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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 2021 30: 200190; DOI: 10.1183/16000617.0190-2020
J. Alberto Neder
1Respiratory Investigation Unit and Laboratory of Clinical Exercise Physiology, Queen's University and Kingston General Hospital, Kingston, ON, Canada
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Danilo C. Berton
1Respiratory Investigation Unit and Laboratory of Clinical Exercise Physiology, Queen's University and Kingston General Hospital, Kingston, ON, Canada
2Division of Respiratory Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
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Devin B. Phillips
1Respiratory Investigation Unit and Laboratory of Clinical Exercise Physiology, Queen's University and Kingston General Hospital, Kingston, ON, Canada
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Denis E. O'Donnell
1Respiratory Investigation Unit and Laboratory of Clinical Exercise Physiology, Queen's University and Kingston General Hospital, Kingston, ON, Canada
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  • FIGURE 1
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    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].

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    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.

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    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.

Tables

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  • 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

    Subjects nDisease severityMain result
    Structural and functional determinants
     O’Donnell (2002) [15]20FEV1 34±3%⇓ V′E at a given V′CO2 in CO2 retainers compared to non-retainers
     Nakamoto (2007) [16]10FEV1 27–70%V′E–V′CO2 slope not related to increased muscle ergoreflex activity
     Paoletti (2011) [17]16FEV1 54±18%⇓ V′E–V′CO2 slope in more extensive emphysema
     Chin (2013) [18]40FEV1 87±11%⇑ V′E/V′CO2with added external dead space in mild COPD
     Neder (2015) [19]276GOLD 1–4⇑ V′E–V′CO2 slope associated with ventilation inhomogeneity in GOLD 1 and 2
     Elbehairy (2015) [20]22FEV1 94±10%⇑ V′E/V′CO2 associated with greater VD/VTphys in symptomatic GOLD 1
     Crisafulli (2016) [21]51FEV1 55±16%⇑ V′E–V′CO2 slope associated with emphysema extension on chest CT
     Elbehairy (2017) [22]62FEV1 65±8%⇑ V′E/V′CO2 associated with ⇓ TLCO and ⇓ V′O2 peak in smokers with mild obstruction
     Jones (2017) [23]19FEV1 82±13%⇑ V′E/V′CO2 linked ⇑ emphysema and ⇓ TLCO to exercise intolerance in mild COPD
     Behnia (2017) [24]32FEV1 56±16%⇑ V′E/V′CO2 inversely related to exercise TLCO
     Smith (2018) [25]67GOLD 1–4⇑ V′E/V′CO2 positively related to emphysema extent
     Tedjasaputra (2018) [26]17FEV1 94±11%V′E/V′CO2 nadir ≥34 associated with ⇓ pulmonary capillary blood volume and ⇑ dyspnoea
     Elbehairy (2019) [27]300FEV1 61±25%⇑ V′E/V′CO2 nadir in tandem with progressively ⇓ TLCO across FEV1 and IC tertiles
     Rinaldo (2020) [28]50FEV1 56±16%⇑ V′E/V′CO2 nadir in patients with an emphysematous phenotype
    Influence on physiological and sensory responses to exercise
     Palange (2000) [29]9FEV1 <50%⇑ V′E–V′CO2 slope in walking than cycling
     Ofir (2008) [30]42FEV1 91±8%⇑ V′E/V′CO2 nadir in smokers with chronic dyspnoea
     Ora (2009) [31]36FEV1 49±10%⇓ V′E/V′CO2 nadir in obese patients with COPD
     Guenette (2011) [32]64FEV1 86±11%No sex effect on V′E/V′CO2 nadir
     Caviedes (2012) [33]35FEV1 59±22%⇑ V′E/V′CO2 nadir associated with lower maximal exercise capacity
