highly reproducible in normal subjects [74] and in patients with COPD [25]. The V′E/V′CO2 nadir, however, might underestimate ventilatory efficiency if the V′E/V′CO2 descending curve is prematurely interrupted (dashed line in figure 1b), e.g. premature lactic acidosis or an excessively short test duration [79]. As expected, end-exercise V′E/V′CO2 is higher than the nadir as the former incorporates the hyperventilatory response to late-exercise acidosis. In other words, end-exercise V′E/V′CO2, by definition, does not constitute an index of ventilatory efficiency in those who are able to exercise beyond the RCP. Most patients with moderate-to-severe COPD, however, either do not reach the RCP or are unable to further increase V′E. Thus, nadir and end-exercise V′E/V′CO2 are often equivalent in most patients, with the exception of some less impaired patients with milder disease [29].

It is important to recognize that the V′E/V′CO2 response contour is intrinsically linked to how V′E dynamically changes in relation to V′CO2 taking into consideration its starting point [2, 4, 71, 72, 76]. The former is reflected by the slope of the regression line between V′E and V′CO2 and the latter by its intercept (i.e. V′E when V′CO2=0) (figure 1 and figure S1). Considering that in normal subjects the V′E intercept is often a small positive number (<3 L min−1 on average) [74], V′E/V′CO2 equals the slope of the V′E−V′CO2 relationship at high V′CO2 values (refer to the supplementary material for further elaboration) [67, 70, 76]. It should be noted that considering all data points (i.e. including those after the RCP) will necessarily increase the computed slope and reduce the computed intercept. Although this might be advantageous for prognostication in heart failure [80] and PAH [11], not only it underestimates ventilatory efficiency (equation 1) but it also does not accurately describe the underlying response profile. As mentioned, however, most patients with moderate-to-severe COPD are unable to exercise beyond the RCP. In other words, there is no upward inflection in the V′E versus V′CO2 response in most of these patients. Thus, in practice, drawing a single line from unloaded to peak exercise fits well the overall V′E response in this particular sub-group of patients [29].

Some studies have examined the influence of potential modifiers on ventilatory efficiency. Ageing has been consistently associated with higher VD/VT and poorer ventilatory efficiency, regardless the method of expression (ratio or slope) [74, 79, 81] or level of fitness [82]. Females typically present with slightly greater V′E−V′CO2 slopes than males [79], likely a consequence of a lower VT [83]. The fact that PaCO2 does not differ between younger versus elderly or men versus women [1, 73] provides another piece of evidence that exercise V′E increases precisely to maintain a stable alveolar ventilation/V′CO2 ratio [1, 2, 4, 73]. It is also remarkable that exercise modality (walking versus cycling) does not seem to influence ventilatory efficiency in normal subjects [74, 81] though the V′E−V′CO2 slope was higher during treadmill walking compared with cycling in moderate-to-severe COPD [13].

Ventilatory efficiency and exercise intolerance

A substantial body of evidence has accumulated indicating that abnormalities in ventilatory efficiency across the continuum of disease severity in COPD (table 1). Poor ventilatory efficiency has been found to be a key physiological abnormality in symptomatic patients with largely preserved forced expiratory volume in 1 s (FEV1) (figure S4) [29, 21, 26, 28, 30, 33]. The physiological basis for these derangements seems to stem from an enlarged VD per se rather than a small VT or a low PaCO2 [30]. In fact, external (series) VD predictably increased V′E/V′CO2 in these patients [21]. Additional research is warranted to investigate the structural correlates of increased VD in mild COPD, e.g. microvascular disease [84], early emphysema [32, 85, 86], ventilation distribution heterogeneity [27, 86]. Regardless of the mechanism(s), high V′E/V′CO2 nadir is linked to earlier attainment of critical dynamic mechanical constraints: inspiratory reserve volume becomes critically reduced. This explains, in part, the increased exertional dyspnoea and reduced exercise capacity in mild COPD compared with age-matched healthy controls [21, 23, 26, 28, 30, 45]. This pattern of abnormalities was also seen in most patients with moderate airflow obstruction (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2) [29]. Collectively, these studies point to the important contribution of reduced ventilatory efficiency to dyspnea and reduced exercise capacity in smokers with only mild-to-moderate airflow obstruction [87, 88]. Interestingly, V′E/V′CO2 nadir was also increased in symptomatic [16], but not in asymptomatic [33], smokers without COPD. These findings are consistent with the notion that poor ventilatory efficiency is instrumental to explain exertional dyspnoea at the earlier stages of the disease [87].

