Pulmonary function in ambulatory asthmatics

J Chron Dis 1976, Vol. 29, pp. 233-242. Pergamon Press. Printed in Great Britain

PULMONARY

FUNCTION IN AMBULATORY ASTHMATICS*

BRUCE J. SOBOL

and CEMIL EMJRGIL

The Cardiopulmonary Laboratory, Westchester County Medical Center (Formerly Grasslands Hospital); Department of Medicine, New York Medical College, Valhalla, NY 10595

(Received in revised form 4 Max 1975)

Abstract-Sixty-one ambulatory and working asthmatic out-patients were studied at a time when they were free of acute exacerbation of their disease. Only one patient had entirely normal function and only seven patients had their function returned completely to normal by the administration of bronchodilator. These patients had the mildest impairment both in degree and number of abnormal functions. Their per cent improvement was no different than that of the other patients. Of the plethysmographic and spirometric functions tested, the maximal mid-expiratory flow was abnormal in the highest percentage of cases both before and after bronchodilator. On the other hand the percentage of subjects improving and returning to normal was highest for airway conductance and specific conductance. On the average the diffusing capacity was normal and there was no tendency for it to deteriorate with duration of disease. Likewise, there was no tendency for the other function tests to worsen with the duration of the asthma.

INTRODUCTION

Beale et al. attempted to determine whether asthma leads to emphysema [l]. They did this by performing pulmonary function studies on patients with known bronchial asthma during symptom free periods. It rapidly became apparent to these workers that although the patients were symptom free, they still had the functional stigmata of asthma. The percentage of such patients who have abnormal function during periods free of symptoms, or at least free of acute exacerbation, has not been determined. However, it has been the experience of others, since that of Beale et al., that functional abnormalities in the intervals between attacks is common. This has been found both in children and adults [2-61. As a matter of fact, it has been our experience that normal function in such subjects is the exception rather than the rule. This study was performed on patients with bronchial asthma who were ambulatory and working. It was undertaken for several reasons: (1) To determine whether the maximal mid-expiratory flow (MMF), which had proven so sensitive in the early detection of bronchitis and emphysema [7] would prove equally sensitive IN 1952,

*This work was supported in part by the Westchester of ANNE REEDand JANETWALDIF. 233

Heart Association also with the assistance

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BRUCE J.SOBOLand CEMILEMIRGII

for detection of airway obstruction in mild asthma. (2) To determine the extent to which functional abnormalities are returned to normal by the administration of an aerosol bronchodilator. (3) To determine whether the findings on a large group of subjects would substantiate previous findings on a smaller group of patients [S] regarding the usefulness of various pulmonary function tests in assessing the response to bronchodilator. (4) To test whether asthma leads to permanent functional changes or indeed whether the duration of asthma is in any way related to the severity of functional abnormalities.

METHODS

The records of all patients over 19 yr of age in whom a primary diagnosis of bronchial asthma was made were reviewed. The diagnosis of bronchial asthma was made on the basis of a clinical history of episodic shortness of breath with wheezing not related to respiratory infections. These attacks of shortness of breath were ameliorated or relieved by bronchodilator. There were 73 such patients. Twelve patients were eliminated because of minimal tuberculosis or because of a suspicion that the functional abnormalities might be due in whole or in part to co-existing heart disease or other forms of lung disease. Patients were not eliminated because of prior acute pulmonary infections-pneumonia, acute bronchitis or pleurisy. The onset of what clinically appears to be asthma but occurring in the older age groups always raises the question of whether or not one is dealing with heart disease or some other form of lung disease. In this study an age of onset of 40yr or over was arbitrarily taken as a cutoff point. There were 14 such subjects. However, when the functional data of these subjects was compared to the remaining 47, there was no difference in any of the parameters tested. Therefore, it was considered legitimate to include them. Physiological data had been obtained on all these patients in the following manner: Spirometry was performed on a Pulmonor with the patient seated and the nose occluded. Three slow vital capacities (VC) which agreed within 200 cm3 and 3 forced expiratory vital capacities (FVC) which agreed within 200 cm3 were obtained. The largest FVC was used to determine the MMF, the first and third second timed vital capacities (FEV,“,b, FEV$/,), the first second volume (FEV,). The expiratory reserve volume (ERV) was also determined spirometrically. Functional residual capacity (FRC) was determined plethysmographically. Residual volume (RV) was derived from the difference between FRC and ERV; TLC from RV + VC. RV and TLC were also used to determine the RV/TLC ratio. Single breath diffusing capacity (SBDCO) was performed by the method of Ogilvie et al. [9]. Body plethysmography was performed by techniques previously described [lo, 1 l] and subsequently modified [12]. Conductance (Gawk the reciprocal of resistance is used rather than resistance throughout this presentation. Specific conductance (SGaw) was determined by measuring the lung volume at which conductance was obtained, rather than using FRC which was determined separately, This was done because the volume at which patients pant for the determination of Gaw is usually in excess of FRC. Arterial blood, obtained from the brachial or radial artery prior to bronchodilator. was tested for oxygen saturation by means

