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Flow Limitation and Dynamic Hyperinflation During Exercise in COPD Patients After Single Lung Transplantation^*

^* From the INSERM U408 (Drs. Murciano, Ferretti, Boczkowski, Sleiman, and Fournier), Service de Pneumologie, Hopital Beaujon, Clichy, France; and Meakins-Christie Laboratories (Dr. Milic-Emili), McGill University, Montreal, Canada.

Correspondence to: Daniele Murciano, MD, Service de Pneumologie, Hopital Beaujon, 100 boulevard du Général Leclerc, 92118 Clichy Cedex, France; e-mail: daniele.murciano{at}bjn.ap-hop-paris.fr

	Abstract

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Study objective: Using the negative expiratory pressure (NEP) method, we have previously shown that patients receiving single lung transplantation (SLT) for COPD do not exhibit expiratory flow limitation and have little dyspnea at rest. In the present study, we assessed whether SLT patients exhibit flow limitation, overall hyperinflation, and dyspnea during exercise.

Methods: Expiratory flow limitation assessed by the NEP method and inspiratory capacity maneuvers used to determine end-expiratory lung volume (EELV) and end-inspiratory lung volume (EILV) were performed at rest and during symptom-limited incremental cycle exercise in eight SLT patients.

Results: At the time of the study, the mean (± SD) FEV₁, FVC, functional residual capacity, and total lung capacity (TLC) amounted to 55 ± 14%, 67 ± 12%, 137 ± 16%, and 110 ± 11% of predicted, respectively. At rest, all patients did not experience expiratory flow limitation and were without dyspnea. At peak exercise, the maximal mechanical power output and maximal oxygen consumption amounted to 72 ± 20% and 65 ± 8% of predicted, respectively, with a maximal dyspnea Borg score of 6 ± 3. All but one patient exhibited flow limitation and dynamic hyperinflation; the EELV and EILV amounted to 74 ± 5% and 95 ± 9% TLC, respectively. The patient who did not exhibit flow limitation during exercise had the lowest dyspnea score.

Conclusion: Most SLT patients for COPD exhibit expiratory flow limitation and dynamic hyperinflation during exercise, whereas maximal dyspnea is variable.

Key Words: exercise tolerance • expiratory flow limitation • hyperinflation

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The highest pulmonary ventilation is ultimately limited by the highest flow rates that a subject can generate. In general, normal subjects do not exhibit expiratory flow limitation even during maximal exercise.^{1 2} In contrast, patients with COPD often exhibit expiratory flow limitation even at rest,^{2 3} as first suggested by Hyatt.⁴ Expiratory flow limitation (FL) during tidal breathing promotes dynamic hyperinflation and intrinsic positive end-expiratory pressure, with a concomitant increase in inspiratory work, impairment of inspiratory muscle function, and adverse effects on hemodynamics.⁵ This may contribute to dyspnea and reduced exercise performance.^{2 3 6}

Single lung transplantation (SLT) is used to treat severe COPD, and its role is to increase the patient’s ventilatory capacity. Using the conventional approach for detecting expiratory FL based on superimposition of tidal and maximal flow-volume curves, Martinez et al⁷ showed that after SLT, three of seven COPD patients at rest breathed tidally along their maximal expiratory flow-volume curves. Using the same approach, Murciano et al⁸ found similar results in 9 of 13 COPD patients after SLT. However, using the negative expiratory pressure (NEP) method, tidal expiratory FL was observed in only one of their patients. This discrepancy was attributed to the fact that the conventional method for assessing FL is not valid even if measurements of volume are performed using a body plethysmograph.⁸ In the present study using the NEP method, we have assessed whether SLT patients become FL and hyperinflated during exercise, and to what extent exertional dyspnea limits exercise performance.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Patients
We studied eight COPD patients (five men and three women), whose mean (± SD) age, weight, and height were 58 ± 7 years (range, 48 to 71 years), 62 ± 13 kg (range, 51 to 87 kg), and 169 ± 9 cm (range, 159 to 180 cm), respectively. They underwent SLT 26 to 79 months before the study because of severe COPD caused by panacinar emphysema. The anthropometric characteristics, the side on which SLT was performed, and the time elapsed after SLT are listed in Table 1 . The lung function data before and after SLT are given in Table 2 . At the time of the study, all patients were in a stable clinical and functional state. All patients had substantial improvement of lung function after SLT. Lung function data were obtained with a pressure-flow body plethysmograph (Pulmed 3303; Hyco-Aulas S.A.; Ecully, France). Lung volumes were expressed as percent of normal predicted values according to the European Coal and Steel Community.⁹ Maximal voluntary ventilation (MVV) was predicted according to Dillard and coworkers¹⁰ according to the following formula:

The study was approved by the local ethics committee, and all subjects gave informed consent.

