Lung (2015) 193:223–229 DOI 10.1007/s00408-015-9698-6
The Effect of Pulmonary Hypertension on Aerobic Exercise Capacity in Lung Transplant Candidates with Advanced Emphysema Yochai Adir • Jacob E. Ollech • Baruch Vainshelboim Yael Shostak • Arie Laor • Mordechai R. Kramer
•
Received: 30 August 2014 / Accepted: 24 February 2015 / Published online: 7 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Purpose Mild pulmonary hypertension (PH) in patients with advanced COPD is common, but its effects on exercise capacity are controversial. The objective of our study was to investigate the effects of mild PH (35 [ mPAP C 25 mmHg) on exercise capacity in patients with advanced emphysema, candidates for lung transplantation. Methods We retrospectively reviewed and compare the data from right heart catheterization and cardiopulmonary exercise test, performed in patients with advanced emphysema, candidate for lung transplantation. Results Twenty patients with emphysema and no PH and 24 patients with emphysema associated with mild PH included in the study. Both patient groups had severe airways obstruction with markedly reduced FEV1 (24.9 % P ± 8.9 and 25.9 % P ± 11.7, respectively), and severely reduced DLCO (35.2 % P ± 17.3 and 39.2 % P ± 15.9). Both patients group demonstrated mark reduction in maximum workload and peak VO2 together with increased ventilatory equivalent for CO2 and extremely low breathing reserve.
Yochai Adir and Jacob E. Ollech have contributed equally to this work. Y. Adir B. Vainshelboim A. Laor Pulmonary Division, Lady Davis Carmel Medical Center, Faculty of Medicine, The Technion–Israel Institute of Technology, Haifa, Israel J. E. Ollech Y. Shostak M. R. Kramer Pulmonary Division, Rabin Medical Center Petach Tikva, Sakler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel M. R. Kramer (&) Pulmonary Institute, Rabin Medical Center, Beilinson Campus, 49100 Petach Tikva, Israel e-mail: [email protected]
There was no correlation between mPAP and any of the exercise measurement. Conclusions Our study suggests that exercise capacity in patients with advanced emphysema is limited by the ventilatory impairment and the presence of mild PH has no farther impact on exercise capability. Keywords Pulmonary hypertension COPD Exercise capacity Lung transplantation
Introduction The prevalence of pulmonary hypertension (PH) in patients with advanced chronic obstructive pulmonary disease (COPD) is common and considers being an independent prognostic factor [1, 2]. The presence of even moderate PH is a strong predictor of mortality in COPD, with an inverse correlation between mean pulmonary artery pressure (mPAP) and/or pulmonary vascular resistance (PVR) values and survival [2–5]. The functional implication of PH in patients with severe COPD is not well established. Pynnaert et al. [6] in an echocardiographic study reported that exercise capacity in unselected patients with advanced COPD and mild to moderate PH is essentially limited by exhaustion of the ventilatory reserve. However, two large studies, [where PH was defined by right heart catheterization (RHC)], demonstrated a clear functional implication of the presence of PH and even mild elevations of pulmonary pressures have effects on patient function [7, 8]. Furthermore, Boerrigter et al. reported that COPD patients with severe PH (mPAP C 40 mmHg) were limited on exercise due to exhausted circulatory reserve and not by the respiratory disease, while a profile of circulatory reserve in combination with ventilator impairments was found to be the limited
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factor of exercise capacity in patients with COPD and moderate or no PH [9]. As a results of these contradictory finding, we investigated whether in patients with severe emphysema and mild PH (25 B mPAP \ 35 mmHg), limited circulatory reserve is the main factor which affects exercise capacity or both patient groups are limited by ventilatory impairment.
Methods Subjects We retrospectively reviewed the charts of patients, followed between 2010 and 2012 with a diagnosis of severe emphysema, candidates for lung transplantation. Patients fulfilling the American Thoracic Society/European Respiratory Society criteria [10, 11], with compatible highresolution chest CT scan results and pulmonary function tests were included in the study. All subjects underwent RHC and cardio-pulmonary exercise test (CPET) as part of evaluation for lung transplantation. All patients were evaluated using ERS/ESC guidelines to determine the etiology of PH [12, 13]. Patients who had any of the following conditions were excluded: congenital heart disease, connective tissue disease, HIV infection, portal hypertension, appetite suppressant exposure, and chronic thrombo-embolic disease. Patients with evidence of left heart disease based on Doppler echocardiography and RHC were excluded from the study. Based on the resting mPAP, patients were divided into two groups: (1) no PH (mPAP \25 mmHg) and (2) moderate PH (25 B mPAP \ 35 mmHg). The study was approved by the local ethics committee, approval number 6963.
