Ventilatory compensation during the incremental exercise test is inversely correlated with air trapping in COPD

Abbreviations

BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in the first second; GOLD, global initiative for chronic obstructive lung disease; IC, inspiratory capacity; RV, residual volume; TLC, total lung capacity; VCO₂, CO₂ output; V_E, minute ventilation; V_E/VCO₂, ventilatory equivalent for CO₂; V_E/VO₂, ventilatory equivalent for oxygen; ΔV_E/VCO₂, nadir to peak value of V_E/VCO₂; ΔV_E/VO₂, nadir to peak value of V_E/VO₂; VO₂, oxygen consumption; Vt/VC, tidal volume to vital capacity ratio

Introduction

Chronic obstructive pulmonary disease (COPD) patients often demonstrate significant exercise limitation, chiefly resulting from gas exchange abnormalities and ventilation-perfusion mismatching¹. This situation is often compounded by hyperinflation and air trapping with dynamic hyperinflation during exercise and gradual reduction of inspiratory capacity². To evaluate exercise capacity and determine the degree of exercise limitation and its mechanisms, the incremental exercise test is often applied, during which several ventilatory events occur and draw close attention.

During incremental cardiopulmonary exercise testing, the ratio of minute ventilation (V_E) to carbon dioxide output (VCO₂) and to oxygen consumption (VO₂), also known as ventilatory equivalent for carbon dioxide (V_E/VCO₂) and oxygen (V_E/VO₂), respectively, serve to evaluate ventilatory efficiency. The ventilatory threshold, a term coined in the context of gas exchange measurements and represents to a great extent the VO₂ at anaerobic threshold, heralds the onset of the isocapnic buffering phase, in which there is an increased contribution of anaerobic metabolism to provide the energy required for the increasing demands of exercise, accompanied by increased CO₂ production with corresponding ventilation increase. With the accumulation of lactic acid and H⁺ protons, as the bicarbonate reserves are decreased beyond the isocapnic buffering phase, an augmented ventilatory response starts at the ventilatory compensation point, which is disproportionate to the degree of CO₂ production, leading to V_E/VCO₂ surge towards peak exercise, a phenomenon termed the ventilatory compensation phase.

The V_E/VCO₂ is often increased as a result of ventilation-perfusion mismatching^1,3. The nadir V_E/VCO₂ value during incremental exercise is inversely related to the degree of exercise limitation⁴, as well as the severity of airway obstruction, as determined by the values of forced expiratory volume in first second (FEV₁)^5,6. The nadir value is considered to reflect ventilatory efficiency as higher values obtained at the early stages of the incremental exercise test result from frequently encountered hyperventilation. Interestingly, marked hyperinflation and reduced ventilatory capacity tend to reduce ventilatory equivalents as ventilation may become constrained. Both baseline and peak exercise V_E/VCO₂ values were found to be lower in patients with more severe airway obstruction as V_E is decreased relative to VCO₂ in these patients^5,6.

Although COPD patients may terminate exercising at an early stage during the incremental exercise test due to airflow obstruction and air trapping, suboptimal effort and deconditioning, the latter of which may be associated with somewhat earlier development of metabolic acidosis, may also lead to early termination of the exercise test. Regardless of the reason causing decreased exercise performance, the ventilatory compensation phase may not be demonstrated. Ventilatory equivalents during incremental exercise may be affected by the above-mentioned processes in different directions. In this exploratory study we sought to confirm the presumption that the ability to achieve ventilatory compensation in response to acidosis is related to the degree of air trapping, with the hypothesis that the ability to augment ventilation beyond the ventilatory compensation point in COPD patients is inversely correlated with the degree of air trapping.

Methods

Results

In total, 20 patients were included in our analysis with a mean ± SD age of 63 ± 10 years (range 37–77). None of the patients had cardiac failure. Two patients were receiving beta blockers. Table 1 summarizes clinical data of these patients.

