Ventilatory efficiency testing as prognostic value in patients with pulmonary hypertension

Most patients with pulmonary hypertension (PH) have exercise limitation attributing to an impaired vasodilator response of the pulmonary arteries during exercise. Cardiopulmonary exercise testing (CPET) describes the underlying physiologic abnormalities associated with the underperfusion of the pulmonary vascular bed seen in PH [1‐6]. Additionally, CPET allows reproducible assessment of functional capacity and treatment efficacy in patients with PH [2, 5, 7‐10].

Peak oxygen uptake (VO2) is the most frequently analyzed CPET parameter and has consistently demonstrated prognostic significance. Other ventilatory expired gas parameters obtained during exercise testing have recently demonstrated prognostic value. The relationship between minute ventilation and carbon dioxide production (Ve/VCO2 slope) is one of such CPET parameter that appears to have clinical value. It can be derived from submaximal exercise testing and is independent of patient motivation. The Ve/VCO2 slope is inversely related to cardiac output at peak exercise [11] and is at least partly explained by a decrease in pulmonary perfusion [12, 13]. Ventilatory efficiency was found to be reliable predictor of prognosis in patients with chronic heart failure [14‐22].

Since inefficiency of ventilation results from decreased perfusion of the ventilated lung, for example by an increased physiological dead space ventilation, a high ventilatory response relative to metabolic demand would be expected [23]. If a simple non-invasive measurement, such as the VE/VCO2 ratio, could be shown to be useful in evaluating pulmonary vascular disease, it might serve to supplement other methods currently used to monitor clinical course and treatment. At now, few studies have investigated the relationship between exercise capacity and VE/VCO2 slope in patients with PH [24, 25].

Despite recent advances in pharmacological treatment of patients with PH, mortality rates, especially in patients with severe pulmonary artery hypertension (PAH), remain high. Reliable risk stratification is a continuing challenge and the identification of patients at highest risk for early death from right heart failure is of special importance. Functional capacity, as defined by peak VO2 during CPET is established as a powerful predictor of mortality in PAH [26, 27] and a peak VO2 below 10.4 mL/kg/min is now considered a key criterion for early mortality [2]. To date however, differences in the prognostic value of peak VO2 and the Ve/VCO2 slope have not been widely emphasized.

In this study, we determine the predictive value of ventilatory efficiency parameters for estimating the 2-years survival of patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and compare these parameters with survival predicted by peak VO2.

To our knowledge, this is one of the first studies of CPET data in patients with PAH/CTEPH to compare ventilatory efficiency parameters as a predictor of 24-months mortality. In our study, ventilatory equivalent for carbon dioxide at anaerobic threshold with a cutoff value of 55 identifies patients with an over seven fold increased risk of death within 24 months after initial evaluation. The Ve/VCO2 slope with a cutoff value of 60 had an over five fold increased risk of death within the same time interval. In our study group the parameters of ventilatory efficiency significantly better predicted the clinical outcome compared to peak oxygen uptake with a cut-off value of 10.4 ml/min/kg. Taken together, these results support the concept that for example the VE/VCO2 slope or the ventilatory equivalents may be prognostically superior to peak VO2.

Symptoms in PAH-patients develop during exercise because recruitment of pulmonary vascular bed needed for exercise is impaired. Three pathophysiologies could be easily identified: [1] failure to perfuse the ventilated lung, thereby increasing the physiologic dead space and ventilatory requirement [5, 24, 32]; [2] failure to increase cardiac output (oxygen transport) appropriately in response to exercise, causing a low work rate lactic acidosis (increased CO2 production relative to O2 consumption), thereby increasing acid ventilatory drive [11, 33]; and [3] exercise-induced hypoxemia in most PH patients, thereby increasing the hypoxic ventilatory drive. Ventilatory inefficiency could be measured as an increase in ventilatory equivalents for oxygen and carbon dioxide. Reindl et al. [11] showed that ventilatory efficiency is influenced by cardiac output and by pulmonary vasoconstriction. Alveolar hypoperfusion, caused by impaired or defective vasodilation, probably represents the link to the impairment of ventilatory efficiency.