Lung (2015) 193:223–229
exchange were recorded during 5 min of rest and 5 min of unloaded pedaling at 60 revolutions per minute, followed by a progressive increase in workload of 5–20 W every minute until exhaustion. The chosen protocol was based on the patient’s medical history (daily life exercise performance) in combination with pulmonary function results, thereby aiming at duration of the test between 6 and 15 min. The anaerobic threshold was determined using the V-slope method. Maximal voluntary ventilation (MVV) was calculated as 40 9 FEV1, and the breathing reserve was noted in absolute numbers (L/min) or as (MVV– maximal ventilation)/MVV 9 100 %. Six-min walking distance was measured according to the established guidelines. Right Heart Catheterization Right heart catheterization was performed using a standard protocol with zeroing calibration in mid-axillary line [12, 13]. Cardiac output was done using a thermo-dilution method and whenever a wedge pressure wave form was not considered as sufficient for analysis, a direct left ventricular end-diastolic pressure was recorded. PVC was calculated using the RHC data. Statistics Data are presented as mean ± SD. Continuous variables were assessed with the student’s t test. Categorial variables were compared with the v2 test. Distribution is also presented graphically as box plots.
Results Patient’s Characteristics
Pulmonary Function Measurements Spirometry, body plethysmography, and single-breath carbon monoxide diffusing capacity (Zan 530 Oberthulba, Germany) were measured according to the European Respiratory Society guidelines [14, 15]. Cardio-Pulmonary Exercise Test (CPET) Patients performed a standardized, incremental maximal exercise test using an electromagnetically braked cycle ergometer (Ergoline-800S) according to the American Thoracic Society/American College of Chest Physicians guidelines [16]. Breath-by-breath measurements were made of oxygen consumption (VO2), CO2 output, and ventilation (Zan 600, Oberthulba, Germany). Ventilatory equivalents for CO2 were calculated. Heart rate and gas
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We review the charts of 70 patients with advanced emphysema, candidate for lung transplantation who underwent evaluation including RHC and CPET. Twenty six patients were excluded due to concomitant heart failure with elevated pulmonary capillary artery pressure. Forty four patients were included in the study. Twenty patients were with severe COPD with no PH (mPAP \ 25 mmHg), and 24 patients with severe COPD and mild PH (mPAP C 25 mmHg). There was no significant difference between the two patient groups regarding age or BMI (Table 1). Both patient groups had severe airways obstruction with markedly reduced FEV1 (24.9 % P ± 8.9 and 25.9 % P ± 11.7, respectively), severely reduced DLCO (35.2 % P ± 17.3 and 39.2 % P ± 15.9), and significant air trapping (Table 1). The hemodynamic data are shown in Table 2.
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Table 1 Pulmonary function test variables and 6-min walk distance in the two patient groups, COPD with no PH group and COPD with mild PH Clinical characteristics
COPD
COPD–PH
P value
Age
61.1 ± 4.4
59.4 ± 6.3
0.46
BMI
22.1 ± 4.8
25.5 ± 4.7
0.06
FEV1 (percent predicted) FVC (percent predicted)
24.9 ± 8.9 41.3 ± 10.5
25.9 ± 11.6 54.4 ± 16.7
0.82 0.005
FEV1/FVC
37.9 ± 10.2
32.7 ± 7.2
0.07
TLC (percent predicted)
116.5 ± 23.3
130.4 ± 24.6
0.29
RV (percent predicted)
234.6 ± 63.6
263.6 ± 68.8
0.68
DLCO (percent predicted)
35.2 ± 17.3
39.2 ± 15.9
0.68
RV/TLC (percent)
199 ± 2.2
198 ± 2.6
0.85
6MWD
326.9 ± 105.7
305.9 ± 93.4
0.56
SAT PRE 6MWD
96.2 ± 0.9
93.5 ± 2.7
0.001
SAT POST 6MWD
92.0 ± 3.9
88.6 ± 7.2
0.1
BMI body mass index, DLCO diffusion capacity for carbon monoxide, 6MWD 6-min walk distance, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, RV residual volume, TLC total lung capacity
Table 2 Hemodynamic variable in the two patient groups, COPD with no PH group and COPD with mild PH Hemodynamic parameters
COPD
COPD–PH
P value
Systolic PAP (mmHg) (range, mean)
(28–38) 33.1 ± 3.5
44.2 ± 8.6
0.0001
Diastolic PAP (mmHg) (range, mean)
(5–22) 13.9 ± 4.7
21.1 ± 4.6
0.0001
mPAP (mmHg)
20.2 ± 2.2
28.6 ± 2.7
PVR wood unit
2.7 ± 0.9
3.3 ± 0.9
CI (L/min/m2)
2.6 ± 0.7
2.7 ± 0.6
0.52
PCWP (mmHg)
9.8 ± 3.5
13.0 ± 1.9
0.001
0.0001 0.08
CI cardiac index, PAP pulmonary artery pressure, mPAP mean pulmonary artery pressure, PCWP pulmonary capillary wedge pressure, PVR pulmonary vascular resistance
Cardiopulmonary Exercise Test There was no difference between the two patient groups in 6-min walking distance. Emphysema patients with no PH walked 326.9 ± 105.7 with reduction of oxygen saturation from 96 ± 0.9 to 93 ± 2.6, whereas emphysema patients with mild PH walked 305.9 ± 93.4 and the oxygen saturation decreased from 92 ± 3.9 to 89 ± 7.29 (Table 3). Both patients group demonstrated mark reduction in maximum workload and peak VO2 together with increased ventilatory equivalent for CO2 and extremely low breathing reserve. There was no significant difference in any of the exercise test variables between the two patient groups except for heart rate and the ventilatory equivalent
for CO2 (Table 3; Figs. 1, 2). Patients with mild PH tend to have increased HR at rest and at the end of exercise 110.5 ± 12.9 and 123 ± 12.9, respectively (vs 89.7 ± 12.9 and 102.2 ± 14.9). The ventilatory equivalent for CO2 was higher than the normal values in both groups of patients although it was significantly higher in patients with advanced COPD and no PH.
