Respiratory Physiology & Neurobiology 197 (2014) 9–14
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Excess ventilation and ventilatory constraints during exercise in patients with chronic obstructive pulmonary disease Elisabetta Teopompi, Panagiota Tzani, Marina Aiello, Maria Rosaria Gioia, Emilio Marangio, Alfredo Chetta ∗ Respiratory Disease and Lung Function Unit, Department of Clinical and Experimental Medicine, University of Parma, Italy
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Article history: Accepted 7 March 2014 Available online 19 March 2014 Keywords: COPD Exercise Ventilatory response
a b s t r a c t We assessed the relationship between minute ventilation/carbon dioxide output (VE/VCO2 ) and ventilatory constraints during an incremental cardiopulmonary exercise testing (CPET) in patients with chronic obstructive pulmonary disease (COPD). Slope and intercept of the VE/VCO2 linear relationship, the ratios of inspiratory capacity/total lung capacity (IC/TLC) and of tidal volume (VT) over vital capacity (VTpeak /VC) and IC (VTpeak /IC) and over forced expiratory volume at 1st second (VTpeak /FEV1 ) at peak of exercise were measured in 52 COPD patients during a CPET. The difference peak-rest in end-tidal pressure of CO2 (PETCO2 ) was also measured. VE/VCO2 intercept showed a negative correlation with IC/TLC peak (p < 0.01) and a positive one with VTpeak /FEV1 (p < 0.01) and with PETCO2 peak-rest (p < 0.01). VE/VCO2 slope was negatively related to VTpeak /VC, VTpeak /IC and VTpeak /FEV1 (all correlations p < 0.05) and to PETCO2 peak-rest (p < 0.01). In COPD, VE/VCO2 slope and intercept provide complementary information on the ventilatory limitation to exercise, as assessed by changes in the end-expiratory lung volume and in tidal volume excursion. © 2014 Elsevier B.V. All rights reserved.
1. Introduction An excess in exercise ventilation for a given metabolic rate may occur in patients with chronic obstructive pulmonary disease (COPD). The minute ventilation (VE) to the carbon dioxide output (VCO2 ) ratio, also known as ventilatory equivalent for CO2 (VE/VCO2 ) (Wasserman et al., 1994), may be increased in patients with COPD during exercise, as compared to control subjects (O’Donnell et al., 2001; Paoletti et al., 2011). In addition, in COPD patients the slope of the VE/VCO2 linear relationship was found to be negatively related to the peak oxygen uptake (VO2 peak) during a rapidly incremental cardiopulmonary exercise
Abbreviations: AT, anaerobic threshold; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CPET, cardiopulmonary exercise test; FEV1, forced expiratory volume in 1st second; FVC, forced vital capacity; IC, inspiratory capacity; RER, respiratory exchange ratio; SD, standard deviation; SpO2 , oxygen saturation; TLC, total lung capacity; TLco, lung diffusion capacity for carbon monoxide; VC, vital capacity; VCO2 , carbon dioxide production; VE, minute ventilation; VE/VCO2 , ventilatory equivalent for CO2 ; VO2 , oxygen uptake; VT, tidal volume. ∗ Corresponding author at: Unità di Malattie Respiratorie e Funzionalità Polmonare, Università di Parma, Padiglione Rasori, via G. Rasori 10, 43100 Parma, Italy. Tel.: +39 0521 703475; fax: +39 0521 292615. E-mail address: [email protected] (A. Chetta). http://dx.doi.org/10.1016/j.resp.2014.03.002 1569-9048/© 2014 Elsevier B.V. All rights reserved.
testing (CPET) (Caviedes et al., 2012; Teopompi et al., 2013). Interestingly, the VE/VCO2 slope values were found to be decreased in patients with more severe emphysema, by indicating a relationship between VE/VCO2 slope and ventilatory limitation (Paoletti et al., 2011). Furthermore, even the intercept of the VE/VCO2 relationship has the potential for understanding the ventilatory response to exercise in patients with chronic cardiopulmonary disabling conditions (Agostoni et al., 2011; Teopompi et al., 2013). Patients with COPD experience ventilatory constraints on exertion. In these patients, the development of dynamic hyperinflation limits exercise capacity and plays a key role in the perception of exertional breathlessness (O’Donnell, 2008). Indeed, COPD patients while exercising, may breathe in before achieving a full exhalation and, accordingly, trap air within the lungs with each further breath with serious mechanical and sensory consequences. Notably, dynamic lung hyperinflation may progressively restrict the tidal volume excursion and exercise ventilation can increase only by quickening the breathing frequency, thereby inducing a further hyperinflation in a vicious circle. Furthermore, in COPD patients dynamic hyperinflation may be associated with a poor cardiovascular response to exercise (Tzani et al., 2011). Up to now, no study has been specifically aimed to assess the relationship between the excess in exercise ventilation for a given metabolic rate and the ventilatory limitation in COPD patients. The
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aim of the present study was, therefore, to measure in a cohort of COPD patients the VE/VCO2 value, both in terms of slope and in terms of intercept, and to ascertain whether or not these parameters may be related to the development of dynamic hyperinflation and to the tidal volume constraints. We hypothesized that the VE/VCO2 slope and intercept values might be differently associated to the ventilatory constraints during exercise in COPD patients. 2. Methods 2.1. Patients We consecutively enrolled over a 9-month period, from January 2013 to September 2013, patients affected by COPD, who were admitted to a pulmonary rehabilitation program. COPD was diagnosed according to the GOLD criteria (Pauwels et al., 2001) and patients with moderate to severe airflow obstruction, i.e. forced expiratory volume in 1 s/vital capacity ratio (FEV1 /VC) < 70% and FEV1 ≤ 80% of predicted value, were included. Eligibility criteria of patients were (1) ex-smoking habit; (2) no long-term oxygen therapy; (3) BMI ≥ 20 and ≤30 kg/m2 ; (4) stable clinical condition for at least 6 weeks; (5) absence of any comorbidity affecting exercise performance (anemia, chronic heart failure, neuromuscular disorders, or malignancies); (6) no other concomitant chronic respiratory disease, such as asthma or pulmonary fibrosis; (7) ability to perform a CPET with a peak of respiratory exchange ratio (RER) ≥ 1.05 in order to exclude poor motivation (American Thoracic Society, 2003); (8) CPET stopped for muscle fatigue and/or dyspnea. To be included, patients were considered as former smokers when they were abstinent from smoking from at least six months. Patients were not pretreated with beta2 -agonists before exercise testing, but were allowed to continue with their regular therapy during the study. All the procedures and their risks were explained to the patients, who gave their written informed consent to enter the study, which was conducted according to the Declaration of Helsinki. The protocol was approved by the ethical committee of the University Hospital of Parma. All participants’ data were analyzed and reported anonymously. 