INTRODUCTION

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Keywords: pulmonary emphysema; chronic obstructive pulmonary disease (COPD); lung volume reduction surgery; right ventricular function; thermodilution

Lung volume reduction surgery (LVRS) has shown promise in improving the functional capacity of selected patients with severe emphysema and markedly curtailed activities of daily living (1).

Reduced lung hyperinflation with increased expiratory flows and better neuromuscular coupling are quite probably among the physiologic effects involved in the clinical improvement with LVRS (4, 5). In addition, echocardiographic study has suggested an improvement in right ventricular systolic function at rest, possibly due to a reduction in pulmonary vascular resistance (Rpv) (4). On the other hand, increases in both Rpv (6) and pulmonary artery pressure (Ppa) (7), possibly due to excessive removal of the pulmonary vascular bed, have also been reported with LVRS, and may precipitate cor pulmonale despite the improvement in expiratory airflow. So far, there is still lack of knowledge about the physiologic effects of LVRS on right ventricular function.

In patients with emphysema, right ventricular function is often normal or nearly normal at rest, whereas during exercise, a reduced stroke volume may limit changes in cardiac output (CO), and the right ventricular ejection fraction (RVEF) may fail to increase physiologically (8). Although exercise-induced pulmonary hypertension may play a role in this, other mechanisms are thought to be involved, including a reduced venous return from the inferior vena cava due to a flattened diaphragm (9), and hampered diastolic filling of the atria and ventricles from the compressive effect of hyperinflated lungs on cardiac surfaces and vascular structures (10).

As a result, we have hypothesized that physiologic effects of LVRS on right ventricular performance stem primarily from relief of lung hyperinflation. We have reasoned that owing to reduced hyperinflation, venous return and right ventricular filling could improve with LVRS, possibly leading to an increase in stroke volume and RVEF. We have also believed that these effects should be maximized during upright exercise, when dynamic hyperinflation worsens and right ventricular dysfunction is more likely to develop (8, 11).

To help clarify the effects of LVRS on right ventricular function, we investigated changes in pulmonary hemodynamics and right ventricular function indexes through right heart catheterization and fast-thermistor-thermodilution (12, 13), done both on subjects at rest and during submaximal upright exercise, before and 6 mo after bilateral thoracoscopic LVRS.

	METHODS

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Twelve consecutive patients undergoing one-stage bilateral thoracoscopic LVRS between January 1999 and February 2001 were included in this study. The protocol was approved by the institutional review board of University Tor Vergata, and all patients provided written informed consent.

Selection criteria for LVRS have been described previously (3) and included a postbronchodilator FEV₁ of less than 40% predicted, an RV of more than 180% predicted, and heterogeneously distributed severe emphysema documented by high-resolution computed tomography (HRCT). No patient had giant bullae, clinically dominant bronchitis, bronchiectasis, asthma, or a systolic pulmonary artery pressure > 55 mm Hg.

All patients were former smokers and had quit smoking at least 4 mo before LVRS; no patient had homozygous 1-antitrypsin deficiency. Six patients were receiving long-term oxygen therapy, of whom three had only nocturnal oxygen therapy and the other three had oxygen therapy for 16 of 24 h. All patients were receiving optimal medical treatment with inhaled steroids and bronchodilators.

Physiologic assessment included timed spirometry, total body plethysmography for measurement of static thoracic gas volumes, single-breath diffusing capacity for carbon monoxide (DL_CO), and arterial blood gas analysis. Reference spirometric values were those of the European Respiratory Society (14). Exercise tolerance was assessed by means of the 6-min walk test (6MWT) with standardized encouragement and an oxygen supply adequately titrated to maintain Sa_O2 above 90%. A two-dimensional and Doppler transthoracic echocardiographic study was done preoperatively on each patient to exclude left ventricular dysfunction and right ventricular hypertrophy; in addition, tricuspid regurgitation was semiquantitated by color-coded flow mapping.

Radiologic assessment of the morphology of emphysema was done by means of digital chest radiography, HRCT, and magnetic resonance imaging. Severity and heterogeneity of emphysema were graded with a surgically-oriented visual scoring system that had been previously validated (15).

The LVRS operation done on the study subjects was aimed at reducing the volume of each lung by about 25%. Bilateral lung reduction was done in a single-stage procedure by means of sequential unilateral, video-assisted, thoracoscopic staple resection of functionless lung tissue. Reassessment of respiratory function indexes and exercise capacity was performed every 6 mo postoperatively.