Discussion The main finding in our study is that in patients with advanced emphysema, candidate for lung transplantation, with mild PH, ventilatory impairment is the main limiting factor of exercise capacity. As opposed to previously reported studies, we were not able to demonstrate that circulatory impairment has a major role in functional limitation in this patient group. There are several factors which may contribute to the decreased exercise capacity in severe COPD patients including dynamic hyperinflation, decreased ventilatory reserve, and respiratory and peripheral muscle dysfunctions [17–19]. Furthermore, in patients with COPD, pulmonary artery pressure may abnormally rise during physical activity due to the fact that PVR does not decrease or might even increase during exercise, limiting the increase in cardiac output [3, 20]. Indeed, Holverda et al. [21] demonstrated that stroke volume fails to increase during exercising COPD patients, in proportion to severity of resting pulmonary pressure. However, the contribution of mild-to-moderate PH to exercise limitation in patients with advanced COPD is controversial. Sims et al. [7] evaluated the effect of PH measured by RHC on exercise performance assessed by 6MWD in 362 patients with severe COPD who were evaluated for lung transplantation. They concluded that higher pulmonary artery pressures were associated with reduced exercise function even after controlling for demographics, anthropomorphic, severity of airflow obstruction, and PCWP. Cuttica et al. [8] found an association between mPAP and 6MWD independent of lung function and pulmonary artery occlusion pressure in 1154 advanced COPD patients candidate for lung transplantation. In contrast to these studies that show a clear functional implication of the presence of mild PH, other studies reported that mild-to-moderate PH has no impact on exercise capacity in severe COPD patients. Pynnaert et al. [6] evaluated exercise capacity by 6MWD and CPET, in 29 advanced stable COPD patients. Mean pulmonary artery pressure was calculated from the acceleration time of pulmonary flow on echocardiography. No correlation was found between PAP and any of the exercise measurements, and the conclusion was that patients with advanced COPD and mild to moderate PH are essentially limited by
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226 Table 3 Cardiopulmonary exercise tests variable in the two patient groups, COPD no PH group and COPD with mild PH
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CPET parameters
COPD
P value
Limits of normal
Saturation rest
96.3 ± 1.1
95.2 ± 2.2
0.05
Saturation peak
92.9 ± 3.3
90.6 ± 4.6
0.08
95–100
Work rate (W)
35.7 ± 19.0
40.4 ± 20.4
0.46
129–241 23–32
VO2 peak VO2 (mL/min)
38.9 ± 11.2
0.27
646.1 ± 267.6
34.9 ± 11.2
640.1 ± 308
0.94
35.4 ± 10.9
39.4 ± 11
0.26
VO2 (mL/kg/min %) VO2 (mL/kg/min)
9.5 ± 2.9
9.3 ± 2.3
0.81
VE (L/m)
26.0 ± 6.4
27.9 ± 13.1
0.55
MVV (L/m)
24.0 ± 6.6
24.0 ± 6.6
0.7
3.5 ± 3.9
5.4 ± 7.9
0.35
Vd/Vt (%) rest
43.5 ± 13.7
43.1 ± 5.2
0.91
Vd/Vt (%)
40.1 ± 11.1
39.0 ± 4.9
0.96
VE/VO2 rest (L/min)
53.9 ± 9.4
48.9 ± 14.3
0.26
VE/VO2 (L/min)
42.6 ± 13.9
37.3 ± 8.8
0.16
VE/VCO2 rest (L/min) VE/VCO2 (L/min)
56.1 ± 9.1 44.1 ± 7.8
49.5 ± 8.8 37.6 ± 7.3
0.04 0.01
Breathing reserve
MVV maximal voluntary ventilation, VO2 oxygen uptake, VE ventilation, VCO2 carbon dioxide output, HR heart rate, Vd/Vt the ratio of physiologic dead space over tidal volume, VE/VO2 the ventilatory equivalent ratio for oxygen, VE/ VCO2 the ventilatory equivalent ratio for carbon dioxide, VO2/ HR oxygen pulse- oxygen uptake per heartbeat
COPD–PH
HR rest HR exercise
89.7 ± 12.9
102.2 ± 14.9
0.007
110.5 ± 12.9
123.8 ± 16.3
0.007
68.6 ± 8.9
75.9 ± 9.8
0.02
5.7 ± 2.3
0.75
51.8 ± 15.9
0.44
HR (%) VO2/HR (mL/min) VO2/HR (%)
5.5 ± 2.1 47.815 ± 4
70–108 38
33–35
150–178
Fig. 1 Individual values of CPET characteristics in the two patient groups, COPD no PH group and COPD with mild PH. No significant difference in work rate (a), peak VO2 per kilogram body weight (b), breathing reserve (c), and maximal O2-pulse (d) was observed between both groups
exhaustion of the ventilatory reserve. Furthermore, Boerrigter et al. [9] evaluated forty-seven patients, COPD patients by underwent CPET and RHC at rest and during
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exercise. Patients were divided into three groups based on mPAP at rest: no PH (mPAP \25 mmHg), moderate PH (39 C mPAP C 25 mmHg), and severe PH
