Total Respiratory Resistance and Reactance in Patients with Asthma, Chronic Bronchitis, and Emphysema1- 3
J. A. VAN NOORD, J. CLEMENT, K. P. VAN DE WOESTIJNE, and M. DEMEDTS
Introduction
Since the original description of the forced oscillation technique by Dubois and colleagues (1) in 1956, a number of studies have been published concerning the application of the method in patients with chronic obstructive lung disease (COPD) (2-12) and with asthma (11-14). In these patients total respiratory resistance (Rrs) and reactance (Xrs) versusfrequency curves are characterized by an increase in Rrs, a decrease in Rrs with frequency, and a decrease in Xrs (12). It has been shown in a heterogeneous group of patients with COPD and asthma that the alterations of the curves were most pronounced in the patients with the most severe obstruction as assessed by the reduction in the FEV 1 (12). Furthermore, Rrs measured at low frequencies has been shown to have an excellent correlation with airway resistance (Raw) (15). Airflow obstruction and narrowing of the airways can be caused by different pathologic conditions. Asthma is characterized by variable widespread airway narrowing due to bronchial muscle contraction, edema and infiltration of the bronchial mucosa, and mucus plugging. Studies of changes in the density dependence of maximal flows suggest that the major site of airflow limitation may vary from the large to the peripheral airways (16). In COPD the morphologic basis of the largely irreversible airflow limitation are varying combinations of inflammatory and fibrotic narrowing of the peripheral airways (17) and loss of elastic lung recoil with enhanced collapsibility of central airways (18, 19). Detailed comparative studies on Rrs and Xrs in wellcharacterized groups of patients with asthma, chronic bronchitis, and emphysema are lacking. Particularly it is not known whether the different mechanisms of airflow obstruction in asthma, chronic bronchitis, and emphysema produce different patterns of Rrs and Xrs versus frequency curves. In the present study we compared Rrs 922
SUMMARY A comparison was made of total respiratory resistance (Rrs) and reactance (Xrs) determined between 6 and 26 Hz by means of a forced oscillation technique in 27 patients with asthma (group A), 28 patients with chronic bronchitis (group B), and 20 patients with emphysema (group E) to examine whether the method can provide data capable of distinguishing among these diseases. The three groups demonstrated a similar reduction In the FEV1 • In addition, static and dynamic lung volumes, maximal expiratory flows, diffusing capacity for CO, airway resistance (Raw), and elastic lung recoil were measured. The observed alterations of Rrs and Xrs consisted of an increase in Rrs, a decrease in Rrs with frequency, and a decrease in Xrs. However, significant differences were found between the three groups: Rrs at 6 Hz and average Rrs were most increased In group A, whereas the negative frequency dependence of Rrs and the decrease in Xrs were least pronounced In group E. In all groups Rrs at 6 Hz, the average slope of Rrs, and the average level of Xrs were tightly interrelated and showed in addition a high correlation with airway resistance; the correlations with FEV1 were less satisfactory. Discriminant analysis performed on the complete set of data, excluding diffusing capacity and elastic lung recoil, which were used as selection criteria, demonstrated that forced oscillation parameters were the most important factors discriminating AM REV RESPIR DIS 1991; 143:922-927 among the groups.
and Xrs in clearly defined groups with an on-average similar reduction in FEV 1 due to asthma, chronic bronchitis, and emphysema. The changes in Rrs and Xrs wererelated to those in routine lung function tests, and a discriminant analysis was performed to investigate which pulmonary function measurement discriminated best among the three groups. Methods Patients A total of 27 patients, 6 females and 21males, with asthma (group A), 28 patients, all males, with chronic bronchitis (group B), and 20 patients, all males, with emphysema (group E) were selected. All patients in group A had a history of varying dyspnea, cough, and wheezing. The onset of the disease had to be before the age of 35 yr, and airway obstruction had to be largely reversible at some time in the preceding 3 yr, although in some patients this was achieved only during admission and treatment with high doses of corticosteroids. Of the patients 6 were smokers and 14wereatopic. They all had documented airway hyperresponsiveness to histamine (PD 20 FEV 1 < 8 mg/ml). Bronchial hyperreactivity was not taken as a selection criterion, however, as it can be found in patients with both asthma and COPD (20). For group Band E only patients with COPD who could be easily categorized as predominantly bronchitic or emphysematous were selected. All were middle-aged or
older persons and current or exsmokers and had negative skin tests. The patients in group B had a history of chronic cough and sputum production for at least 3 months of each of the 2 preceding yr (21). Diffusing capacity (Dtco) had to be more than 800/0 of predicted (22). All patients of group E had exertional dyspnea and little sputum production, DLco had to be less than 70% of predicted (22), and static lung compliance more than 150070 of predicted (23). In many patients the chest radiograph demonstrated overinflation and vascular attenuation. However, the latter findings were not used in the selection. None of the patients in groups A, B, and E had clinical or radiologic evidence of other complicating lung diseases. They abstained from all medication, except for corticosteroids, for at least 12 h before the measurements.
Methods The pulmonary function measurements con(Receivedin originalform November 17, 1989 and in revised form November 16, 1990) 1 From the Clinic for Pneumology, Catholic University, Leuven, Belgium. 2 Supported by a grant from the Nederlands Astrna Fonds, the Fonds voor Geneeskundig Wetenschappelijk Onderzoek, and the European Community for Coal and Steel. 3 Correspondence and requests for reprints should be addressed to M. Demedts, Kliniek voor Longziekten, Universitaire Ziekenhuizen, Weligerveld 1, B-3041 Pellenberg, Belgium.