2.2. Lung function Pulmonary function tests were performed according to international recommendations (Miller et al., 2005; Wanger et al., 2005). A flow-sensing spirometer and a body plethysmograph connected to a computer for data analysis (Vmax 22 and 6200, Sensor Medics, Yorba Linda, U.S.A.) were used for the measurements. VC, forced vital capacity (FVC), FEV1 and forced expiratory flow at 50% of FVC (FEF50 in L/s) and forced inspiratory flow at 50% of FVC (FIF50 in L/s) were recorded. FEV1 /VC and FEF50 /FIF50 ratios were taken as indices of airflow obstruction and airway collapsibility, respectively. Thoracic gas volume (TGV) was measured by body plethysmography with the subject panting against a closed shutter at a frequency slightly 1.15, (3) peak workload > 80% predicted, (4) peak VO2 > 84% predicted, 5) peak heart rate > 90% predicted, (6) ventilatory reserve < 15%, (7) ECG significant ST-segment depression, (8) drop in systolic blood pressure or oxygen saturation (SpO2 ) ≤ 84 (American Thoracic Society, 2003). Predicted values were calculated according to equations by Wasserman et al. (Wasserman et al., 1994). Peak workload and peak VO2 were recorded as the mean value of watts and VO2 during the last 20 s of the test. Peak VO2 was expressed as absolute value in mL/kg/min. Anaerobic threshold (AT) was non-invasively determined by both V-slope and ventilatory equivalents methods (“dual method approach”), as the respiratory exchange ratio approximated 1.0 (American Thoracic Society, 2003), and was expressed as absolute value in mL/min. The AT was determined by two non-blinded physicians (ET and PT) attending to the CPET. The ventilatory response during exercise was expressed as a linear regression function by plotting VE against VCO2 obtained every 10 s, excluding data above the ventilatory compensation point (American Thoracic Society, 2003). Then, the slope and Y intercept values were obtained from the VE/VCO2 regression line. The end-tidal pressure of CO2 (PETCO2 , in mmHg) was measured as mean of PETCO2 during the 3-min rest period and during the last 20 s of the test and was recorded as the difference between PETCO2 peak and PETCO2 rest (PETCO2 peak-rest). Changes in operational lung volumes were assessed every two min during exercise and at peak exercise, taking the IC measured at rest, as the baseline. After a full explanation to each patient of the procedure, satisfactory technique and reproducibility of IC maneuvers were established during an initial practice session at rest. Assuming that TLC remains constant during exercise in COPD (Stubbing et al., 1980), changes in IC reflect changes in endexpiratory lung volume. Accordingly, dynamic hyperinflation may be defined as a decline in the IC greater than zero. According to IC/TLC ratio at peak of exercise, patients were divided in two categories: patients with IC/TLC ≤ 0.25 or >0.25. The patients with the
E. Teopompi et al. / Respiratory Physiology & Neurobiology 197 (2014) 9–14 Table 1 Demographic and baseline characteristics of 52 COPD patients (13 females). Mean ± SD Age (years) BMI (kg/m2 ) TLC (% pred) FEV1 (% pred) FEV1 /VC (%) Rest IC/TLC FEF50 /FIF50 TLCO (% pred) Rest SpO2 (%)
64 26 118 53 51 0.32 0.32 65 96
± ± ± ± ± ± ± ± ±
8 3 24 16 11 0.09 0.20 21 2
Table 2 Exercise characteristics of COPD patients (13 females). Mean ± SD
Range 42–75 20–30 80–189 26 ± 80 30–69 0.10–0.56 0.07–0.93 28–114 91–99
IC/TLC ratio at the peak of exercise ≤0.25 may be defined as “heavy hyperinflators” (Tzani et al., 2011). The ratios of VT at peak of exercise over VC (VTpeak /VC) and over IC (VTpeak /IC), as indices of volume excursion (Wasserman et al., 1994), were measured. In addition, the ratio of VT at peak of exercise over FEV1 (VTpeak /FEV1 ), which is associated to severe emphysema when it is greater than 1 (Paoletti et al., 2011), was also measured. 2.4. Statistical analysis This is a pilot, cross-sectional study. Due to the explorative nature of the study no formal sample size calculation was performed. Data are reported as mean ± standard deviation (SD), unless otherwise specified. The distribution of variables was assessed by means of Kolmogorov–Smirnov Goodness-of-Fit test. According to the median values of VE/VCO2 slope and intercept, the patients were subdivided in four groups: A (patients with a VE/VCO2 slope value ≥ median value and with a VE/VCO2 intercept value < median value), B (patients with a VE/VCO2 slope value ≥ median value and with a VE/VCO2 intercept value ≥ median value), C (patients with a VE/VCO2 slope value < median value and with a VE/VCO2 intercept value < median value), D (patients with a VE/VCO2 slope value < median value and with a VE/VCO2 intercept value ≥ median value). Relationships between variables were assessed by the Pearson’s correlation coefficient (r) and linear regression analysis or Spearman correlation coefficient (rs), when appropriate. Comparisons between variables were determined by unpaired t test. Comparisons of proportions of patients with VTpeak /FEV1 < 1 in the four groups were evaluated by means of 2 for trend. A p value of less than 0.05 was taken as significant.
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Peak VO2 (mL/kg/min) Peak Workload (watts) AT (mL/min) VE (L/min) VTpeak (L) VE/VCO2 slope (L) VE/VCO2 intercept (L/min) Peak IC/TLC VTpeak /VC VTpeak /IC VTpeak /FEV1 Peak SpO2 (%)
16.9 89.6 905 43.7 1.41 29.6 3.96 0.27 0.47 0.65 1.00 94
± ± ± ± ± ± ± ± ± ± ± ±
5.3 38.5 289 14.8 0.41 6.8 1.9 0.09 0.12 0.21 0.25 3
Range 7.7–30.2 34–220 510–1577 20.2–79.0 0.65 ± 2.61 19.3–52.0 0.9–9.91 0.09–0.54 0.27–0.83 0.32–1.54 0.61–1.61 88–99
patients, SpO2 , at rest and at peak were 95.7% ± 1.7 and 94.1% ± 3.1, (p < 0.001) respectively. Dynamic hyperinflation was experienced by 41 out of 52 patients (79%). In all patients, IC/TLC values at rest and at peak of exercise were 0.32 ± 0.09 and 0.27 ± 0.09 (p < 0.001), respectively. Peak IC/TLC was significantly related to the resting FEV1 (% pred) (r = 0.615; p < 0.01). VE/VCO2 intercept, but not VE/VCO2 slope was significantly and negatively related with IC/TLC rest (r = −0.341; p = 0.013) and IC/TLC peak (r = −0.446; p = 0.001) (Fig. 1). Twentyfour out of 52 patients showed a peak exercise IC/TLC ≤ 0.25. They significantly differed in VE/VCO2 intercept (4.8 L/min ± 1.8 vs 3.2 L/min ± 1.7, p = 0.002), but not in VE/VCO2 slope (30.3 L ± 6.2 vs 29.1 L ± 7.4, p = 0.548), as compared to the remaining patients. When the breathing pattern was analyzed at peak of the exercise, mean VTpeak /VC and VTpeak /IC values were respectively 0.47 ± 0.12, ranging from 0.27 to 0.83 and 0.65 ± 0.21, ranging from 0.32 to 1.54. Three out of 52 patients showed a VTpeak /IC ratio greater than 1. No correlation was found between the severity of disease, expressed as FEV1% pred, and VTpeak /IC and VTpeak /VC. In all patients, VE/VCO2 slope, but not VE/VCO2 intercept was
3. Results Fifty-six stable COPD patients, aged between 42 and 75 years were studied. According to the GOLD classification (Pauwels et al., 2001) 29 patients were moderate, 18 severe and 5 very severe. At study entry, patients were receiving regular therapy with inhaled steroids (60%), long-acting beta2 -agonists (62%) and tiotropium (51%). All of them were ex-smokers. Patients completed the exercise test without any complication and no patient was excluded because of poor motivation. In addition, no patient needs supplemental oxygen during exercise. In four patients, randomly distributed among GOLD stages, changes in operational lung volumes failed to be recorded, thus 52 patients (13 females) were considered for analysis (Table 1). Among them wide ranges of peak workload (from 30 to 221 W) and peak VO2 values (from 7.70 to 30.20 mL/kg/min) were found (Table 2). VE/VCO2 slope, but not VE/VCO2 intercept showed a negative correlation with peak workload (r = −0.429; p = 0.002) and peak VO2 (r = −0.317; p = 0.022). On the other hand, VE/VCO2 intercept, but not VE/VCO2 slope showed a negative correlation with the severity of disease, expressed as FEV1 (% pred) (r = −0.482; p < 0.001). In all
Fig. 1. Relationship between VE/VCO2 intercept and IC/TLC peak (upper panel) and between VE/VCO2 slope and VTpeak /VC (lower panel) in 52 COPD patients.