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Fig. 2 Plots of correlations between mPAP and exercise parameters in the two patient groups, COPD no PH group and COPD with mild PH. Work rate (a), breathing reserve (b), maximal O2-pulse (c), and peak VO2 per kilogram body weight (d)
(mPAP C40 mmHg). The authors found that patients with severe PH demonstrated an exhausted circulatory reserve at the end of exercise, whereas a profile of circulatory reserve in combination with ventilatory impairments was found in patients with COPD and moderate or no PH. These contradictory findings led us to study whether mild PH at rest, defined by RHC, contributes to exercise limitation in patients with advanced emphysema, candidates for lung transplantation. Our patient population demonstrated mark reduction in maximum workload and peak VO2 together with extremely low breathing reserve, with no correlation between mPAP and any of the exercise measurements. It is considered that in normal subjects the ventilator reserve is normally amounts to an average of 38 L/min, whereas a value of \11 L/min is strongly indicates ventilatory limitation [22]. In the present study, both groups of emphysema patients with mild PH or no PH had reduced MVV as well as severely low breathing reserve (24.0 ± 6.6 and 3.5 ± 3.9, and 24.0 ± 6.6 and 5.4 ± 7.9,
respectively), suggesting that exercise capacity was limited due to ventilatory impairment not only in the advanced emphysema with no PH patients but also in those with mild PH. Furthermore, significant hyperinflation and air trapping at rest have been found in both patient groups with and without PH. It is possible that substantial air trapping, dynamic hyperinflation, and possibly skeletal muscle dysfunction all played a major role limiting exercise capacity and reduced maximum workload (40.4 ± 20 and 35.7 ± 19.0, respectively). In patients with pulmonary vascular disease, we will expect to find on CPET a reduced peak VO2, reduced anaerobic threshold, increased ventilator equivalent for CO2 but with normal breathing reserve, and low O2 pulse with impaired chronotropic response [23]. Interestingly, none of these indexes were found to characterize the group of patients with advanced emphysema and mild PH. The increased ventilatory equivalent for CO2 which was found in both patient groups in concert with reduced breathing
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reserve support ventilatory impairment as the major limiting factor for exercise capacity. Only HR at rest and at the end of exercise was significantly increased in the mild PH group (89.7 ± 12.9, 102.2 ± 14.9 and 102.2 ± 14.9, 123.8 ± 16.3, respectively). The O2 pulse was markedly reduced in both patient groups imply a limitation in stroke volume increased during exercise. Previous studies on the effects of exercise and the subsequent rise in pulmonary artery pressure on cardiac function have shown that right ventricular end-diastolic volume increases and right ventricular ejection fraction fails to augment during exercise in most COPD patients [21, 24–27]. Moreover, a previous study reported that 3 months of vasodilator therapy with sildenafil, failed to neither reduce PVR and improved stroke volume nor exercise capacity [28]. It seems that hyperinflation at rest and dynamic hyperinflation may exert an important detrimental effect on cardiac function, manifested as low O2 pulse, and play a role in the reduced exercise performance of patients with severe COPD [29–32]. Dynamic hyperinflation may impair cardiac function either by decreasing blood returns to the right heart or by increasing the afterload to the left ventricle due to increase intrathoracic pressure swings. The effects of dynamic hyperinflation on cardiac patients support the notion that in patients with advanced COPD and mild PH, ventilatory impairment is the main limiting factor on exercise, and the low oxygen pulse is not the results of diseased pulmonary circulation [32]. A small sample of patients is an important limitation of our study; however, our results confirm the results of Boerrigter et al. on the effect of mild PH on exercise capacity. In summary, exercise capacity in patients with advanced emphysema, candidate for lung transplantation, and mild PH is essentially limited by a decreased ventilatory reserved. Therefore, it seems that specific pulmonary vasodilators would not improve exercise capacity in this patient population.
Conflict of interest of interest.
The authors declare that they have no conflict
Ethical standard This study complies with the current laws of Israel and was approved by the institutional IRB.
