INTRODUCTION

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In acute exacerbation of chronic airway obstruction, the increase in FRC or hyperinflation plays a central role in causing ventilatory failure (1). The mechanisms of hyperinflation are complex, and may result both from changes in the mechanical properties of the respiratory system and in the control of breathing. In this context, however, expiratory flow limitation (i.e., inability to further increase flow over the prevailing tidal volume [VT] range by increasing transpulmonary pressure at a given lung volume) plays a paramount role (1, 4). During resting breathing in the sitting or supine position in patients with chronic obstructive pulmonary disease (COPD), there is a high prevalence of tidal expiratory flow limitation even if the subjects are in a stable clinical and functional state and the degree of airway obstruction, as assessed in terms of FEV₁ (% predicted), is only mild to moderate (5, 6). In the studies in which this was found, the detection of expiratory flow limitation was based on the negative-expiratory-pressure (NEP) technique, which provides more reliable results than the conventional method for measuring flow limitation, based on comparison of tidal with maximal flow-volume (-V) curves (5). The NEP technique has been previously validated by concomitant determination of isovolume flow-pressure relationships (4).

In the present investigation, we used the NEP technique in 13 patients with stable asthma before and after salbutamol administration, in order to assess: (1) the prevalence of expiratory flow limitation during resting breathing in both the seated and supine positions; and (2) whether the limitation can be reversed with a bronchodilator. In addition, we compared these data with those obtained by comparison of tidal and maximal -V curves measured in a body plethysmograph, which was used to avoid errors in thoracic gas compression (7).

	METHODS

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Patients

We studied 13 asthmatic patients (seven males and six females) whose mean (± SD) age, height, and weight were 45 ± 16 yr (range: 18 to 65 yr), 165 ± 8 cm (range: 153 to 177 cm), and 67 ± 10 kg (range: 49 to 78 kg), respectively. All patients presented a typical history of bronchial asthma according to the criteria of the American Thoracic Society (ATS) (8). The patients' anthropometric characteristics and duration of their asthma are listed in Table 1. At the time of the study, all the patients were in a stable clinical and functional state. All had refrained from use of inhaled bronchodilators for at least 6 h prior to the study. The lung-function data, together with the maximal and resting -V curves, were collected with the patient in the sitting position with a pressure/flow body plethysmograph (Pulmed 3303; Hyco-Aulas S.A., Ecully, France). The study was approved by the local ethics committee, and all subjects gave informed consent.

NEP Method for Detecting Expiratory Flow Limitation

"Flow limitation" is a term often used to indicate that in a given patient, the flows during the FVC maneuver are reduced below the predicted normal values. In the present study, the term "flow limitation" is used to indicate that the expiratory flow rates achieved during the entire tidal expiration or part of it are the maximal achievable rates under the prevailing conditions (5, 6).

Figure 1 depicts the experimental setup used in the present study to detect expiratory flow limitation with NEP. A flanged mouthpiece was connected in series with a Fleisch No. 2 pneumotachograph (Fleisch, Lausanne, Switzerland) and a Venturi device capable of generating a negative pressure during expiration (Aeromech Devices Ltd., Almonte, Ontario, Canada). One end of the device was open to the atmosphere and the other was connected to the cone of the pneumotachograph. Rigid tubing (I.D. = 8 mm) was used to connect a side port on the Venturi device, via an electrically operated solenoid valve, to a source of compressed air. A pressure regulator was used to obtain a preset level of NEP at the airway opening (about 3 cm H₂O). The solenoid valve (Ascott electrical valve Model 8262G2; Ascoletric Ltd., Toronto, Ontario, Canada), which was controlled by a computer (Direc Physiologic Recording System; Raytech Instruments, Vancouver, Canada), has an opening time of 29 ms. The solenoid valve was activated when the expiratory flow reached a preset threshold value (30 ml/s in the present study), and could be kept open for any desired time. With this threshold, the overall time required to trigger the valve and reach the preset level of NEP (T_NEP) was about 100 ms from the onset of expiration. However, T_NEP could be prolonged by introducing a computer-controlled delay time between the time when the flow reached the preset threshold and the triggering of the valve. Airflow () was measured with the heated pneumotachograph connected to a differential pressure transducer (Validyne MP45, ± 2 cm H₂O; Validyne Corp., Northridge, CA). The pneumotachograph was linear over the experimental range of flow. Artifacts on the flow record due to the common-mode rejection ratio (CMRR) were negligible (9). Volume was obtained by numerical integration of the flow signal. Pressure at the airway opening (Pao) was measured through a side port on the mouthpiece, using a differential pressure transducer (Validyne MP45, ± 100 cm H₂O). The pressure transducer was calibrated before and after each study with a water manometer. The breathing assembly has a dead space of 50 ml, and its pressure-flow relationship was characterized by the following equation: P = 0.45 + 0.02² (R² = 0.996), where pressure is in cm H₂O and flow in L · s¹. 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 analogue-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 done with ANADAT software (version 5.1; RHT-InfoDat Inc., Montreal, Canada). During the study, the time course of flow, volume, and pressure were continuously monitored on the screen of the computer, together with the corresponding flow-volume curves.