     Teopompi (2014) [34]56FEV1 26–80%⇑ V′E–V′CO2 intercept related to greater dynamic hyperinflation
    ⇑ V′E–V′CO2 slope associated with lower maximal exercise capacity
     Guenette (2014) [35]32FEV1 93±9%⇑ V′E/V′CO2 throughout incremental exercise in mild COPD
     Ciavaglia (2014) [36]12FEV1 60±13%No effect of exercise modality on V′E/V′CO2 in obese patients with COPD
     Barron (2014) [9]24FEV1 60±13%V′E/V′CO2 nadir showed excellent test–retest reliability (superior to V′E–V′CO2 slope)
    V′E/V′CO2 nadir showed better test–retest reliability in COPD than HF
     O’Donnell (2014) [37]208GOLD 1 and 2⇑ V′E/V′CO2 throughout incremental treadmill tests in GOLD 1 and 2
     Elbehairy (2015) [38]20FEV1 91±10%⇑ V′E/V′CO2 nadir in GOLD grade 1B
     Neder (2015) [39]316GOLD 1–4⇑ V′E–V′CO2 intercept from GOLD 1 to 4 associated with exertional dyspnoea
    ⇑ V′E–V′CO2 slope in GOLD 1 and 2, but lower slopes in GOLD 3 and 4
     Faisal (2016) [40]48FEV1 63±22%⇑ V′E/V′CO2 in COPD and ILD presenting with similar resting inspiratory capacity
     Elbehairy (2016) [41]20FEV1 101±13%Similar V′E–V′CO2 in smokers without COPD and healthy controls
     Crisafulli (2018) [42]254FEV1 51±14%V′E–V′CO2 slope >32 and inspiratory constraints associated with impaired HR recovery
     Bravo (2018) [43]16FEV1 42±9%⇑ V′E/V′CO2 accelerates mechanical constraints and dyspnoea during interval exercise
     Neder (2019) [44]288GOLD 1–4Ventilatory inefficiency and inspiratory constraints best predicted dyspnoea severity
     Kuint (2019) [45]20FEV1 63±21%Worsening gas trapping associated with lower ΔV′E/V′CO2 peak-nadir
     Neder (2020) [46]284GOLD 1–4Resting V′E/V′CO2 predicts V′E/V′CO2 nadir and exertional dyspnoea
     Neder (2020) [5]NANARegardless of ventilatory capacity, major ⇓ in modelled WR peak as V′E/V′CO2 ⇑
    Influence of comorbidities
     Holverda (2008) [47]25NA⇑ V′E/V′CO2 nadir associated with mean pulmonary artery pressure
     Vonbank (2008) [48]42FEV1 1.1±0.5 L⇑ V′E/V′CO2 rest and peak in patients with associated PAH
     Boerrigter (2012) [49]47FEV1 55±17%Pronounced ⇑ V′E–V′CO2 slope in a sub-group (n=9) with severe PAH
     Thirapatarapong (2013) [50]48FEV1 31±10%No effect of β-blockers on V′E/V′CO2 nadir in a retrospective study
     Thirapatarapong (2014) [51]98FEV1 20±7%No association of V′E/V′CO2 peak with PAH in severe to very severe COPD
     Teopompi (2014) [52]46FEV1 52±16%⇓ V′E–V′CO2 slope in COPD compared to HF in patients with poorer exercise capacity
    ⇑ V′E–V′CO2 intercept in COPD compared to HF
     Thirapatarapong (2014) [53]108FEV1 26±14%⇑ V′E/V′CO2 nadir in COPD patients with coexistent coronary artery disease
     Apostolo (2015) [54]95FEV1 53±13%⇑ V′E–V′CO2 intercept in COPD and COPD-HF compared to HF
     Arbex (2016) [55]98FEV1 55±17%⇑ V′E–V′CO2 slope and V′E/V′CO2 nadir in COPD-HF compared to COPD
    ⇓ V′E–V′CO2 intercept in COPD-HF compared to COPD
     Rocha (2016) [56]68FEV1 60±18%⇑ V′E–V′CO2 slope in COPD-HF with exercise oscillatory ventilation
     Rocha (2017) [57]22FEV1 60±11%⇑ V′E/V′CO2 more associated with hyperventilation than ⇑ VD/VTphys in COPD-HF
     Muller (2018) [58]40FEV1 43±13%V′E/V′CO2 not related to diastolic dysfunction
     Cherneva (2019) [59]104FEV1 1.4±0.4 L⇑ V′E–V′CO2 slope associated with stress-induced diastolic dysfunction
     Smith (2019) [60]22FEV1 60±11%⇑ V′E–V′CO2 intercept in COPD compared to HF with preserved and low ejection fraction
     Goulart (2020) [61]10FEV1 1.6±0.1 L⇑ V′E–V′CO2 slope associated with disease severity in COPD-HF
     Costa (2020) [62]42FEV1 52±14%⇑ V′E/V′CO2 was a key correlate of dyspnoea and exercise intolerance in CPFE
