Abstract
BACKGROUND: Ventilatory inefficiency increases ventilatory demand; corresponds to an abnormal increase in the ratio of minute ventilation (V̇E) to CO2 production (V̇CO2); represents increased dead space, deregulation of respiratory control, and early lactic threshold; and is associated with expiratory flow limitation that enhances dynamic hyperinflation and may limit exercise capacity.
OBJECTIVE: To evaluate the influence of ventilatory inefficiency over exercise capacity in COPD patients.
METHODS: Prospective study of 35 COPD subjects with different levels of severity, in whom cardiopulmonary stress test was performed. Ventilatory inefficiency was represented by the V̇E/V̇CO2 relation. Its influence over maximal oxygen consumption (V̇O2max), power (W), and ventilatory threshold was evaluated. Surrogate parameters of cardiac function, like oxygen pulse (V̇O2/heart rate) and circulatory power (%V̇O2max × peak systolic pressure), were also evaluated.
RESULTS: Cardiopulmonary stress test was stopped due to dyspnea with elevated V̇E and marked reduction of breathing reserve. A severe increase in V̇E/V̇CO2 (mean ± SD 35.9 ± 5.6), a decrease of V̇O2max (mean ± SD 75.2 ± 20%), and a decrease of W (mean ± SD 68.6 ± 23.3%) were demonstrated. Twenty-eight patients presented dynamic hyperinflation. Linear regression showed a reduction of 2.04% on V̇O2max (P < .001), 2.6% on W (P < .001), 1% on V̇O2/heart rate (P = .049), and 322.7 units on circulatory power (P = .02) per each unit of increment in V̇E/V̇CO2, respectively.
CONCLUSIONS: Ventilatory inefficiency correlates with a reduction in exercise capacity in COPD patients. Including this parameter in the evaluation of exercise limitation in this patient population may mean a contribution toward the understanding of its pathophysiology.
Introduction
Emphasis has been placed on the importance of dynamic hyperinflation, represented by a decrease in inspiratory capacity during exercise, as the main limiting factor for physical activity in patients with COPD.1,2 Theoretically, patients with greater bronchial obstruction should exhibit greater limitations in exercise; however, this does not occur in clinical practice, where patients with a lesser degree of obstruction may exhibit greater limitations. This indicates the presence of multiple mechanisms involved in the development of these limitations. In this context, the importance of ventilatory inefficiency, which increases ventilatory demand, has not yet been assessed.
Ventilatory inefficiency represents an abnormal increase in the ratio of minute ventilation (V̇E) to carbon dioxide production (V̇CO2) (Fig. 1). It is a multi-dependent parameter that corresponds with an increased physiological dead space, poor regulation of respiratory control, and early lactic acidosis, factors that are present in COPD. This alteration enhances the ventilatory demand and respiratory rate, which, when associated with an increased expiratory resistance in COPD, results in a reduction of the time available for expiration, due to expiratory flow limitation. This mechanism impedes deflation, causes expiratory flow limitation, enhances the obstruction mechanism, and potentially cause dynamic hyperinflation.1,3,4 The greater the ventilatory demand to eliminate CO2, the greater the V̇E, and the greater the expiratory flow limitation and dynamic hyperinflation decreases the breathing reserve during exercise.1,3,4 The impact of this mechanism on the exercise capacity of patients with COPD is an antecedent that has not been evaluated, and information on the effect of these processes on cardiocirculatory function is also unavailable.
A 57-year-old patient with COPD: increase in the CO2 equivalent (minute ventilation versus carbon dioxide production [V̇CO2]) due to ventilatory inefficiency. The curve presents a leftward deviation, compared with a normal reference shape.
Hypothesis: Ventilatory inefficiency increases ventilatory requirement, enhancing dynamic hyperinflation when associated with expiratory flow limitation. Due to these mechanisms, ventilatory inefficiency limits exercise capacity.
Objectives: To quantify the magnitude of V̇E/V̇CO2 measured at anaerobic threshold in patients with COPD during a cardiopulmonary exercise test (cardiopulmonary stress test), and to show that V̇E/V̇CO2 translates into a limitation on exercise.
QUICK LOOK
Current knowledge
Ventilatory inefficiency increases the ratio of minute ventilation to CO2 production (V̇E/V̇CO2) and ventilatory demand. In association with expiratory flow limitation, ventilatory inefficiency causes dynamic hyperinflation and impacts exercise capacity.
What this paper contributes to our knowledge
A large increase in V̇E/V̇CO2 is inversely related with a reduction in oxygen consumption and power. Ventilatory inefficiency correlates with a reduction in exercise capacity in patients with COPD.