OBSTRUCTIVE LUNG DISEASE AND RESPIRATORY IMPEDANCE
sisted of static and dynamic lung volumes, maximal expiratory flow-volume (MEFV) curves, diffusing capacity (Dtoo), airway resistance (Raw), specific airway conductance (SGaw), elastic lung recoil, and Rrs and Xrs versus frequency curves. Vital capacity (VC), total lung capacity (TLC), residual volume (VR), and FEV 1 were obtained by standard methods of spirometry and multibreath helium equilibration. In addition TLC was determined in a body plethysmograph. Peak expiratory flow (PEF) and maximal expiratory flow at 50070 of the forced vital capacity (MEF 50) were obtained from MEFV curves measured at the mouth. DLCO was measured with the single-breath method, breath-holding time was calculated after Jones and Meade (24), and alveolar volume (VA) was determined as the sum of the inspired volume and VR, separately measured with the multibreath helium equilibration. All values were related to the reference values of the European Community for Coal and Steel (ECCS) (22). Raw and SGaw were measured in a pressure-compensated integrated flow plethysmograph (Sensormedics 2800 Autobox) as the chord slopes between inspiratory and expiratory flows of 0.5 Lis at a respiratory rate of 0.5 Hz. Static trans pulmonary pressurevolume curves were determined during apnea from volume recorded at the mouth and from esophageal pressure (esophageal balloon: length 10cm, perimeter 5 em, containing 0.5 ml air, positioned at 40 em from the nares). The static expiratory compliance was calculated as the mean slope (of three curves) between FRC and FRC + 0.5 L. For maximal inspiratory transpulmonary pressure the highest value of three maneuvers was selected. Measured values wererelated to the reference values of Yernault and coworkers (23). Rrs and Xrs were determined by means of a forced oscillation technique described in detail previously (25, 26). Briefly, a pseudorandom noise signal containing all harmonics of 2 to 26 Hz is applied at the mouth. The impedance of the respiratory system obtained from pressures and flows measured at the mouth is partitioned into a real (or Rrs) and an imaginary part (or Xrs). Only values with a coherence function equal to or exceeding 0.95 are retained. The means of three measurements recorded over a period of 16s during quiet breathing with firm support of the cheeks were calculated. Measured values of Rrs and Xrs were related to the reference values of Landser and coworkers (27). To describe the Rrs and Xrs versus frequency relationships, the mean of Rrs and Xrs (Rrs and Xrs) and the average values of the first and second derivatives of Rrs and Xrs with respect to frequency Rrs(l), RrS(2), XfS{1), XfS{2), respectively, were calculated from 6 to 26 Hz according to a method described previously (26). The first and second derivatives represent the slope and the curvature of the Rrsand Xrs-frequency relationships, respectively. In addition, the value of Rrs at a frequency of 6 Hz (Rrs.) was added to the previous parameters. This procedure of computing
923 TABLE 1 RESULTS OF THE PULMONARY FUNCTION TESTS IN ASTHMA (A), CHRONIC BRONCHITIS (B), AND EMPHYSEMA (E)* Group A (n = 27) Age, yr Height, cm Weight, kg VC, % predicted VRpl, % predicted TLCpl, % predicted TLChe, % predicted FRC, % predicted FEV 1, % predicted FEV 1N C, % PEF, % predicted MEF so, % predicted DLCO, % predicted Raw, kPalUs SGaw, s-1/kPa erst, % predicted Ptpmax, % predicted
34 173 74 96 179 118 104 146 55 47 61 25 113 0.37 0.73 113 80
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
9 9 13 15 48 12 11 36 18 13 21 13 20 0.18 0.37 30 25
Group B (n = 28) 63 171 77 91 173 118 100 156 56 46 62 25 103 0.31 0.72 103 79
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
9 8 11 15 43 13 11 30 16 10 16 12 17 0.12 0.40 36 18
Group E (n = 20)
Duncan Test
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
A-BE ABE AB-E AB-AE ABE ABE AB-AE AB-BE ABE ABE ABE ABE A-B-E AB-E ABE AB-E AB-E
61 173 66 102 170 122 109 174 57 41 59 23 55 0.22 0.87 210 50
11 7 11 22 48 10 11 30 23 11 20 14 13 0.10 0.38 53 16
Definition of abbreviations: VC = vital capacity; VRpl = residual volume (body plethysmograph); TLCpl = total lung capacity (body plethysmograph); TLChe = total lung capacity (helium dilution); FRC functional residual capacity; FEV 1 forced expiratory flow in 1 s; PEF peak expiratory flow; MEF 50 = maximal expiratory flow at 50% of the forced 'Vitalcapacity; OLeo = single breath diffusion capacity for CO; Raw airway resistance; SGaw specific airway conductance; Ct.st static lung compliance; Ptpmax = transpulmonary pressure at TLC. • Values are mean ± SO. The fourth column indicates the statistical differences between groups A, B, and E; the groups that are not separated by a hypen do not differ (p > 0.05).
=
=
=
purely descriptive indices to characterize the impedance data, instead of the more frequently used expressions resistance, compliance, and inertance, was preferred because the latter implicitly assume a model of the respiratory system that may not be valid in patients with obstructive lung disease. A Duncan test was used to determine the significance of differences between groups A, B, and E. Correlation coefficients between the various lung function parameters were calculated by linear regression analysis. A discriminant analysis with a backward elimination program was performed on the complete set of indices in groups A, B, and E, with the exception of elastic lung recoil and DLco, which were used as selection criteria.
Results
Routine Lung Function Tests Anthropometric data and mean values of pulmonary function tests are presented in table 1. By virtue of selection asthmatic patients were significantly younger than those with chronic bronchitis and emphysema. The three groups were comparable with regard to height, but the patients with emphysema had significantly lower weight. Groups A, B, and E demonstrated a similar reduction in FEV 1 and in the ratio FEV I/VC. There was no difference in the values of PEF and MEF50 among the three groups. The highest value for Raw was found in group A and the lowest in group E. The difference in Raw between group A and B was not significant. As FRC was most in-
=
=
=
creased in group E, SGaw turned out to be similar in the three groups.
Total Respiratory Resistance and Reactance The mean values of Rrs and Xrs in groups A, B, and E are shown in figure 1 and table 2. The highest values of Rrs were found in group A and the lowest in group E. Rrs, and Rrs were not significantly different between groups Band E. The negative frequency dependence of Rrs and decrease in Xrs were least pronounced in group E. The mean value of the resonant frequency (the frequency at which Xrs is zero) was> 26 Hz for group A, between 24 and 26 Hz for group B, arid between 20 and 22 Hz for group E. When the patients in each of the three groups were subdivided into those with Raw < 0.25 kPa/L/s and those with Raw > 0.25 kPa/L/s, no significant differences in the most relevant forced oscillation indices [Rrs6' RrS(I), Xrs, and Xrs(l)] were found between the corresponding subgroups of A, B, and E. Correlation Between the Various Variables and Discriminant Analysis Table 3 shows the results of the correlation analysis relating FEV 1 (070 of predicted) to Raw, SGaw, and FRC in groups A, B, and E and the combined group (A + B + E). Correlation coefficients between FEV 1 and Raw ranged from - 0.53 to -0.75, the correlation being best in
924
VAN NOORD, CLEMENT, VAN DE WOESTlJNE, AND DEMEDTS
!
!
10
14
,
18
22
,
26
Fig. 1. Mean values and standard errors of total respiratory resistance (Rrs) and reactance (Xrs) as a function of oscillatory frequency in three groups of patients (solidline = A, asthma; dotted line = B, chronic bronchitis; and broken line = E, emphysema). The dashed zone shows the range of corresponding normal values (mean ± 2 SO) (From reference 27formen; unpublished values for women.)
(Hz)
TABLE 2 FORCED OSCILLATION INDICES IN ASTHMA (A), CHRONIC BRONCHITIS (B), AND EMPHYSEMA (E)
Rrs 8 , kPalUs Rrs, kPalUs Rrs(l), kPalUs2 Rrs(2), kPalUs3 Xrs, kPalUs Xrs(1), kPalUs2 Xrs(2), kPalUs3
0.59 0.46 - 0.009 0.001 -0.13 0.012 - 0.0007
± ± ± ± ± ± ±
Group E = 20)
Group B (n = 28)
Group A (n = 27) 0.26 0.14 0.010 0.002 0.16 0.006 0.00015
0.47 0.35 - 0.008 0.001 -0.12 0.013 - 0.0007
± ± ± ± ± ± ±
Duncan Test
(n
0.11 0.06 0.005 0.001 0.08 0.006 0.0012
0.38 0.33 -0.004 - 0.00004 -0.04 0.009 - 0.0007
± ± ± ± ± ± ±
0.13 0.10 0.004 0.00108 0.08 0.004 0.0009
A-BE A-BE AB-E AB-E AB-E AB-AE ABE
Definition of abbreviations: Rrs, = total respiratory resistanceof 6 Hz; Rrs, Rrs(1), and Rrs(2) = mean value, first (slope), and second derivatives(curvature) of total respiratory resistance; Xrs, Xrs(1) and Xrs(2) = mean value,first, and second derivativesof total respiratory reactance. For additional abbreviations, see table 1. Values are means ± 1 SO.
TABLE 3 CORRELATION COEFFICIENTS BETWEEN FEV 1 AND AIRWAY RESISTANCE, SPECIFIC AIRWAY CONDUCTANCE, FUNCTIONAL RESIDUAL CAPACITY· FEV 1 (% predicted)
Raw, kPalUs SGaw, s-l/kPa FRC, % predicted
Group A (n = 27)
Group B (n = 28)
Group E (n = 20)
-0.53t 0.81:t: -0.58t
-0.75:t: 0.81:t: -0.63§
-0.65t 0.88:t: -0.5611
Group A + B (n = 75)
+ E
-0.55:t: 0.82:t: -0.54:t:
• For definition of abbreviations, see table 1.
t p < 0.01. t p < 0.0001. < 0.001. II P < 0.05.