For the purpose of the study, CO was measured by thermodilution at rest and during submaximal upright exercise at both 24 h before surgery and 6 mo postoperatively.

Exercise for the assessment of cardiopulmonary variables was done on a treadmill-ergometer system (Oxycon Delta S/N807389; Erich Jaeger, GmBH & Co., Höchberg, Germany; Treadmill RAM 770, CE Padova, Italy). To maintain submaximal steady-state aerobic exercise conditions, the workload was set at 25 W and the duration of exercise was 3 minutes. A fraction of inspired oxygen (FI_O2) sufficient to maintain adequate oxygenation (Sa_O2 > 90%) was estimated from walking oxygen saturations and was provided throughout the exercise period. Both the workload and the FI_O2 were the same for a given patient before and after lung volume reduction.

No patient had electrocardiographic evidence of arrhythmia or manifested clinical evidence of associated systemic hypertension, valvular heart disease, coronary artery disease, primary myocardial disease, or cor pulmonale. Administration of all cardiopulmonary drugs, including methylxanthines, ₂-receptor agonists, corticosteroids, and diuretics, was discontinued at least 48 h before heart catheterization.

Thermodilution Technique

A flow-directed, fast thermistor-tipped, volumetric pulmonary artery catheter (Baxter Healthcare Corp., Irvine, CA) was inserted in the pulmonary artery through the internal jugular vein. Signals from this catheter were analyzed through a thermodilution ejection fraction computer (REF-1; Baxter). CO was determined by computing the area under the thermodilution curve. After rapid injection into the right atrium of a 10-ml bolus of iced (< 10° C) saline solution, the rate of temperature decay between two successive right ventricular contractions was calculated and transformed into RVEF. Right ventricular stroke volume (RVSV) was computed as the ratio of CO to heart rate (HR). Right ventricular end-diastolic volume (RVEDV) and right ventricular end-systolic volume (RVESV) were computed from RVSV and RVEF measurements. The results obtained at each time point and used in the study represent the average of three clustered measurements with less than 10% variation. Patients were studied in the upright position and in an unsedated, postabsorptive state.

Mean pulmonary artery pressure (), pulmonary artery occlusion pressure (Ppao), and right atrial pressure (Pra) were measured with the pulmonary artery catheter, and systemic mean arterial pressure (MAP_mean) was measured by means of radial artery cannulation. Vascular pressures were determined at the end of exhalation, and were electrically averaged.

In addition, right ventricular stroke work (RVSW) was computed as (  Pra) × RVSV × 0.0136, where 0.0136 is the conversion factor from pressure to work. Rpv was computed as 80 × (  Ppao)/cardiac index (CI). CO, RVEDV, RVESV, RVSV, RVSW, and Rpv were indexed to the patient's body surface area.

Statistics

Group-descriptive statistics are presented as mean ± SD. Because of the small sample size and nonnormal distribution of data in the study, comparison of paired data was performed with Wilcoxon's rank sum test. The relationship among different variables was assessed with Spearman's rank correlation.

	RESULTS

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Pulmonary Function Testing

The patient cohort comprised 11 males and 1 female with an age of 62 ± 9.8 [mean ± SD] yr. Emphysema was prevalent in the upper lobes and was graded as heterogeneous in all patients (Table 1).

Preoperative characteristics are summarized in Table 2. Despite maximized medical therapy, all patients suffered from severe limitation of physical activity and a severe obstructive defect, with a postbronchodilator FEV₁ ranging between 15% and 41% predicted. Six patients had an FEV₁ of less than 20% predicted. TLC was only minimally increased, whereas RV was markedly increased, with 10 patients having an RV of more than 200% predicted. DL_CO was reduced in all patients, with three patients having a DL_CO of less than 20% predicted.

Doppler echocardiography showed no tricuspid regurgitation or only trivial regurgitation in six patients, mild tricuspid regurgitation in four patients, and moderate tricuspid regurgitation in two patients.

No patient died postoperatively or was lost during follow-up. Significant improvements occurred at 6 mo in most clinical parameters: FEV₁ had increased by 59%, to 1.08 ± 0.23 L, a change of 0.39 ± 0.14 L (p = 0.002), whereas RV had decreased by 35%, to 3.6 ± 0.58 L, a change of 1.82 ± 0.49 L (p = 0.002). The RV/TLC ratio had decreased, from 0.67 ± 0.03 to 0.52 ± 0.06 (p = 0.002); FVC improved by 24%, to 2.97 ± 0.38 L (p = 0.002); 6MWT improved by 37%, to 462 ± 81 m (p = 0.002), and arterial oxygen tension (Pa_O2) at rest increased by 5.7%, to 73.1 ± 7.4 mm Hg (p = 0.008). On the other hand, neither arterial carbon dioxide tension (1.4 mm Hg) nor DL_CO (+0.4 mmol · min¹ · kPa¹, or +5.4%) changed significantly from before to 6 mo after surgery.