     Plachi (2020) [63]28NAMechanical constraints modulate dyspnoea-V′E differently in COPD and HF
    Risk assessment/prognosis
     Torchio (2010) [64]145FEV1 73±16%⇑ V′E–V′CO2 slope predicted mortality after lung resection surgery
     Brunelli (2012) [65]70FEV1 81±18%V′E–V′CO2 slope >35 predicted poor outcome after lung resection surgery
     Shafiek (2016) [66]55FEV1 60±17%V′E–V′CO2 slope >35 predicted poor outcome after lung resection surgery
     Neder (2016) [67]288FEV1 18–148%V′E/V′CO2 nadir >34 added to resting hyperinflation to predict mortality
     Alencar (2016) [68]30FEV1 57±17%V′E/V′CO2 nadir >34 and right ventricular function predicted mortality in COPD-HF
     Torchio (2017) [69]263GOLD 1–4⇑ V′E–V′CO2 slope was the best predictor of death after pneumonectomy
     Miyazaki (2018) [70]974FEV1 78±23%V′E–V′CO2 slope predicted 90-day and 2-year survival after lung resection for cancer
     Ellenberger (2018) [71]151FEV1 82±21%V′E/V′CO2 nadir >40 predicted 4-year survival after lung resection for cancer
     Crisafulli (2018) [42]254FEV1 51±14%⇑ V′E–V′CO2 slope associated with a delay in post-exercise heart rate
    Effects of interventions
     Orens (1995) [72]5FEV1 57±4%Single lung Tx decreased V′E/V′CO2 peak
     Somfay (2001) [73]10FEV1 31±10%Decrements in V′E with hyperoxia correlated with decreases in V′CO2
     O’Donnell (2001) [74]11FEV1 31±3%Proportional decrements V′E and V′CO2 with hyperoxia in advanced COPD
     O’Donnell (2004) [75]23FEV1 42±3%Salmeterol proportionally increased V′E and V′CO2 during constant work rate exercise
     Palange (2004) [76]12FEV1 <50% predHeliox increased V′E/V′CO2 during constant work rate exercise
     O’Donnell (2004) [77]187FEV1 44±13%⇑ V′E (due to higher VT) at a given V′CO2 with tiotropium compared to placebo
     Porszasz (2005) [78]24FEV1 36±8%Exercise training proportionally reduced V′E and V′CO2 during constant exercise
     Bobbio (2005) [79]11FEV1 53±20%Lobectomy increased V′E–V′CO2 slope
     Eves (2006) [80]10FEV1 47±17%Normoxic heliox increased V′E/V′CO2 more than hyperoxic heliox
     Chiappa (2009) [81]12FEV1 45±13%Heliox increased V′E/V′CO2 during constant work rate exercise
     Habedank (2011) [82]8NABilateral lung Tx decreased V′E–V′CO2 slope
     Gagnon (2012) [83]8FEV1 7±8%Spinal anesthesia reduced V′E/V′CO2 during constant work rate exercise
     Kim (2012) [84]1475FEV1 <45%LVRS reduced V′E/V′CO2 during unloaded exercise
     Guenette (2013) [85]15FEV1 86±15%⇑ V′E/V′CO2 at isotime with fluticasone/salmeterol compared to placebo
     Queiroga (2013) [86]24FEV1 35±10%Heliox increased V′E/V′CO2 during constant work rate exercise
     Armstrong (2015) [87]55FEV1 26±7%LVRS reduced V′E/V′CO2 peak and nadir
     Gloeckl (2017) [88]10FEV1 38±8%No effect of whole-body vibration training on V′E/V′CO2 in severe COPD
     Langer (2018) [89]20FEV1 47±19%No effect of inspiratory muscle training on V′E/V′CO2 during constant-WR exercise
     O’Donnell (2018) [90]14FEV1 62±10%No effect of dual bronchodilation on V′E/V′CO2 during constant-WR exercise
     Behnia (2018) [91]25FEV1 1.5±0.6 LNo effect of dietary nitrate supplementation on V′E/V′CO2 nadir
     Elbehairy (2018) [92]20FEV1 50±15%No effect of acute bronchodilation on VD/VT and V′E/V′CO2
     Perrotta (2019) [93]25FEV1 61±22%⇓ V′E–V′CO2 slope and ⇑ peak V′O2 after high-intensity exercise training
     Gravier (2019) [94]50FEV1 62±19%No effect of pulmonary rehabilitation on lung cancer patients undergoing PR
     Hasler (2020) [95]20FEV1 64±19%⇓ V′E/V′CO2 and ⇑ WR peak with supplemental O2 in non-hypoxaemic patients