§p
group B and worst in group A. When airway resistance was substituted by airway conductance a better correlation was achieved only in the emphysematous group. The correlation between FEV 1 and SGaw was good and similar in the various groups (r between 0.81 and 0.88) (figure 2). Table 4 shows the correlation coefficients between, on the one hand, FEV 1 , Raw, SGaw, and on the other hand forced oscillation indices. Among the latter Rrs., Rrs(l), and Xrs correlated best with routine lung function indices. Correlation coefficients (Positive or negative) between FEV 1 and Rrs6' Rrs(l), and Xrs ranged from 0.63 to 0.81 in groups Band E and from 0.44 to 0.56 in group A. In general Rrs., Rrs(l), and Xrs correlated better with Raw than with SGaw or
FEV i - In all groups correlations between FRC and forced oscillation indices were poor, r being as a rule less than 0.50. The three most relevant forced oscillation indices [that is, Rrs., Rrs(l), and XfS] were tightly interrelated (figure 3). Discriminant analysis demonstrated that the complete set of variables (routine lung function tests and forced oscillation indices), excluding DLcOand elastic lung recoil (static compliance and transpulmonary pressure at TLC), allowed a significant yet not very good separation between the three groups (A versus B, r = 0.74; A versus E, r = 0.66; B versus E, r = 0.74). A stepwise regression program showed that the indices contributing mostly to the discriminant function between groups A and B were Rrs(l) and Rrs, (r = 0.54), between
groups A and E Rrs, (r = 0.45), and between groups Band E FEV 1 (0/0 of predicted) and Xrs (r = 0.54). Discussion To the best of our knowledge, this is the first study comparing changes in Rrs and Xrs in clearly defined groups of patients with asthma, chronic bronchitis, and emphysema. The patients were carefully selected in an attempt to include only those with relatively pure forms of asthma, chronic bronchitis, and emphysema. The selection of patients with asthma was generally straightforward. In contrast there may be more debate on the division of the COPD patients into the bronchitic (B) and the emphysematous (E) group. The patients with COPD were chosen on the basis of clinical assessment and functional data. It has been shown that pulmonary function tests are more sensitive indicators of emphysema than the standard chest roentgenogram (28) and that the combined measurements of DLcO and lung elastic recoil are useful in vivo predictors of emphysema (29-31). However, Pare and colleagues (32) demonstrated that DLcO cannot detect mild emphysema [score < 20 according to Thurlbeck (33)]. Furthermore, Petty and coworkers (34) found in excised lungs that changes in elastic recoil and small airways disease are generally interrelated. For these reasons it can be assumed that group B included patients with predominant intrinsic airway disease and little emphysema, whereas group E consisted of patients with predominant emphysema and a certain amount of intrinsic airway narrowing. The mean reduction in FEV 1 in groups A, B, and E was comparable. This result is connected with the fact that group E included several patients with early emphysema with little airway obstruction (35, 36). DLCO was the only parameter among the routine lung function tests that could distinguish between groups A, B, and E (table 1). Airway resistance was significantly lower in group E than in groups A and B, whereas SGaw was not significantly different among the three groups. Previous studies (18, 19) demonstrated that lung conductance measured at FRC cannot reliably differentiate between asthma and emphysema or bronchitis and emphysema because both intrinsic airway narrowing and the decrease in lung elastic recoil cause an increase in airway resistance. This study indicates that the
925
OBSTRUCTIVE WNG DISEASE AND RESPIRATORY IMPEDANCE
FEV1
(% Pred )
•
••
100
o * o * o * 0 ... cv* if2 ~ * • *0 •• ***@ 0 . . , 00 0 o ** 'b*. * I
80
Fig. 2. Relationship between FEV, (% of predicted) and specific airway conductance in asthma (asterisks = group A). chronic bronchitis (open circles = group B), and emphysema (closed circles = group E).
*
*
60 40
* 0". ~.. * *
20
.2
.4
•
•
* ·0
0
0
*
•
.8
.6
1.0
1.2
1.4
sGaw
(s-1· k p a-1)
1.6
TABLE 4 CORRELATION COEFFICIENTS BETWEEN FORCED OSCILLATION INDICES AND FEV1 , AIRWAY RESISTANCE, SPECIFIC AIRWAY CONDUCTANCE· Group
Indices
Rrs6
Rrs
Rrs(1)
Xrs
Xrs(1)
A (n
= 27)
FEV1 Raw SGaw
- 0.44t 0.86§ -0.66§
-0.33 0.78§ -0.54+
0.46t -0.84§ 0.67§
0.56+ -0.89t 0.73§
-0.42t 0.49+ -0.47t
B (n
= 28)
FEV1 Raw SGaw
-0.70§ 0.84§ -0.77§
-0.33 0.45t -0.37
0.72§ -0.88§ 0.80§
0.70§ -0.86§ 0.77§
-0.69§ 0.67§ -0.68§
E (n
=
FEV, Raw SGaw
-0.63+ 0.79§ -0.70§
-0.43 0.61+ -0.50t
0.81§ -0.80§ 0.86§
0.75§ -0.86§ 0.81§
-0.29 0.73§ -0.47t
FEV 1 Raw SGaw
-0.47§ 0.86§ -0.63§
-0.31+ 0.71§ -0.44§
0.53§ -0.85§ 0.69§
0.57§ -0.88§ 0.72§
-0.45§ 0.58§ -0.56§
20)
A + B + E (n
= 75)
• For definition of abbreviations, (% predicted). t p < 0.05. :j: P < 0.01. § p < 0.001.
see table 1. All parameters in absolute values, except for FEV,
correlation between SGaw and FEV 1 in the different entities is high and comparable, despite the different methods of measurement (that is, quiet breathing versus forced expiration) and despite the different mechanisms of airway narrowing. This observation is in line with the results of Pelzer and Thomson (37).Accordingly the weaker correlation between Raw and FEV 1 must be because this relationship is not linear and the influence of FRe at which Raw is obtained cannot be ignored. In all groups alterations of Rrs and Xrs consisted of an increase in Rrs with a negative frequency dependence and a decrease in Xrs, a pattern characteristic of obstructive lung disease (12). The changes in the forced oscillation indices were proportional to that in Raw. Thus Rrs and Xrs can be used as an alternative for Raw. Rrs, and Rrs were increased most in group A, whereas Rrs(l) and xrs were changed least in group E. Among the forced oscillation indices Rrs., Rrs(l), and Xrs correlated best with Raw. The relationship between Raw and Rrs is com-
plex; however, Rrs is obtained at higher frequencies than Raw, Rrs includes tissue resistance, and Rrs underestimates resistance in the presence of airway obstruction due to shunt of the upper airway (38, 39). Because of the frequency dependence of Rrs the correlation between Rrs and Raw tended to be less than that between Rrs, and Raw. FEV 1 is by far the most important parameter to evaluate airflow obstruction and the only test generally recommended for routine use (40). Hence to be acceptable for diagnostic purposes new tests to assess airway obstruction must be highly correlated with FEV 1 or provide important additional information. With regard to the first point, in the present study forced oscillation indices were poorly correlated with FE V1 at least in group A and in the combined group. Several mechanisms may be responsible for this lack of good correlation. First, Rrs and Xrs are measured during quiet breathing and FEV 1 is obtained during a forced expiration with high flows and dynamic compression of the central air-
ways. As pointed out earlier this factor seems not to be of major influence, as the correlation between SGaw and FEV 1 is good. Second, the influence of the volume at which Rrs and Xrs are measured cannot be ignored. The increase in resistance due to airway narrowing is obscured by the concurrent increase in FRC. As a result a poor correlation was found between Rrs and FRe in all groups. Third, the deep inspiration before the forced expiration can cause bronchoconstriction at least in asthmatic patients (41). This factor may account for the fact that the correlation between FEV 1 and resistance parameters was poorest in group A. Our findings are in contrast with those of Konig and colleagues (14), who found a good correlation between forced oscillation and spirometric indices, both expressed in absolute values, in asthmatic children between 4 and 17 yr of age. It can be supposed that in the latter study the correlation not only reflected the effects of asthma but also those of growth on the indices. The second point concerns the question of whether forced oscillation data provide additional information with respect to FEV l • With the method that we used Rrs and Xrs can be obtained rapidly over a wide range of frequencies, and when a specific model of the respiratory system is assumed values for resistance, compliance, and inertance can be derived. Michaelson and coworkers (5) concluded that Rrs and Xrs curves in patients with COPD were best explained by Mead's model of the lung (42), and on the basis of this model attempts have been made to estimate central and peripheral airway resistance (15). However, from more recent studies it became obvious that a precise correction for the shunt properties of the upper airway is a prerequisite for such an analysis (38). Furthermore it is obvious that even complex models are at best a crude representation of the respiratory system, in particular in disease, and are based on assumptions that may be not realistic, for instance a non-frequency-dependent behavior of tissues. Lutchen and colleagues (43) pointed out that extracting parameter estimates from a given model is technically demanding and requires a statistical evaluation of the reliability of the procedure. Even then the physiologic appropriateness of the estimates may be questionable (44). For these reasons we decided not to carry out a model simulation of the measured impedance data, but preferred to characterize the impedance
926
VAN NOORD, CLEMENT, VAN DE WOESTIJNE, AND DEMEDTS
'02~
.00
-.02
•....... *
-.04
... ... I
.5
.0
~
0 •
1.0
1.5 Rrs6 (kPa'l. -l. s )
.01
•• ~* # ....