A significant finding in our study was the confirmation that Ve/VCO2 slope is a strong, independent predictor of death in patients suffering from PAH/CTEPH. This observation is in agreement with other studies from patients with chronic heart failure which have examined the prognostic significance of the Ve/VCO2 slope [15, 19, 34, 35]. Patients with chronic heart failure ventilate more during exercise than controls, resulting in an increase in the Ve/VCO2 slope [36]. The increased Ve/VCO2 slope could be a result of different mechanism. Ventilation perfusion mismatch [12, 37], impaired diffusion of metabolic gases [38], respiratory muscle weakness [39], and heightened sensitivity of peripheral receptors [40, 41] have all been postulated as possible causes. Additionally, one of the proposed mechanisms for an increase in Ve/VCO2 slope in chronic heart failure patients is an abnormal pulmonary perfusion [42]. Furthermore, Ukkonen et al. [43] showed that the right ventricular oxidative metabolism correlates with Ve/VCO2 slope in chronic heart failure patients. This supports the hypothesis that pulmonary vascular resistance is a main determinant of the Ve/VCO2 slope [43]. Because of the increased pulmonary vascular resistance in PH, pulmonary blood flow (cardiac output) fails to increase normally during exercise. The blunted cardiac output response to exercise results in an increase in anaerobic glycolysis with development of a lactic acidosis at low work rates. The lactic acidosis produces acid stimuli that increases ventilatory drive [44].

Mitani et al. [25] suggested that it is necessary – when performing a CPET in PAH patients – to observe not only VO2 or VCO2, but also Ve/VCO2, in order to prevent aggravation of the ventilation/perfusion inequality, which leads to exercise-induced hypoxemia. A higher VE/VCO2 ratio describes a greater ventilatory requirement for eliminating the CO2 produced by aerobic metabolism and defines a reduced ventilatory efficiency. The reduced ventilatory efficiency is therefore caused by an increase in physiological dead space and a reduced PaCO2 set-point [45]. Ting et al. [23] demonstrated that patients with higher Ve/VCO2 ratio would be patients with higher pulmonary vascular resistance. On the other side, the authors showed that the improvement in VE/VCO2 ratio paralleled the improvement in VD/VT following dosing with prostanoids. This supports the concept that a reduction in Ve/VCO2 ratio reflects an improvement in blood flow to the ventilated lung. Reybrouck et al. [24] found that the Ve/VCO2 slope was steeper in patients with PH than the slope in patients with normal PAP, and these authors found a significant correlation between the slope and PAP and the VD/VT. Because of ventilation-perfusion inequalities, the VD/VT is increased, making gas exchange less efficient than normal. This causes PetCO2 to be diluted relative to PaCO2. Because pulmonary vascular disease is the hallmark of patients with PH, it is likely that the remarkably low PetCO2 seen in our patients with PH is partially due to underperfusion of ventilated lung.

Our data indicate that abnormally reduced ventilatory efficiency parameters are powerful and independent predictors of mortality in patients with PAH/CTEPH. Our study demonstrates that an increased ventilatory response to exercise is associated with a lower survival in patients with stable PAH. For several years, peak VO2 was the “gold standard” and remains widely used to risk stratify this type of patients [2]. However, the limitations of peak VO2 have prompted the search for other indices of CPET that can serve as alternative prognostic factors. The main disadvantage of peak VO2 is the need for maximal exercise, which may be difficult to achieve, particularly in PAH patients, whose daily activity levels are far below the effort required by the test. In addition, peak VO2 may be underestimated because of low patient motivation or because of premature termination of the test by the physician. Thus supplementary indices are needed to sharpen the risk stratification [46]. Unlike peak VO2, for example the Ve/VCO2 slope is generally independent from subject effort. In addition, variation in the Ve/VCO2 slope appears to rely closely on central function in patients with PH. The closer reliance the Ve/VCO2 slope has on cardiac performance may contribute to its prognostic accuracy relative to peak VO2.

The ventilatory efficiency parameters are easily measurable and highly reproducible parameters obtained from CPET, and the prognostic value of a reduced ventilatory efficiency suggests higher than the peak VO2 alone. Thus, a rational and pragmatic risk stratification process should include both peak VO2 and ventilatory efficiency parameters, and in particular, the measurement of the Ve/VCO2 slope and ventilatory equivalent for carbon dioxide should be performed in patients with PAH/CTEPH. In summary, based upon these preliminary results, we propose that these indices of CPET might be helpful in the care of these patients and could play a role as a prognostic effort-independent marker in the evaluation of PAH/CTEPH patients.