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Fig. 2. Relationship between VE/VCO2 intercept and VE/VCO2 slope values in 52 COPD patients (r = −0.254; p = 0.068). A–D indicate four groups of patients, categorized according to the median values of VE/VCO2 slope (29 L) and intercept (3.54 L/min). When compared the number of patients with VTpeak /FEV1 < 1 to those with VTpeak /FEV1 >/=1 in the four groups, a significant trend from group A (high slope and low intercept; 10 vs 5 pts) to group B (high slope and high intercept; 8 vs 5 pts), group C (low slope and low intercept; 7 vs 4 pts) and group D (low slope and high intercept; 2 vs 11) was found (2 for trend: 6.336; p < 0.05). Closed and open circles represent respectively patients with VTpeak /FEV1 ≥ 1 and patients with VTpeak /FEV1 < 1; interrupted lines represent median values.
negatively related to VTpeak /VC (r = −0.309; p = 0.026) (Fig. 1) and to VTpeak /IC (rs = −0.347; p = 0.012). In 25 out of 52 the VTpeak /FEV1 ratio was greater than 1, ranging in all patients from 0.61 to 1.61 (mean 1.00 ± 0.25). As compared to patients with VTpeak /FEV1 < 1, patients with VTpeak /FEV1 ≥ 1 had lower resting values of FEV1 /VC (44.2% ± 8.7 vs 57.7% ± 8.9; p = 0.001), FEF50 /FIF50 (0.21 ± 0.12 vs 0.42 ± 0.21; p < 0.001), IC/TLC (0.29 ± 0.009 vs 0.34 ± 0.07; p = 0.028) and TLco (57.9% ± 17.9 vs 72.7% ± 20.8; p = 0.012). In addition, the plot of VE/VCO2 intercept versus VE/VCO2 slope values (r = −0.254; p = 0.068) showed that patients with VTpeak /FEV1 ≥ 1 tended to have low values in VE/VCO2 slope and high values in VE/VCO2 intercept (Fig. 2). When we compared the number of patients with VTpeak /FEV1 < 1 to those with VTpeak /FEV1 ≥ 1 in the four subgroups of patients, categorized according to the median values of VE/VCO2 slope (29 L) and intercept (3.54 L/min), we found a significant trend from group A (10 vs 5 pts) to group B (8 vs 5 pts), group C (7 vs 4 pts) and group D (2 vs 11 pts) (2 for trend: 6.336; p < 0.05) (Fig. 2). In all patients, when related to VE/VCO2 intercept and to VE/VCO2 slope values, VTpeak /FEV1 values showed a positive (r = 0.430; p = 0.001) and a negative significant correlation (r = −0.327; p = 0.018), respectively (Fig. 3). In all patients, PETCO2 peak-rest values ranged from −2 to 19 mmHg and, when related to VE/VCO2 intercept and to VE/VCO2 slope values, they showed a positive (r = 0.592; p < 0.001) and a negative significant correlation (r = −0.642; p < 0.001), respectively (Fig. 4).
Fig. 3. Relationship between VE/VCO2 intercept and VTpeak /FEV1 (upper panel) and between VE/VCO2 slope and VTpeak /FEV1 (lower panel) in 52 COPD patients.
to VTpeak /FEV1 . In addition, when related to the PETCO2 values, the VE/VCO2 intercept and slope values showed a positive and a negative significant relationship, respectively. Finally, we found that VE/VCO2 slope value, but not VE/VCO2 intercept value was negatively related to the VO2 peak during a rapidly incremental exercise. In a large cohort of healthy adults, the intercepts on the Y-axis of the VE/VCO2 linear relationship were positive 90%, negative 5%, and very near zero 5% and had an average value of 2.4 L/min (Sun et al., 2002). A positive value of intercept on Y-axis of the VE/VCO2 linear relationship means that there is ventilation without CO2 exchange. Accordingly, the VE/VCO2 intercept value should identify
4. Discussion The main finding of this study is that in COPD patients intercept and slope values of the VE/VCO2 linear relationship are differently associated to the indices of ventilatory limitation during exercise. Notably, the VE/VCO2 intercept value increased as more as the dynamic hyperinflation was severe, as expressed by the reduction in IC/TLC during exercise. Furthermore, the VE/VCO2 intercept values were positively related to the corresponding values of VTpeak /FEV1 ratio, which may be considered as an exercise index of emphysema severity, i.e. the highest VTpeak /FEV1 ratio the most severe emphysema (Paoletti et al., 2011). Whereas, the VE/VCO2 slope value progressively increased as the indices of the volume excursion during exercise, i.e. VTpeak /VC and VTpeak /IC, were decreased. The VE/VCO2 slope values were also inversely related
Fig. 4. Relationship between VE/VCO2 intercept and PETCO2 peak-rest (upper panel) and between VE/VCO2 slope and PETCO2 peak-rest (lower panel) in 52 COPD patients.