Hemodynamic Measurements

No procedure-related complication was observed during right heart catheterization. Results of pre- and postoperative hemodynamic measurements are given in Table 3. Six patients had pulmonary hypertension at rest, with pressures ranging from 22 mm Hg to 30 mm Hg, whereas during exercise, all patients developed pulmonary hypertension, with pressures ranging from 26 mm Hg to 47 mm Hg. Similarly, Ppao increased dur- ing exercise in all patients, with values ranging from 13 mm Hg to 27 mm Hg. Rpv increased with exercise in seven patients. CI at rest was lower than 3.5 L in all but one patient, with seven patients having a CI of 2.5 L or less. Resting RVEF ranged from 20% to 43%, with nine patients having a value below 40%. Exercise resulted in a significant increase in HR, MAP, CI, Pra, , Ppao, and Rpv. Eight patients had an abnormal response of RVEF to exercise, not reaching the expected augmentation of at least 5% (16). Exercise RVEF was directly correlated with RVSV (R = 0.86, p = 0.0003), whereas it was inversely correlated with RVESV (R = 0.73, p = 0.0002), RVEDV (R = 0.67, p = 0.01), Ppa (R = 0.81, p = 0.001), and Ppao (R = 0.73, p = 0.006). Exercise also resulted in significant changes in RVEDV, RVESV, and RVSW, which increased by means of 19%, 21%, and 94%, respectively.

After LVRS, a significant increase occurred in both resting and exercise RVEDV CI, RVSV, and RVSW, whereas MAP increased significantly at rest but not with exercise. No significant change occurred in resting or exercise RVESV or , nor in resting Ppao. Exercise HR, Ppao, Pra, and Rpv decreased significantly after LVRS. RVEF remained unchanged at rest, but increased by 20% on exercise. Also, the exercise response of RVEF became normal in seven patients. Comparative responses to exercise before and after LVRS showed significant increases in RVSV, CI, RVSW, and RVEF, whereas Ppao decreased (Figures 1-3 and Table 4). There was no significant relationship between either RVSV or CI and RVEDV, nor between RVEF and RVEDV; a slight inverse relationship was found between RVEF and RVESV (R = 0.56, p = 0.05). In addition, RVSV and RVEF were significantly correlated with the RV/TLC ratio (R = 0.68, p = 0.01; R = 0.65, p = 0.02, respectively) (Figures 4 and 5).

View larger version (14K): [in this window] [in a new window]   Figure 1.   Exercise response of CI before versus after LVRS. Horizontal bars indicate mean value ± SD.

View larger version (15K): [in this window] [in a new window]   Figure 2.   Exercise response of RVSV before versus after LVRS. Horizontal bars indicate mean value ± SD.

View larger version (15K): [in this window] [in a new window]   Figure 3.   Exercise response of RVEF before versus after LVRS. Horizontal bars indicate the mean value ± SD.

View larger version (13K): [in this window] [in a new window]   Figure 4.   Relationship between exercise response of RVSV and changes in RV/TLC ratio before and after LVRS.

View larger version (13K): [in this window] [in a new window]   Figure 5.   Relationship between exercise response of RVEF and changes in RV/TLC ratio before and after LVRS.

During follow-up, no patient developed cardiac arrhythmia or right heart failure. No changes occurred from preoperative to 6-month postoperative hemoglobin concentration.

	DISCUSSION

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The main finding of our study was that 6 mo after bilateral thoracoscopic LVRS, RVSV, and CI increased significantly both at rest and during submaximal upright exercise. In addition, changes from rest to exercise in RVSV, CI, and RVEF increased significantly after LVRS. Moreover, changes in rest versus exercise RVSV and RVEF after LVRS correlated with the reduction in RV/TLC ratio, suggesting that reduced lung hyperinflation was a major determinant of the overall improvement in right ventricular performance. These changes occurred in conjunction with significant improvements in respiratory function indexes, walking distance, and resting Pa_O 2, confirming previous study data (1).