Pulmonary Function in Ambulatory Asthmatics

23s

of an American Optical oximeter. pH and PCOZ were determined on a Beckman Model 160 gas analyzer. All tests were performed in the morning. The patients had been instructed not to use any bronchodilator drugs the morning of testing. After all function tests, administered in random order, were performed, the patient was given one ‘pump’ from a hand nebulizer or isoproterenol (Medihaler-iso, Riker) during the performance of each of two maximal inhalations. Ten minutes were allowed to elapse. then plethysmography and spirometry were repeated in that order. The limits of normal for the various functions were determined by criteria previously published for FVC, FEV1, FEV 1% and MMF [13]: for the single breath diffusing capacity from a regression equation kindly supplied by Dr. Abraham Kuperman (personal communication) on 111 normal males and females 35 yr and older, DC0 = height in cm3 (8046 age)/lO’ _t 6.6; on subjects 34 yr and younger, DC0 = height in cm3 x 6/105 + 6.6; for RV, TLC and RV/TLC for males from Boren et al. [14]. The normal RV/TLC for women was assumed to be the same as for men. Regression equations for RV and TLC for women were developed from the tables of normal for these values published by Bates et ul. [lS]. In all instances the standard error of the estimate (SEE) was multiplied by 1.64 and added to or subtracted from the predicted value. In this fashion the upper, or lower, 5”,, of the normal population was excluded. Since abnormalities in asthma are in one direction only, e.g. for RV/TLC higher than predicted is abnormal while for MMF the reverse is true, this method was used rather than the conventional predicted + 2 SEE. The latter also excludes 59; of the normal population, but it does so by excluding 2.5% from each end, high and low. Since only one end is abnormal in asthma, excluding 5O/, from the end in question seemed a more valid approach. This has been dealt with in more detail in the past [13]. The limits of normal for Gaw and SGaw are not defined by a mean and standard deviation nor by a regression equation and a standard error of the estimate. Rather a single limit of normal is usually applied for all subjects. In this laboratory the limits used are 0.5 I/cm H,O/sec for Gaw and 0.155 l/cm HIO/sec/l for SGaw. No prediction equation was used for FEV, or ERV. All comparisons were analyzed statistically by means of the students t test.

RESULTS

Of the 61 patients in this study, only one had no abnormality in any function measured. In the statistical analyses which follow, this patient has been excluded. Table 1 is a summary of the data on the remaining 60 patients. SBDCO was normal for the group, averaging 103% of predicted, although values for an individual patient were as low as 6435. It was unrelated to the severity of obstruction, not correlating with Gaw, SGaw or per cent predicted MMF. All patients had a PaC02 below 45 mm Hg and pH and hematocrit within the limits of normal for this laboratory and these data are. therefore, not listed in Table 1. However, the mean value for oxygen saturation was just at the limit of normal (95%) and ranged as low as 91%. Gaw and SGaw were impressively different on the average from their lower limit of normal. Of those functions for which regression equations were available, the mean values which deviate most markedly from normal (using

BRUCEJ.

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SOBOL

TABLE 1. SUMMARYOF FUNCTIONAL DATAON THE 60 PATIENTSWITH ONE OR MOREPHYSIOLOGICAL ABNORMALITY

N X S.D.

Age

Dur.

Gaw SGaw FRC

60 19 15

Obs Obs Obs 60 60 58 0.357 0.089 3.68 0.193 0.057 1.10

Obs

60 42 13

FEV,

FEV,%

FVC Obs N X S.D.