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the waste or dead space ventilation, by assuming a constant waste ventilation during the exercise and excluding from the analysis the exercise above the isocapnic buffering period and the beginning of the exercise (Agostoni et al., 2011). The assumption that VE/VCO2 intercept value may be considered as an estimate of the waste ventilation has been further supported by a recent report (Gargiulo et al., 2014), which showed that in patients with heart failure as well as in healthy subjects while exercising, adding a large external dead space can increase the Y intercept of the VE/VCO2 linear relationship without changing the slope. Moreover, the authors found that dead space volumes estimated by Y intercepts were similar to those measured both in patients and healthy controls. Our study is a non-invasive study and in the present setting we cannot prove that dead space is constant trough exercise and, accordingly, we cannot assume that the Y intercept value is an estimate of the waste ventilation in COPD patients. Thus, a further study with dead space ventilation measurements is needed to give a meaning on Y intercept of the VE/VCO2 linear relationship in patients with COPD. Our data show that in COPD patients, the average Y intercept value was 3.96 L/min, ranging from 0.88 to 9.91 L/min, and these values were positively related to the development of the dynamic hyperinflation during exercise, as assessed by means of the IC/TLC ratio. Furthermore, in our COPD patients, higher VE/VCO2 intercept values were associated to higher VTpeak /FEV1 values. In healthy subjects, VT at peak of exercise does not exceed the resting FEV1 and the VTpeak /FEV1 ratio never is greater than 1. In patients with pulmonary emphysema and in controls, 1.17 and 0.76 have been respectively reported as average values of VTpeak /FEV1 ratio (Paoletti et al., 2011). In line with these findings, we found that patients with a VTpeak /FEV1 ratio ≥1, as compared to patients with a VTpeak /FEV1 ratio < 1, had a predominant pulmonary emphysema profile, thereby showing a higher degree of airflow obstruction, resting hyperinflation and airway collapsibility and a lower lung diffusion capacity. Lastly, we found that the VE/VCO2 intercept values were also directly related to the PETCO2 peak-rest values, which may be considered as an estimate of ventilatory limitation to exercise (Stickland et al., 2012; Thirapatarapong et al., 2013), even if the end-tidal CO2 might underestimate the corresponding arterial pressure in lung disease (Stickland et al., 2012). The levels of ventilation needed to clear the CO2 production during exercise, i.e. the VE/VCO2 slope values, provide a non-invasive assessment of the appropriateness or efficiency of minute ventilation during exercise. Since the minute ventilation is the sum of alveolar and dead space ventilation, high values in VE/VCO2 slope simply refer to an excessive ventilation to the metabolic stress. They indicate ventilatory inefficiency only if the excess ventilation results from an increase in dead space owing to ventilation/perfusion imbalance. On the other hand, elevated VE/VCO2 slope values with normal dead space ventilation ensue from alveolar hyperventilation. In the present study, we found that the VE/VCO2 slope values were inversely related to the values of VTpeak , expressed as a fraction either of VC or of IC. In healthy subjects, the VT increases during exercise in non-linear fashion reaching a plateau value, which roughly corresponds to 50–60% of VC (Wasserman et al., 1994). COPD patients use a greater VTpeak /VC ratio, as compared to controls because of high pulmonary resistance and/or low elastic recoil pressure (Marin et al., 1993). Moreover, VT does not normally exceed approximately 70% of the IC during exercise, but may reach the value approaching 100% in patients with ventilatory limitation (Wasserman et al., 1994). Accordingly, our results show that higher values of VE/VCO2 slope are associated to a lower ventilatory constraint degree, expressed as the ratio of the volume of air actually breathed during a breath to the volume potentially available for that breath. This association is further supported by the finding of an inverse significant correlation between the VE/VCO2
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slope values and the corresponding values of PETCO2 peak-rest in our patients. Furthermore, we provided the evidence that in our patients the pulmonary emphysema profile, as expressed by elevated VTpeak /FEV1 values, was significantly associated to low values of VE/VCO2 slope (below 29 L) and to high values of VE/VCO2 intercept (above 3.54 L/min) (Fig. 2). Our results are in line with those of a recent retrospective study (Thirapatarapong et al., 2013), which reported in a large cohort of COPD patients, that the airflow obstruction severity, as ranked by GOLD criteria, was directly related to the PETCO2 and inversely to VE/VCO2 values. In this study, PETCO2 and VE/VCO2 values were measured at peak of exercise. Moreover, our study confirms and further extends the findings by a previous study (Paoletti et al., 2011), which in a small sample of patients with moderate to severe emphysema, showed that VE/VCO2 slope decreased more as the emphysema was severe, as assessed by high resolution computed tomography (HRCT). These authors also found that an emphysema HRCT score greater than 50% was associated to higher values of the ratios of VT over VC, IC and FEV1 and to higher values of PETCO2 at peak of exercise. Taken together, the findings by Paoletti et al. (2011) and ours suggest that, when COPD patients reach critical volume constraints during exercise, may likely reduce the minute ventilation in order to decrease the effort of breathing and keep metabolic demands in a reasonable range. The limited minute ventilation may be a response to the overwhelming effort of breathing leading to hypercapnia. This study has some limitations and strengths. Firstly, our sample of patients was characterized by a predominance of male subjects and our results are not generalizable to female patients. However, the predominance of male gender in our study is in line with the epidemiology of the disease. We cannot also exclude the presence of any degree of reactive airway disease in our population since no assessment of pre and post bronchodilator response was done at baseline. However, all patients were ex-smokers and denied any history of bronchial asthma. Lastly, the study population was not representative of all stages of GOLD severity, thus the results may not be generalizable to the entire COPD population. Strengths include the size of the study, pretty large for a pilot study, and the control over the variables and the number of patients who completed the testing (only 4 failed to get the complete data). In summary, our study shows that the slope and intercept of the VE/VCO2 linear relationship may provide an assessment of the ventilatory limitation to exercise in patients with COPD. The changes may be seen in the alterations in end expiratory lung volumes and the tidal volume. The combined analysis of the excess ventilation and the ventilatory constraints during exercise may better define the COPD phenotypes both in clinical and research setting.
Conflict of interest This work had no conflict of interest and no extramural funding was used to support the study.
Authors’ contributions E.T. served as the primary author. She developed the study protocol, participated in the patients recruitment and statistical analysis and drafted the manuscript and she is the guarantor of the entire manuscript. P.T. and M.A. participated in the design of the study and helped to patients recruitment. M.R.G. helped to patients recruitment. E.M. participated in the coordination of the study. A.C. developed the study protocol, interpreted study data, contributed to and reviewed drafts of the manuscript. All authors read and approved the final manuscript.