Methods
We performed a prospective study over 2 years in patients with mild to severe COPD, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.5 The sample size was calculated considering V̇E/V̇CO2 as the principal variable. We used a design of mean comparison with an average difference of 20% with respect to the normal value of V̇E/V̇CO2. The minimal estimated sample was 33 patients. For the estimation we used the following suppositions: CI of 95%, and power of 99% (ß error of 10%), and one standard deviation of 25% with respect to the mean of both samples.
All participants met the following entry criteria: pulmonary emphysema by axial computed tomography. The radiological criteria were: well defined 1–2 mm centrilobular holes in the secondary pulmonary lobule with no discernible wall, preserved anatomical borders of the secondary pulmonary lobule, and involvement predominantly in the upper lung zones.6 All participants were in a nonacute phase of their disease and were receiving a stable drug regimen. Participants had no coexisting medical conditions that would interfere with physiologic testing. Exclusionary criteria included the presence of cardiac disease or claudication in the legs, which limits exercise capacity. Measurement of the pulmonary function tests consisted of spirometry and a CO diffusion test. The demographics and pulmonary function tests of the patients are presented in Table 1. Each patient authorized their participation by signing an informed consent agreement. The protocol was approved by the ethics and research committees of our institution.
Demographic Characteristics and Functional Study at Rest (n = 35)
Cardiopulmonary Exercise Test
An incremental cardiopulmonary stress test, with an increase of the work load of 10–15 Watts every minute, was performed according to the American Thoracic Society/American College of Chest Physicians regulations.3,4,7 A metabolic cart (Oxycon Pro, Erich Jaeger, Höchberg, Germany) was utilized. The reference values of Jones et al for V̇O2, power (Ẇ), V̇E, and V̇O2/heart rate were used.8,9 Dyspnea and fatigue of the lower extremities were recorded according to the Borg scale. The study recorded maximum power (Ẇmax), maximum oxygen consumption (V̇O2max), and the anaerobic threshold, according to the V-slope method.3,7 The V̇O2 measured at anaerobic threshold was represented as a percent-of-predicted V̇O2max.
The V̇E, breathing reserve (breathing reserve = 1 –V̇Emax/predicted maximal voluntary ventilation) and the V̇E/V̇CO2 determined at the anaerobic threshold were measured.3,4,7,10,11 The expiratory flow limitation was determined by superimposing the flow/volume dynamic curve over the maximum expiratory flow-volume curve, and was calculated at the final work load of the test, plotting the volume with flow overlap, over the tidal volume in the horizontal axis. The value of expiratory flow limitation was expressed as a percentage (Fig. 2A shows a subject without expiratory flow limitation and Fig. 2B shows the same subject with expiratory flow limitation at the final step of the exercise). In each work load a forced inspiratory capacity was determined, and the decrease (Δ inspiratory capacity) was calculated by its difference between the beginning and the end of the exercise.12–15
A: Dynamic flow-volume curve superimposed on the maximum expiratory flow-volume curve: subject without expiratory flow limitation in the middle of the test. B: The same subject at the final step of the exercise: a 100% limitation of the expiratory flow is observed. FEF25 = forced expiratory flow at 25% of the expiratory maneuver.
As substitute parameters of cardiac function, the oxygen pulse (V̇O2/heart rate) and the circulatory power were calculated at peak exercise.15–18 The V̇O2/heart rate is a surrogate for the systolic volume by the Fick equation: V̇O2 = cardiac output × ΔC(a-v)O2, and circulatory power (%V̇O2max × peak systolic blood pressure) is a surrogate for cardiac power (cardiac output × mean arterial pressure × K).16–21
Statistical Analysis
Statistical descriptive analysis was performed using the Pearson coefficient of correlation for variables with a normal distribution. The normal distribution was verified with the Shapiro-Wilk test. The association between the independent continuous variable (V̇E/V̇CO2) and response continuous variables (V̇O2, Ẇ, anaerobic threshold, V̇O2/heart rate, and circulatory power) was assessed by bivariate linear regression.
We further constructed 5 multiple regression models analyzing the independent variables V̇E/V̇CO2, age, body mass index, expiratory flow limitation, and dynamic hyperinflation, and their association over each of the following dependent continuous variables: V̇O2, Ẇ, anaerobic threshold, V̇O2/heart rate, and circulatory power.