Exercise Tests
A first exercise test was performed on an electronically braked bicycle ergometer (Ergoline 950; Ergometriesystem; Truchtelfingerstz Elitz, Germany) connected to an automated exercise system (model 2900; Medical Graphics; Minneapolis, MN). After 2 min of steady-state resting breathing, subjects completed a progressive exercise test in which cycling began at a work rate of 20 W during 2 min of cycling, and thereafter the load was increased by 25 W every 2 min until exhaustion. Subjects cycled at a rate of 50 to 70 revolutions/min and were encouraged to exercise to the limit of their tolerance. In all cases, exercise tests were terminated at the point of symptom limitation (peak exercise). During the first exercise test, the maximal mechanical power output (max), maximal oxygen consumption (O₂max), maximal minute ventilation (Emax), and the corresponding exertional dyspnea score (Borg scale) were determined (Table 3 ). The former variables were compared with predicted normal values of Jones and Campbell.¹³

where pressure is in centimeters of water and flow is in liters per second. The pressure, volume, and flow signals were amplified (AC Bridge amplifier-ACB module; Raytech Instruments), low-pass filtered at 50 Hz, and digitized at 100 Hz by a 16-bit analog-to-digital converter (Direc Physiologic Recording System; Raytech Instruments). The digitized data were stored on the computer hard disk for subsequent analysis. Data analysis was performed using ANADAT software (version 5.1; RHT-InfoDat; Montreal, Canada).

During the test, patients breathed room air through the equipment assembly while wearing nose clips. At-rest measurements were made with subjects seated on the bicycle ergometer in the same position as during exercise. Each subject had an initial 5-min trial to become accustomed to the apparatus and procedure. The time course of airway opening pressure, flow, and volume, together with the corresponding flow-volume loops, was continuously monitored on the computer screen. After regular breathing had been achieved, a series of three to five test breaths was performed in which NEP (-3 cm H₂O) was applied during early expiration and maintained throughout the ensuing expiration. Then the subjects were asked to perform two inspiratory capacity (IC) maneuvers at intervals of approximately 20 s. Subsequently, at each level of exercise, the NEP tests and IC maneuvers were repeated in a manner similar to that during resting breathing. At each exercise level, it was assumed that total lung capacity (TLC) was reached with the highest IC, and this IC was used to determine the end-expiratory lung volume (EELV) (EELV = TLC - IC) and the end-inspiratory lung volume (EILV) (EILV = EELV + tidal volume [VT]).^{2 12} Before exercise testing, the IC maneuvers were explained and then practiced by the patients until consistently reproducible values were obtained.

Analysis of data obtained with NEP consisted of comparing the expiratory flow-volume curve of a control tidal expiration with that obtained during the subsequent expiration in which NEP was applied. Subjects in whom application of NEP did not elicit an increase of flow over part or all the control tidal expiration were considered FL, whereas subjects in whom flow increased with NEP over the entire range of the control tidal expiration were considered not flow limited (NFL). Figure 1 illustrates the flow-volume loops obtained with NEP together with the preceding control loop in patient 6 at rest and at three increasing levels of exercise. At rest, the subject was NFL because flow increased above control throughout expiration with NEP. At a work rate of 20 W, expiratory flow increased with NEP up to 47% of the control VT but not thereafter. In this case, FL encompassed 47% of control VT. At work rates of 45 W and 70 W, FL encompassed essentially the entire control VT (FL > 80% VT).