View larger version (19K): [in this window] [in a new window]   Figure 1.   Schematic diagram of equipment setup. Pao = pressure at airway opening; = flow.

In all patients, the severity of chronic dyspnea was rated according to the modified Canadian Medical Research Council (MRC) scale shown in Table 2 (6, 10).

Procedure and Data Analysis

Subjects were studied in random order while seated upright in a comfortable chair or lying supine on a comfortable couch. They were asked to breathe room air through the equipment assembly (Figure 1) while wearing a noseclip. Each subject had an initial 5-min trial in order to become accustomed to the apparatus and procedure. After regular breathing had been achieved, we performed a series of test breaths in which NEP (about 3 cm H₂O) was applied about 0.2 s after the onset of expiration, and was maintained throughout the ensuing expiration. Analysis of data obtained with NEP consisted of comparing the expiratory -V curve of a control tidal expiration with that obtained during the subsequent expiration in which NEP was applied. In the absence of preexisting flow limitation, the increase in pressure gradient between the alveoli and the airway opening caused by NEP should result in increased flow, whereas in flow-limited (FL) subjects NEP should enhance dynamic airway compression downstream from the flow-limiting segments of the airway without substantial effect on pressure or flow upstream. Accordingly, when flow limitation is present, expiratory flow does not change with NEP, except for a brief transient (spike), which is thought to reflect enhanced dynamic airway compression and a sudden reduction in volume of the compliant oral and neck structures (4). Such spikes, although useful markers of flow limitation, do not affect its detection.

Subjects in whom application of NEP did not elicit an increase of flow over part or all of the control range of VT were considered FL. By contrast, subjects in whom flow increased with NEP over the entire range of the control VT were considered as not flow-limited (NFL). The FL portion of the tidal expiration was expressed as percentage of the control VT (%VT) (4, 6).

During the application of NEP, air may leak around the lips and into the expiration line, and contribute to the expiratory flow. Such leaks, however, are easily detected because they result in a sustained decrease of the end-expiratory lung volume during the tidal breaths following application of NEP. Accordingly, great care was taken to avoid such leaks by proper positioning of the mouthpiece and by asking the subjects to compress their lips tightly around it.

In accord with the finding in previous studies (5, 6), the application of NEP was not associated with unpleasant sensations or cough. With NEP, the expiratory flow either increased (reflecting absence of flow limitation) or did not change during part of the expiration (reflecting presence of flow limitation). In no instance did the application of NEP result in a sustained decrease of expiratory flow as a consequence of upper-airway collapse or narrowing.

With subjects in the sitting position, flow limitation was also assessed by comparison of the tidal -V curves with the maximal expiratory flow-volume (MEFV) curves, both of which were recorded with the subject in a body plethysmograph in order to avoid artifacts due to thoracic gas compression (7). With this method, henceforth defined as the "conventional method," patients in whom, at comparable lung volumes, flows during tidal expiration were similar to or greater than those obtained during the FVC maneuver were considered as FL (5, 11).

To ensure the same FRC, care was taken that the sitting posture for each subject was the same in the body plethysmograph as on the chair used for the NEP experiments. In both instances care was also taken to keep the subject's neck fixed in the neutral position.

After the foregoing measurements were made, the subjects were asked to inhale 400 µg of salbutamol via a metered-dose inhaler. After 15 min, the measurements were repeated.

Statistical Analysis

Statistical analysis was done with the paired t test. Values are given as means ± SD, and a value of p < 0.05 was taken as statistically significant.

	RESULTS

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Lung Function and Chronic Dyspnea

Individual and mean (± SD) values of baseline lung function and the MRC dyspnea scale are listed in Table 3. The mean FEV₁ (± SD) amounted to 68 ± 13% predicted (12), with a range of 94 to 48% predicted, indicating that the group of patients studied included those with asthma of mild to moderate severity. In many subjects the FEV₁/FVC ratio and RV were outside the normal limits, whereas FVC, TLC, and FRC were in most instances within the normal range. Ten patients had a slight degree of dyspnea (MRC Category 1, Table 2), one exhibited a moderate degree of dyspnea (MRC Category 2), and two had a moderately severe degree of dyspnea (MRC Category 3). No significant correlation was found between any of the lung function variables in Table 3 and the degree of chronic dyspnea.