.00
,~ o ~
-.01
-.02
*.:.
•
-.03 -.04
,
.0
Fig. 3. Correlations between the indices of the forced oscillation technique: total respiratory resistance at 6 Hz, Rrs 8 ; average slope of Rrs, Rrs(l); average level of Xrs, Xrs. Asterisks = asthma; open circles == bronchitis; closed circles = emphysema.
...
•
I
1.0
.5
1.5 RrS6(kPa.I-1.s)
'OOf -.02
... -.04
•
• -.6
-.5
-.4
-.3
-.2
-.1
.0
.1 Xrs
curves by descriptive indices and subsequently to determine the relationships between the various routine lung function and forced oscillation parameters. This analysis yielded a number of clues of interest to clinical use. First, in all groups Rrs., Rrs(l), and Xrs were all highly correlated. Especially between Rrs(l) and Xrs a very tight linear relationship was found (figure 3). Second, for comparable values of FEV 1 in asthma, chronic bronchitis, and emphysema Rrs, and Rrs were significantly larger in asthma than in the other groups, and Xrs was significantly less negative in emphysema than in the other groups (table 2). This indicates that the use of two indices may be of interest for diagnostic purposes: an index of resistance to separate asthma and an index of reactance to separate emphysema from the other two groups. In addition, a discriminant analysis retained forced oscillation parameters as the most important factors among the lung function indices investigated, discriminating best among the three groups. The separation is weak and cannot be used for diagnosis in a particular subject. It is possible, however, that the technique, because it did not correct for the shunt
.2
.3
1.s) CkPa·I·
properties of the upper airway, obscured some of the distinctive features of the impedance curves between the groups. A correction calculated on the basis of the average upper airway shunt characteristics determined in healthy adults (45) showed, indeed, that the increase in Rrs due to the correction is more pronounced in asthma than in chronic bronchitis and emphysema. This improves the separation between the asthmatic group and the other two groups. It is therefore likely that a modified forced oscillation technique reducing the upper airway shunt (38) would discriminate better between asthma and the other obstructive lung diseases. This should be verified by direct measurements. References 1. Dubois AB, Brody AW, LewisDH, Burgess BF Jr. Oscillation mechanics of lungs and chest in man. J Appl Physiol 1956; 8:587-94. 2. Grimby G, Takishima T, Graham W, Macklem P, Mead J. Frequency dependence of flow resistance in patients with obstructive lung disease. J Clin Invest 1968; 47:1455-65. 3. Hyatt RE, Zimmerman IR, Peters EM, Sullivan WJ. Direct writeout of total respiratory resistance. J Appl Physiol 1970; 28:675-8. 4. Stanescu DC, Fesler R, Veriter C, Frans A, Brasseur L. A modified measurement of respira-
tory resistance by forced oscillation during normal breathing. J Appl Physiol 1975; 39:305-11. 5. MichaelsonED, Grassman ED, PetersWR. Pulmonary mechanics by spectral analysis of forced random noise. J Clin Invest 1975; 1210-30. 6. Fisher AB, Dubois AB, Hyde RW.Evaluation of the forced oscillation technique for the determination of resistance to breathing. J Clin Invest 1968; 47:2045-57. 7. Petro W, Von Nieding G, Boll W, Schmidt V. Determination of respiratory resistance by an oscillation method. Respiration 1981; 42:243-51. 8. Sobol BJ. Tests of ventilatory function not requiring maximal subject effort. II. The measurement of total respiratory impedance. Am RevRespir Dis 1968; 97:868-79. 9. Hayes DA, Pimmel RL, Fullton JM, Bromberg PA. Detection of respiratory mechanical dysfunction by forced random noise impedance parameters. Am Rev Respir Dis 1979; 120:1095-100. 10. Muller E, Vogel J. Messung und Modellinterpretation neuer atemmechanischer Parameter. Z Erkr Atmungsorgane 1981; 157:340-4. 11. Holle JP, Landser FJ, Schuller B, Hartmann V, Magnussen H. Measurement of respiratory mechanics with forced oscillations. Comparison of two methods (Siregnost FD 5 versus a pseudorandom noise technique). Respiration 1981; 41:119-27. 12. Clement J, Landser FJ, Van de Woestijne KP. Total resistance and reactance in patients with respiratory complaints with and without airway obstruction. Chest 1983; 83:215-20. 13. Aronsson H, Solymar L, Dempsey J, Bjure J, Olsson T, Bake B. A modified forced oscillation technique for measurements of respiratory resistance. J Appl Physiol 1977; 42:650-5. 14. Konig P, Hordvik NL, Pimmel RL. Forced random noise resistancedetermination in childhood asthma. Chest 1984; 86:884-90. 15. Pimmel RL, Fullton JM, Ginsberg JF, et al. Correlation of airway resistance with forced random noise resistance parameters. J Appl Physiol 1981; 51:33-9. 16. Despas PJ, Leroux M, Macklem PT. Site of airways obstruction in asthma as determined by measuring maximal expiratory flow breathing air and a helium-oxygen mixture. J Clin Invest 1972; 51:3235-43. 17. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968; 278: 1355-60. 18. Leaver CG, Tattersfield AE, Pride NB. Contributions of loss of lung recoil and of enhanced airways collapsibility to the airflow obstruction of chronic bronchitis and emphysema. J Clin Invest 1973; 52:2117-28. 19. Colebatch HJH, Finucane KE, Smith MM. Pulmonary conductance and elastic recoil relationship in asthma and emphysema. J Appl Physiol 1973; 34:143-53. 20. Verma VK, Cockcroft DW, Dosman JA. Airway responsiveness to inhaled histamine in chronic obstructive airways disease. Chronic bronchitis vs. emphysema. Chest 1988; 94:457-61. 21. Ciba Guest Symposium. Terminology,definitions and classifications of chronic pulmonary emphysema and related conditions. Thorax 1959; 14:286-99. 22. Quanjer PH, ed. Standardized lung function testing. Report Working Party Standardization of lung function tests. Bull Eur Physiopathol Respir 1983; 19(5uppl 5:1-95). 23. Yernault JC, Baran D, Engbert M. Effect of growing and aging on the static mechanical lung properties. Bull Eur Physiopathol Respir 1977;
OBSTRUCTIVE LUNG DISEASE AND RESPIRATORY IMPEDANCE
13:777-88. 24. Jones RS, Meade F. A theoretical and experimental analysis of anomalies in the estimation of pulmonary diffusing capacity by the singlebreath method. Q J Exp Physiol1961; 46:131-43. 25. Landser FJ, Nagels J, Demedts M, Billiet L, Van de Woestijne KP. A new method to determine frequency characteristics of the respiratory system. J Appl Physiol 1976; 41:101-6. 26. Nagels J, Landser FJ, Van der Linden L, Clement J, Van de Woestijne KP. Mechanical properties of lungs and chest wall during spontaneous breathing. J Appl Physiol 1980; 49:408-16. 27. Landser FJ, Clement J, Van de Woestijne KP. Normal values of total respiratory resistance and reactance determined by forced oscillations. Influence of smoking. Chest 1982; 81:586-91. 28. Thurlbeck WM. Overview of the pathology of pulmonary emphysemain the human. Clin Chest Med 1983; 4:337-50. 29. Park SS, Janis M, Shim CS, Williams MH Jr. Relationship of bronchitis and emphysema to altered pulmonary function. Am RevRespir Dis 1970; 102:927-36. 30. Boushy SF, Aboumrad MH, North LB, Helgason AH. Lung recoil pressure, airway resistance and forced flows related to morphologic emphysema. Am Rev Respir Dis 1971; 104:551-61.
