Journal of Applied Physiology
Vol. 82, No. 3, pp. 723-731, March 1997
EXERCISE AND MUSCLE

Detection of expiratory flow limitation during exercise in COPD patients

Nickolaos G. Koulouris, Ioanna Dimopoulou, Päivi Valta, Richard Finkelstein, Manuel G. Cosio, and J. Milic-Emili

Meakins-Christie Laboratories and Respiratory Division, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H2X 2P2

ABSTRACT

INTRODUCTION

METHODS

RESULTS

DISCUSSION

ACKNOWLEDGEMENTS

FOOTNOTES

REFERENCES

ABSTRACT

Koulouris, Nickolaos G., Ioanna Dimopoulou, Päivi Valta, Richard Finkelstein, Manuel G. Cosio, and J. Milic-Emili. Detection of expiratory flow limitation during exercise in COPD patients. J. Appl. Physiol. 82(3): 723-731, 1997.The negative expiratory pressure (NEP) method was used to detect expiratory flow limitation at rest and at different exercise levels in 4 normal subjects and 14 patients with chronic obstructive pulmonary disease (COPD). This method does not require performance of forced expirations, nor does it require use of body plethysmography. It consists in applying negative pressure (5 cmH₂O) at the mouth during early expiration and comparing the flow-volume curve of the ensuing expiration with that of the preceding control breath. Subjects in whom application of NEP does not elicit an increase in flow during part or all of the tidal expiration are considered flow limited. The four normal subjects were not flow limited up to 90% of maximal exercise power output (_max). Five COPD patients were flow limited at rest, 9 were flow limited at one-third _max, and 12 were flow limited at two-thirds _max. Whereas in all patients who were flow limited at rest the maximal O₂ uptake was below the normal limits, this was not the case in most of the other patients. In conclusion, NEP provides a rapid and reliable method to detect expiratory flow limitation at rest and during exercise.

negative expiratory pressure; chronic obstructive pulmonary disease; exercise performance; dynamic hyperinflation

INTRODUCTION

THE HIGHEST PULMONARY ventilation that a subject can achieve is ultimately limited by the highest flow rates that can be generated. Most normal subjects do not exhibit expiratory flow limitation, even during maximal exercise (2, 10, 13). In contrast, patients with chronic obstructive pulmonary disease (COPD) may exhibit expiratory flow limitation at rest or at low work rates, as first suggested by Potter et al. (25). They observed that patients with severe COPD often breathe tidally along their maximal expiratory flow-volume curve and suggested that this reflects the presence of expiratory flow limitation (i.e., inability to further increase flow at a given lung volume). By use of this approach, expiratory flow limitation has been extensively studied in COPD patients at rest and during exercise (1, 10, 17, 28). In many instances, however, the flows obtained during tidal breathing actually exceeded those of the maximal expiratory flow-volume curve (1, 10, 25). Several explanations for this phenomenon have been offered: The first explanation involves thoracic gas compression artifacts. In nearly all previous studies, the flow-volume loops were obtained from measurements of expired gas volume, although Ingram and Schilder (14) pointed out that, to avoid gas compression artifacts, volume should be measured with a body plethysmograph. The second explanation is incorrect alignment of tidal and maximal expiratory flow-volume curves. Such alignment is usually made on the assumption that the total lung capacity (TLC) does not change during exercise and, hence, that changes in inspiratory capacity (IC) reflect changes in end-expiratory lung volume (EELV). Although several investigators have reported that TLC does not change with exercise (21, 28, 32), others found that it increases (11). Furthermore, this approach is based on the assumption that during exercise the subjects can perform a truly maximal inspiration. During exercise, however, some COPD patients may be incapable of performing IC maneuvers. The third explanation is the effect of previous volume and time history. The maximal flows that can be achieved during expiration depend on the volume and time history of the preceding inspiration (4, 6, 9, 18). Because, by definition, the previous volume and time history varies between tidal breathing and maximal inspiration, it follows that assessment of flow limitation on the basis of comparison of tidal and maximal flow-volume curves may lead to erroneous conclusions, even if the measurements are done with a body plethysmograph. The fourth explanation is the effect of muscular exercise on lung mechanics. Exercise may result in bronchodilatation and other changes in lung mechanics, which may affect tidal and maximal flow-volume curves (2, 28).