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Flow-volume loops of NEP test breaths and preceding control breaths of patient 6 at rest and three different levels of external power output (). Zero volume represents TLC. The FRC at rest is indicated. Top left, A: NFL inasmuch as with NEP, flow exceeds control flow throughout expiration. Top right, B: FL encompasses the last 47% of the control VT because at higher volume, flow increased with NEP (FL = 47% VT). Bottom left, C, and bottom right, D: FL is 84% VT and 81% VT, respectively. Arrows indicate onset and removal of NEP. The onset of FL is indicated by the vertical broken lines. The degree of dyspnea (Borg score) is indicated.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Relationships of dyspnea (Borg score) to external power () of eight SLT subjects. Open circles = NFL; half-filled circles indicate FL of 50% VT; filled circles indicate FL > 50% VT.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Subdivisions of lung volume, expressed as percentage of TLC, at different levels of external power () of eight SLT subjects. IRV = inspiratory reserve volume. Values are mean ± SD (bars). *Significant (p < 0.05) change from rest.

	Results

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Rest
In agreement with previous results,^{7 8} lung function data were significantly improved for the eight COPD patients after SLT (Table 2) . However, the FEV₁, FVC, and IC of the SLT patients remained significantly lower than predicted normal, whereas functional residual capacity (FRC) and residual volume were higher (Table 2) . In line with previous results obtained with the NEP method,⁸ none of the SLT patients were FL during resting breathing.

Exercise
In all patients, max and O₂max were below the predicted values (Table 3) . There was a significant correlation of FEV₁ to max (r = 0.91; p < 0.005) and to O₂max (r = 0.78; p < 0.05).

Except for subject 2, the patients terminated exercise with substantial breathlessness; the Borg dyspnea scores ranged from 4 (somewhat severe) to 10 (maximal). Patient 2, who stopped exercise because of leg fatigue, exhibited the lowest level of exertional dyspnea at peak exercise, Borg score 2 (slight).

Although at rest all eight of the SLT patients were NFL, seven of them became FL at exercise levels ranging from 20 to 95 W (Fig 2) . Although subject 2 was NFL over the entire range of work rates studied, his max amounted to only 56% of predicted. At max, his Borg dyspnea score was the lowest of the group (score 2; Table 3 ), and his max was limited by leg fatigue. In contrast, in four of the patients who became FL during exercise (patients 1, 4, 6, and 7), max was limited by severe dyspnea, with Borg scores during peak exercise ranging from 7 to 10 (Fig 2) . In the other three patients who became FL during exercise (patients 3, 5, and 8), it may be argued that max was probably limited by a combination of dyspnea and leg fatigue.

The increase of VT during peak exercise was associated with a decrease in IC in all patients (Table 4) . Because TLC does not change appreciably during exercise,^{12 14} the decrease in IC reflects increased EELV. As shown in Figure 3 , both EELV and EILV increased progressively with increasing exercise load. At peak exercise, the EILV amounted to 95 ± 9% TLC (range, 91 to 100%), whereas EELV was 74 ± 5% TLC (Table 4) .

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The resting lung function of our SLT patients for COPD was similar to that in previous studies.^{7 8} In line with previous results obtained with the NEP method,⁸ we found that at rest all SLT patients were NFL. Nevertheless, their FRC was substantially higher than predicted (Table 2) . This probably reflects the presence of expiratory FL and concomitant dynamic hyperinflation in the native lung, leading to an increase in overall FRC.⁷ In spite of this, none of our SLT patients complained of dyspnea at rest (Fig 2) . During exercise, however, seven of our patients become FL and complained of dyspnea of progressively increasing severity, in agreement with previous results.⁷ The fact that most of our patients exhibited FL during exercise is not surprising, because (1) ventilation had to be sustained essentially by the transplanted lung and hence the maximal expiratory flows were necessarily reduced; (2) the transplanted lung may not be normal as a result of stenosis at the level of the anastomosis, obliterative bronchiolitis, airway hyperresponsiveness, etc.; and (3) the markedly hyperinflated native lung causes a displacement of the mediastinum toward the transplanted lung and concomitant decrease in its volume, promoting expiratory FL in the grafted lung. In this connection, it should be noted that patients with double lung transplantation for COPD do not exhibit FL during exercise whereas SLT patients do.⁷ We have no direct evidence of whether FL during exercise was the normal response of SLT recipients or was related to dysfunction of the graft. None of our patients had evidence of bronchiolitis obliterans syndrome after SLT. However, the fact that during exercise virtually all of our subjects developed FL suggests that it is a normal response. Further studies based on methods such as CT scans are needed to answer this question.