31. West WW, Nagai A, Hodgkin JE, Thurlbeck WM. The National Institutes of Health intermittent positive pressure breathing trial- pathology studies. III. The diagnosis of emphysema. Am Rev Respir Dis 1987; 135:123-9. 32. Pare PD, Brooks LA, Bates J, Lawson LM, Nelems JMB, Wright JL, Hogg JC. Exponential analysis of the lung pressure volume curve as a predictorof pulmonary emphysema.Am RevRespir Dis 1982; 126:54-61. 33. Thurlbeck WM. Measurement of pulmonary emphysema. Am Rev Respir Dis 1967; 95:752-64. 34. Petty TL, SilversGW,Stanford RE. Small airwaydisease is associated with elastic recoil changes in excised human lungs. Am Rev Respir Dis 1984; 130:42-5. 35. Demedts M, Aumann J. Early emphysema. Ten years' evolution. Chest 1988; 94:337-42. 36. Gelb AF, Gold WM, Wright RR, Bruch HR, Nadel JA. Physiologic diagnosis of subclinical emphysema. Am Rev Respir Dis 1973; 107:50-63. 37. Pelzer AM, Thomson ML. Body plethysmographic measurements of airway conductance in obstructive pulmonary diseases.Am RevRespir Dis 1969; 99:194-204. 38. Peslin R, Duvivier C, Gallina C, Cervantes P. Upper airway artifact in respiratory impedance measurements. Am RevRespirDis 1985; 132:712-4.
927 39. Cauberghs M, Van de Woestijne KP. Mechanical properties of the upper airway. J Appl Physiol 1983; 55:335-42. 40. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987; 136:225-44. 41. Gayrard P, Orehek J, Grimaud C, Charpin J. Bronchoconstrictor effects of a deep inspiration in patients with asthma. Am Rev Respir Dis 1975; 111:433-9. 42. Mead J. Contribution of compliance of airways to frequency-dependent behavior of lungs. J Appl Physiol 1969; 26:670-3. 43. Lutchen KR, Jackson AC. Reliability of parameter estimates from models applied to the respiratory impedance data. J Appl Physiol 1987; 62:403-13. 44. Lutchen KR, Hantos Z, Jackson AC. Importance of low-frequency impedance data for reliably quantifying parallel inhomogeneities of respiratory mechanics. IEEE Trans Biomed Eng 1988; 35:472-80. 45. Cauberghs M, Van de Woestijne KP. Effect of upper airway shunt and series properties on respiratory impedance measurements. J Appl Physiol 1989; 66:2274-9.
J. A. VAN NOORD, J. CLEMENT, K. P. VAN DE WOESTIJNE, and M. DEMEDTS
Introduction
Since the original description of the forced oscillation technique by Dubois and colleagues (1) in 1956, a number of studies have been published concerning the application of the method in patients with chronic obstructive lung disease (COPD) (2-12) and with asthma (11-14). In these patients total respiratory resistance (Rrs) and reactance (Xrs) versusfrequency curves are characterized by an increase in Rrs, a decrease in Rrs with frequency, and a decrease in Xrs (12). It has been shown in a heterogeneous group of patients with COPD and asthma that the alterations of the curves were most pronounced in the patients with the most severe obstruction as assessed by the reduction in the FEV 1 (12). Furthermore, Rrs measured at low frequencies has been shown to have an excellent correlation with airway resistance (Raw) (15). Airflow obstruction and narrowing of the airways can be caused by different pathologic conditions. Asthma is characterized by variable widespread airway narrowing due to bronchial muscle contraction, edema and infiltration of the bronchial mucosa, and mucus plugging. Studies of changes in the density dependence of maximal flows suggest that the major site of airflow limitation may vary from the large to the peripheral airways (16). In COPD the morphologic basis of the largely irreversible airflow limitation are varying combinations of inflammatory and fibrotic narrowing of the peripheral airways (17) and loss of elastic lung recoil with enhanced collapsibility of central airways (18, 19). Detailed comparative studies on Rrs and Xrs in wellcharacterized groups of patients with asthma, chronic bronchitis, and emphysema are lacking. Particularly it is not known whether the different mechanisms of airflow obstruction in asthma, chronic bronchitis, and emphysema produce different patterns of Rrs and Xrs versus frequency curves. In the present study we compared Rrs 922
SUMMARY A comparison was made of total respiratory resistance (Rrs) and reactance (Xrs) determined between 6 and 26 Hz by means of a forced oscillation technique in 27 patients with asthma (group A), 28 patients with chronic bronchitis (group B), and 20 patients with emphysema (group E) to examine whether the method can provide data capable of distinguishing among these diseases. The three groups demonstrated a similar reduction In the FEV1 • In addition, static and dynamic lung volumes, maximal expiratory flows, diffusing capacity for CO, airway resistance (Raw), and elastic lung recoil were measured. The observed alterations of Rrs and Xrs consisted of an increase in Rrs, a decrease in Rrs with frequency, and a decrease in Xrs. However, significant differences were found between the three groups: Rrs at 6 Hz and average Rrs were most increased In group A, whereas the negative frequency dependence of Rrs and the decrease in Xrs were least pronounced In group E. In all groups Rrs at 6 Hz, the average slope of Rrs, and the average level of Xrs were tightly interrelated and showed in addition a high correlation with airway resistance; the correlations with FEV1 were less satisfactory. Discriminant analysis performed on the complete set of data, excluding diffusing capacity and elastic lung recoil, which were used as selection criteria, demonstrated that forced oscillation parameters were the most important factors discriminating AM REV RESPIR DIS 1991; 143:922-927 among the groups.