Similarly to heart failure [89–91], VD/VT worsens as disease severity increases in patients with COPD [88]. Interestingly, however, while the most commonly used parameter of ventilatory efficiency in the clinical literature (the V′E−V′CO2 slope) increases from mild to severe heart failure [4–7, 10], the V′E−V′CO2 slope decreases and the V′E intercept increases in severe-to-very-severe COPD compared with milder disease. Consequently, the V′E/V′CO2 nadir may remain stable (but still higher than in health) if the effects of a low slope in the nadir are cancelled out by a high intercept or even diminished if the slope is markedly reduced in severe-to-very-severe COPD (figure 2 and figure S3 for representative patients) [29]. The seemingly paradoxical finding of lower V′E−V′CO2 slope in advanced COPD is likely explained by worsening mechanical constraints to V′E increase [88] and, in end-stage disease, to hypercapnia (see section Physiological bases) [14, 92]. Increases in V′E intercept in COPD were associated with worsening dynamic hyperinflation, greater exertional dyspnoea and poorer exercise tolerance as the disease evolved [29]. Interestingly, obesity in COPD also decreased V′E/V′CO2 nadir, likely due to greater ventilatory constraints and, conceivably, a higher PaCO2 set-point [17].

FIGURE 2
FIGURE 2

Effects of chronic obstructive pulmonary disease (COPD) severity on different parameters of ventilatory efficiency. Ventilation (V′E)−carbon dioxide output (V′CO2) intercept increased (a) and V′E−V′CO2 slope diminished (b) as the disease progressed from Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1 to 4. As the V′E/V′CO2 nadir depends on both slope and intercept, it remained elevated (compared with controls (C)) across disease stages (c). Increasing nadir–slope differences from GOLD stages 1 to 4 reflects the impact of a progressively higher intercept (d). Reproduced from [29] with permission from the publisher.

Little is known about the structural correlates of the V′E−V′CO2 slope and the V′E intercept in COPD. Adding external VD in normal subjects had a more discernible effect on the V′E intercept than the V′E− V′CO2 slope both in health [68, 93, 94] and mild COPD [21]. However, in-series VD may not perfectly mimic alveolar (in-parallel) VD as found in patients with pulmonary diseases. Thus, the former is associated with a greater CO2 loading in the airways (re-breathing), which might further challenge ventilatory control [71, 72]. It could be argued that as the V′E−V′CO2 slope is reduced by progressive mechanical respiratory constraints in severe-to-very-severe COPD [29], a high V′E intercept is a necessary and empirical consequence of a shallower slope independent of the VD [92]. Nevertheless, some patients with COPD do present with shallow slopes but high intercepts and vice versa [29, 43]. Additional studies examining changes in V′E−V′CO2 slope and V′E intercept across the continuum of COPD severity in the context of structural abnormalities (emphysema severity, pulmonary microvascular abnormalities, small airway disease) and CO2 chemosensitivity might shed new light on the topic (table 2).

View this table:
TABLE 2

Key unanswered clinical questions on exercise ventilatory efficiency in chronic obstructive pulmonary disease (COPD)

Impact of co-morbidities on ventilatory efficiency

Poor ventilatory efficiency has been consistently reported in PAH [11, 12], heart failure [4–7, 10] and, to a lesser extent, coronary artery disease [95]. This is likely secondary to a complex interaction among increased ventilatory drive from multiple afferent sources (chemo-, baro- and ergoreception) and high VD/VT [96]. Impaired ventilatory efficiency persists in COPD with associated PAH [36, 37] with the highest V′E−V′CO2 slope found in severe, out-of-proportion pulmonary hypertension [38]. Interestingly, the V′E−V′CO2 slope did not differ in severe to very severe COPD regardless if they had coexistent PAH or not [40]. These findings support the notion that severe respiratory mechanical constraints in COPD dampen an excessive ventilatory response despite potential increases in “wasted” ventilation and other sources of afferent stimuli [29].