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Lung (2015) 193:223–229 24. Mahler DA, Brent BN, Loke J et al (1984) Right ventricular performance and central circulatory hemodynamics during upright exercise in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 130:722–729 25. Matthay RA, Berger HJ, Davies RA et al (1980) Right and left ventricular exercise performance in chronic obstructive pulmonary disease: radionuclide assessment. Ann Intern Med 93: 234–239 26. Morrison DA, Adcock K, Collins CM et al (1987) Right ventricular dysfunction and the exercise limitation of chronic obstructive pulmonary disease. J Am Coll Cardiol 9:1219–1229 27. Oliver RM, Fleming JS, Waller DG (1993) Right ventricular function at rest and during exercise in chronic obstructive pulmonary disease. Comparison of two radionuclide techniques. Chest 103:74–80
229 28. Rietema H, Holverda S, Bogaard HJ et al (2008) Sildenafil treatment in COPD does not affect stroke volume or exercise capacity. Eur Respir J 31:759–764 29. Montes de Oca M, Rassulo J, Celli BR (1996) Respiratory muscle and cardiopulmonary function during exercise in very severe COPD. Am J Respir Crit Care Med 154:1284–1289 30. Travers J, Laveneziana P, Webb KA et al (2007) Effect of tiotropium bromide on the cardiovascular response to exercise in COPD. Respir Med 101:2017–2024 31. Jo¨rgensen K, Mu¨ller MF et al (2007) Reduced intrathoracic blood volume and left and right ventricular dimensions in patients with severe emphysema: an MRI study. Chest 131:1050–1057 32. Vassaux C, Torre-Bouscoulet L, Zeineldine S et al (2008) Effects of hyperinflation on the oxygen pulse as a marker of cardiac performance in COPD. Eur Respir J 32:1275–1282
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The Effect of Pulmonary Hypertension on Aerobic Exercise Capacity in Lung Transplant Candidates with Advanced Emphysema Yochai Adir • Jacob E. Ollech • Baruch Vainshelboim Yael Shostak • Arie Laor • Mordechai R. Kramer
•
Received: 30 August 2014 / Accepted: 24 February 2015 / Published online: 7 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Purpose Mild pulmonary hypertension (PH) in patients with advanced COPD is common, but its effects on exercise capacity are controversial. The objective of our study was to investigate the effects of mild PH (35 [ mPAP C 25 mmHg) on exercise capacity in patients with advanced emphysema, candidates for lung transplantation. Methods We retrospectively reviewed and compare the data from right heart catheterization and cardiopulmonary exercise test, performed in patients with advanced emphysema, candidate for lung transplantation. Results Twenty patients with emphysema and no PH and 24 patients with emphysema associated with mild PH included in the study. Both patient groups had severe airways obstruction with markedly reduced FEV1 (24.9 % P ± 8.9 and 25.9 % P ± 11.7, respectively), and severely reduced DLCO (35.2 % P ± 17.3 and 39.2 % P ± 15.9). Both patients group demonstrated mark reduction in maximum workload and peak VO2 together with increased ventilatory equivalent for CO2 and extremely low breathing reserve.
Yochai Adir and Jacob E. Ollech have contributed equally to this work. Y. Adir B. Vainshelboim A. Laor Pulmonary Division, Lady Davis Carmel Medical Center, Faculty of Medicine, The Technion–Israel Institute of Technology, Haifa, Israel J. E. Ollech Y. Shostak M. R. Kramer Pulmonary Division, Rabin Medical Center Petach Tikva, Sakler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel M. R. Kramer (&) Pulmonary Institute, Rabin Medical Center, Beilinson Campus, 49100 Petach Tikva, Israel e-mail: [email protected]
There was no correlation between mPAP and any of the exercise measurement. Conclusions Our study suggests that exercise capacity in patients with advanced emphysema is limited by the ventilatory impairment and the presence of mild PH has no farther impact on exercise capability. Keywords Pulmonary hypertension COPD Exercise capacity Lung transplantation
Introduction The prevalence of pulmonary hypertension (PH) in patients with advanced chronic obstructive pulmonary disease (COPD) is common and considers being an independent prognostic factor [1, 2]. The presence of even moderate PH is a strong predictor of mortality in COPD, with an inverse correlation between mean pulmonary artery pressure (mPAP) and/or pulmonary vascular resistance (PVR) values and survival [2–5]. The functional implication of PH in patients with severe COPD is not well established. Pynnaert et al. [6] in an echocardiographic study reported that exercise capacity in unselected patients with advanced COPD and mild to moderate PH is essentially limited by exhaustion of the ventilatory reserve. However, two large studies, [where PH was defined by right heart catheterization (RHC)], demonstrated a clear functional implication of the presence of PH and even mild elevations of pulmonary pressures have effects on patient function [7, 8]. Furthermore, Boerrigter et al. reported that COPD patients with severe PH (mPAP C 40 mmHg) were limited on exercise due to exhausted circulatory reserve and not by the respiratory disease, while a profile of circulatory reserve in combination with ventilator impairments was found to be the limited
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224
factor of exercise capacity in patients with COPD and moderate or no PH [9]. As a results of these contradictory finding, we investigated whether in patients with severe emphysema and mild PH (25 B mPAP \ 35 mmHg), limited circulatory reserve is the main factor which affects exercise capacity or both patient groups are limited by ventilatory impairment.
Methods Subjects We retrospectively reviewed the charts of patients, followed between 2010 and 2012 with a diagnosis of severe emphysema, candidates for lung transplantation. Patients fulfilling the American Thoracic Society/European Respiratory Society criteria [10, 11], with compatible highresolution chest CT scan results and pulmonary function tests were included in the study. All subjects underwent RHC and cardio-pulmonary exercise test (CPET) as part of evaluation for lung transplantation. All patients were evaluated using ERS/ESC guidelines to determine the etiology of PH [12, 13]. Patients who had any of the following conditions were excluded: congenital heart disease, connective tissue disease, HIV infection, portal hypertension, appetite suppressant exposure, and chronic thrombo-embolic disease. Patients with evidence of left heart disease based on Doppler echocardiography and RHC were excluded from the study. Based on the resting mPAP, patients were divided into two groups: (1) no PH (mPAP \25 mmHg) and (2) moderate PH (25 B mPAP \ 35 mmHg). The study was approved by the local ethics committee, approval number 6963.