    ⇓: decreased; ⇑: increased; FEV1: forced expiratory volume in 1 s; CO2: carbon dioxide; GOLD: Global Initiative for Chronic Obstructive Lung Disease; VD/VTphys: physiological dead space; CT: computed tomography; TLCO: transfer factor of the lung for carbon monoxide; V′O2: oxygen uptake; IC: inspiratory capacity; HF: heart failure; ILD: interstitial lung disease; NA: not available/not applicable; WR: work rate; PAH: pulmonary arterial hypertension; CPFE: combined pulmonary fibrosis and emphysema; Tx: transplant; LVRS: lung volume reduction surgery; PR: pulmonary rehabilitation; O2: oxygen; VT: tidal volume; HR: heart rate.

    • TABLE 2

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

      Exercise intoleranceWhat are the structural determinants of increased VD/VTphys in milder disease?
      What is the relevance of alveolar hyperventilation to increase V′E/V′CO2? Does it change with disease severity?
      What is the physiological meaning (if any) of the V′E–V′CO2 intercept?
      Is the V′E/V′CO2 consistently associated with specific disease phenotypes?
      How does very severe, end-stage disease influence V′E/V′CO2?
      Is resting V′E/V′CO2 useful to predict exercise intolerance and dyspnoea in patients unable to exercise?
      Influence of comorbiditiesDo emphysema severity and COPD phenotype influence V′E/V′CO2 in COPD-HF?
      Do HF aetiology and HF with preserved ejection fraction influence V′E/V′CO2 in COPD-HF?
      What is the effect of exertional hypoxia on V′E/V′CO2 in hypoxaemic patients with COPD-HF?
      Does V′E/V′CO2 relate to right ventricular–pulmonary arterial coupling in COPD?
      How does the severity of restriction influence V′E/V′CO2 in CPFE?
      Risk assessment/prognosisWhy does a high V′E/V′CO2 predict poor peri-operative outcome in lung resection surgery?
      What is the best V′E/V′CO2 parameter to predict poor surgical outcome across the spectrum of disease severity?
      Does V′E/V′CO2 independently predict poor outcome in severe to very severe patients?
      How to best associate V′E/V′CO2 with clinical data to determine prognosis?
      Does the longitudinal assessment of V′E/V′CO2 improve prognosis estimation?
      Effects of interventionsWhat is the most sensitive parameter to detect improvement in V′E/V′CO2?
      Can exercise training and/or inspiratory muscle training improve V′E/V′CO2 in selected patients?
      Do interventions aimed to improve pulmonary vascular function impact on V′E/V′CO2?
      Is there any beneficial effect of specific pharmacological interventions on V′E/V′CO2 in COPD-HF and disproportionate pulmonary hypertension?
      Can long-term bronchodilation improve V′E/V′CO2 in selected patients?

      VD/VTphys: physiological dead space; HF: heart failure; CPFE: combined pulmonary fibrosis and emphysema.

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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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      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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      • Article
        • Abstract
        • Abstract
        • Introduction
        • Structural and functional determinants of V′E/V′CO2 in COPD
        • Influence of V′E/V′CO2 on the physiological and sensory responses to exercise in COPD
        • Impact of COPD comorbidities on V′E/V′CO2
        • V′E/V′CO2 for risk assessment and prognosis in COPD
        • Effects of interventions on V′E/V′CO2 in COPD
        • Applying V′E/V′CO2 to clinical management of COPD
        • Conclusions
        • Supplementary material
        • Footnotes
        • References
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