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Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am. J. Respir. Crit. Care Med. 163, 1256–1276. Quanjer, P.H., Tammeling, G.J., Cotes, J.E., Pedersen, O.F., Peslin, R., Yernault, J.C., 1993. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur. Respir. J. Suppl. 16, 5–40. Stickland, M.K., Butcher, S.J., Marciniuk, D.D., Bhutani, M., 2012. Assessing exercise limitation using cardiopulmonary exercise testing. Pulm. Med. 2012, 824091. Stubbing, D.G., Pengelly, L.D., Morse, J.L., Jones, N.L., 1980. Pulmonary mechanics during exercise in subjects with chronic airflow obstruction. J. Appl. Physiol. 49, 511–515. Sun, X.-G., Hansen, J.E., Garatachea, N., Storer, T.W., Wasserman, K., 2002. Ventilatory efficiency during exercise in healthy subjects. Am. J. Respir. Crit. Care Med. 166, 1443–1448. Teopompi, E., Tzani, P., Aiello, A., Ramponi, S., Visca, D., Gioia, M.R., Marangio, E., Serra, W., Chetta, A., 2013. Ventilatory response to carbon dioxide output in patients with chronic heart failure and in patients with chronic obstructive pulmonary disease with comparable exercise capacity. Respir. Care (September) (Epub ahead of print). Thirapatarapong, W., Amstrong, H.F., Thomashow, B.M., Bartels, M.N., 2013. Differences in gas exchange between severities of chronic obstructive pulmonary disease. Respir. Physiol. Neurobiol. 186, 81–86. Tzani, P., Aiello, M., Elia, D., Foracchia, L., Marangio, E., Olivieri, D., Clini, E., Chetta, A., 2011. Dynamic hyperinflation is associated with a poor cardiovascular response to exercise in COPD patients. Respir. Res. 12, 150. Wanger, J., Clausen, J.L., Coates, A., Pedersen, O.F., Brusasco, V., Burgos, F., Casaburi, R., Crapo, R., Enright, P., van der Grinten, C.P., Gustafsson, P., Hankinson, J., Jensen, R., Johnson, D., Macintyre, N., McKay, R., Miller, M.R., Navajas, D., Pellegrino, R., Viegi, G., 2005. Standardisation of the measurement of lung volumes. Eur. Respir. J. 26, 511–522. Wasserman, K., Hansen, J.E., Sue, D.Y., Casaburi, R., Whipp, B.J., 1994. Normal values. In: Wasserman, K., Hansen, J.E., Sue, D.Y., Casaburi, R., Whipp, B.J. (Eds.), Principles of Exercise Testing & Interpretation. Lippincott Williams & Wilkins, Philadelphia, USA, pp. 143–162.
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Excess ventilation and ventilatory constraints during exercise in patients with chronic obstructive pulmonary disease Elisabetta Teopompi, Panagiota Tzani, Marina Aiello, Maria Rosaria Gioia, Emilio Marangio, Alfredo Chetta ∗ Respiratory Disease and Lung Function Unit, Department of Clinical and Experimental Medicine, University of Parma, Italy
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Article history: Accepted 7 March 2014 Available online 19 March 2014 Keywords: COPD Exercise Ventilatory response
a b s t r a c t We assessed the relationship between minute ventilation/carbon dioxide output (VE/VCO2 ) and ventilatory constraints during an incremental cardiopulmonary exercise testing (CPET) in patients with chronic obstructive pulmonary disease (COPD). Slope and intercept of the VE/VCO2 linear relationship, the ratios of inspiratory capacity/total lung capacity (IC/TLC) and of tidal volume (VT) over vital capacity (VTpeak /VC) and IC (VTpeak /IC) and over forced expiratory volume at 1st second (VTpeak /FEV1 ) at peak of exercise were measured in 52 COPD patients during a CPET. The difference peak-rest in end-tidal pressure of CO2 (PETCO2 ) was also measured. VE/VCO2 intercept showed a negative correlation with IC/TLC peak (p < 0.01) and a positive one with VTpeak /FEV1 (p < 0.01) and with PETCO2 peak-rest (p < 0.01). VE/VCO2 slope was negatively related to VTpeak /VC, VTpeak /IC and VTpeak /FEV1 (all correlations p < 0.05) and to PETCO2 peak-rest (p < 0.01). In COPD, VE/VCO2 slope and intercept provide complementary information on the ventilatory limitation to exercise, as assessed by changes in the end-expiratory lung volume and in tidal volume excursion. © 2014 Elsevier B.V. All rights reserved.
1. Introduction An excess in exercise ventilation for a given metabolic rate may occur in patients with chronic obstructive pulmonary disease (COPD). The minute ventilation (VE) to the carbon dioxide output (VCO2 ) ratio, also known as ventilatory equivalent for CO2 (VE/VCO2 ) (Wasserman et al., 1994), may be increased in patients with COPD during exercise, as compared to control subjects (O’Donnell et al., 2001; Paoletti et al., 2011). In addition, in COPD patients the slope of the VE/VCO2 linear relationship was found to be negatively related to the peak oxygen uptake (VO2 peak) during a rapidly incremental cardiopulmonary exercise
Abbreviations: AT, anaerobic threshold; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CPET, cardiopulmonary exercise test; FEV1, forced expiratory volume in 1st second; FVC, forced vital capacity; IC, inspiratory capacity; RER, respiratory exchange ratio; SD, standard deviation; SpO2 , oxygen saturation; TLC, total lung capacity; TLco, lung diffusion capacity for carbon monoxide; VC, vital capacity; VCO2 , carbon dioxide production; VE, minute ventilation; VE/VCO2 , ventilatory equivalent for CO2 ; VO2 , oxygen uptake; VT, tidal volume. ∗ Corresponding author at: Unità di Malattie Respiratorie e Funzionalità Polmonare, Università di Parma, Padiglione Rasori, via G. Rasori 10, 43100 Parma, Italy. Tel.: +39 0521 703475; fax: +39 0521 292615. E-mail address: [email protected] (A. Chetta). http://dx.doi.org/10.1016/j.resp.2014.03.002 1569-9048/© 2014 Elsevier B.V. All rights reserved.
testing (CPET) (Caviedes et al., 2012; Teopompi et al., 2013). Interestingly, the VE/VCO2 slope values were found to be decreased in patients with more severe emphysema, by indicating a relationship between VE/VCO2 slope and ventilatory limitation (Paoletti et al., 2011). Furthermore, even the intercept of the VE/VCO2 relationship has the potential for understanding the ventilatory response to exercise in patients with chronic cardiopulmonary disabling conditions (Agostoni et al., 2011; Teopompi et al., 2013). Patients with COPD experience ventilatory constraints on exertion. In these patients, the development of dynamic hyperinflation limits exercise capacity and plays a key role in the perception of exertional breathlessness (O’Donnell, 2008). Indeed, COPD patients while exercising, may breathe in before achieving a full exhalation and, accordingly, trap air within the lungs with each further breath with serious mechanical and sensory consequences. Notably, dynamic lung hyperinflation may progressively restrict the tidal volume excursion and exercise ventilation can increase only by quickening the breathing frequency, thereby inducing a further hyperinflation in a vicious circle. Furthermore, in COPD patients dynamic hyperinflation may be associated with a poor cardiovascular response to exercise (Tzani et al., 2011). Up to now, no study has been specifically aimed to assess the relationship between the excess in exercise ventilation for a given metabolic rate and the ventilatory limitation in COPD patients. The