Obs

%P 60

3.46 1.08

2.59 1.01

60 90 18

2.16 0.93

161 55

Obs

%P

6.19 1.44

72 16

Obs

%P

Obs

%P 60

42 12

161 43

MMF

Obs 60 83 11

VC

58 110 15

FEV3’;;

%P

61 14

RV,TLC (%,

58

60 68 24

Obs

%P 58

Obs

%P

TLC

RV

3.61 1.07

94 17

SBDCO 9;P

Obs

60

Sat

%P

Obs 50 94.6 1.5

49

1.35 1.04

36 22

26 7

103 26

Abbreviations used: N, number; x, mean; SD, standard deviation; Dur, years patient had asthma; Gaw, conductance in liters/cm H,O/sec; SGaw, specific conductance in liters/cm H,O/sec/liter; FRC, functional residual capacity, liters; RV, residual volume, liters; TLC, total lung capacity, liters; VC, slow vital capacity, liters; FVC, forced vital capacity, liters; FEV,, first second forced expiratory volume, liters; FEV1%, FEVJFVC x 100; FEV3%, volume expired in the third second/FVC x 100; MMF, maximum mid-expiratory flow, liters/set; SBDCO, single breath diffusing capacity, cm3/min/mm Hg; Sat, arterial oxygen saturation; Obs, observed; “/,:P. per cent predicted.

TABLE2. SUMMARY OF PULMONARY FUNCTIONPRIORTO AND FOLLOWING BRONCHODILATOR Gaw

a N

x

A% P No. No. No. No.

Abn Improve Worse No change

SGaw

F

a 60

0.357 0.549 +64
0.089 0.152 +86
E

N

F

a

Abn Improve Worse No change

3.9 +9 < 0.001 14 3 43 10 6

P

6.08 - 1.0 >O.lO 9 8 32 21

P

3.8 +12 < 0.001 19 5 48 6 5

2.17 2.50 +21
a

F

a

65 +8
37 -10
F

a

P

59

59

85 f3 < 0.005

1.35 1.79 f43
59 61

42

FEV,

FEV,?,

59

P 55

6.16

2.26 -11
H

a

F 58

2.61

FEV,

RViTLC (“/,I

a

F

59 3.5

TLC

55

FVC

59 3.6

a

P

60

vc

X A% P No. No. No. No.

RV

83

34 19 6

Abbreviations used: A%, per cent change (this is the mean of the individual per cent changes, not the per cent difference of the means); No. Abn, number of patients abnormal; 2, prior to bronchodilator; jj following bronchodilator. Remaining abbreviations are the same as in Table 1. Only patients tested before and after bronchodilator are included in each column.

231

Pulmonary Function in Ambulatory Asthmatics 100

r Bronchodllator

80

60

40

20

0 MMF

FEV,%

SGow

Gaw

RWTLC

FEV,

FVC

VC

FIG. 1. Ordinate-per

cent of subjects abnormal. Percentage of 61 subjects abnormal in various measures of pulmonary function before and after bronchodilator. Note that although MMF, FEV,T/, and SGaw all have about the same per cent abnormal prior to bronchodilator, the MMF has the highest percentage abnormal after bronchodilator.

per cent predicted) were the MMF, RV and RV/TLC, while TLC and VC, on the average, were close to predicted. Table 2 presents the changes seen following bronchodilator. The mean value of these changes, regardless of their magnitude were, in all instances save for TLC, significant. It is true that in some individual cases there was no change or worsening of function but the increases in abnormality, when they occurred, tended to be very small and were not consistent for all functions. The most striking improvement in mean values after bronchodilator is seen in Gaw and SGaw. The next largest mean change was in the MMF. Despite this, the number of subjects remaining abnormal in this function after bronchodilator was quite high (Fig. 1). This was also true for the FEV1%. Although about the same number of subjects had abnormal Gaw and SGaw as MMF, the per cent who improved following bronchodilator was larger in the former two. Of all the tests, the highest per cent of subjects were abnormal in terms of the MMF, both prior to and following bronchodilator. A large percentage of subjects were abnormal in terms of the FEV,%, but this test became normal in a significant number following bronchodilator. In this regard, it came midway between Gaw, SGaw and MMF. The most striking improvement following bronchodilator could be seen in those with the most severe impairment prior to bronchodilator. However, there was no good correlation between severity of impairment and response to bronchodilator. Figures 2a and b illustrate this phenomenon for one plethysmographic and one spirometric function. There wefe 7 patients whose function became totally normal following bronchodilator (Table 3). The percentage who were smokers or who had major pulmonary infections in their lifetime was not different in this group of 7 than in the remaining patients. DISCUSSION

Aside from the characteristic finding of airway obstruction, as a group these patients also presented with other findings which are common to asthmatics who

BRUCE J. SOBOL and CEMIL EMIRGIL

238

(a)

120 f

100 80

-

l .