Lung (2015) 193:223–229
exchange were recorded during 5 min of rest and 5 min of unloaded pedaling at 60 revolutions per minute, followed by a progressive increase in workload of 5–20 W every minute until exhaustion. The chosen protocol was based on the patient’s medical history (daily life exercise performance) in combination with pulmonary function results, thereby aiming at duration of the test between 6 and 15 min. The anaerobic threshold was determined using the V-slope method. Maximal voluntary ventilation (MVV) was calculated as 40 9 FEV1, and the breathing reserve was noted in absolute numbers (L/min) or as (MVV– maximal ventilation)/MVV 9 100 %. Six-min walking distance was measured according to the established guidelines. Right Heart Catheterization Right heart catheterization was performed using a standard protocol with zeroing calibration in mid-axillary line [12, 13]. Cardiac output was done using a thermo-dilution method and whenever a wedge pressure wave form was not considered as sufficient for analysis, a direct left ventricular end-diastolic pressure was recorded. PVC was calculated using the RHC data. Statistics Data are presented as mean ± SD. Continuous variables were assessed with the student’s t test. Categorial variables were compared with the v2 test. Distribution is also presented graphically as box plots.
Results Patient’s Characteristics
Pulmonary Function Measurements Spirometry, body plethysmography, and single-breath carbon monoxide diffusing capacity (Zan 530 Oberthulba, Germany) were measured according to the European Respiratory Society guidelines [14, 15]. Cardio-Pulmonary Exercise Test (CPET) Patients performed a standardized, incremental maximal exercise test using an electromagnetically braked cycle ergometer (Ergoline-800S) according to the American Thoracic Society/American College of Chest Physicians guidelines [16]. Breath-by-breath measurements were made of oxygen consumption (VO2), CO2 output, and ventilation (Zan 600, Oberthulba, Germany). Ventilatory equivalents for CO2 were calculated. Heart rate and gas
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We review the charts of 70 patients with advanced emphysema, candidate for lung transplantation who underwent evaluation including RHC and CPET. Twenty six patients were excluded due to concomitant heart failure with elevated pulmonary capillary artery pressure. Forty four patients were included in the study. Twenty patients were with severe COPD with no PH (mPAP \ 25 mmHg), and 24 patients with severe COPD and mild PH (mPAP C 25 mmHg). There was no significant difference between the two patient groups regarding age or BMI (Table 1). Both patient groups had severe airways obstruction with markedly reduced FEV1 (24.9 % P ± 8.9 and 25.9 % P ± 11.7, respectively), severely reduced DLCO (35.2 % P ± 17.3 and 39.2 % P ± 15.9), and significant air trapping (Table 1). The hemodynamic data are shown in Table 2.
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Table 1 Pulmonary function test variables and 6-min walk distance in the two patient groups, COPD with no PH group and COPD with mild PH Clinical characteristics
COPD
COPD–PH
P value
Age
61.1 ± 4.4
59.4 ± 6.3
0.46
BMI
22.1 ± 4.8
25.5 ± 4.7
0.06
FEV1 (percent predicted) FVC (percent predicted)
24.9 ± 8.9 41.3 ± 10.5
25.9 ± 11.6 54.4 ± 16.7
0.82 0.005
FEV1/FVC
37.9 ± 10.2
32.7 ± 7.2
0.07
TLC (percent predicted)
116.5 ± 23.3
130.4 ± 24.6
0.29
RV (percent predicted)
234.6 ± 63.6
263.6 ± 68.8
0.68
DLCO (percent predicted)
35.2 ± 17.3
39.2 ± 15.9
0.68
RV/TLC (percent)
199 ± 2.2
198 ± 2.6
0.85
6MWD
326.9 ± 105.7
305.9 ± 93.4
0.56
SAT PRE 6MWD
96.2 ± 0.9
93.5 ± 2.7
0.001
SAT POST 6MWD
92.0 ± 3.9
88.6 ± 7.2
0.1
BMI body mass index, DLCO diffusion capacity for carbon monoxide, 6MWD 6-min walk distance, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, RV residual volume, TLC total lung capacity
Table 2 Hemodynamic variable in the two patient groups, COPD with no PH group and COPD with mild PH Hemodynamic parameters
COPD
COPD–PH
P value
Systolic PAP (mmHg) (range, mean)
(28–38) 33.1 ± 3.5
44.2 ± 8.6
0.0001
Diastolic PAP (mmHg) (range, mean)
(5–22) 13.9 ± 4.7
21.1 ± 4.6
0.0001
mPAP (mmHg)
20.2 ± 2.2
28.6 ± 2.7
PVR wood unit
2.7 ± 0.9
3.3 ± 0.9
CI (L/min/m2)
2.6 ± 0.7
2.7 ± 0.6
0.52
PCWP (mmHg)
9.8 ± 3.5
13.0 ± 1.9
0.001
0.0001 0.08
CI cardiac index, PAP pulmonary artery pressure, mPAP mean pulmonary artery pressure, PCWP pulmonary capillary wedge pressure, PVR pulmonary vascular resistance
Cardiopulmonary Exercise Test There was no difference between the two patient groups in 6-min walking distance. Emphysema patients with no PH walked 326.9 ± 105.7 with reduction of oxygen saturation from 96 ± 0.9 to 93 ± 2.6, whereas emphysema patients with mild PH walked 305.9 ± 93.4 and the oxygen saturation decreased from 92 ± 3.9 to 89 ± 7.29 (Table 3). Both patients group demonstrated mark reduction in maximum workload and peak VO2 together with increased ventilatory equivalent for CO2 and extremely low breathing reserve. There was no significant difference in any of the exercise test variables between the two patient groups except for heart rate and the ventilatory equivalent
for CO2 (Table 3; Figs. 1, 2). Patients with mild PH tend to have increased HR at rest and at the end of exercise 110.5 ± 12.9 and 123 ± 12.9, respectively (vs 89.7 ± 12.9 and 102.2 ± 14.9). The ventilatory equivalent for CO2 was higher than the normal values in both groups of patients although it was significantly higher in patients with advanced COPD and no PH.
