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

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.

Importance of Cardiopulmonary Exercise Testing Amongst Subjects Recovering from COVID-19

The cardiopulmonary exercise test (CPET) provides an objective assessment of ventilatory limitation, related to the exercise minute ventilation (VE) coupled to carbon dioxide output (VCO2) (VE/VCO2); high values of VE/VCO2 slope define an exercise ventilatory inefficiency (EVin). In subjects recovered from hospitalised COVID-19, we explored the methodology of CPET in order to evaluate the presence of cardiopulmonary alterations. Our prospective study (RESPICOVID) has been proposed to evaluate pulmonary damage’s clinical impact in post-COVID subjects. In a subgroup of subjects (RESPICOVID2) without baseline confounders, we performed the CPET. According to the VE/VCO2 slope, subjects were divided into having EVin and exercise ventilatory efficiency (EVef). Data concerning general variables, hospitalisation, lung function, and gas-analysis were also collected. The RESPICOVID2 enrolled 28 subjects, of whom 8 (29%) had EVin. As compared to subjects with EVef, subjects with EVin showed a reduction in heart rate (HR) recovery. VE/VCO2 slope was inversely correlated with HR recovery; this correlation was confirmed in a subgroup of older, non-smoking male subjects, regardless of the presence of arterial hypertension. More than one-fourth of subjects recovered from hospitalised COVID-19 have EVin. The relationship between EVin and HR recovery may represent a novel hallmark of post-COVID cardiopulmonary alterations.

Respiratory compensation point

This chapter describes how acidaemia stimulates ventilation in the later stages of a cardiopulmonary exercise test (CPET). This happens after the anaerobic threshold, once the capacity of the blood to buffer lactic acid has been used up. The respiratory compensation point (RCP) can be identified from an increase in the slope when minute ventilation (VE) is plotted against carbon dioxide output (VCO2), or from a rise in the ventilatory equivalents for carbon dioxide (VeqCO2). The presence of a clear RCP indicates that the subject has made a fairly maximal effort during the CPET. An RCP also argues against significant lung disease, since it implies the ability to increase ventilation in response to acidaemia.

Carbon dioxide output

This chapter describes how carbon dioxide is produced from metabolism and also from buffering of lactic acid. The volume of carbon dioxide exhaled (VCO2) is calculated from the concentration in exhaled gas and minute ventilation. If the lungs are less efficient than normal, with a high dead space, the amount of ventilation needed to achieve any given VCO2 is much higher. This index, known as the ventilatory equivalent for carbon dioxide, is an important prognostic marker. Early on in a cardiopulmonary exercise test (CPET), VCO2 is slightly less than the oxygen uptake (VO2). As exercise reaches its maximum, VCO2 increases more quickly when acidaemia starts to stimulate ventilation.

Respiratory exchange ratio

This chapter describes how the respiratory exchange ratio (RER) is calculated by dividing carbon dioxide output (VCO2) by the oxygen uptake (VO2). At the start of a cardiopulmonary exercise test (CPET), this ratio is less than 1.0. Once anaerobic metabolism starts to kick in, more carbon dioxide is produced from buffering of lactic acid and the RER starts to climb. At peak exercise, RER values of 1.4 or higher indicate that the subject’s effort is pretty maximal. An erratic RER trace is seen in dysfunctional breathing, when psychological, rather than physiological, processes are involved in controlling breathing.

Intercept of minute ventilation vs. carbon dioxide output relationship in chronic obstructive pulmonary disease: utility as an index of ventilatory inefficiency

Background: Ventilatory inefficiency is known to be a contributor to exercise intolerance in chronic obstructive pulmonary disease (COPD). The intercept of the minute ventilation (V̇E) vs. carbon dioxide output (V̇CO2) plot is a key ventilator inefficiency parameter. However, its relationships with lung hyperinflation (LH) and airflow limitation are not known. This study aimed to evaluate the correlations between the V̇E/V̇CO2 intercept and LH in COPD to determine its utility as an index of functional impairment.Methods: We conducted a retrospective analysis of data from 53 COPD patients and 14 healthy controls performed incremental cardiopulmonary exercise tests and resting pulmonary function. Ventilatory inefficiency was represented by parameters reflecting the V̇E/V̇CO2 nadir and slope (linear region), and intercept of the V̇E/V̇CO2 plot. Their correlations with measures of LH and airflow limitation were evaluated.Results: Compared to the control, the slope (30.58±3.62) and intercept (4.85±1.11) higher in COPDstages1-2, leading to a higher nadir (31.47±4.47) (p<0.05). Despite an even higher intercept in COPDstages3-4 (7.16±1.41), the slope diminished with disease progression (from 30.58±3.62 in COPDstages1-2 to 28.36±4.58 in COPDstages3-4). Compared to the V̇E/V̇CO2 nadir and V̇E/V̇CO2 slope, the intercept was better correlated with peak V̇E/maximal voluntary ventilation (MVV) (r=0.489, p<0.001) and peak V̇O2/watt (r=0.354, p=0.003). The intercept was also significantly correlated with RV/TLC (r=0.588, p<0.001), IC/TLC (r=-0.574, p<0.001), peak VT/TLC (r=-0.585, p<0.001); and airflow limitation forced expiratory volume in 1s (FEV1) % predicted (r=-0.606, p<0.001) and FEV1/forced vital capacity (FVC) (r=-0.629, p<0.001).Conclusion: V̇E/V̇CO2intercept was consistently better correlated with worsening static and dynamic lung hyperinflation and airflow limitation in COPD. V̇E/V̇CO2 intercept emerged as a useful index of ventilatory inefficiency across the severity spectrum of COPD patients.