The postoperative increase in RVSV appeared to be related to the Frank-Starling mechanism, since a parallel increase in RVEDV and RVSW occurred as well. It is also worth noting that despite the increase in RVEDV, Pra decreased, probably reflecting a reduction in lung hyperinflation and mean intrathoracic pressure. Reduced intrathoracic pressure may have increased venous return and right ventricular filling. This effect can be attributed to different mechanisms acting alone or in combination, and including reconfiguration of the diaphragmatic dome with improvement in venous return from the inferior vena cava during inspiration, an increased pressure gradient for venous return, and reduced pressures around heart chambers and mediastinal structures, leading to improved right ventricular filling (17). On the other hand, decreased intrathoracic pressure could have also increased transmural wall stress across the left ventricle during systole, increasing left ventricular afterload and possibly reducing stroke volume. Moreover, an increase in RVEDV could have inhibited the filling of the opposite ventricle, through a leftward shift in the interventricular septum (18). The significant increase in RVSV that we observed after LVRS suggests, however, that relief from limitation on venous return and right ventricular filling predominated over interdependence effects limitating left ventricular filling. Also, increased intrathoracic pressure is thought to reduce left ventricular transmural pressure and to increase CO in subjects with congestive heart failure, whereas if cardiac function is normal, increased intrathoracic pressure is associated with a decrease in CO (19).

Burrows and associates (11) identified a "low-output pattern" group among patients with chronic obstructive pulmonary disease (COPD) consisting of subjects with a CI below 2.5 L/min/m² and a nearly normal resting Ppa. In addition, Even and associates (20) described a syndrome in patients with giant bullous or diffuse panlobular emphysema (i.e., emphysematous cardiac tamponade) characterized by dyspnea with severe limitation of exercise capacity, absence of cor pulmonale, reduced cardiac volume, a low CI at rest (2.4 L/min/ m²), absence of resting pulmonary hypertension, and wide diastolic swings of Ppa that were attributed to an increased intrathoracic expiratory pressure reducing venous return from the venae cavae. These changes could be partially reversed by surgical removal of the bullae. Furthermore, Hutsebaut and associates (21) found that in patients with emphysema, those with more severe hyperinflation and low diffusing capacity showed the lowest CO at rest and during exercise. Also, they found that a low CO was slightly related to smaller cardiac size, which may suggest reduced ventricular filling due to compression in the cardiac fossa from hyperinflated lungs.

All of the patients in our series had a resting CI of less than 3.5 L, whereas seven patients had a CI of 2.5 L or less. The increase in CI that we observed after LVRS is similar to that observed by Kubo and associates (22) who, however, did not investigate changes in indexes of right ventricular function. Several mechanisms have been indicated as possibly increasing CO after LVRS, including increased venous return, capillary recruitment as a result of the improved pulmonary mechanics in the lung zones previously subjected to compression by hyperinflated alveoli, and tethering of extraalveolar vessels from improved elastic recoil of the lung. We hypothesize that in emphysematous patients, changes in CO are governed by a mechanism similar to that acting in patients ventilated with intermittent positive pressure. Indeed, in both circumstances, regional pressures around the heart may become positive due to increased end-expiratory pressure, impeding venous return as the lungs distend. Gas trapping and lung distension may cause an increase in Pra, reducing venous return, RVEDV, RVSV, and CI. These changes are maximized by rapid respiration during exercise, but may already be present at rest in severely hyperinflated patients. In accordance with this hypothesis, Tschernko and colleagues (23), have found that dynamic intrinsic positive end-expiratory pressure, reflecting increased intrathoracic pressure, was elevated not only during exercise but also at rest before LVRS, whereas it was markedly reduced 3 mo after the operation. The hemodynamic effects of increased end-expiratory pressure are not negligible, and have even been suggested as a cause of cardiovascular collapse in COPD patients (24).

In our series, Rpv during exercise was slightly reduced after LVRS, whereas Ppa did not change. This result agrees with the findings of other investigators (22, 25) but contrasts with those of Weg and colleagues (7), who reported the development of pulmonary hypertension at rest in patients undergoing bilateral LVRS.

A possible explanation for these discrepant findings may relate to differences in the different studies' inclusion criteria. In our series, there was no patient with homogeneous emphysema in whom LVRS might have led to removal of a considerable portion of the pulmonary vascular bed, thus increasing Rpv. On the other hand, better mechanical properties of the respiratory system, with less hyperinflation and improvement of lung elastic recoil, may counterbalance these detrimental effects on right ventricular afterload. Also, smaller variations in intrathoracic pressure could induce less functional compression of the pulmonary vascular bed, especially during exercise (26, 27). In fact, large swings in intrathoracic pressure are generated in emphysematous patients to overcome the effects of the loss of lung elastic recoil. These pressure swings, caused by increased airway resistances, may partly explain pulmonary hypertension in patients with COPD (28) who show an increase in Rpv during expiration but no corresponding decrease during inspiration, as a result of failure of the pulmonary resistance vessels to distend with an increasing transmural pressure during inspiration (25).