The relationship between dynamic hyperinflation and the parameters of interest were evaluated by a comparison of means through analysis of variance and subject to demonstration of a normal distribution in each group. Values of P < .05 (CI 95%) were considered significant. Software was used (SPSS, version 18.0, SPSS, Chicago, Illinois). The sample size was calculated (EPIDAT 3.1, Dirección Xeral de Saúde Pública, A Coruña, Espana, http://www.sergas.es).
Results
Thirty-five subjects with COPD were studied, including 24 men and 11 women, with a mean ± SD age of 64 ± 8.2 y (range 49–80 y). All suffered from pulmonary emphysema, as demonstrated by axial computed tomography. They did not have a prior history of cardiopathy, and their electrocardiograms at rest did not demonstrate alterations. The demographic and functional characteristics are presented in Table 1.
The subjects finished the test secondary to dyspnea and leg fatigue (mean ± SD Borg scale scores 5 ± 1.7 and 4 ± 1.6, respectively), with elevated levels of V̇E (mean ± SD 87 ± 20.9% of the maximum predicted value), and accentuated decreases in breathing reserve (mean ± SD 13.5 ± 19.4%). They presented a decrease in Ẇmax and in the V̇O2max. A severe increase in V̇E/V̇CO2 was demonstrated (mean ± SD 35.9 ± 5.6), along with severe expiratory flow limitation (mean ± SD 75 ± 25.3%). Twenty-eight subjects presented dynamic hyperinflation. The mean ± SD Δ inspiratory capacity was 360 ± 280 mL. The results of the cardiopulmonary stress tests are presented in Table 2.
Results of Cardiopulmonary Stress Test
It was suggested by linear regression that V̇E/V̇CO2 may translate into an exercise limitation. Each unit of increase in V̇E/V̇CO2 decreased V̇O2max by 2.0% (95% CI −3 to −0.9), reduced Ẇmax by 2.6% (95% CI −3.8 to −1.4), and decreased anaerobic threshold by 1.6% (95% CI −2.6 to −0.67) (P < .001, P < .001, and P = .003, respectively), as shown in Table 3 and Figure 3. In relation to cardiocirculatory parameters, V̇E/V̇CO2 reduced V̇O2/heart rate by 1% (95% CI −2.1 to 0) and reduced circulatory power by 322.7 units (95% CI −594 to −51) for each unit of increase in V̇E/V̇CO2 (P = .049 and P = .02, respectively).
Influence of Ventilatory Inefficiency Over the Evaluated Parameters
A: Statistical correlation between maximal power (Ẇmax) and the ratio of minute ventilation (V̇E) to carbon dioxide production (V̇CO2). B: Statistical correlation between maximal oxygen consumption (V̇O2max) and V̇E/V̇CO2. C: Statistical correlation between anaerobic threshold and V̇E/V̇CO2.
In the multiple regression analysis none of the models independently associated with the response continuous variables (V̇O2, Ẇ, anaerobic threshold, V̇O2/heart rate, and circulatory power) were significant, meaning that the relation between V̇E/V̇CO2 was confounded by differences in age, body mass index, expiratory flow limitation, and dynamic hyperinflation.
Effect of Dynamic Hyperinflation
The mean ± SD V̇O2max was 75.2 ± 20%; in the 7 subjects without dynamic hyperinflation, it reached 93.4 ± 17.1%, and it decreased to 70.7 ± 18.2% in the 28 subjects with dynamic hyperinflation (P = .005) (Fig. 4A). The mean ± SD Ẇmax was 68.6 ± 23.3%; in the 7 subjects without dynamic hyperinflation it reached 87 ± 18.5%, and it decreased to 64 ± 22.3% in the 28 subjects with dynamic hyperinflation (P = .02) (see Fig. 4B).
A: Descriptive statistics of maximal oxygen consumption (V̇O2max) in patients with and without dynamic hyperinflation. B: Descriptive statistics of maximal power (Ẇmax) in subjects with and without dynamic hyperinflation.