We found a statistically significant inverse correlation between both ΔV_E/VCO₂ (r = -0.5058, 95% CI -0.7750 to -0.08149, p = 0.0234) and ΔV_E/VO₂ (r = -0.5588, 95% CI -0.8029 to -0.1545, p = 0.0104), with the degree of air trapping as estimated by the RV/TLC ratio (Table 2). In this cohort, there was a significant correlation between Nadir VE/VCO2 and VE/VCO2 slope (r=0.82, 95% CI 0.59 to 0.92, p<0.0001).In contrast to increments in ventilatory equivalents, there was no correlation between the nadir values of the ventilatory equivalents and RV/TLC (Table 2). Interestingly, inspiratory capacity to total lung capacity ratio (IC/TLC), which reflects pulmonary expansion in emphysema, did not show a correlation with either ΔV_E/VCO₂ or ΔV_E/VO₂ (Table 2).

We examined possible correlation between ΔV_E/VCO₂ and other static parameters of pulmonary function or findings on exercise testing (summarized in Table 2). Notably, we found no significant correlation between neither ΔV_E/VCO₂ nor nadir V_E/VCO₂ and peak VO₂ (% of predicted VO₂max) or FEV₁ (% of predicted). There was a correlation between ΔV_E/VCO₂ and peakVO₂ (in ml/kg/min) which just achieved a significance at p= 0.0462, (Table 2). As expected¹, nadir values of V_E/VCO₂ correlated with TL_CO (r = -0.5281, 95% CI -0.7923 to -0.09708, p = 0.0201); however, we did not find a correlation between ΔV_E/VCO₂ and TL_CO (Table 2).

In an attempt to identify factors related to the lack of increment of V_E/VCO₂ besides those related to air trapping, we compared values of parameters related to static pulmonary functions and those related to performance of exercise in patients with and without increment in V_E/VCO₂ (i.e., ΔV_E/VCO₂ = 0) (Table 3). We noted a statistically important difference in peak RER, VO2 (in ml/kg/min), peak WR; However, FEV₁, IC/TLC, TL_CO, peak VO₂ (as % of predicted VO₂), and nadir V_E/VCO₂ were not different between these two groups. RV/TLC had a statistically important difference between the two groups. However, RV/TLC as well as peak VO₂ adjusted to body weight are inherently derived from the parameters that the correlation study had examined and therefore, this difference is not surprising. There was also a significant difference in the values of peak exercise end-tidal PCO₂ between the two groups with lower values of end-tidal PCO₂ in patients who had ΔV_E/VCO₂>0. Interestingly, patients who did not have a V_E/VCO₂ increment at peak exercise, had a trend towards a higher peak exercise end-tidal PCO₂ than their baseline values (37.3±8.1 vs 32.5±6.7) although the difference did not achieve a statistically important difference (p=0.1651). Moreover, the value of V_E/VCO₂ y-abcissa intercept (i.e., V_E intercept) in patients who did not have an increment of V_E/VCO₂ (i.e., ΔV_E/VCO₂=0) was significantly higher than in those who had a ΔV_E/VCO₂>0. Variables that could be affected by ventilatory mechanical constraints during exercise, the breathing reserve and peak tidal volume to vital capacity ratio (Vt/VC) were not different between the two groups.

Discussion

Inefficient ventilation in patients with COPD and particularly emphysema is often evidenced by elevated nadir V_E/VCO₂. The elevation of nadir V_E/VCO₂ may be related to the extent and severity of emphysematous changes in the lungs. It has been shown that in patients with mild to moderate airflow decrease, the values of nadir V_E/VCO₂ correlated with the percentage of low attenuation areas on computerized tomography^8,9 as well as the decrease in pulmonary perfusion, as estimated by the inert gas rebreathing method⁹. Interestingly, in smokers without COPD, the degree of CO diffusion decrease correlated with elevation of nadir V_E/VCO₂ during the incremental exercise test¹⁰, again pointing to a strong relation between impaired ventilation efficiency and gas exchange ability. Notably, significantly increased ventilatory constraints, as occurs in marked air trapping, decrease V_E, thus leading to lower nadir V_E/VCO₂ in more severe airway obstruction^2,6.

