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