Discussion
In our studied subjects with various degrees of COPD, the exercise test ended due to dyspnea and leg fatigue.19,20 They used a large part of their breathing reserves and presented a severe increase of V̇E/V̇CO2 measured at anaerobic threshold, which is indicative of ventilatory inefficiency. In association they also presented an accentuated limitation in expiratory flow, and the majority had dynamic hyperinflation. An inverse relationship between V̇E/V̇CO2 and a decrease in V̇O2max and in Ẇ suggest participation of this mechanism in limiting exercise capacity in COPD patients.18,19,21,22
Role of Ventilatory Inefficiency in Limiting Exercise
Ventilatory inefficiency is a multi-dependent parameter that represents an increase in the physiological dead space and early lactic acidosis (due to a deficit between O2 muscle transport and requirement). Ventilatory inefficiency also involves deregulation of central and peripheral respiratory control and an augment in ergoreceptor activity, factors that are present in COPD.19–22 On the other side, expiratory flow limitation during respiration causes dynamic hyperinflation and enhances respiratory work. This behavior increases when the closing volume exceeds the residual functional capacity, until expiratory flow limitation and dynamic hyperinflation develop.12–15,19,23–25
In healthy young subjects the mean V̇E/V̇CO2 is about 25, and near 30 in older individuals. Usually it is less than 32 at or near the anaerobic threshold. Values over 34 are considered ventilatory inefficiency.3,4,26–28 Ventilatory inefficiency enhances the ventilatory requirement, which, when associated with an increase in expiratory resistance, impedes deflation and enhances dynamic hyperinflation.12,13,19–21,23,24 During exercise there is a strong evidence of the limitation imposed by dynamic hyperinflation, a situation that has also been demonstrated in daily activities and in the 6-min walk test.23,24 Dynamic hyperinflation is one of the main determinants of exercise limitation, and is commonly measured as Δ inspiratory capacity, as was performed in our study.23–25
In this regard, we postulated that ventilatory inefficiency may be an independent contribution to pathophysiologic understanding of exercise limitation in COPD. In particular, V̇E/V̇CO2 is an independent indicator of a negative prognosis in other diseases such as congestive heart failure.10,11,22 In this study we have shown that ventilatory inefficiency, represented by V̇E/V̇CO2, may increase ventilatory demand and dynamic hyperinflation, which translates into a limitation of functional capacity in COPD patients, reducing V̇O2max and power (see Table 3).
Ventilatory Inefficiency and Deterioration of the Surrogate Parameters of Cardiocirculatory Function
The right ventricle is sensitive to afterload changes, which is a relevant factor in COPD, where dynamic hyperinflation increases the impedance of the right ventricle by decreasing the vascular compliance due to alveolar pressure.26–32 Our observations allow us to postulate that ventilatory inefficiency may deteriorate systolic volume of these patients (represented by V̇O2/heart rate), possibly enhancing expiratory flow limitation and dynamic hyperinflation.32,33
Cardiac power (cardiac output × mean arterial pressure × K) represents the flow generated by the heart and the perfusion pressure that it sustains. Because V̇O2max increases linearly, it is postulated that circulatory power (circulatory power = %V̇O2max × peak systolic blood pressure) adequately represents this parameter. To detect the influence of ventilatory inefficiency over cardiac power, we used circulatory power, which has not previously been evaluated in conjunction with COPD.34–37 Our results showed a reduction in circulatory power related with ventilatory inefficiency. To the best of our knowledge this is the first study to describe a reduction of cardiocirculatory function, through surrogate parameters of systolic volume and cardiac power, due to a ventilatory inefficiency.
A limitation to our study is the small number of subjects. We believe the increased ventilatory demand caused by ventilatory inefficiency, potentiating dynamic hyperinflation, might be bigger in patients with advanced COPD. We think that studies with higher numbers of COPD subjects, stratified by their severity degree, will support this hypothesis. On the other hand, the influence of ventilatory inefficiency on the prognosis of COPD patients deserves to be demonstrated.
Conclusions
The strength of this study is that it suggests that ventilatory inefficiency, which manifests itself as an abnormal increase of V̇E/V̇CO2, may have implications in the deterioration of the exercise capacity of patients with COPD as an independent parameter. The inclusion of this parameter in the study of these patients may mean a contribution toward the understanding of its physiopathology. Upon evaluating the surrogate parameters of cardiocirculatory function, we showed that V̇E/V̇CO2 detrimentally influences this function. We consider a weakness of our study the limited number of subjects. Randomized clinical controlled trials with a greater number of subjects and a better stratification of the degrees of COPD are needed to consider ventilatory inefficiency's influence over the exercise capacity in COPD.
Acknowledgments
The authors thank Sebastián Fernández-Bussy MD, Chief of Interventional Pneumology, Clínica Alemana de Santiago, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile, for reviewing the manuscript.
Footnotes
- Correspondence: Iván R Caviedes MD, Servicio y Laboratorio Broncopulmonar, Clínica Alemana de Santiago, Chile, Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo, Avenida Vitacura 5951, Santiago, Chile 6681920. E-mail: icaviedes{at}alemana.cl.
The authors have disclosed no conflicts of interest.
- Copyright © 2012 by Daedalus Enterprises Inc.