NEP Technique

According to the NEP technique, none of the patients exhibited expiratory flow limitation during resting breathing in the sitting position, as exemplified by the curves for Subject 12 in Figure 2. Only two patients were FL in the supine position: Patient 6, in whom FL encompassed 60% of the control VT (Figure 3), and Patient 8, in whom FL encompassed 40% of the control VT. In both of these patients, the FRC was above the normal limits, whereas in the other 11 subjects it was within the normal range.

View larger version (14K): [in this window] [in a new window]   Figure 2.   Flow-volume curves of Patient 12 during resting breathing in sitting position. A control breath is shown, together with the subsequent expiration, during which NEP was applied at the point indicated by the first arrow. The second arrow indicates termination of NEP. Expiratory flow increased throughout application of NEP, indicating absence of tidal-flow limitation.

View larger version (14K): [in this window] [in a new window]   Figure 3.   Flow-volume curves of Patient 6 as in Figure 2, but in supine position. In this case, flow increased only above 60% of control VT. Accordingly, the flow-limitation (FL) portion of the control VT is 60%. The initial increase in flow with NEP includes a small component due to sudden reduction in volume of the compliant oral and neck structures and enhanced dynamic airway compression.

Plethysmographic Method

Expiratory flow limitation was also assessed with subjects in the sitting position by comparing the resting expiratory -V curves with the corresponding MEFV curves. Assuming that at comparable volumes, similar or higher flows during resting expiration than during the FVC maneuver reflecting expiratory flow limitation (Types 2 and 3 in Figure 4), six of the 13 asthmatic patients would have been classified as FL. None of these patients was FL in the sitting position according to the NEP technique. The other seven patients were classified as NFL according to both the body-plethysmographic method (Type 1 in Figure 4) and the NEP technique (Figure 2).

View larger version (13K): [in this window] [in a new window]   Figure 4.   Tidal and maximal flow-volume curves of three representative asthmatic subjects sitting in a body plethysmograph. In Type 1, tidal expiratory flows are lower, in Type 2 tidal expiratory flows are superimposed, and in Type 3 tidal expiratory flows are higher than those obtained during the FVC maneuvers. The number (n) of patients with different patterns is indicated.

Effects of Inhalation of Salbutamol

As shown in Table 4, significant bronchodilation was observed after inhalation of salbutamol, the FEV₁ increasing significantly, to 2.28 ± 0.40 L, from 1.99 ± 0.40 L during the control state. The FEV₁ amounted to 16 ± 10% of the control value. No significant modification in FVC or inspiratory capacity (IC) was observed after salbutamol inhalation. Since in asthma the actual TLC is essentially independent of bronchomotor tone (13, 14), the failure of IC to change after salbutamol implies that there was no change in FRC.

According to the NEP technique, expiratory flow limitation was absent in all patients, in both body positions studied, after administration of salbutamol (Table 5). By contrast, according to the conventional method based on comparison of tidal with maximal expiratory -V curves, the six patients who under control conditions were FL in the sitting position would still have been classified as FL after the administration of salbutamol.

	DISCUSSION

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The main findings of the present study are that in patients with mild to moderately severe asthma: (1) expiratory flow limitation during resting breathing is uncommon in both the sitting and supine positions; and (2) the degree of chronic dyspnea (MRC scale) is generally slight. In addition, our results indicate that assessment of expiratory flow limitation based on comparison of tidal with maximal -V curves is not valid, even if the measurements are made with a body plethysmograph.

According to the NEP technique, none of our asthmatic patients exhibited expiratory flow limitation during resting breathing in the sitting position, and only two (15%) were FL in the supine position. In contrast, in stable COPD patients there is a high prevalence of flow limitation during resting breathing (6). Indeed, 22 (19%) of 117 COPD patients in one study were found to be FL in the supine position alone, and another 69 (59%) were found to be FL in both the sitting and supine positions (6). Only 26 (22%) of the COPD patients were NFL in both the sitting and supine positions. It should be noted, however, that the severity of the COPD was more pronounced in those patients in whom the FEV₁ (% predicted) averaged less than 40%, as compared with a figure of 68% in the asthmatic subjects in the present study. However, even considering only those COPD patients whose FEV₁ was within the range of that of our asthmatic subjects (FEV₁ 48% predicted; Table 3), there still remains a high prevalence of flow limitation in COPD. Indeed, 10 (48%) of the 21 COPD patients with FEV₁  48 (% predicted) were FL in the sitting and/or supine position (6), as compared with 15% of our asthmatic subjects. This discrepancy between asthma and COPD may reflect lower lung elastic recoil in the latter condition.