and Xrs in clearly defined groups with an on-average similar reduction in FEV 1 due to asthma, chronic bronchitis, and emphysema. The changes in Rrs and Xrs wererelated to those in routine lung function tests, and a discriminant analysis was performed to investigate which pulmonary function measurement discriminated best among the three groups. Methods Patients A total of 27 patients, 6 females and 21males, with asthma (group A), 28 patients, all males, with chronic bronchitis (group B), and 20 patients, all males, with emphysema (group E) were selected. All patients in group A had a history of varying dyspnea, cough, and wheezing. The onset of the disease had to be before the age of 35 yr, and airway obstruction had to be largely reversible at some time in the preceding 3 yr, although in some patients this was achieved only during admission and treatment with high doses of corticosteroids. Of the patients 6 were smokers and 14wereatopic. They all had documented airway hyperresponsiveness to histamine (PD 20 FEV 1 < 8 mg/ml). Bronchial hyperreactivity was not taken as a selection criterion, however, as it can be found in patients with both asthma and COPD (20). For group Band E only patients with COPD who could be easily categorized as predominantly bronchitic or emphysematous were selected. All were middle-aged or
older persons and current or exsmokers and had negative skin tests. The patients in group B had a history of chronic cough and sputum production for at least 3 months of each of the 2 preceding yr (21). Diffusing capacity (Dtco) had to be more than 800/0 of predicted (22). All patients of group E had exertional dyspnea and little sputum production, DLco had to be less than 70% of predicted (22), and static lung compliance more than 150070 of predicted (23). In many patients the chest radiograph demonstrated overinflation and vascular attenuation. However, the latter findings were not used in the selection. None of the patients in groups A, B, and E had clinical or radiologic evidence of other complicating lung diseases. They abstained from all medication, except for corticosteroids, for at least 12 h before the measurements.
Methods The pulmonary function measurements con(Receivedin originalform November 17, 1989 and in revised form November 16, 1990) 1 From the Clinic for Pneumology, Catholic University, Leuven, Belgium. 2 Supported by a grant from the Nederlands Astrna Fonds, the Fonds voor Geneeskundig Wetenschappelijk Onderzoek, and the European Community for Coal and Steel. 3 Correspondence and requests for reprints should be addressed to M. Demedts, Kliniek voor Longziekten, Universitaire Ziekenhuizen, Weligerveld 1, B-3041 Pellenberg, Belgium.
OBSTRUCTIVE LUNG DISEASE AND RESPIRATORY IMPEDANCE
sisted of static and dynamic lung volumes, maximal expiratory flow-volume (MEFV) curves, diffusing capacity (Dtoo), airway resistance (Raw), specific airway conductance (SGaw), elastic lung recoil, and Rrs and Xrs versus frequency curves. Vital capacity (VC), total lung capacity (TLC), residual volume (VR), and FEV 1 were obtained by standard methods of spirometry and multibreath helium equilibration. In addition TLC was determined in a body plethysmograph. Peak expiratory flow (PEF) and maximal expiratory flow at 50070 of the forced vital capacity (MEF 50) were obtained from MEFV curves measured at the mouth. DLCO was measured with the single-breath method, breath-holding time was calculated after Jones and Meade (24), and alveolar volume (VA) was determined as the sum of the inspired volume and VR, separately measured with the multibreath helium equilibration. All values were related to the reference values of the European Community for Coal and Steel (ECCS) (22). Raw and SGaw were measured in a pressure-compensated integrated flow plethysmograph (Sensormedics 2800 Autobox) as the chord slopes between inspiratory and expiratory flows of 0.5 Lis at a respiratory rate of 0.5 Hz. Static trans pulmonary pressurevolume curves were determined during apnea from volume recorded at the mouth and from esophageal pressure (esophageal balloon: length 10cm, perimeter 5 em, containing 0.5 ml air, positioned at 40 em from the nares). The static expiratory compliance was calculated as the mean slope (of three curves) between FRC and FRC + 0.5 L. For maximal inspiratory transpulmonary pressure the highest value of three maneuvers was selected. Measured values wererelated to the reference values of Yernault and coworkers (23). Rrs and Xrs were determined by means of a forced oscillation technique described in detail previously (25, 26). Briefly, a pseudorandom noise signal containing all harmonics of 2 to 26 Hz is applied at the mouth. The impedance of the respiratory system obtained from pressures and flows measured at the mouth is partitioned into a real (or Rrs) and an imaginary part (or Xrs). Only values with a coherence function equal to or exceeding 0.95 are retained. The means of three measurements recorded over a period of 16s during quiet breathing with firm support of the cheeks were calculated. Measured values of Rrs and Xrs were related to the reference values of Landser and coworkers (27). To describe the Rrs and Xrs versus frequency relationships, the mean of Rrs and Xrs (Rrs and Xrs) and the average values of the first and second derivatives of Rrs and Xrs with respect to frequency Rrs(l), RrS(2), XfS{1), XfS{2), respectively, were calculated from 6 to 26 Hz according to a method described previously (26). The first and second derivatives represent the slope and the curvature of the Rrsand Xrs-frequency relationships, respectively. In addition, the value of Rrs at a frequency of 6 Hz (Rrs.) was added to the previous parameters. This procedure of computing
923 TABLE 1 RESULTS OF THE PULMONARY FUNCTION TESTS IN ASTHMA (A), CHRONIC BRONCHITIS (B), AND EMPHYSEMA (E)* Group A (n = 27) Age, yr Height, cm Weight, kg VC, % predicted VRpl, % predicted TLCpl, % predicted TLChe, % predicted FRC, % predicted FEV 1, % predicted FEV 1N C, % PEF, % predicted MEF so, % predicted DLCO, % predicted Raw, kPalUs SGaw, s-1/kPa erst, % predicted Ptpmax, % predicted
34 173 74 96 179 118 104 146 55 47 61 25 113 0.37 0.73 113 80
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
9 9 13 15 48 12 11 36 18 13 21 13 20 0.18 0.37 30 25
Group B (n = 28) 63 171 77 91 173 118 100 156 56 46 62 25 103 0.31 0.72 103 79
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
9 8 11 15 43 13 11 30 16 10 16 12 17 0.12 0.40 36 18
Group E (n = 20)
Duncan Test
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
A-BE ABE AB-E AB-AE ABE ABE AB-AE AB-BE ABE ABE ABE ABE A-B-E AB-E ABE AB-E AB-E
61 173 66 102 170 122 109 174 57 41 59 23 55 0.22 0.87 210 50
11 7 11 22 48 10 11 30 23 11 20 14 13 0.10 0.38 53 16
Definition of abbreviations: VC = vital capacity; VRpl = residual volume (body plethysmograph); TLCpl = total lung capacity (body plethysmograph); TLChe = total lung capacity (helium dilution); FRC functional residual capacity; FEV 1 forced expiratory flow in 1 s; PEF peak expiratory flow; MEF 50 = maximal expiratory flow at 50% of the forced 'Vitalcapacity; OLeo = single breath diffusion capacity for CO; Raw airway resistance; SGaw specific airway conductance; Ct.st static lung compliance; Ptpmax = transpulmonary pressure at TLC. • Values are mean ± SO. The fourth column indicates the statistical differences between groups A, B, and E; the groups that are not separated by a hypen do not differ (p > 0.05).
=
=
=
purely descriptive indices to characterize the impedance data, instead of the more frequently used expressions resistance, compliance, and inertance, was preferred because the latter implicitly assume a model of the respiratory system that may not be valid in patients with obstructive lung disease. A Duncan test was used to determine the significance of differences between groups A, B, and E. Correlation coefficients between the various lung function parameters were calculated by linear regression analysis. A discriminant analysis with a backward elimination program was performed on the complete set of indices in groups A, B, and E, with the exception of elastic lung recoil and DLco, which were used as selection criteria.
Results
Routine Lung Function Tests Anthropometric data and mean values of pulmonary function tests are presented in table 1. By virtue of selection asthmatic patients were significantly younger than those with chronic bronchitis and emphysema. The three groups were comparable with regard to height, but the patients with emphysema had significantly lower weight. Groups A, B, and E demonstrated a similar reduction in FEV 1 and in the ratio FEV I/VC. There was no difference in the values of PEF and MEF50 among the three groups. The highest value for Raw was found in group A and the lowest in group E. The difference in Raw between group A and B was not significant. As FRC was most in-
=
=
=
creased in group E, SGaw turned out to be similar in the three groups.