Joint analysis of three independent investigations [41, 43, 44] indicates that patients with COPD–heart failure overlap present with higher V′E−V′CO2 slopes but lower V′E intercepts than patients with COPD alone (figure S5). Moreover, overlap patients had greater V′E intercepts compared with heart failure in isolation [43]. Thus, though heart failure further worsened ventilatory efficiency in COPD, lung mechanical constraints (and increased CO2 “set-point” in more advanced COPD) blunted the overall ventilatory response compared with heart failure alone. Importantly, impaired ventilatory efficiency in COPD–heart failure overlap was associated with greater exertional dyspnoea and poorer exercise tolerance [44]. There is also recent evidence that periodic breathing, which is associated with increased VD and poor ventilatory efficiency [96], increases dyspnoea and reduces exercise tolerance in these patients [45]. Of note, the ventilatory oscillations were associated with higher operating lung volumes; moreover, they consistently ceased when critical inspiratory constraints were reached (figure S4) [45]. This observation highlights the overriding influence of abnormal mechanics in constraining exercise ventilation in COPD, even in the presence of a heightened ventilatory drive.

It remains unclear whether emphysema extent, disease phenotype, heart failure aetiology and heart failure with preserved ejection fraction [97] influence ventilatory efficiency in individual COPD–heart failure overlap patients. For instance, coronary artery disease, even without overt heart failure, also increased ventilatory inefficiency in COPD [42]. Arterial hypoxemia leading to high hypoxic drive does not seem to contribute to poor ventilatory efficiency in overlap [44]; however, few hypoxaemic patients were enrolled in previous studies [41, 43, 44]. Although β-blockers failed to decrease the V′E/V′CO2 nadir in COPD [39], the impact of prospective pharmacological interventions on ventilatory efficiency remains unknown in COPD–heart failure overlap and in COPD patients with out-of-proportion pulmonary hypertension. Potential improvements in ventilatory efficiency might prove valuable to decrease exertional dyspnoea and improve exercise tolerance in selected patients, particularly when cardiocirculatory abnormalities predominate over mechanical constraints (table 2) [38].

Risk assessment and prognosis

Most patients submitted to lung resection surgery due to lung cancer present with COPD [98]. Resting pulmonary function tests and, to a lesser extent, peak O2 uptake (V′O2) [99] have been used to assess perioperative risk in these patients. There is mounting evidence that a high V′E−V′CO2 slope is also a powerful predictor of poor surgical outcome for lung resection surgery [46–48], likely superior to peak V′O2 [48]. In this context, a high V′E−V′CO2 slope might indicate greater VD due to more extensive emphysema and/or high pulmonary vascular pressures, poorer cardiac performance, higher sympathetic drive, worse exertional hypoxemia and greater ergorreceptor stimulation [100]. Of note, however, few patients with severe to very severe COPD (who usually present with lower V′E−V′CO2 slopes) (figure 2) undergo extensive lung resection surgery and/or pre-operative CPET [46–48]. Thus, it remains to be investigated whether a low V′E−V′CO2 slope predicts poor outcome in selected patients who despite severe to very severe airflow obstruction are potential candidates for resection, e.g. young patients with limited disease and no major co-morbidities.

Poor ventilatory efficiency (increased V′E−V′CO2 slope or V′E/V′CO2 nadir) has a powerful negative association with survival in heart failure independent of peak V′O2 [4–7, 10]. A recent study extended these observations to patients with COPD, regardless the presence of coexistent heart failure. Moreover, only resting lung hyperinflation added value to V′E/V′CO2 nadir as a prognosticator [49]. Interestingly, a high V′E/V′CO2 nadir predicted mortality due to respiratory and non-respiratory causes, suggesting that the above-mentioned abnormal cardiorespiratory mechanisms may also underlie increased risk of earlier mortality (figure 3) [49]. A small prospective investigation found that a high V′E/V′CO2 nadir added to impaired resting right ventricular systolic function in predicting poor outcome in COPD–heart failure overlap [50]. If these findings are confirmed in larger multicentre studies, ventilatory efficiency might become an important effort-independent prognostic parameter in patients with COPD with or without heart failure as co-morbidity (table 2).