Assessment of expiratory flow limitation may also be based on comparison of tidal flow-volume curves with those obtained during partial forced expirations. In this way, the previous volume history is kept constant. The previous time history should also be kept constant. Indeed, Wellman et al. (31) showed that in normal subjects the flows attained during a partial forced expiratory maneuver depend on the previous time history, similar to the maximal forced vital capacity (FVC) maneuver (4). Whereas normal subjects may be trained to produce partial FVC maneuvers with previous volume and time history similar to that of the preceding tidal breaths, this is seldom feasible in most patients with COPD, especially during exercise.

From the above considerations, it appears that detection of expiratory flow limitation on the basis of comparison of tidal with maximal flow-volume curves is questionable. Recently, however, an alternate approach [negative expiratory pressure (NEP) method] has been introduced (16, 30). This method does not require performance of FVC maneuvers on the part of the patient, nor does it require use of a body plethysmograph. It consists in applying a negative pressure at the mouth during a tidal expiration and comparing the ensuing expiratory flow-volume curve with that of the previous control expiration. Accordingly, with this method the volume and time history of the control and test expiration is the same. The NEP technique has been previously applied and validated in mechanically ventilated patients in the intensive care unit by concomitant determination of isovolume flow-pressure relationships (30). It has also been used in stable COPD patients at rest (16). The present investigation is designed to test the feasibility of using this method during exercise in COPD patients and normal subjects and to assess the implications of flow limitation on exercise performance. We have also assessed expiratory flow limitation by comparison of tidal with maximal expiratory flow-volume curves.

METHODS

Four normal subjects and 14 patients with COPD ranging from mild to severe were studied. Their anthropometric characteristics and lung function data are given in Table 1. All COPD patients, who were recruited from the respiratory outpatient clinic, were in a stable clinical and functional state at the time of the study and had no contraindications for exercise testing. None had a history of obstructive sleep apneas (OSA) or any evidence of upper airway obstruction. Routine spirometry was performed with a calibrated dry spirometer (1070 system, Medical Graphics, Minneapolis, MN), and thoracic gas volumes were determined with a body plethysmograph (P. K. Morgan, Kent, UK). The predicted normal values for spirometric measurements were those of Morris and co-workers (20), and for thoracic gas volumes the values of Goldman and Becklake were used (8). The study was approved by the local Ethics Committee. All subjects gave informed consent.

Table 1. Anthropometric and lung function data of normal subjects and COPD patients n Age, yr Height, cm Weight, %pred Gender FVC, %pred FEV1, %pred FEV1/FVC, %  IC, %pred FRC, %pred TLC, %pred RV, %pred Normal subjects 4 32 ± 3  177 ± 8  94 ± 6  2M, 2F 106 ± 7  108 ± 5  83 ± 4  COPD patients 14 64 ± 9  166 ± 8  117 ± 20  10M, 4F 78 ± 20  58 ± 20  53 ± 11  80 ± 22  149 ± 37  117 ± 16  173 ± 42 Values are means ± SD. IC, inspiratory capacity; FRC, functional residual capacity; TLC, total lung capacity; RV, residual volume; FEV1, forced expired volume in 1 s; FVC, forced vital capacity; COPD, chronic obstructive pulmonary disease; %pred, percentage of predicted.

Figure 1 depicts the experimental setup used to assess expiratory flow limitation. A flanged plastic mouthpiece is connected to a Fleisch no. 3 or 4 pneumotachograph (Fleisch, Lausanne, Switzerland) and a T tube. One side of the T tube is open to the atmosphere, and the other side is equipped with a one-way pneumatic valve that allows for the subject to be rapidly switched to negative pressure generated by a vacuum cleaner (Hoover Heavy Duty Portapower, model S7065-060, Hoover, Dayton, OH). The pneumatic valve (occlusion valve setup, series 9300, Hans Rudolph, Kansas City, MO) consists of an inflatable balloon connected to a gas cylinder filled with helium and a manual pneumatic controller (Hans-Rudolph control switch 9301). The latter permits remote-control balloon deflation, which is accomplished quickly (30-60 ms) and quietly, allowing rapid exposure to negative pressure during expiration (NEP). The NEP (usually set at about 5 cmH₂O) (16) could be adjusted with a potentiometer (Powerstat, Superior Electric, Bristol, CT).