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aim of the present study was, therefore, to measure in a cohort of COPD patients the VE/VCO2 value, both in terms of slope and in terms of intercept, and to ascertain whether or not these parameters may be related to the development of dynamic hyperinflation and to the tidal volume constraints. We hypothesized that the VE/VCO2 slope and intercept values might be differently associated to the ventilatory constraints during exercise in COPD patients. 2. Methods 2.1. Patients We consecutively enrolled over a 9-month period, from January 2013 to September 2013, patients affected by COPD, who were admitted to a pulmonary rehabilitation program. COPD was diagnosed according to the GOLD criteria (Pauwels et al., 2001) and patients with moderate to severe airflow obstruction, i.e. forced expiratory volume in 1 s/vital capacity ratio (FEV1 /VC) < 70% and FEV1 ≤ 80% of predicted value, were included. Eligibility criteria of patients were (1) ex-smoking habit; (2) no long-term oxygen therapy; (3) BMI ≥ 20 and ≤30 kg/m2 ; (4) stable clinical condition for at least 6 weeks; (5) absence of any comorbidity affecting exercise performance (anemia, chronic heart failure, neuromuscular disorders, or malignancies); (6) no other concomitant chronic respiratory disease, such as asthma or pulmonary fibrosis; (7) ability to perform a CPET with a peak of respiratory exchange ratio (RER) ≥ 1.05 in order to exclude poor motivation (American Thoracic Society, 2003); (8) CPET stopped for muscle fatigue and/or dyspnea. To be included, patients were considered as former smokers when they were abstinent from smoking from at least six months. Patients were not pretreated with beta2 -agonists before exercise testing, but were allowed to continue with their regular therapy during the study. All the procedures and their risks were explained to the patients, who gave their written informed consent to enter the study, which was conducted according to the Declaration of Helsinki. The protocol was approved by the ethical committee of the University Hospital of Parma. All participants’ data were analyzed and reported anonymously. 2.2. Lung function Pulmonary function tests were performed according to international recommendations (Miller et al., 2005; Wanger et al., 2005). A flow-sensing spirometer and a body plethysmograph connected to a computer for data analysis (Vmax 22 and 6200, Sensor Medics, Yorba Linda, U.S.A.) were used for the measurements. VC, forced vital capacity (FVC), FEV1 and forced expiratory flow at 50% of FVC (FEF50 in L/s) and forced inspiratory flow at 50% of FVC (FIF50 in L/s) were recorded. FEV1 /VC and FEF50 /FIF50 ratios were taken as indices of airflow obstruction and airway collapsibility, respectively. Thoracic gas volume (TGV) was measured by body plethysmography with the subject panting against a closed shutter at a frequency slightly 1.15, (3) peak workload > 80% predicted, (4) peak VO2 > 84% predicted, 5) peak heart rate > 90% predicted, (6) ventilatory reserve < 15%, (7) ECG significant ST-segment depression, (8) drop in systolic blood pressure or oxygen saturation (SpO2 ) ≤ 84 (American Thoracic Society, 2003). Predicted values were calculated according to equations by Wasserman et al. (Wasserman et al., 1994). Peak workload and peak VO2 were recorded as the mean value of watts and VO2 during the last 20 s of the test. Peak VO2 was expressed as absolute value in mL/kg/min. Anaerobic threshold (AT) was non-invasively determined by both V-slope and ventilatory equivalents methods (“dual method approach”), as the respiratory exchange ratio approximated 1.0 (American Thoracic Society, 2003), and was expressed as absolute value in mL/min. The AT was determined by two non-blinded physicians (ET and PT) attending to the CPET. The ventilatory response during exercise was expressed as a linear regression function by plotting VE against VCO2 obtained every 10 s, excluding data above the ventilatory compensation point (American Thoracic Society, 2003). Then, the slope and Y intercept values were obtained from the VE/VCO2 regression line. The end-tidal pressure of CO2 (PETCO2 , in mmHg) was measured as mean of PETCO2 during the 3-min rest period and during the last 20 s of the test and was recorded as the difference between PETCO2 peak and PETCO2 rest (PETCO2 peak-rest). Changes in operational lung volumes were assessed every two min during exercise and at peak exercise, taking the IC measured at rest, as the baseline. After a full explanation to each patient of the procedure, satisfactory technique and reproducibility of IC maneuvers were established during an initial practice session at rest. Assuming that TLC remains constant during exercise in COPD (Stubbing et al., 1980), changes in IC reflect changes in endexpiratory lung volume. Accordingly, dynamic hyperinflation may be defined as a decline in the IC greater than zero. According to IC/TLC ratio at peak of exercise, patients were divided in two categories: patients with IC/TLC ≤ 0.25 or >0.25. The patients with the
E. Teopompi et al. / Respiratory Physiology & Neurobiology 197 (2014) 9–14 Table 1 Demographic and baseline characteristics of 52 COPD patients (13 females). Mean ± SD Age (years) BMI (kg/m2 ) TLC (% pred) FEV1 (% pred) FEV1 /VC (%) Rest IC/TLC FEF50 /FIF50 TLCO (% pred) Rest SpO2 (%)
64 26 118 53 51 0.32 0.32 65 96
± ± ± ± ± ± ± ± ±
8 3 24 16 11 0.09 0.20 21 2
Table 2 Exercise characteristics of COPD patients (13 females). Mean ± SD
Range 42–75 20–30 80–189 26 ± 80 30–69 0.10–0.56 0.07–0.93 28–114 91–99
IC/TLC ratio at the peak of exercise ≤0.25 may be defined as “heavy hyperinflators” (Tzani et al., 2011). The ratios of VT at peak of exercise over VC (VTpeak /VC) and over IC (VTpeak /IC), as indices of volume excursion (Wasserman et al., 1994), were measured. In addition, the ratio of VT at peak of exercise over FEV1 (VTpeak /FEV1 ), which is associated to severe emphysema when it is greater than 1 (Paoletti et al., 2011), was also measured. 2.4. Statistical analysis This is a pilot, cross-sectional study. Due to the explorative nature of the study no formal sample size calculation was performed. Data are reported as mean ± standard deviation (SD), unless otherwise specified. The distribution of variables was assessed by means of Kolmogorov–Smirnov Goodness-of-Fit test. According to the median values of VE/VCO2 slope and intercept, the patients were subdivided in four groups: A (patients with a VE/VCO2 slope value ≥ median value and with a VE/VCO2 intercept value < median value), B (patients with a VE/VCO2 slope value ≥ median value and with a VE/VCO2 intercept value ≥ median value), C (patients with a VE/VCO2 slope value < median value and with a VE/VCO2 intercept value < median value), D (patients with a VE/VCO2 slope value < median value and with a VE/VCO2 intercept value ≥ median value). Relationships between variables were assessed by the Pearson’s correlation coefficient (r) and linear regression analysis or Spearman correlation coefficient (rs), when appropriate. Comparisons between variables were determined by unpaired t test. Comparisons of proportions of patients with VTpeak /FEV1 < 1 in the four groups were evaluated by means of 2 for trend. A p value of less than 0.05 was taken as significant.