FIGURE 3
FIGURE 3

Value of poor ventilatory efficiency (high ventilation (V′E)/carbon dioxide output (V′CO2) nadir) in isolation and associated with resting lung hyperinflation (low inspiratory/total lung capacity ratio (IC/TLC)) to predict all cause and respiratory mortality in patients with mild-to-severe COPD. Reproduced from [49] with permission from the publisher.

Effects of interventions

The effects of interventions on ventilatory efficiency have been helpful to uncover the underlying mechanisms of exercise intolerance and dyspnoea in COPD while providing a physiological rationale for their main mechanism of action. For instance, interventions primarily aimed at releasing the mechanical constraints (heliox [55, 59, 60, 65], lobectomy [58], and bronchodilators [54, 56, 64]) increased V′E at a given V′CO2. These findings fit well with the concept that an increased slope of the V′E−V′CO2 relationship should not be uniformly interpreted as indicative of poor ventilatory efficiency in advanced COPD, at least from a “quantitative” perspective. Nevertheless, these interventions also reduced the operating lung volumes and exertional breathlessness; thus, it could be argued that ventilation became “qualitatively” and subjectively more efficient [88].

A different scenario emerged in response to another group of interventions which decreased V′E at a given V′CO2. Thus, single- [51] and double-lung [61] transplantation and lung volume reduction surgery [63, 66] lessened VD and increased VT thereby reducing VD/VT with consequent benefits to ventilatory efficiency. This suggests that the marked effects of these interventions on VD/VT (which would lessen V′E) relatively outweighed the consequences of lower mechanical constraints, which would otherwise increase V′E [39, 46–49, 98–100]. Lower neural drive (e.g. supplemental O2 [59], spinal anaesthesia [62]) also diminished V′E at a given V′CO2. Interestingly, some investigations found proportional decrements in V′E and V′CO2 with O2 supplementation [52, 53]. This suggests that lower chemoreceptor drive to breathe is not the only mechanism underlying reduction in V′E during hyperoxia in COPD. Limited evidence also suggests that V′E tends to decrease in tandem with V′CO2 after exercise training in COPD [57]. This is somewhat surprising considering the potential beneficial effects on breathing pattern (high VT leading to a low VD/VT) and peripheral muscle afferent stimuli [101]. Additional studies are warranted to further investigate the consequences of training on ventilatory efficiency, including the potential beneficial effects of inspiratory muscle training [102].

These considerations raise the question of why inhaled bronchodilators have not consistently changed the V′E−V′CO2 relationship in COPD [103]. However, it should be recognised that ventilatory efficiency has not been specifically investigated in bronchodilator trials. Since high-intensity, constant work rate exercise testing is more sensitive than incremental CPET for the purpose of bronchodilator evaluation [104, 105], there are only sparse data on effects of bronchodilators on V′E−V′CO2 slope and V′E intercept during incremental tests. For instance, less mechanical constraints tending to increase V′E [39, 46–49, 98–100] may be off-set by a lower VD/VT, which tends to decrease V′E [50, 55, 59, 60]. Such complex interactions would probably vary among subjects in large clinical trials. This topic also merits more detail analysis as inter-individual changes in ventilatory efficiency may explain the reported variability on exercise tolerance and dyspnoea despite apparent beneficial effects on resting lung mechanics in recent trials (table 2) [103]. For example, in mild COPD, effective bronchodilation and lung deflation may not translate into improved dyspnoea and exercise endurance if decreased ventilatory efficiency (and consequent increased inspiratory neural drive) remain unchanged [16, 106].