Airflow was measured with the heated Fleisch pneumotachographs connected to a differential pressure transducer (Validyne MP45, ±2 cmH₂O). This is one of the most symmetrical transducers available, with a common-mode rejection ratio of 70 dB at 30 Hz (7). The response of the pneumotachographs, calibrated with a rotameter, was linear over the experimental range of flows. Pressure at the airway opening (Pao) was measured through a side port on the mouthpiece using a differential pressure transducer (Validyne MP45, ±88 cmH₂O). With this system there was no appreciable shift or alteration in pressure amplitude up to 20 Hz. The breathing assembly had a dead space of 220 and 410 ml with Fleisch pneumotachographs no. 3 and 4, respectively, and the corresponding pressure-flow relationships were characterized by the following equations: P = 0.16 + 0.31² and P = 0.17 + 0.22², where P is pressure (in cmH₂O) and is flow (in l/s). The Fleisch no. 4 pneumotachograph was used only by the normal subjects. In two normal subjects and two COPD patients we also measured the esophageal pressure (Pes), as previously described in detail (3). The flow and pressure signals were amplified (model 8085, Hewlett-Packard, Waltham, MA) and sampled simultaneously at a rate of 100 Hz using a computer data acquisition system with a built-in 16-bit analog-to-digital converter (AT-Codas, DATAQ Instruments, Akron, OH). Collected data were stored on a computer disk for subsequent analysis. Volume was obtained by numerical integration of the flow signal. The flow signal was corrected for any offset on the basis of the assumption that inspired and expired volume of the preceding control breath were the same (24). This analysis was made using ANADAT data analysis software (ANADAT 5.1, RHT-InfoDat, Montreal, Quebec, Canada).

Table 2. Maximal exercise data of normal subjects and COPD patients n  max, W  O2 max  Emax, l/min HRmax, beats/min l/min %pred Normal subjects 4 222 ± 55  2.79 ± 0.69  118 ± 22  95 ± 17  COPD patients 14 90 ± 25 1.45 ± 0.26 85 ± 21* 51 ± 13 139 ± 19 Values are means ± SD. max, maximal power output; O2 max, maximal O2 uptake; Emax, maximal exercise ventilation; HRmax, maximal exercise heart rate. * P < 0.02; P < 0.001.

RESULTS

Figure 2 depicts flow-volume loops obtained at rest and at three levels of steady-state exercise in a representative normal subject. In all instances the application of NEP resulted in increased expiratory flow over the entire range of control tidal volume (VT), indicating absence of expiratory flow limitation up to 90% _max. Also shown in Fig. 2 is the maximal expiratory flow-volume curve obtained at rest. In all instances the latter exceeded those used to sustain resting and exercise ventilation. With increasing exercise level, the end-inspiratory lung volume (EILV) increased while the EELV tended to decrease. Similar results were found in the other three normal subjects studied. In all instances the results were reproducible with repeated NEP tests. The average values of EILV and EEVL during exercise of the four normal subjects are depicted in Fig. 3.

Figure 4 illustrates flow-volume loops of COPD patient 4 at rest and during exercise. In all instances, the application of NEP did not elicit an increase in flow, except for a transient increase (i.e., spike) coincident with NEP application. This transient mainly reflects reduction in volume of the airways and heralds flow limitation (see METHODS). Thus, according to NEP, this patient had expiratory flow limitation at rest as well as during exercise. Also shown in Fig. 4 is the maximal expiratory flow-volume curve. The tidal expiratory flows largely exceeded the maximal flows at rest and during exercise. Thus, according to the conventional method for detecting flow limitation, this patient would also be classified as flow limited. In this patient, EILV and EELV increased progressively with increasing exercise load. Similar results were found in patients 2, 5, 8, and 14.

Figure 5 depicts results obtained in COPD patient 1, who, according to the NEP test, was not flow limited at rest but became flow limited at one-third and two-thirds _max. At rest the tidal flows were essentially superimposed on the maximal expiratory flow-volume curve, whereas during exercise the tidal flows exceeded the maximal expiratory flow-volume curve. Thus at rest the patient would be classified as flow limited with the conventional method but not flow limited with the NEP test. During exercise, flow limitation was detected with both methods. However, at one-third _max, flow limitation with NEP encompassed only the last 30% of VT, whereas the maximal expiratory flow-volume curve was superimposed with a larger fraction of the tidal expiratory flow-volume curve (~70% VT). In this patient, EILV was close to TLC even at rest, and during exercise there was little change in EELV or VT.