In this study we examined the ability of COPD patients during incremental exercise testing to increase ventilation towards peak exercise, focusing on the increase in V_E/VCO₂ and V_E/VO₂ that occur following the ventilatory compensation point. We quantified this phenomenon measuring the difference between the values of V_E/VCO₂ and V_E/VO₂ at nadir and peak exercise obtained post the ventilatory compensation point, which we termed ΔV_E/VCO₂ and ΔV_E/VO₂, respectively. We found that the ability to increase ventilation during incremental exercise testing in response to metabolic acidosis, as normally occurs in higher exercise intensities beyond the ventilatory compensation point, was diminished in COPD patients and in correlation with the severity of air trapping as represented by RV/TLC obtained at rest. Furthermore, this may implicate a difficulty in coping with the ventilatory demands of metabolic acidosis resulting from states such as acute renal failure or septic shock, thus ΔV_E/VCO₂ (and seemingly ΔV_E/VO₂) may allow assessment of the ability of COPD patients to withstand such metabolic challenges. Limited ventilatory compensation is clinically significant as it has been shown that people with COPD have higher arterial PCO₂ and lower pH in response to blood lactate elevation during exercise, compared to people without COPD¹¹. In our cohort, peak end-tidal PCO₂ in patients without V_E/VCO₂ increment had a non-significant trend towards higher values than baseline end-tidal PCO₂ thus pointing to a limited ability to compensate for acidosis. Our findings also show that patients who did not have an increment in V_E/VCO₂ had higher average V_E intercept value of the V_E/VCO₂ slope than patients with ΔV_E/VCO₂>0, thus suggesting a role for the presence of higher dead space breathing⁵ in patients who do not increase ventilatory equivalents and produce ventilatory compensation.

One way in which pulmonary hyperinflation can be expressed is by the increased ratio of RV/TLC, which reflects air trapping and is associated with airway narrowing. Alternatively, IC/TLC may also be decreased because of lung expansion associated with emphysematous changes and reduced lung recoil. A recent study showed that either increased RV/TLC or decreased IC/TLC or both simultaneously can be present, with airway narrowing on imaging being associated with increased RV/TLC and emphysema associated with deceased IC/TLC⁷. Therefore, it seems that the lack of increments in ventilatory equivalents in our study is correlated with air trapping but not to the mere presence of emphysema.

One may argue that the limited rise of ventilatory equivalents beyond the ventilatory threshold during the incremental exercise test may reflect sub-optimal exercise performance; however, we think that the lower respiratory exchange ratio at peak exercise may represent another manifestation of the decreased ventilatory response.

Although both ΔV_E/VO₂ and ΔV_E/VCO₂ seem to show similar correlation to RV/TLC and utility in estimating the ventilation response to acidosis under these conditions, a further study with larger numbers of patients may help distinguish the different roles of these parameters.

This study has several limitations. The retrospective design and the small number of patients included are important limitations, in particular when comparing two subgroups. However, these limitations may be of lesser significance when searching for correlations. Measured increment of ventilatory equivalents in a significant number of patients was nil, with a value =0. This may point to an important limitation of this measurement. Future studies should be designed to utilize a lower ramp than the ramps that were used in our patients studied retrospectively, to allow time for patients to adjust and generate ventilatory compensation, something that may be more difficult to do exercising at high work rates. Some patients were obese, which may have caused mild restriction, somewhat contributing to air trapping. However, we didn’t find a correlation between body mass index (BMI) and either ΔV_E/VCO₂ or ΔV_E/VO₂. Unfortunately, dynamic hyperinflation, a well-known phenomenon that is associated with ventilatory constraints during exercise in COPD, was not assessed by performing repeated inspiratory capacity maneuvers during exercise and therefore, we cannot describe the relation between dynamic hyperinflation (i.e. changes in IC/TLC) and ventilatory equivalents increment in this cohort. However, dynamic hyperinflation developing during exercise is associated with changes in Vt/VC at peak exercise with lower value than the expected portion of 50–60% at peak incremental exercise¹² as dynamic hyperinflation develops with increasing work rate during exercise performance². The average Vt/VC at peak exercise of all patients in our cohort was 46±8%, without a statistically meaningful difference in peak exercise Vt/VC between those who had V_E/VCO₂ increment and those who didn’t (Table 3). Therefore, it is unlikely that development of dynamic hyperinflation can differentiate between ventilatory equivalent increment patterns during exercise in our patients.

In conclusion, ventilation augmentation during incremental exercise testing at exercise intensities beyond the ventilatory compensation point in COPD patients was diminished in correlation with the severity of air trapping. Future studies will confirm the clinical usefulness of measuring ΔV_E/VCO₂ and ΔV_E/VO₂, including their potential role as serially measured physiologic parameters to assess effects of interventions (e.g. pulmonary rehabilitation) in COPD.

Data availability