20 -

.* l

-2oL 20

'.

a..

0

.

.

l

0" l f -.-

%

:O

;O

.

; ..

I :o

40

;O

,b FE’.’

90

>

l

I I00

- GI I 110 135

%Predlcted

FIG. 2. The percentagechange in function following bronchodilator

for 61 patients and 59 patients respectively. (a) An example of a plethysmographic function while (b) is an example of a spirometric function. Both demonstrate that the per cent improvement tends to be greater the more impaired function was prior to bronchodilator. However, this is not a verv striking relationship. It is more a negative finding suggesting that improvement tends to be rather random and not maximum at some degree of abnormality.

are ambulatory. Hypoxemia without hypercapnia has been a frequent observation in such patients and has been attributed to ventilation/perfusion imbalance [13,16,17]. The finding of a normal FVC in most patients is also in keeping with the observations of others [18]. However, the low incidence of an abnormal TLC (9 out of 58) is in contrast with the observations of Palmer and Diament (4) that abnormal FVC but elevated TLC distinguishes the asthmatic from the bronchitic. On the other hand, the SBDCO in our patients as in theirs was at worst not markedly abnormal. It has been our experience, that although the SBDCO may be substantially elevated in asthma, on the average it is normal. In most respects the purpose for which this study was undertaken appear to have been satisfied. The question of whether or not asthma leids to emphysema, might be considered unsuitable for analysis here since the patients with evident emphysema were eliminated from the study. There were few such patients. Furthermore, should asthma lead to emphysema one would expect to find some degree

Pulmonary TABLE 3. COMPARISONOF

Function

in Ambulatory

739

Asthmatics

MEAN VALUESOF 7 PATIENTS WHO BECAME ENTIRELY NORMAL CHODILATOR AND 53 WHO DID NOT

x

29

P

44

23

14

15

19 NS

> O.M)l

> 0.005

RRON-

Duration

Age onset

Age

FOLLOWING

Per cent predrcted

x P

RV

TLC

RV/TLCY,,

VC

FVC

FEV,

FEV,“,,

MMF

106* 168 -co.01

104* 111 NS

117* 166 < 0.01

104 92 NS

103 88 cc 0.05

96 64
91 69 < 0.001

75 31 < 0.001

NS = Not significant, P = >0.05. Age Onset = The age at which asthma began. Duration = Time in years from onset of asthma until the present. *There were only 6 and 52 patients in the two groups who were tested for these functions before and after bronchodilator. Other abbreviations are as in previous tables, In the group who became completely normal, 57”,, were smokers and 43:~ had previous pulmonary infections while for the remainder of the patients these figures were 40 and 38% respectively. There was no significant difference between the groups. Under each heading, column on the left represents those who became normal after bronchodilator. Column on the right are the remaining patients. In both columns the mean values are those obtained prior to the administration of bronchodilator.

of correlation between the duration of asthma and the SBDCO. This was not the case. RV/TLC, elevated both in asthma and emphysema, did not correlate with duration. Expiratory flow rate, as determined by the MMF, also did not relate to duration. If asthma leads to emphysema, then the MMF and RV/TLC would be affected by both diseases and might be expected to show some correlation with duration. But the failure of the SBDCO to worsen with duration appears the most cogent reason for supporting the view that asthma does not lead to emphysema. There were 7 patients whose functions became normal following bronchodilator. The findings on these patients suggests that those whose functions return completely to normal following bronchodilator have the mildest degree of obstruction prior to bronchodilator. This being the case, no general statement can be made regarding the percent of subjects in a given group who will be returned to normal function following bronchodilator therapy. Although these seven were younger than the parent group, for the entire 61 patients there was no relationship between the duration of the disease and the functions measured. This is in contrast with the work of Irnell [6], for which there is no apparent explanation. lrnell [6] also concluded that the response to bronchodilator would be maximum in patients with moderate impairment and minimum in those severely or slightly impaired. The findings here do not support the observation, (Figs. 2a and b). In the same study he also concluded that a worsening in the maximum voluntary ventilation was attributable to an unfavorable affect of bronchodilator. We noted nothing that could be considered an adverse reaction to bronchodilator. It is true that in some patients some functions worsened. However, the changes were generally small and were not true of all functions for that patient. For example, one patient had a 5”;, decrease in VC but a 62”:; increase in SGaw. We, therefore, attributed any worsening of function