Figure 6 depicts the time course of flow, volume, Pao, and Pes during a control breath and the subsequent expiration with NEP, together with the corresponding flow-volume and Pes-volume loops, at rest in a COPD patient who was flow limited and in a normal subject. In the flow-limited patient, the time course of flow, volume, and Pes was not affected by NEP, except for the characteristic initial flow transient. Apart from the latter, the flow-volume and Pes-volume loops obtained with NEP were essentially the same as in the preceding control breath. This indicates that NEP did not elicit changes in respiratory muscle activity. By contrast, in the non-flow-limited subject, the increase in flow elicited by NEP was associated with a slower increase in Pes at any given time during expiration (Fig. 6Ba). An increase in flow would per se be expected to result in more negative Pes at any given time of expiration because of 1) increased pressure dissipations due to the Newtonian resistance of the chest wall, 2) decreased elastic recoil pressure of the chest wall due to faster lung deflation, and 3) increased antagonistic pressure exerted by the breaking action of the inspiratory muscles, which are active during expiration (19, 27). That is, during pliometric contraction the force exerted by a muscle increases with increased velocity of lengthening (19). With NEP, Pes at any given volume was more negative than during the control expiration (Fig. 6Bb). Apart from mechanisms 1 and 3, this phenomenon was also related to the postinspiratory activity of the inspiratory muscles (PIIA) (19, 27). Indeed, even if the magnitude and rate of decay of PIIA were the same with and without NEP, Pes at any given lung volume should be lower with NEP, because, as a result of faster exhalation, PIIA has less time to decay. Thus, also in the subject without flow limitation, there was no evidence that NEP elicited appreciable changes in activity of the respiratory pump muscles. Similar results were found in the other two subjects in whom Pes was measured.

According to the NEP results, our 14 COPD patients could be subdivided into four groups: 1) flow limited from rest (n = 5), 2) flow limited from one-third _max (n = 4), 3) flow limited from two-thirds _max (n = 3), and 4) not flow limited up to two-thirds _max (n = 2). Assessment of flow limitation based on comparison of tidal with maximal flow-volume curves yielded different results (Table 3). With the conventional method, nine COPD patients would have been classified flow limited at rest, whereas with NEP flow limitation was present in only five of the COPD patients. Similarly, at one-third _max, 12 patients were flow limited according to the conventional method but only 9 were flow limited with NEP. Furthermore, one patient who was not flow limited according to the conventional method was found to be flow limited with NEP. Thus, at one-third _max, consistent results were obtained with the two methods in only 8 patients, whereas consistent results were found in 10 patients at two-thirds _max.

Table 3. Comparison of NEP and conventional method of detecting expiratory flow limitation in COPD patients Method Rest Exercise Level NEP Conventional 1/3 max 2/3 max FL FL 5 8 10 NFL FL 4 4 2 FL NFL 0 1 2 NFL NFL 5 1 0 NEP, negative expiratory pressure; Conventional, method based on comparison of tidal and maximal expiratory flow-volume curves; FL, flow limited; NFL, not flow limited; n = 14.

In all our COPD patients who were flow limited from rest or one-third _max, flow limitation at two-thirds _max encompassed >60% of the VT (flow-limited range 64-78% VT; Fig. 5). In contrast, in the three patients who became flow limited only at two-thirds _max, flow limitation at this level of exercise was 13-55% of control VT.

The presence of flow limitation at rest implies that the increased ventilation during exercise should be associated with dynamic pulmonary hyperinflation (25, 26). Indeed, in our COPD patients who were flow limited at rest, the EELV increased significantly at both exercise levels studied (Fig. 7, left). Similarly, in the patients who became flow limited at one-third _max, there was a significant increase in EELV only at two-thirds _max (Fig. 7, middle). In contrast, in the other patients there was no significant change in EELV over the entire exercise range studied (Fig. 7, right).

