Overview of cardiopulmonary exercise testing-based studies on the minute ventilation (VE)/carbon dioxide output (VCO2) relationship in different clinical scenarios in COPD

Subjects nDisease severityMain result
Structural and functional determinants
 ODonnell (2002) [15]20FEV1 34±3%VE at a given VCO2 in CO2 retainers compared to non-retainers
 Nakamoto (2007) [16]10FEV1 27–70%VEVCO2 slope not related to increased muscle ergoreflex activity
 Paoletti (2011) [17]16FEV1 54±18%VEVCO2 slope in more extensive emphysema
 Chin (2013) [18]40FEV1 87±11%VE/VCO2with added external dead space in mild COPD
 Neder (2015) [19]276GOLD 1–4VEVCO2 slope associated with ventilation inhomogeneity in GOLD 1 and 2
 Elbehairy (2015) [20]22FEV1 94±10%VE/VCO2 associated with greater VD/VTphys in symptomatic GOLD 1
 Crisafulli (2016) [21]51FEV1 55±16%VEVCO2 slope associated with emphysema extension on chest CT
 Elbehairy (2017) [22]62FEV1 65±8%VE/VCO2 associated with ⇓ TLCO and ⇓ VO2 peak in smokers with mild obstruction
 Jones (2017) [23]19FEV1 82±13%VE/VCO2 linked ⇑ emphysema and ⇓ TLCO to exercise intolerance in mild COPD
 Behnia (2017) [24]32FEV1 56±16%VE/VCO2 inversely related to exercise TLCO
 Smith (2018) [25]67GOLD 1–4VE/VCO2 positively related to emphysema extent
 Tedjasaputra (2018) [26]17FEV1 94±11%VE/VCO2 nadir ≥34 associated with ⇓ pulmonary capillary blood volume and ⇑ dyspnoea
 Elbehairy (2019) [27]300FEV1 61±25%VE/VCO2 nadir in tandem with progressively ⇓ TLCO across FEV1 and IC tertiles
 Rinaldo (2020) [28]50FEV1 56±16%VE/VCO2 nadir in patients with an emphysematous phenotype
Influence on physiological and sensory responses to exercise
 Palange (2000) [29]9FEV1 <50%VEVCO2 slope in walking than cycling
 Ofir (2008) [30]42FEV1 91±8%VE/VCO2 nadir in smokers with chronic dyspnoea
 Ora (2009) [31]36FEV1 49±10%VE/VCO2 nadir in obese patients with COPD
 Guenette (2011) [32]64FEV1 86±11%No sex effect on VE/VCO2 nadir
 Caviedes (2012) [33]35FEV1 59±22%VE/VCO2 nadir associated with lower maximal exercise capacity
 Teopompi (2014) [34]56FEV1 26–80%VEVCO2 intercept related to greater dynamic hyperinflation
VEVCO2 slope associated with lower maximal exercise capacity
 Guenette (2014) [35]32FEV1 93±9%VE/VCO2 throughout incremental exercise in mild COPD
 Ciavaglia (2014) [36]12FEV1 60±13%No effect of exercise modality on VE/VCO2 in obese patients with COPD
 Barron (2014) [9]24FEV1 60±13%VE/VCO2 nadir showed excellent test–retest reliability (superior to VEVCO2 slope)
VE/VCO2 nadir showed better test–retest reliability in COPD than HF
 ODonnell (2014) [37]208GOLD 1 and 2VE/VCO2 throughout incremental treadmill tests in GOLD 1 and 2
 Elbehairy (2015) [38]20FEV1 91±10%VE/VCO2 nadir in GOLD grade 1B
 Neder (2015) [39]316GOLD 1–4VEVCO2 intercept from GOLD 1 to 4 associated with exertional dyspnoea
VEVCO2 slope in GOLD 1 and 2, but lower slopes in GOLD 3 and 4
 Faisal (2016) [40]48FEV1 63±22%VE/VCO2 in COPD and ILD presenting with similar resting inspiratory capacity
 Elbehairy (2016) [41]20FEV1 101±13%Similar VEVCO2 in smokers without COPD and healthy controls
 Crisafulli (2018) [42]254FEV1 51±14%VEVCO2 slope >32 and inspiratory constraints associated with impaired HR recovery
 Bravo (2018) [43]16FEV1 42±9%VE/VCO2 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 ΔVE/VCO2 peak-nadir
 Neder (2020) [46]284GOLD 1–4Resting VE/VCO2 predicts VE/VCO2 nadir and exertional dyspnoea
 Neder (2020) [5]NANARegardless of ventilatory capacity, major ⇓ in modelled WR peak as VE/VCO2
Influence of comorbidities
 Holverda (2008) [47]25NAVE/VCO2 nadir associated with mean pulmonary artery pressure
 Vonbank (2008) [48]42FEV1 1.1±0.5 LVE/VCO2 rest and peak in patients with associated PAH
 Boerrigter (2012) [49]47FEV1 55±17%Pronounced ⇑ VEVCO2 slope in a sub-group (n=9) with severe PAH
 Thirapatarapong (2013) [50]48FEV1 31±10%No effect of β-blockers on VE/VCO2 nadir in a retrospective study
 Thirapatarapong (2014) [51]98FEV1 20±7%No association of VE/VCO2 peak with PAH in severe to very severe COPD
 Teopompi (2014) [52]46FEV1 52±16%VEVCO2 slope in COPD compared to HF in patients with poorer exercise capacity
VEVCO2 intercept in COPD compared to HF
 Thirapatarapong (2014) [53]108FEV1 26±14%VE/VCO2 nadir in COPD patients with coexistent coronary artery disease