Total Respiratory Resistance and Reactance The mean values of Rrs and Xrs in groups A, B, and E are shown in figure 1 and table 2. The highest values of Rrs were found in group A and the lowest in group E. Rrs, and Rrs were not significantly different between groups Band E. The negative frequency dependence of Rrs and decrease in Xrs were least pronounced in group E. The mean value of the resonant frequency (the frequency at which Xrs is zero) was> 26 Hz for group A, between 24 and 26 Hz for group B, arid between 20 and 22 Hz for group E. When the patients in each of the three groups were subdivided into those with Raw < 0.25 kPa/L/s and those with Raw > 0.25 kPa/L/s, no significant differences in the most relevant forced oscillation indices [Rrs6' RrS(I), Xrs, and Xrs(l)] were found between the corresponding subgroups of A, B, and E. Correlation Between the Various Variables and Discriminant Analysis Table 3 shows the results of the correlation analysis relating FEV 1 (070 of predicted) to Raw, SGaw, and FRC in groups A, B, and E and the combined group (A + B + E). Correlation coefficients between FEV 1 and Raw ranged from - 0.53 to -0.75, the correlation being best in
924
VAN NOORD, CLEMENT, VAN DE WOESTlJNE, AND DEMEDTS
!
!
10
14
,
18
22
,
26
Fig. 1. Mean values and standard errors of total respiratory resistance (Rrs) and reactance (Xrs) as a function of oscillatory frequency in three groups of patients (solidline = A, asthma; dotted line = B, chronic bronchitis; and broken line = E, emphysema). The dashed zone shows the range of corresponding normal values (mean ± 2 SO) (From reference 27formen; unpublished values for women.)
(Hz)
TABLE 2 FORCED OSCILLATION INDICES IN ASTHMA (A), CHRONIC BRONCHITIS (B), AND EMPHYSEMA (E)
Rrs 8 , kPalUs Rrs, kPalUs Rrs(l), kPalUs2 Rrs(2), kPalUs3 Xrs, kPalUs Xrs(1), kPalUs2 Xrs(2), kPalUs3
0.59 0.46 - 0.009 0.001 -0.13 0.012 - 0.0007
± ± ± ± ± ± ±
Group E = 20)
Group B (n = 28)
Group A (n = 27) 0.26 0.14 0.010 0.002 0.16 0.006 0.00015
0.47 0.35 - 0.008 0.001 -0.12 0.013 - 0.0007
± ± ± ± ± ± ±
Duncan Test
(n
0.11 0.06 0.005 0.001 0.08 0.006 0.0012
0.38 0.33 -0.004 - 0.00004 -0.04 0.009 - 0.0007
± ± ± ± ± ± ±
0.13 0.10 0.004 0.00108 0.08 0.004 0.0009
A-BE A-BE AB-E AB-E AB-E AB-AE ABE
Definition of abbreviations: Rrs, = total respiratory resistanceof 6 Hz; Rrs, Rrs(1), and Rrs(2) = mean value, first (slope), and second derivatives(curvature) of total respiratory resistance; Xrs, Xrs(1) and Xrs(2) = mean value,first, and second derivativesof total respiratory reactance. For additional abbreviations, see table 1. Values are means ± 1 SO.
TABLE 3 CORRELATION COEFFICIENTS BETWEEN FEV 1 AND AIRWAY RESISTANCE, SPECIFIC AIRWAY CONDUCTANCE, FUNCTIONAL RESIDUAL CAPACITY· FEV 1 (% predicted)
Raw, kPalUs SGaw, s-l/kPa FRC, % predicted
Group A (n = 27)
Group B (n = 28)
Group E (n = 20)
-0.53t 0.81:t: -0.58t
-0.75:t: 0.81:t: -0.63§
-0.65t 0.88:t: -0.5611
Group A + B (n = 75)
+ E
-0.55:t: 0.82:t: -0.54:t:
• For definition of abbreviations, see table 1.
t p < 0.01. t p < 0.0001. < 0.001. II P < 0.05.
§p
group B and worst in group A. When airway resistance was substituted by airway conductance a better correlation was achieved only in the emphysematous group. The correlation between FEV 1 and SGaw was good and similar in the various groups (r between 0.81 and 0.88) (figure 2). Table 4 shows the correlation coefficients between, on the one hand, FEV 1 , Raw, SGaw, and on the other hand forced oscillation indices. Among the latter Rrs., Rrs(l), and Xrs correlated best with routine lung function indices. Correlation coefficients (Positive or negative) between FEV 1 and Rrs6' Rrs(l), and Xrs ranged from 0.63 to 0.81 in groups Band E and from 0.44 to 0.56 in group A. In general Rrs., Rrs(l), and Xrs correlated better with Raw than with SGaw or
FEV i - In all groups correlations between FRC and forced oscillation indices were poor, r being as a rule less than 0.50. The three most relevant forced oscillation indices [that is, Rrs., Rrs(l), and XfS] were tightly interrelated (figure 3). Discriminant analysis demonstrated that the complete set of variables (routine lung function tests and forced oscillation indices), excluding DLcOand elastic lung recoil (static compliance and transpulmonary pressure at TLC), allowed a significant yet not very good separation between the three groups (A versus B, r = 0.74; A versus E, r = 0.66; B versus E, r = 0.74). A stepwise regression program showed that the indices contributing mostly to the discriminant function between groups A and B were Rrs(l) and Rrs, (r = 0.54), between
groups A and E Rrs, (r = 0.45), and between groups Band E FEV 1 (0/0 of predicted) and Xrs (r = 0.54). Discussion To the best of our knowledge, this is the first study comparing changes in Rrs and Xrs in clearly defined groups of patients with asthma, chronic bronchitis, and emphysema. The patients were carefully selected in an attempt to include only those with relatively pure forms of asthma, chronic bronchitis, and emphysema. The selection of patients with asthma was generally straightforward. In contrast there may be more debate on the division of the COPD patients into the bronchitic (B) and the emphysematous (E) group. The patients with COPD were chosen on the basis of clinical assessment and functional data. It has been shown that pulmonary function tests are more sensitive indicators of emphysema than the standard chest roentgenogram (28) and that the combined measurements of DLcO and lung elastic recoil are useful in vivo predictors of emphysema (29-31). However, Pare and colleagues (32) demonstrated that DLcO cannot detect mild emphysema [score < 20 according to Thurlbeck (33)]. Furthermore, Petty and coworkers (34) found in excised lungs that changes in elastic recoil and small airways disease are generally interrelated. For these reasons it can be assumed that group B included patients with predominant intrinsic airway disease and little emphysema, whereas group E consisted of patients with predominant emphysema and a certain amount of intrinsic airway narrowing. The mean reduction in FEV 1 in groups A, B, and E was comparable. This result is connected with the fact that group E included several patients with early emphysema with little airway obstruction (35, 36). DLCO was the only parameter among the routine lung function tests that could distinguish between groups A, B, and E (table 1). Airway resistance was significantly lower in group E than in groups A and B, whereas SGaw was not significantly different among the three groups. Previous studies (18, 19) demonstrated that lung conductance measured at FRC cannot reliably differentiate between asthma and emphysema or bronchitis and emphysema because both intrinsic airway narrowing and the decrease in lung elastic recoil cause an increase in airway resistance. This study indicates that the
925
OBSTRUCTIVE WNG DISEASE AND RESPIRATORY IMPEDANCE
FEV1
(% Pred )
•
••
100
o * o * o * 0 ... cv* if2 ~ * • *0 •• ***@ 0 . . , 00 0 o ** 'b*. * I
80
Fig. 2. Relationship between FEV, (% of predicted) and specific airway conductance in asthma (asterisks = group A). chronic bronchitis (open circles = group B), and emphysema (closed circles = group E).