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Peak VO2 (mL/kg/min) Peak Workload (watts) AT (mL/min) VE (L/min) VTpeak (L) VE/VCO2 slope (L) VE/VCO2 intercept (L/min) Peak IC/TLC VTpeak /VC VTpeak /IC VTpeak /FEV1 Peak SpO2 (%)
16.9 89.6 905 43.7 1.41 29.6 3.96 0.27 0.47 0.65 1.00 94
± ± ± ± ± ± ± ± ± ± ± ±
5.3 38.5 289 14.8 0.41 6.8 1.9 0.09 0.12 0.21 0.25 3
Range 7.7–30.2 34–220 510–1577 20.2–79.0 0.65 ± 2.61 19.3–52.0 0.9–9.91 0.09–0.54 0.27–0.83 0.32–1.54 0.61–1.61 88–99
patients, SpO2 , at rest and at peak were 95.7% ± 1.7 and 94.1% ± 3.1, (p < 0.001) respectively. Dynamic hyperinflation was experienced by 41 out of 52 patients (79%). In all patients, IC/TLC values at rest and at peak of exercise were 0.32 ± 0.09 and 0.27 ± 0.09 (p < 0.001), respectively. Peak IC/TLC was significantly related to the resting FEV1 (% pred) (r = 0.615; p < 0.01). VE/VCO2 intercept, but not VE/VCO2 slope was significantly and negatively related with IC/TLC rest (r = −0.341; p = 0.013) and IC/TLC peak (r = −0.446; p = 0.001) (Fig. 1). Twentyfour out of 52 patients showed a peak exercise IC/TLC ≤ 0.25. They significantly differed in VE/VCO2 intercept (4.8 L/min ± 1.8 vs 3.2 L/min ± 1.7, p = 0.002), but not in VE/VCO2 slope (30.3 L ± 6.2 vs 29.1 L ± 7.4, p = 0.548), as compared to the remaining patients. When the breathing pattern was analyzed at peak of the exercise, mean VTpeak /VC and VTpeak /IC values were respectively 0.47 ± 0.12, ranging from 0.27 to 0.83 and 0.65 ± 0.21, ranging from 0.32 to 1.54. Three out of 52 patients showed a VTpeak /IC ratio greater than 1. No correlation was found between the severity of disease, expressed as FEV1% pred, and VTpeak /IC and VTpeak /VC. In all patients, VE/VCO2 slope, but not VE/VCO2 intercept was
3. Results Fifty-six stable COPD patients, aged between 42 and 75 years were studied. According to the GOLD classification (Pauwels et al., 2001) 29 patients were moderate, 18 severe and 5 very severe. At study entry, patients were receiving regular therapy with inhaled steroids (60%), long-acting beta2 -agonists (62%) and tiotropium (51%). All of them were ex-smokers. Patients completed the exercise test without any complication and no patient was excluded because of poor motivation. In addition, no patient needs supplemental oxygen during exercise. In four patients, randomly distributed among GOLD stages, changes in operational lung volumes failed to be recorded, thus 52 patients (13 females) were considered for analysis (Table 1). Among them wide ranges of peak workload (from 30 to 221 W) and peak VO2 values (from 7.70 to 30.20 mL/kg/min) were found (Table 2). VE/VCO2 slope, but not VE/VCO2 intercept showed a negative correlation with peak workload (r = −0.429; p = 0.002) and peak VO2 (r = −0.317; p = 0.022). On the other hand, VE/VCO2 intercept, but not VE/VCO2 slope showed a negative correlation with the severity of disease, expressed as FEV1 (% pred) (r = −0.482; p < 0.001). In all
Fig. 1. Relationship between VE/VCO2 intercept and IC/TLC peak (upper panel) and between VE/VCO2 slope and VTpeak /VC (lower panel) in 52 COPD patients.
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Fig. 2. Relationship between VE/VCO2 intercept and VE/VCO2 slope values in 52 COPD patients (r = −0.254; p = 0.068). A–D indicate four groups of patients, categorized according to the median values of VE/VCO2 slope (29 L) and intercept (3.54 L/min). When compared the number of patients with VTpeak /FEV1 < 1 to those with VTpeak /FEV1 >/=1 in the four groups, a significant trend from group A (high slope and low intercept; 10 vs 5 pts) to group B (high slope and high intercept; 8 vs 5 pts), group C (low slope and low intercept; 7 vs 4 pts) and group D (low slope and high intercept; 2 vs 11) was found (2 for trend: 6.336; p < 0.05). Closed and open circles represent respectively patients with VTpeak /FEV1 ≥ 1 and patients with VTpeak /FEV1 < 1; interrupted lines represent median values.
negatively related to VTpeak /VC (r = −0.309; p = 0.026) (Fig. 1) and to VTpeak /IC (rs = −0.347; p = 0.012). In 25 out of 52 the VTpeak /FEV1 ratio was greater than 1, ranging in all patients from 0.61 to 1.61 (mean 1.00 ± 0.25). As compared to patients with VTpeak /FEV1 < 1, patients with VTpeak /FEV1 ≥ 1 had lower resting values of FEV1 /VC (44.2% ± 8.7 vs 57.7% ± 8.9; p = 0.001), FEF50 /FIF50 (0.21 ± 0.12 vs 0.42 ± 0.21; p < 0.001), IC/TLC (0.29 ± 0.009 vs 0.34 ± 0.07; p = 0.028) and TLco (57.9% ± 17.9 vs 72.7% ± 20.8; p = 0.012). In addition, the plot of VE/VCO2 intercept versus VE/VCO2 slope values (r = −0.254; p = 0.068) showed that patients with VTpeak /FEV1 ≥ 1 tended to have low values in VE/VCO2 slope and high values in VE/VCO2 intercept (Fig. 2). When we compared the number of patients with VTpeak /FEV1 < 1 to those with VTpeak /FEV1 ≥ 1 in the four subgroups of patients, categorized according to the median values of VE/VCO2 slope (29 L) and intercept (3.54 L/min), we found a significant trend from group A (10 vs 5 pts) to group B (8 vs 5 pts), group C (7 vs 4 pts) and group D (2 vs 11 pts) (2 for trend: 6.336; p < 0.05) (Fig. 2). In all patients, when related to VE/VCO2 intercept and to VE/VCO2 slope values, VTpeak /FEV1 values showed a positive (r = 0.430; p = 0.001) and a negative significant correlation (r = −0.327; p = 0.018), respectively (Fig. 3). In all patients, PETCO2 peak-rest values ranged from −2 to 19 mmHg and, when related to VE/VCO2 intercept and to VE/VCO2 slope values, they showed a positive (r = 0.592; p < 0.001) and a negative significant correlation (r = −0.642; p < 0.001), respectively (Fig. 4).
Fig. 3. Relationship between VE/VCO2 intercept and VTpeak /FEV1 (upper panel) and between VE/VCO2 slope and VTpeak /FEV1 (lower panel) in 52 COPD patients.
to VTpeak /FEV1 . In addition, when related to the PETCO2 values, the VE/VCO2 intercept and slope values showed a positive and a negative significant relationship, respectively. Finally, we found that VE/VCO2 slope value, but not VE/VCO2 intercept value was negatively related to the VO2 peak during a rapidly incremental exercise. In a large cohort of healthy adults, the intercepts on the Y-axis of the VE/VCO2 linear relationship were positive 90%, negative 5%, and very near zero 5% and had an average value of 2.4 L/min (Sun et al., 2002). A positive value of intercept on Y-axis of the VE/VCO2 linear relationship means that there is ventilation without CO2 exchange. Accordingly, the VE/VCO2 intercept value should identify
4. Discussion The main finding of this study is that in COPD patients intercept and slope values of the VE/VCO2 linear relationship are differently associated to the indices of ventilatory limitation during exercise. Notably, the VE/VCO2 intercept value increased as more as the dynamic hyperinflation was severe, as expressed by the reduction in IC/TLC during exercise. Furthermore, the VE/VCO2 intercept values were positively related to the corresponding values of VTpeak /FEV1 ratio, which may be considered as an exercise index of emphysema severity, i.e. the highest VTpeak /FEV1 ratio the most severe emphysema (Paoletti et al., 2011). Whereas, the VE/VCO2 slope value progressively increased as the indices of the volume excursion during exercise, i.e. VTpeak /VC and VTpeak /IC, were decreased. The VE/VCO2 slope values were also inversely related
Fig. 4. Relationship between VE/VCO2 intercept and PETCO2 peak-rest (upper panel) and between VE/VCO2 slope and PETCO2 peak-rest (lower panel) in 52 COPD patients.