Discussion The main finding in our study is that in patients with advanced emphysema, candidate for lung transplantation, with mild PH, ventilatory impairment is the main limiting factor of exercise capacity. As opposed to previously reported studies, we were not able to demonstrate that circulatory impairment has a major role in functional limitation in this patient group. There are several factors which may contribute to the decreased exercise capacity in severe COPD patients including dynamic hyperinflation, decreased ventilatory reserve, and respiratory and peripheral muscle dysfunctions [17–19]. Furthermore, in patients with COPD, pulmonary artery pressure may abnormally rise during physical activity due to the fact that PVR does not decrease or might even increase during exercise, limiting the increase in cardiac output [3, 20]. Indeed, Holverda et al. [21] demonstrated that stroke volume fails to increase during exercising COPD patients, in proportion to severity of resting pulmonary pressure. However, the contribution of mild-to-moderate PH to exercise limitation in patients with advanced COPD is controversial. Sims et al. [7] evaluated the effect of PH measured by RHC on exercise performance assessed by 6MWD in 362 patients with severe COPD who were evaluated for lung transplantation. They concluded that higher pulmonary artery pressures were associated with reduced exercise function even after controlling for demographics, anthropomorphic, severity of airflow obstruction, and PCWP. Cuttica et al. [8] found an association between mPAP and 6MWD independent of lung function and pulmonary artery occlusion pressure in 1154 advanced COPD patients candidate for lung transplantation. In contrast to these studies that show a clear functional implication of the presence of mild PH, other studies reported that mild-to-moderate PH has no impact on exercise capacity in severe COPD patients. Pynnaert et al. [6] evaluated exercise capacity by 6MWD and CPET, in 29 advanced stable COPD patients. Mean pulmonary artery pressure was calculated from the acceleration time of pulmonary flow on echocardiography. No correlation was found between PAP and any of the exercise measurements, and the conclusion was that patients with advanced COPD and mild to moderate PH are essentially limited by
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226 Table 3 Cardiopulmonary exercise tests variable in the two patient groups, COPD no PH group and COPD with mild PH
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CPET parameters
COPD
P value
Limits of normal
Saturation rest
96.3 ± 1.1
95.2 ± 2.2
0.05
Saturation peak
92.9 ± 3.3
90.6 ± 4.6
0.08
95–100
Work rate (W)
35.7 ± 19.0
40.4 ± 20.4
0.46
129–241 23–32
VO2 peak VO2 (mL/min)
38.9 ± 11.2
0.27
646.1 ± 267.6
34.9 ± 11.2
640.1 ± 308
0.94
35.4 ± 10.9
39.4 ± 11
0.26
VO2 (mL/kg/min %) VO2 (mL/kg/min)
9.5 ± 2.9
9.3 ± 2.3
0.81
VE (L/m)
26.0 ± 6.4
27.9 ± 13.1
0.55
MVV (L/m)
24.0 ± 6.6
24.0 ± 6.6
0.7
3.5 ± 3.9
5.4 ± 7.9
0.35
Vd/Vt (%) rest
43.5 ± 13.7
43.1 ± 5.2
0.91
Vd/Vt (%)
40.1 ± 11.1
39.0 ± 4.9
0.96
VE/VO2 rest (L/min)
53.9 ± 9.4
48.9 ± 14.3
0.26
VE/VO2 (L/min)
42.6 ± 13.9
37.3 ± 8.8
0.16
VE/VCO2 rest (L/min) VE/VCO2 (L/min)
56.1 ± 9.1 44.1 ± 7.8
49.5 ± 8.8 37.6 ± 7.3
0.04 0.01
Breathing reserve
MVV maximal voluntary ventilation, VO2 oxygen uptake, VE ventilation, VCO2 carbon dioxide output, HR heart rate, Vd/Vt the ratio of physiologic dead space over tidal volume, VE/VO2 the ventilatory equivalent ratio for oxygen, VE/ VCO2 the ventilatory equivalent ratio for carbon dioxide, VO2/ HR oxygen pulse- oxygen uptake per heartbeat
COPD–PH
HR rest HR exercise
89.7 ± 12.9
102.2 ± 14.9
0.007
110.5 ± 12.9
123.8 ± 16.3
0.007
68.6 ± 8.9
75.9 ± 9.8
0.02
5.7 ± 2.3
0.75
51.8 ± 15.9
0.44
HR (%) VO2/HR (mL/min) VO2/HR (%)
5.5 ± 2.1 47.815 ± 4
70–108 38
33–35
150–178
Fig. 1 Individual values of CPET characteristics in the two patient groups, COPD no PH group and COPD with mild PH. No significant difference in work rate (a), peak VO2 per kilogram body weight (b), breathing reserve (c), and maximal O2-pulse (d) was observed between both groups
exhaustion of the ventilatory reserve. Furthermore, Boerrigter et al. [9] evaluated forty-seven patients, COPD patients by underwent CPET and RHC at rest and during
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exercise. Patients were divided into three groups based on mPAP at rest: no PH (mPAP \25 mmHg), moderate PH (39 C mPAP C 25 mmHg), and severe PH