Effects of a high-intensity pulmonary rehabilitation program on the minute ventilation/carbon dioxide output slope during exercise in a cohort of patients with COPD undergoing lung resection for non-small cell lung cancer

ABSTRACT Objective: Preoperative functional evaluation is central to optimizing the identification of patients with non-small cell lung cancer (NSCLC) who are candidates for surgery. The minute ventilation/carbon dioxide output (VE/VCO2) slope has proven to be a predictor of surgical complications and mortality. Pulmonary rehabilitation programs (PRPs) could influence short-term outcomes in patients with COPD undergoing lung resection. Our objective was to evaluate the effects of a PRP on the VE/VCO2 slope in a cohort of patients with COPD undergoing lung resection for NSCLC. Methods: We retrospectively evaluated 25 consecutive patients with COPD participating in a three-week high-intensity PRP prior to undergoing lung surgery for NSCLC, between December of 2015 and January of 2017. Patients underwent complete functional assessment, including spirometry, DLCO measurement, and cardiopulmonary exercise testing. Results: There were no significant differences between the mean pre- and post-PRP values (% of predicted) for FEV1 (61.5 ± 22.0% vs. 62.0 ± 21.1%) and DLCO (67.2 ± 18.1% vs. 67.5 ± 13.2%). Conversely, there were significant improvements in the mean peak oxygen uptake (from 14.7 ± 2.5 to 18.2 ± 2.7 mL/kg per min; p < 0.001) and VE/VCO2 slope (from 32.0 ± 2.8 to 30.1 ± 4.0; p < 0.01). Conclusions: Our results indicate that a high-intensity PRP can improve ventilatory efficiency in patients with COPD undergoing lung resection for NSCLC. Further comprehensive prospective studies are required to corroborate these preliminary results.

Ventilatory Responses During Submaximal Exercise in Children With Prader–Willi Syndrome

Purpose: Prader–Willi syndrome (PWS) is a genetic neurobehavioral disorder presenting hypothalamic dysfunction and adiposity. At rest, PWS exhibits hypoventilation with hypercapnia. We characterized ventilatory responses in children with PWS during exercise. Methods: Participants were children aged 7–12 years with PWS (n = 8) and without PWS with normal weight (NW; n = 9, body mass index ≤ 85th percentile) or obesity (n = 9, body mass index ≥ 95th percentile). Participants completed three 5-minute ambulatory bouts at 3.2, 4.0, and 4.8 km/h. Oxygen uptake, carbon dioxide output, ventilation, breathing frequency, and tidal volume were recorded. Results: PWS had slightly higher oxygen uptake (L/min) at 3.2 km/h [0.65 (0.46–1.01) vs 0.49 (0.34–0.83)] and at 4.8 km/h [0.89 (0.62–1.20) vs 0.63 (0.45–0.97)] than NW. PWS had higher ventilation (L/min) at 3.2 km/h [16.2 (13.0–26.5) vs 11.5 (8.4–17.5)], at 4.0 km/h [16.4 (13.9–27.9) vs 12.7 (10.3–19.5)], and at 4.8 km/h [19.7 (17.4–31.8) vs 15.2 (9.5–21.6)] than NW. PWS had greater breathing frequency (breaths/min) at 3.2 km/h [38 (29–53) vs 29 (22–35)], at 4.0 km/h [39 (29–58) vs 29 (23–39)], and at 4.8 km/h [39 (33–58) vs 32 (23–42)], but similar tidal volume and ventilation/carbon dioxide output to NW. Conclusion: PWS did not show impaired ventilatory responses to exercise. Hyperventilation in PWS may relate to excessive neural stimulation and metabolic cost.