*
*
60 40
* 0". ~.. * *
20
.2
.4
•
•
* ·0
0
0
*
•
.8
.6
1.0
1.2
1.4
sGaw
(s-1· k p a-1)
1.6
TABLE 4 CORRELATION COEFFICIENTS BETWEEN FORCED OSCILLATION INDICES AND FEV1 , AIRWAY RESISTANCE, SPECIFIC AIRWAY CONDUCTANCE· Group
Indices
Rrs6
Rrs
Rrs(1)
Xrs
Xrs(1)
A (n
= 27)
FEV1 Raw SGaw
- 0.44t 0.86§ -0.66§
-0.33 0.78§ -0.54+
0.46t -0.84§ 0.67§
0.56+ -0.89t 0.73§
-0.42t 0.49+ -0.47t
B (n
= 28)
FEV1 Raw SGaw
-0.70§ 0.84§ -0.77§
-0.33 0.45t -0.37
0.72§ -0.88§ 0.80§
0.70§ -0.86§ 0.77§
-0.69§ 0.67§ -0.68§
E (n
=
FEV, Raw SGaw
-0.63+ 0.79§ -0.70§
-0.43 0.61+ -0.50t
0.81§ -0.80§ 0.86§
0.75§ -0.86§ 0.81§
-0.29 0.73§ -0.47t
FEV 1 Raw SGaw
-0.47§ 0.86§ -0.63§
-0.31+ 0.71§ -0.44§
0.53§ -0.85§ 0.69§
0.57§ -0.88§ 0.72§
-0.45§ 0.58§ -0.56§
20)
A + B + E (n
= 75)
• For definition of abbreviations, (% predicted). t p < 0.05. :j: P < 0.01. § p < 0.001.
see table 1. All parameters in absolute values, except for FEV,
correlation between SGaw and FEV 1 in the different entities is high and comparable, despite the different methods of measurement (that is, quiet breathing versus forced expiration) and despite the different mechanisms of airway narrowing. This observation is in line with the results of Pelzer and Thomson (37).Accordingly the weaker correlation between Raw and FEV 1 must be because this relationship is not linear and the influence of FRe at which Raw is obtained cannot be ignored. In all groups alterations of Rrs and Xrs consisted of an increase in Rrs with a negative frequency dependence and a decrease in Xrs, a pattern characteristic of obstructive lung disease (12). The changes in the forced oscillation indices were proportional to that in Raw. Thus Rrs and Xrs can be used as an alternative for Raw. Rrs, and Rrs were increased most in group A, whereas Rrs(l) and xrs were changed least in group E. Among the forced oscillation indices Rrs., Rrs(l), and Xrs correlated best with Raw. The relationship between Raw and Rrs is com-
plex; however, Rrs is obtained at higher frequencies than Raw, Rrs includes tissue resistance, and Rrs underestimates resistance in the presence of airway obstruction due to shunt of the upper airway (38, 39). Because of the frequency dependence of Rrs the correlation between Rrs and Raw tended to be less than that between Rrs, and Raw. FEV 1 is by far the most important parameter to evaluate airflow obstruction and the only test generally recommended for routine use (40). Hence to be acceptable for diagnostic purposes new tests to assess airway obstruction must be highly correlated with FEV 1 or provide important additional information. With regard to the first point, in the present study forced oscillation indices were poorly correlated with FE V1 at least in group A and in the combined group. Several mechanisms may be responsible for this lack of good correlation. First, Rrs and Xrs are measured during quiet breathing and FEV 1 is obtained during a forced expiration with high flows and dynamic compression of the central air-
ways. As pointed out earlier this factor seems not to be of major influence, as the correlation between SGaw and FEV 1 is good. Second, the influence of the volume at which Rrs and Xrs are measured cannot be ignored. The increase in resistance due to airway narrowing is obscured by the concurrent increase in FRC. As a result a poor correlation was found between Rrs and FRe in all groups. Third, the deep inspiration before the forced expiration can cause bronchoconstriction at least in asthmatic patients (41). This factor may account for the fact that the correlation between FEV 1 and resistance parameters was poorest in group A. Our findings are in contrast with those of Konig and colleagues (14), who found a good correlation between forced oscillation and spirometric indices, both expressed in absolute values, in asthmatic children between 4 and 17 yr of age. It can be supposed that in the latter study the correlation not only reflected the effects of asthma but also those of growth on the indices. The second point concerns the question of whether forced oscillation data provide additional information with respect to FEV l • With the method that we used Rrs and Xrs can be obtained rapidly over a wide range of frequencies, and when a specific model of the respiratory system is assumed values for resistance, compliance, and inertance can be derived. Michaelson and coworkers (5) concluded that Rrs and Xrs curves in patients with COPD were best explained by Mead's model of the lung (42), and on the basis of this model attempts have been made to estimate central and peripheral airway resistance (15). However, from more recent studies it became obvious that a precise correction for the shunt properties of the upper airway is a prerequisite for such an analysis (38). Furthermore it is obvious that even complex models are at best a crude representation of the respiratory system, in particular in disease, and are based on assumptions that may be not realistic, for instance a non-frequency-dependent behavior of tissues. Lutchen and colleagues (43) pointed out that extracting parameter estimates from a given model is technically demanding and requires a statistical evaluation of the reliability of the procedure. Even then the physiologic appropriateness of the estimates may be questionable (44). For these reasons we decided not to carry out a model simulation of the measured impedance data, but preferred to characterize the impedance
926
VAN NOORD, CLEMENT, VAN DE WOESTIJNE, AND DEMEDTS
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curves by descriptive indices and subsequently to determine the relationships between the various routine lung function and forced oscillation parameters. This analysis yielded a number of clues of interest to clinical use. First, in all groups Rrs., Rrs(l), and Xrs were all highly correlated. Especially between Rrs(l) and Xrs a very tight linear relationship was found (figure 3). Second, for comparable values of FEV 1 in asthma, chronic bronchitis, and emphysema Rrs, and Rrs were significantly larger in asthma than in the other groups, and Xrs was significantly less negative in emphysema than in the other groups (table 2). This indicates that the use of two indices may be of interest for diagnostic purposes: an index of resistance to separate asthma and an index of reactance to separate emphysema from the other two groups. In addition, a discriminant analysis retained forced oscillation parameters as the most important factors among the lung function indices investigated, discriminating best among the three groups. The separation is weak and cannot be used for diagnosis in a particular subject. It is possible, however, that the technique, because it did not correct for the shunt
.2
.3
1.s) CkPa·I·
properties of the upper airway, obscured some of the distinctive features of the impedance curves between the groups. A correction calculated on the basis of the average upper airway shunt characteristics determined in healthy adults (45) showed, indeed, that the increase in Rrs due to the correction is more pronounced in asthma than in chronic bronchitis and emphysema. This improves the separation between the asthmatic group and the other two groups. It is therefore likely that a modified forced oscillation technique reducing the upper airway shunt (38) would discriminate better between asthma and the other obstructive lung diseases. This should be verified by direct measurements. References 1. Dubois AB, Brody AW, LewisDH, Burgess BF Jr. Oscillation mechanics of lungs and chest in man. J Appl Physiol 1956; 8:587-94. 2. Grimby G, Takishima T, Graham W, Macklem P, Mead J. Frequency dependence of flow resistance in patients with obstructive lung disease. J Clin Invest 1968; 47:1455-65. 3. Hyatt RE, Zimmerman IR, Peters EM, Sullivan WJ. Direct writeout of total respiratory resistance. J Appl Physiol 1970; 28:675-8. 4. Stanescu DC, Fesler R, Veriter C, Frans A, Brasseur L. A modified measurement of respira-
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