With NEP, we found that two patients were FL in the supine but not in the sitting position. Previous studies have shown that in COPD patients there is a greater prevalence of flow limitation in the supine than in the sitting position (5, 6). This probably mainly reflects the lower FRC in the supine than in the sitting position, with a concomitant decrease in expiratory flow reserve (5). As a result, flow limitation is an earlier manifestation of obstructive lung disease in the supine than in the sitting position. After salbutamol administration, both of the asthmatic subjects in the present study who under control conditions were FL in the supine position became NFL. This indicates that flow limitation can be reversed by bronchodilators.

In accord with previous results obtained with stable COPD patients (5), we found that assessment of flow limitation based on comparison of tidal and maximal expiratory -V curves is inaccurate. Indeed, on the basis of the latter approach, six of our patients would have been considered FL in the sitting position, whereas in reality and according to the NEP technique, none of them was FL (Table 5). Such a discrepancy is predictable in view of: (1) the different volume and time history during resting breathing and the FVC maneuver (15, 16); and (2) the time-constant inequality within the lung (17). Furthermore, it has long been recognized that in patients with stable asthma, the maximal inspiration prior to the FVC maneuver tends to elicit bronchoconstriction, thereby reducing maximal expiratory flow (18). Since the volume and time history during resting breathing are necessarily different from those obtained the FVC maneuver, it is axiomatic that detection of flow limitation based on comparison of tidal with maximal -V curves is problematic (5). No such problems pertain to the NEP method because the control and NEP test breaths have similar volume and time histories. Furthermore, the NEP method does not require either a body plethysmograph or the patient's cooperation and coordination. Because a body plethysmograph is not required, the NEP method can be used not only with the patient in the sitting position, but also with any other desired posture, as well as during exercise (19).

In a recent study (6), it was shown that in stable COPD patients there is a close association between the degree of chronic dyspnea (MRC scale) and the degree of flow limitation in the sitting and/or supine position. Since expiratory flow limitation, as assessed with the NEP technique, was absent in most of our asthmatic patients, it is not surprising that their degree of chronic dyspnea was in general slight (MRC Category 1), in accord with previous results obtained in COPD patients (6). Indeed, in 26 COPD patients who were NFL in both the seated and supine positions, the MRC dyspnea score amounted to 1.3 ± 1.2, whereas for the 11 asthmatic subjects in our study who were NFL in both the seated and supine positions, the corresponding value was 1.5 ± 0.8. In COPD patients who were FL in both the seated and supine positions, the MRC dyspnea score amounted to 3.4 ± 1.2.

In 11 asthmatic subjects in the present study, the FRC was within normal limits (Table 3), which is consistent with the absence of expiratory flow limitation in the sitting position based on the NEP technique (Table 5). Not surprisingly, there was no significant change in IC and, by inference, in FRC (= TLC  IC) in these patients after administration of salbutamol, although the latter caused a significant increase in FEV₁ (Table 4). Clearly, in these 11 patients, there was enough time in expiration (both before and after salbutamol) during resting breathing in the sitting position to bring the respiratory system to its relaxation (elastic equilbrium) volume. In Patients 6 and 8, however, the control FRC was above the normal limit (125% predicted and 156% predicted, respectively), even though both patients were NFL in the sitting position. In both of them there was essentially no change in IC after salbutamol administration (4% and 1%, respectively), even though the FEV₁ amounted to 21% and 12%, respectively. However, hyperinflation does not depend solely on the development of expiratory flow limitation (20). In asthma, hyperinflation may occur as a result of loss of lung elastic recoil (21, 22), increased expiratory flow resistance due to narrowing of the intrathoracic airways or reduction in size of the glottic aperture (23, 25), gas trapping due to premature small-airway closure (26), or an enhanced braking action of the inspiratory muscles during expiration (2, 27). Although all or some of these mechanisms could be responsible for the increased FRC observed in Patients 6 and 8 in the absence of flow limitation, it is also possible that their FRC was overestimated. Indeed, it has been shown that in asthmatic individuals, the FRC measured with the body plethysmographic method may overestimate the actual FRC because the transmission of alveolar pressure to the mouth is delayed by increased airway resistance (13, 14). That Patients 6 and 8 were FL in the supine position suggests that they probably had more severe airway narrowing than the other 11 asthmatic subjects, who were not FL. With severe airway narrowing, an overestimation of FRC is more likely to occur with the body plethysmographic method (13, 14).

In conclusion, the results of the present study indicate that most patients with stable, mild to moderately severe asthma do not exhibit expiratory flow limitation during resting breathing in either the sitting or supine position. This is consistent with the fact that in these patients, the degree of chronic dyspnea is generally mild. A corollary of the present investigation is that assessment of flow limitation based on comparison of tidal with maximal flow-volume curves is invalid, particularly in asthma.