The five COPD patients who were flow limited from rest exhibited a significantly lower IC (percent predicted) than the other COPD patients (Table 4). If flow limitation is present at rest, with a concomitant decrease in IC, VT_max during exercise should also be reduced. Indeed, a very low VT_max was a characteristic feature of the five COPD patients who were flow limited from rest (Fig. 8). In four of these patients the low VT_max was associated with a low maximal ventilation, whereas severe tachypnea was present in the fifth patient. In all five of these patients the values of O_{2 max} (percent predicted) were below the normal range (<80% predicted). In contrast, in only two of the other nine COPD patients was the O_{2 max} below the normal range (77 and 78% predicted, respectively). However, there was no significant difference in O_{2 max} (percent predicted) among the three groups of COPD patients (Table 4), probably mainly reflecting the small number of patients studied.

Table 4. Anthropometric, lung function, and maximal exercise data of COPD patients at each exercise level FL at Rest FL at 1/3 max FL and NFL at 2/3 max P (ANOVA, all groups) Age, yr 63 ± 12  62 ± 8  68 ± 5  NS Height, cm 163 ± 6  171 ± 7  166 ± 9  NS Wt, %pred 114 ± 12  121 ± 33  117 ± 19  NS Gender 4 M, 1 F 3 M, 1 F 3 M, 2 F FVC, %pred 60 ± 8  77 ± 7* 97 ± 20* <0.005 FEV1, %pred 40 ± 9  57 ± 16* 75 ± 19* <0.02 FEV1/FVC, %  50 ± 15  52 ± 11  56 ± 9  NS IC, %pred 66 ± 7  73 ± 17* 100 ± 24* <0.03 FRC, %pred 167 ± 52  142 ± 25  135 ± 23  NS TLC, %pred 120 ± 23  109 ± 5  120 ± 16  NS RV, %pred 198 ± 43  163 ± 49  157 ± 29  NS RV/TLC, %  62 ± 9  53 ± 8  50 ± 5  NS  max, W 73 ± 25  94 ± 22  105 ± 20  NS  O2 max, %pred 69 ± 7  92 ± 25  95 ± 21  NS  Emax, l/min 41 ± 10  56 ± 10  57 ± 11  NS VTmax, liters 0.99 ± 0.16  1.52 ± 0.19 1.63 ± 0.17 <0.001 fmax, breaths/min 42 ± 14  38 ± 8  35 ± 4  NS HRmax, beats/min 131 ± 25  134 ± 8  152 ± 14  NS HRmax, %pred 92 ± 22  86 ± 4  98 ± 9  NS SaO2 max, %  90 ± 4  91 ± 2  95 ± 2  NS Values are means ± SD. M, male; F, female; VT, tidal volume; f, respiratory rate; SaO2 max , maximal O2 saturation; ANOVA, analysis of variance. * P < 0.05,  P < 0.001 relative to FL at rest.

In the COPD patients who were flow limited from rest, forced expired volume in 1 s (FEV₁) and FVC were significantly more impaired than in the other COPD patients (Table 4). Figure 9 depicts the individual values of FEV₁ (percent predicted) of the COPD patients classified according to NEP. Although four of the five patients who were flow limited from rest had severe airway obstruction (FEV₁ < 49% predicted), one had only moderate airway obstruction (FEV₁ = 63% predicted) (22). Furthermore, a patient with severe airway obstruction was not flow limited at one-third _max, and another was not flow limited even at two-thirds _max.

Figure 10B depicts the O_{2 max}-FEV₁ relationship of the 14 COPD patients and the 4 normal subjects. Although the correlation was highly significant, there was considerable scatter of the data. Less scatter was found when O_{2 max} was correlated with VT_max (Fig. 10A).

DISCUSSION

The present results indicate that NEP provides a simple and reliable method for on-line detection of expiratory flow limitation at rest and during exercise. Flow limitation at rest is associated with low values of O_{2 max} and VT_max, which are probably mainly due to dynamic pulmonary hyperinflation (3, 21, 26). In agreement with previous results obtained in COPD patients at rest (16), the present study indicates that the conventional method for detecting flow limitation based on comparison of tidal with maximal flow-volume curves is not reliable. Before further discussion of the present results, however, some methodological considerations are required.

ACKNOWLEDGEMENTS

The authors thank Maria Makroyanni for typing the manuscript and Dr. H. Ghezzo for help with the statistical analysis.

FOOTNOTES

Address for reprint requests: J. Milic-Emili, Meakins-Christie Laboratories, McGill University, 3626 St. Urbain St., Montreal, Quebec, Canada H2X 2P2.

Received 5 September 1995; accepted in final form 22 October 1996.

REFERENCES