Applying ventilatory efficiency to clinical management of COPD

Based on the evidence summarised in table 1, there are some specific scenarios in which the V′E−V′CO2 measurement can be useful to address clinically relevant issues in patients with COPD. Firstly, most symptomatic patients with preserved or only mildly reduced FEV1 are chronically sedentary [30]. Establishing an association between excess exercise ventilation and greater dyspnoea scores would provide evidence that patient's exercise intolerance is not a mere consequence of detraining [9, 16, 87]. This might prompt a more proactive approach to early treatment [107]. Secondly, some patients with COPD might present with “out-of-proportion” breathlessness (to FEV1 impairment) [9, 88]. Poor ventilatory efficiency, often driving faster rates of dynamic hyperinflation [9, 16, 87], would provide a mechanistic explanation to patients’ symptoms. This might indicate room for treatment optimisation, including pharmacological (e.g. dual bronchodilatation) [103] and non-pharmacological (e.g. pulmonary rehabilitation to decrease ventilatory demands) [57, 108]. Thirdly, marked increases in V′E/V′CO2 nadir should raise concerns regarding coexisting pulmonary hypertension [36, 39] or, in the right clinical context, heart failure [43, 44]. This is particularly true in the absence of another potential explanation for increased “wasted” ventilation, such as extensive emphysema on chest computed tomography [18]. Identification of co-morbidities increasing exercise ventilation and symptom burden is also important to avoid the potential iatrogenic consequences of excessive bronchodilator inhalation in patients with coexistent cardiovascular disease [109, 110]. Thus, further cardiological assessment might be warranted in these patients. Fourthly, a high V′E/V′CO2 nadir in COPD patients with lung cancer should raise concerns regarding increased risk of peri-operative complications [46–48]. This might influence the decision in favour of a more economical resection in high-risk patients. Fifthly, identification of a high V′E/V′CO2 nadir in a severely hyperinflated patient would indicate higher risk of a life-threatening exacerbation [49]. Thus, the patient would benefit from closer follow up and optimisation of anti-exacerbation measures (e.g. phosphodiesterase inhibitor, action plan, macrolide prophylaxis). Finally, documenting improved ventilatory efficiency after lung transplantation [51, 61] or lung volume reduction surgery [63, 66] would provide objective evidence of efficacy of these costly treatment approaches.

Conclusions

Compared with heart failure, for which the determinants and clinical consequences of an abnormal exercise V′E−V′CO2 relationship have been well established, the value of ventilatory efficiency measurement during exercise has only recently become a target for systematic scrutiny in COPD (table 1). As in heart failure, the V′E−V′CO2 slope and the V′E/V′CO2 nadir are consistently increased in patients with mild to moderate COPD likely exposing unsuspected but clinically significant ventilation/perfusion abnormalities within the lungs. Conversely, while these specific efficiency parameters continue to worsen as heart failure progresses, this is not necessarily the case with advancing COPD due to increasing ventilatory constraints. Thus, a seemingly “normal” V′E−V′CO2 slope does not rule out abnormal ventilatory efficiency in more advanced COPD. Higher V′E intercept as COPD worsens, however, may result in a progressively higher V′E/V′CO2 nadir. In fact, the contribution of a high V′E intercept to V′E/V′CO2 nadir increases as COPD evolves (as detailed in the supplementary material). Thus, the V′E intercept might add important information to the interpretation of ventilatory (in)efficiency in patients with severe to very severe COPD.

Although much remains to be discovered, there is growing evidence that measurement of exercise ventilatory efficiency has potential clinical utility across the spectrum of disease severity in COPD. The V′E/V′CO2 nadir seems a particularly useful index of ventilatory efficiency across the continuum of disease severity, being linked to important clinical outcomes such as dyspnoea, reduced exercise capacity and even mortality (table 1). Based on recent studies, ventilatory efficiency measurements may be important for the individualised assessment of exercise intolerance in mild-to-moderate COPD, notably in individuals with disproportionate dyspnoea (table 1).

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary material ERJ-02036-2016_Supplement

Footnotes

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

  • Support statement: J.A. 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.

  • Conflict of interest: None declared.

  • Received October 17, 2016.
  • Accepted December 12, 2016.

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Physiological and clinical relevance of exercise ventilatory efficiency in COPD
J. Alberto Neder, Danilo C. Berton, Flavio F. Arbex, Maria Clara Alencar, Alcides Rocha, Priscila A. Sperandio, Paolo Palange, Denis E. O'Donnell
European Respiratory Journal Mar 2017, 49 (3) 1602036; DOI: 10.1183/13993003.02036-2016
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