 Apostolo (2015) [54]95FEV1 53±13%VEVCO2 intercept in COPD and COPD-HF compared to HF
 Arbex (2016) [55]98FEV1 55±17%VEVCO2 slope and VE/VCO2 nadir in COPD-HF compared to COPD
VEVCO2 intercept in COPD-HF compared to COPD
 Rocha (2016) [56]68FEV1 60±18%VEVCO2 slope in COPD-HF with exercise oscillatory ventilation
 Rocha (2017) [57]22FEV1 60±11%VE/VCO2 more associated with hyperventilation than ⇑ VD/VTphys in COPD-HF
 Muller (2018) [58]40FEV1 43±13%VE/VCO2 not related to diastolic dysfunction
 Cherneva (2019) [59]104FEV1 1.4±0.4 LVEVCO2 slope associated with stress-induced diastolic dysfunction
 Smith (2019) [60]22FEV1 60±11%VEVCO2 intercept in COPD compared to HF with preserved and low ejection fraction
 Goulart (2020) [61]10FEV1 1.6±0.1 LVEVCO2 slope associated with disease severity in COPD-HF
 Costa (2020) [62]42FEV1 52±14%VE/VCO2 was a key correlate of dyspnoea and exercise intolerance in CPFE
 Plachi (2020) [63]28NAMechanical constraints modulate dyspnoea-VE differently in COPD and HF
Risk assessment/prognosis
 Torchio (2010) [64]145FEV1 73±16%VEVCO2 slope predicted mortality after lung resection surgery
 Brunelli (2012) [65]70FEV1 81±18%VEVCO2 slope >35 predicted poor outcome after lung resection surgery
 Shafiek (2016) [66]55FEV1 60±17%VEVCO2 slope >35 predicted poor outcome after lung resection surgery
 Neder (2016) [67]288FEV1 18–148%VE/VCO2 nadir >34 added to resting hyperinflation to predict mortality
 Alencar (2016) [68]30FEV1 57±17%VE/VCO2 nadir >34 and right ventricular function predicted mortality in COPD-HF
 Torchio (2017) [69]263GOLD 1–4VEVCO2 slope was the best predictor of death after pneumonectomy
 Miyazaki (2018) [70]974FEV1 78±23%VEVCO2 slope predicted 90-day and 2-year survival after lung resection for cancer
 Ellenberger (2018) [71]151FEV1 82±21%VE/VCO2 nadir >40 predicted 4-year survival after lung resection for cancer
 Crisafulli (2018) [42]254FEV1 51±14%VEVCO2 slope associated with a delay in post-exercise heart rate
Effects of interventions
 Orens (1995) [72]5FEV1 57±4%Single lung Tx decreased VE/VCO2 peak
 Somfay (2001) [73]10FEV1 31±10%Decrements in VE with hyperoxia correlated with decreases in VCO2
 ODonnell (2001) [74]11FEV1 31±3%Proportional decrements VE and VCO2 with hyperoxia in advanced COPD
 ODonnell (2004) [75]23FEV1 42±3%Salmeterol proportionally increased VE and VCO2 during constant work rate exercise
 Palange (2004) [76]12FEV1 <50% predHeliox increased VE/VCO2 during constant work rate exercise
 ODonnell (2004) [77]187FEV1 44±13%VE (due to higher VT) at a given VCO2 with tiotropium compared to placebo
 Porszasz (2005) [78]24FEV1 36±8%Exercise training proportionally reduced VE and VCO2 during constant exercise
 Bobbio (2005) [79]11FEV1 53±20%Lobectomy increased VEVCO2 slope
 Eves (2006) [80]10FEV1 47±17%Normoxic heliox increased VE/VCO2 more than hyperoxic heliox
 Chiappa (2009) [81]12FEV1 45±13%Heliox increased VE/VCO2 during constant work rate exercise
 Habedank (2011) [82]8NABilateral lung Tx decreased VEVCO2 slope
 Gagnon (2012) [83]8FEV1 7±8%Spinal anesthesia reduced VE/VCO2 during constant work rate exercise
 Kim (2012) [84]1475FEV1 <45%LVRS reduced VE/VCO2 during unloaded exercise
 Guenette (2013) [85]15FEV1 86±15%VE/VCO2 at isotime with fluticasone/salmeterol compared to placebo
 Queiroga (2013) [86]24FEV1 35±10%Heliox increased VE/VCO2 during constant work rate exercise
 Armstrong (2015) [87]55FEV1 26±7%LVRS reduced VE/VCO2 peak and nadir
 Gloeckl (2017) [88]10FEV1 38±8%No effect of whole-body vibration training on VE/VCO2 in severe COPD
 Langer (2018) [89]20FEV1 47±19%No effect of inspiratory muscle training on VE/VCO2 during constant-WR exercise
 ODonnell (2018) [90]14FEV1 62±10%No effect of dual bronchodilation on VE/VCO2 during constant-WR exercise
 Behnia (2018) [91]25FEV1 1.5±0.6 LNo effect of dietary nitrate supplementation on VE/VCO2 nadir
 Elbehairy (2018) [92]20FEV1 50±15%No effect of acute bronchodilation on VD/VT and VE/VCO2
 Perrotta (2019) [93]25FEV1 61±22%VEVCO2 slope and ⇑ peak VO2 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%VE/VCO2 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; VO2: 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.