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the waste or dead space ventilation, by assuming a constant waste ventilation during the exercise and excluding from the analysis the exercise above the isocapnic buffering period and the beginning of the exercise (Agostoni et al., 2011). The assumption that VE/VCO2 intercept value may be considered as an estimate of the waste ventilation has been further supported by a recent report (Gargiulo et al., 2014), which showed that in patients with heart failure as well as in healthy subjects while exercising, adding a large external dead space can increase the Y intercept of the VE/VCO2 linear relationship without changing the slope. Moreover, the authors found that dead space volumes estimated by Y intercepts were similar to those measured both in patients and healthy controls. Our study is a non-invasive study and in the present setting we cannot prove that dead space is constant trough exercise and, accordingly, we cannot assume that the Y intercept value is an estimate of the waste ventilation in COPD patients. Thus, a further study with dead space ventilation measurements is needed to give a meaning on Y intercept of the VE/VCO2 linear relationship in patients with COPD. Our data show that in COPD patients, the average Y intercept value was 3.96 L/min, ranging from 0.88 to 9.91 L/min, and these values were positively related to the development of the dynamic hyperinflation during exercise, as assessed by means of the IC/TLC ratio. Furthermore, in our COPD patients, higher VE/VCO2 intercept values were associated to higher VTpeak /FEV1 values. In healthy subjects, VT at peak of exercise does not exceed the resting FEV1 and the VTpeak /FEV1 ratio never is greater than 1. In patients with pulmonary emphysema and in controls, 1.17 and 0.76 have been respectively reported as average values of VTpeak /FEV1 ratio (Paoletti et al., 2011). In line with these findings, we found that patients with a VTpeak /FEV1 ratio ≥1, as compared to patients with a VTpeak /FEV1 ratio < 1, had a predominant pulmonary emphysema profile, thereby showing a higher degree of airflow obstruction, resting hyperinflation and airway collapsibility and a lower lung diffusion capacity. Lastly, we found that the VE/VCO2 intercept values were also directly related to the PETCO2 peak-rest values, which may be considered as an estimate of ventilatory limitation to exercise (Stickland et al., 2012; Thirapatarapong et al., 2013), even if the end-tidal CO2 might underestimate the corresponding arterial pressure in lung disease (Stickland et al., 2012). The levels of ventilation needed to clear the CO2 production during exercise, i.e. the VE/VCO2 slope values, provide a non-invasive assessment of the appropriateness or efficiency of minute ventilation during exercise. Since the minute ventilation is the sum of alveolar and dead space ventilation, high values in VE/VCO2 slope simply refer to an excessive ventilation to the metabolic stress. They indicate ventilatory inefficiency only if the excess ventilation results from an increase in dead space owing to ventilation/perfusion imbalance. On the other hand, elevated VE/VCO2 slope values with normal dead space ventilation ensue from alveolar hyperventilation. In the present study, we found that the VE/VCO2 slope values were inversely related to the values of VTpeak , expressed as a fraction either of VC or of IC. In healthy subjects, the VT increases during exercise in non-linear fashion reaching a plateau value, which roughly corresponds to 50–60% of VC (Wasserman et al., 1994). COPD patients use a greater VTpeak /VC ratio, as compared to controls because of high pulmonary resistance and/or low elastic recoil pressure (Marin et al., 1993). Moreover, VT does not normally exceed approximately 70% of the IC during exercise, but may reach the value approaching 100% in patients with ventilatory limitation (Wasserman et al., 1994). Accordingly, our results show that higher values of VE/VCO2 slope are associated to a lower ventilatory constraint degree, expressed as the ratio of the volume of air actually breathed during a breath to the volume potentially available for that breath. This association is further supported by the finding of an inverse significant correlation between the VE/VCO2
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slope values and the corresponding values of PETCO2 peak-rest in our patients. Furthermore, we provided the evidence that in our patients the pulmonary emphysema profile, as expressed by elevated VTpeak /FEV1 values, was significantly associated to low values of VE/VCO2 slope (below 29 L) and to high values of VE/VCO2 intercept (above 3.54 L/min) (Fig. 2). Our results are in line with those of a recent retrospective study (Thirapatarapong et al., 2013), which reported in a large cohort of COPD patients, that the airflow obstruction severity, as ranked by GOLD criteria, was directly related to the PETCO2 and inversely to VE/VCO2 values. In this study, PETCO2 and VE/VCO2 values were measured at peak of exercise. Moreover, our study confirms and further extends the findings by a previous study (Paoletti et al., 2011), which in a small sample of patients with moderate to severe emphysema, showed that VE/VCO2 slope decreased more as the emphysema was severe, as assessed by high resolution computed tomography (HRCT). These authors also found that an emphysema HRCT score greater than 50% was associated to higher values of the ratios of VT over VC, IC and FEV1 and to higher values of PETCO2 at peak of exercise. Taken together, the findings by Paoletti et al. (2011) and ours suggest that, when COPD patients reach critical volume constraints during exercise, may likely reduce the minute ventilation in order to decrease the effort of breathing and keep metabolic demands in a reasonable range. The limited minute ventilation may be a response to the overwhelming effort of breathing leading to hypercapnia. This study has some limitations and strengths. Firstly, our sample of patients was characterized by a predominance of male subjects and our results are not generalizable to female patients. However, the predominance of male gender in our study is in line with the epidemiology of the disease. We cannot also exclude the presence of any degree of reactive airway disease in our population since no assessment of pre and post bronchodilator response was done at baseline. However, all patients were ex-smokers and denied any history of bronchial asthma. Lastly, the study population was not representative of all stages of GOLD severity, thus the results may not be generalizable to the entire COPD population. Strengths include the size of the study, pretty large for a pilot study, and the control over the variables and the number of patients who completed the testing (only 4 failed to get the complete data). In summary, our study shows that the slope and intercept of the VE/VCO2 linear relationship may provide an assessment of the ventilatory limitation to exercise in patients with COPD. The changes may be seen in the alterations in end expiratory lung volumes and the tidal volume. The combined analysis of the excess ventilation and the ventilatory constraints during exercise may better define the COPD phenotypes both in clinical and research setting.
Conflict of interest This work had no conflict of interest and no extramural funding was used to support the study.
Authors’ contributions E.T. served as the primary author. She developed the study protocol, participated in the patients recruitment and statistical analysis and drafted the manuscript and she is the guarantor of the entire manuscript. P.T. and M.A. participated in the design of the study and helped to patients recruitment. M.R.G. helped to patients recruitment. E.M. participated in the coordination of the study. A.C. developed the study protocol, interpreted study data, contributed to and reviewed drafts of the manuscript. All authors read and approved the final manuscript.
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