In addition, large respiratory swings in the pulmonary artery diastolic pressure, reflecting increased intrathoracic pressure, may contribute in augmenting right ventricular afterload and reducing resting CO despite the remaining normal (28). In accordance with this hypothesis, Oswald-Mammoser and colleagues (25) found that Ppa did not change after LVRS, whereas respiratory swings in the pulmonary artery diastolic pressure decreased significantly both at rest and during exercise.

An increased Ppao in COPD may be due to local hypoxia and left ventricular dysfunction (29), although in emphysematous patients it has been attributed to lung hyperinflation leading to an increase in juxtacardiac or intrathoracic pressure (10). The marked reduction in exercise Ppao observed in our patients confirms the results of other investigators (6, 22), and may relate to a decrease in dynamic hyperinflation that may have limited the exercise-induced increase in . On the other hand, the higher CI observed in our patients may have been the reason why Ppa did not also decrease after surgery.

The only study investigating changes in RVEF after LVRS was that of Keller and coworkers (30), who observed that immediately after extubation, resting RVEF increased from 28% to 37% and CI rose from 2.1 L to 3.5 L, whereas Pra, , and Rpv decreased. Furthermore, Sciurba and colleagues (4) found by echocardiographic study that changes in fractional area of the right ventricle increased significantly at rest after LVRS, suggesting improved systolic function. Unfortunately, none of these studies provided data on changes in right ventricular function during exercise. Preoperatively, in our series, RVEF failed to increase during exercise. This pathologic behavior suggests a latent right ventricular dysfunction, and has already been reported in patients with COPD (31, 32) and in candidates for double lung transplantation (33). Several mechanisms may underlie such a paradoxical response. Although resting RVEF depends on right ventricular afterload, multiple physiologic variables may affect RVEF during exercise, including venous return, HR, inotropic state, catecholamine release, and right ventricular afterload (8). We believe that the postoperative increase in exercise RVEF observed in our patients was mainly due to an increased preload (i.e. end-diastolic volume) rather than to a reduced afterload, since mean RVESV did not change in our series, and the change in Rpv, though significant, was small. A further possibility is that better oxygenation improved contractility, although we did not find any significant relationship between improvements in Pa_O2 and indexes of right ventricular function.

The finding that the increase in exercise RVEF after LVRS was paralleled by an increase in RVEDV is quite surprising, since RVEF is usually inversely related to RVEDV. However, it is worth noting that Mahler and associates (8) found that in COPD patients, exercise-induced increases in RVEF (from 45% to 49%) were accompanied by a significant increase in RVEDV but no changes in RVESV. Whatever the mechanism involved, the significant relationship we found between postoperative exercise-related changes in RVSV and RVEF, and changes in the RV/TLC ratio suggest that a reduction in lung hyperinflation was a major determinant of the overall improvement in right ventricular performance.

We acknowledge some limitations of our study. First, we did not measure intrapleural pressures, which affect cardiac surface pressure and Rpv. In fact, although the validity of the standard method (i.e., esophageal balloon) is questionable, since the measured pressures may not be representative of the surface pressures (i.e., epicardial surface pressure) (34), the availability of these data could have allowed a more precise assessment of mechanical heart-lung interactions during the respiratory cycle. Second, we did not assess changes in left ventricular function that might have been affected both by the postoperative increase in RVEDV, owing to ventricular interdependence, and by direct effects of changes in intrathoracic pressures on the left heart chambers (35). Additionally, it must be reminded that with the standard thermodilution method, RVEDV and RVEF may sometimes be under- or overestimated in individual patients, owing to ventilatory cycle-induced variations in right ventricular volumes (36).

In conclusion, we demonstrated that significant changes in indexes of right ventricular function occurred 6 mo after LVRS. These changes are consistent with an improved performance of the right ventricle, as indicated by significant increases in resting and exercise RVSV and CI, as well as by exercise RVEF. The significant relationship found between improvement in the exercise response of RVEF and the reduction in the RV/TLC ratio suggests that reduced lung hyperinflation exerts beneficial effects on right ventricular filling and performance.

Further studies of long-term changes in right and left ventricular function are warranted for evaluating our findings and providing further insights into the cardiovascular effects of LVRS.