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BRUCE J.SOBOL and CEMILEMIRGIL

to the variability of the tests themselves rather than to a negative reaction to bronchodifator. Regarding the ability to identify abnormalities, four tests were positive in a high per cent of cases. Of the total of 60 patients Gaw, SGaw, FEV1% and MMF were abnormal in 82, 87, 90 and 93% in that order. Following bronchodilator the per cent abnormal in the same order were 56, 59, 70 and 82”/,. It was surprising that the MMF was as good, if not better than the plethysmograph in its sensitivity to airway obstruction. The plethysmograph’s lack of sensitivity to early abnormalities has already been suggested in chronic obstructive pulmonary disease [19,20] and apparently it is also no better than the spirometer in asthma. It is less useful than the MMF following bronchodilator. Although this may not be a very important superiority of the MMF, it may occasionally prove useful when the subject has inadvertently taken medication prior to testing. The MMF will still produce an 82% yield under such circumstances while the yield for Gaw and SGaw is only 56 and 59 per cent respectively. This finding is consistent with the high abnormality rate for the MMF in contrast to airway resistance previously noted in asthmatic children [2]. RV/TLC is commonly abnormal in asthma, but produced a yield only slightly better than 1 in 2-59x. As with bronchitis and emphysema [13], the MMF was definitely more sensitive than the FEV,. Only 57% of subjects were abnormal prior to bronchodilator and 43”i, after in this measure of expiratory flow. With regard to detecting improvement in function following bronchodilator, the plethysmograph is apparently the most sensitive (only one patient failing to show an increase in Gaw and SGaw), not only with regard to the number of subjects improving, but the magnitude of the average improvement. This latter criterion could not be used in our previous work [8] because of the small number of subjects. When the group is small, averages can be badly distorted by large changes in one or two subjects, but it seems legitimate here in view of the size of the sample. Contrary to the previous work, MMF and FEVi?,, improved significantly. But even in the study presented here and despite the significant improvement in the mean, there were a large percentage of patients who failed to improve. This percentage was larger than for the plethysmographic functions, FVC or FEVr . FEV3, not tested in the previous work, proved insensitive to bronchodilator, 25 patients showing no improvement. It is tempting to attribute the response of the various tests prior to and following bronchodilator to the site of the airways obstruction. For example, the large improvement in SGaw relative to the poor improvement in MMF could be construed to mean that both asthma and the benefits of bronchodilator are located in the large airways. However, it is likely that the explanation for the phenomena observed here are twofold, one, as pointed out by McFadden and Lyons [21), that small airway resistance remains even after no abnormality in airway resistance is detectable at the mouth and two, that the tests themselves differ in sensitivity [13,20] regardless of the site of airways obstruction which the test reflects. In conclusion, some general remarks are in order regarding pulmonary function testing in asthma. Only one patient in this group of 61 patients had entirely normal function. Although the extent to which patients improved following bronchodilator, and the significance of this improvement is entirely a statistical function, the

Pulmonary

Function

in Ambulatory

Asthmatics

‘JI

number of subjects normal and abnormal before and after broncholilator is entirely a question of the method by which one sets the normal standards. Doubtless, in other laboratories the number of subjects considered normal might have been somewhat different. From a physiological point of view the diagnosis of asthma rests heavily on the response to bronchodilator. Unhapily, for a variety of reasons pulmonary function may not improve following bronchodilator or the improvement may be only slight. Under such circumstances pulmonary function testing is essentially confirmatory of the clinical impression. On the other hand, if pulmonary function tests are negative they do not rule out the diagnosis of asthma if the clinical picture is typical. Because of the uncertain response to bronchodilator, attempts to establish criteria for the magnitude of response to bronchodilator fail to identify a substantial number of patients as asthmatic. By the criteria of Nicklaus et al. [22], for example, only 18 or about one third of our patients, could be diagnosed as having asthma. The patient who clinically has typical asthma but who, though manifesting a large response to bronchodilator, also has features which are not characteristic of asthma presents another facet of the problem. If the clinical picture of asthma is classic and the response to bronchodilator is impressive, one is then bound to conclude that the patient has two diseases. These difficulties plus the variable response to bronchodilator from one occasion to the next plus the uncertain time course of bronchodilator in a given patient, all conspire to make asthma a more certain clinical than physiological diagnosis. Acknowledgements-The authors express their thanks to Deborah P. N. and Deborah Pomier for their assistance in the preparation

Telesco, R. N., Philomena of this work.

Adinaro,

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