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Fig. 2 Plots of correlations between mPAP and exercise parameters in the two patient groups, COPD no PH group and COPD with mild PH. Work rate (a), breathing reserve (b), maximal O2-pulse (c), and peak VO2 per kilogram body weight (d)
(mPAP C40 mmHg). The authors found that patients with severe PH demonstrated an exhausted circulatory reserve at the end of exercise, whereas a profile of circulatory reserve in combination with ventilatory impairments was found in patients with COPD and moderate or no PH. These contradictory findings led us to study whether mild PH at rest, defined by RHC, contributes to exercise limitation in patients with advanced emphysema, candidates for lung transplantation. Our patient population demonstrated mark reduction in maximum workload and peak VO2 together with extremely low breathing reserve, with no correlation between mPAP and any of the exercise measurements. It is considered that in normal subjects the ventilator reserve is normally amounts to an average of 38 L/min, whereas a value of \11 L/min is strongly indicates ventilatory limitation [22]. In the present study, both groups of emphysema patients with mild PH or no PH had reduced MVV as well as severely low breathing reserve (24.0 ± 6.6 and 3.5 ± 3.9, and 24.0 ± 6.6 and 5.4 ± 7.9,
respectively), suggesting that exercise capacity was limited due to ventilatory impairment not only in the advanced emphysema with no PH patients but also in those with mild PH. Furthermore, significant hyperinflation and air trapping at rest have been found in both patient groups with and without PH. It is possible that substantial air trapping, dynamic hyperinflation, and possibly skeletal muscle dysfunction all played a major role limiting exercise capacity and reduced maximum workload (40.4 ± 20 and 35.7 ± 19.0, respectively). In patients with pulmonary vascular disease, we will expect to find on CPET a reduced peak VO2, reduced anaerobic threshold, increased ventilator equivalent for CO2 but with normal breathing reserve, and low O2 pulse with impaired chronotropic response [23]. Interestingly, none of these indexes were found to characterize the group of patients with advanced emphysema and mild PH. The increased ventilatory equivalent for CO2 which was found in both patient groups in concert with reduced breathing
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228
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reserve support ventilatory impairment as the major limiting factor for exercise capacity. Only HR at rest and at the end of exercise was significantly increased in the mild PH group (89.7 ± 12.9, 102.2 ± 14.9 and 102.2 ± 14.9, 123.8 ± 16.3, respectively). The O2 pulse was markedly reduced in both patient groups imply a limitation in stroke volume increased during exercise. Previous studies on the effects of exercise and the subsequent rise in pulmonary artery pressure on cardiac function have shown that right ventricular end-diastolic volume increases and right ventricular ejection fraction fails to augment during exercise in most COPD patients [21, 24–27]. Moreover, a previous study reported that 3 months of vasodilator therapy with sildenafil, failed to neither reduce PVR and improved stroke volume nor exercise capacity [28]. It seems that hyperinflation at rest and dynamic hyperinflation may exert an important detrimental effect on cardiac function, manifested as low O2 pulse, and play a role in the reduced exercise performance of patients with severe COPD [29–32]. Dynamic hyperinflation may impair cardiac function either by decreasing blood returns to the right heart or by increasing the afterload to the left ventricle due to increase intrathoracic pressure swings. The effects of dynamic hyperinflation on cardiac patients support the notion that in patients with advanced COPD and mild PH, ventilatory impairment is the main limiting factor on exercise, and the low oxygen pulse is not the results of diseased pulmonary circulation [32]. A small sample of patients is an important limitation of our study; however, our results confirm the results of Boerrigter et al. on the effect of mild PH on exercise capacity. In summary, exercise capacity in patients with advanced emphysema, candidate for lung transplantation, and mild PH is essentially limited by a decreased ventilatory reserved. Therefore, it seems that specific pulmonary vasodilators would not improve exercise capacity in this patient population.
Conflict of interest of interest.
The authors declare that they have no conflict
Ethical standard This study complies with the current laws of Israel and was approved by the institutional IRB.
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