Although most of our SLT patients exhibited FL and dynamic hyperinflation during exercise, this was associated with high Borg ratings (scores 7 to 10) in only four patients. Thus, only in these four patients did exertional dyspnea play a paramount role in limiting exercise capacity. In the other four patients in whom exertional dyspnea ranged from 2 to 4, the exercise capacity was limited by other factors (eg, peripheral muscle weakness and deconditioning).^{15 16 17} In fact, patient 2, who remained NFL at all exercise levels and had a Borg rating of 2 at peak exercise, had a max of only 56% of predicted. Inasmuch as in this patient the exercise capacity was limited by leg fatigue, it is possible that his Emax was not high enough to elicit FL. Conversely, it may be that he actively increased the EELV to augment the expiratory flow while avoiding FL. Such a breathing strategy has been observed in asthmatic patients by Pellegrino et al.¹⁸ It should be noted, however, that during exercise, dynamic pulmonary hyperinflation may occur with increased expiratory resistance in spite of the absence of FL.⁵

Our assessment of EILV and EELV was made on the assumption that TLC was reached with the highest IC at each level of exercise, an approach widely used in both normal subjects and COPD patients.^{2 7 12 14 19} Nevertheless, it is possible that TLC was not reached in all instances. However, our results in Figure 3 were essentially the same as those found in SLT patients for COPD by Martinez et al,⁷ using the same procedure of the present study. In their study, the increase in EELV from rest to peak exercise averaged 6% of TLC, whereas in the present study, it amounted to 7% of TLC. The changes in EELV during exercise depend on the balance of the changes in EELV of the native lung and those of the transplanted lung. The native (high time constant) lung, which was probably FL already at rest,^{3 7} presumably became severely hyperinflated at relatively low levels of exercise. Furthermore, during exercise, its contribution to the overall ventilation was probably very small.^{8 7} Because ventilation was mainly sustained by the transplanted lung, this also became FL in seven patients, at exercise levels ranging from 20 to 70 W. As a result, during exercise, the seven patients exhibited overall expiratory FL, as detected by NEP. The expiratory FL was associated with increasing Borg dyspnea ratings (Fig 2) .

Although in most of our patients FL at peak exercise encompassed most of the VT (FL > 50% VT), Emax expressed as percentage of predicted MVV amounted to only 59 ± 11% (range, 46 to 80%). It should be stressed, however, that Babb and coworkers¹⁹ have concluded that the MVV predicted from FEV₁ is not the most appropriate variable for determining whether ventilatory limitation is responsible for the reduced exercise capacity. In this connection, it should be noted that in our SLT patients, we found no significant correlation of Emax to FEV₁ (r = 0.29; p = 0.48).

Martinez and coworkers⁷ assessed expiratory FL by comparison of tidal with maximal flow-volume curves in seven SLT patients: three of them were FL already at rest, whereas four of seven were FL during exercise on a cycle ergometer. In contrast, we found that none of our eight SLT patients were FL at rest whereas all but one became FL during exercise. This discrepancy can be attributed in part to the fact that Martinez and coworkers⁷ used expiratory gas volume for determination of the patients’ flow-volume curves, although Ingram and Schilder²⁰ have pointed out that, as a result of thoracic gas compression during the FVC maneuver, the flow-volume curves should be measured with a body plethysmograph. Apart from the latter requirement, however, there are additional factors that make assessment of FL based on comparison of tidal and maximal flow-volume curves problematic.^{21 22 23}

In conclusion, we found that although SLT patients for COPD are not FL at rest, most of them become FL during exercise. Expiratory FL with concomitant dynamic hyperinflation leads to increased inspiratory work and impaired inspiratory muscle function, which probably contribute to exertional dyspnea. However, whereas some SLT patients claim high levels of dyspnea during peak exercise and hence dyspnea is paramount in limiting exercise capacity, in others the reduced exercise tolerance is caused by other mechanisms (eg, peripheral muscle weakness and deconditioning).

	Footnotes

 
Abbreviations: EELV = end-expiratory lung volume; EILV = end-inspiratory lung volume; FL = flow limited, flow limitation; FRC = functional residual capacity; IC = inspiratory capacity; MVV = maximal voluntary ventilation; NEP = negative expiratory pressure; NFL = not flow limited; SLT = single lung transplantation; TLC = total lung capacity; Emax = maximal minute ventilation; O₂max = maximal oxygen consumption; VT = tidal volume; max = maximal mechanical power output

Received for publication September 20, 1999. Accepted for publication May 2, 2000.

	References

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