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Volume Adjustment of Maximal Midexpiratory Flow
Volume Adiustment of Maximal Midexpiratory Flew" Importance of Changes in Total Lung Capacity D. w. Cockcroft, M.D.,andB. A. Berscheid, B.A.
In 21 of 100 consecutive subjects demonstrating
~ 10 percent increase in one second forced expired volume foRowing 200 pog inhaled salbutamol, the forced expired flow over the middle half of the vital capacity (FEF257S%) was unchanged (n 16) or feD ~ 10 percent (n S). Volume adjustment of FEF2S-7S%, to the same volume below total IUDg capacity (TLC) before and after administration of the bronchodilator resulted in significant increases in 18 of these 21 subjecfs. The volumeadjusted FEF2S-75 % increased more (98 percent) following IS00 Pg inhaled metaproterenol in ten ........tic subjects, and decreased more (53 percent) foRowing inhalation of histamine in eight subjects, than did the standard FEF2S-7S% (44 percent increase and 34 per-
cent decrease respectively). When the smaD changes in TLC wblcb were seen foDowing metaproterenol (4.4 ± 4.1 percent reduction, p < 0.01) and histamine (11.0 ± 7.2 percent increase, p < 0.001) were considered, and FEF2S-7S% volume adjusted so it was measured at the same absolute lung volume, greater changes were seen (198 percent increase after use of metaproterenol, and 75 percent decrease after use of histamine). When FEF2S7S % is being examined following administration of a bronchodilator or a bronchoprovocation cbaUenle, It should be volume-adjusted to absolute lung volume. When TLC cannot easily be determined repeatedly (e« routine pulmonary function studies), volume adjustment to the same volume below TLC is advised.
The forced expired flow from 25 percent to 75
inhalation of 200 p.g of saIbutamol, whereas the forced expired volume in one second (FEV1) and forced vital capacity (FVC) improved substantially. In order to standardize the driving pressure at which FEF25-75% is measured, it has recently been advised that FEF25-75~ be "volume-adjusted" following inhalation of a bronchodilator, so that measurement is made at constant lung volume.v' It has been suggested that the spirograms be compared at total lung capacity (TLC), making the assumption
=
=
percent of the forced vital capacity (FEF2575S) has been widely used as a measure of bronchial airflow obstruction since its description in For editorial comment, see page SS1
1955.1 It is easily obtained from the forced expired spirogram by calculation of the slope of the line connecting the points at 25 and 75 percent of the vital capacity. On repeated spirographic tests performed in the presence of different degrees of airHow obstruction, ie following inhalation of a bronchodilating or of a bronchoconstricting agent, the FEF25-75%, when calculated in the standard way, may be measured at a different lung volume. Flow may thus be measured over a range of different elastic recoil and consequently different driving pressure. It has recently been observed that because of this, FEF25-75i may actually decrease paradoxically following inhalation of a bronchodilator drng.2-4 An example of this is shown in Figure 1 where the FEF25-75% decreased from 0.73 to 0.53 following °From the Pulmonary Service, Department of Medicine, University Hospital, University of Saskatchewan, Saskatoon, Canada. Supported in part by a grant from the Medical Research Council of Canada. Manuscript received September 29; revision accepted November 12. Reprint requests: Dr. Cockcroit, University Hospital, Saskatoon, Sask, Canada S7H 486
CHEST, 78: 4, OCTOBER, 1980
o LUNG VOLUME
1
(litres 2 below TLC)
3
0.731/S8C 0.97
I/sec
4
,
024
8
o
,
,
2
4
,
e
,
8
,
,
10 12
TIME (seconds)
FIGURE 1. Forced expired spirograms before (lett) and after inhaling (right) 200 p.gsalbutamol. The vertical axis is volume below TLC in liters and the horizontal axis is time in seconds. The FEF25-751 was 0.73 Lisee before and 0.53 Lisee after bronchodilator inhalation (solid straight lines). When the FEF25-75i was adjusted to the same volume below TLC (dotted parallel lines), this volume-adjusted FEF25-751 (dotted line on right rome) increased to 0.97 Lisee.
VOLUME ADJUSTMENT OF MAXIMAL MIDEXPIRATORY FLOW 595
that TLC does not change in this short period of time. The "volume adjusted FEF25-75f:' can then be calculated from the postbronchodilator curve at the same lung volume below TLC at which it was calculated before administration of the bronchodilator (Fig 1). In this study, we have investigated the frequency of apparent paradoxic changes in FEF25-75% following inhalation of a bronchodilator drug during routine pulmonary function tests, and have evaluated this method of volume adjustment of FEF2575% on the routine function studies, as well as in ten asthmatic patients observed for six hours after inhaling 1,500p.g of metaproterenol sulphate, and in eight subjects receiving histamine bronchoprovocation challenges. Following use of metaproterenol and histamine, changes in TLC were determined, and an improved technique of volume adjustment of FEF25-75~, which takes into consideration changes in TLC, was also evaluated. METHODS
Study 1 Consecutive routine pulmonary function studies were reviewed until 100 studies were found in which the FEV 1 improved by 10 percent or more following inhalation of 200 p.g of salbutamol. The FEF25-751 following inhaled salbutamol was then reviewed for these 100 pulmonary function tests, and was recorded as improved (~ 10 percent increase), unchanged « 10 percent change), or reduced (~ 10 percent decrease) . In studies where the FEF25-75S improved less than 10 percent following inhalation of salbutamol, the post-salbutamol FEF25-75% was recalculated by volume adjustment to the same volume below TLC.
pared at absolute lung volume, and FEF25-751 was remeasured on the postmetaproterenol tracings, between the same points of absolute lung volume that were used in determining the premetaproterenol FEF25-75%. This technique (Method 2) is shown diagramatically in Figure 2. Studf/3 Eight subjects with known nonspecific bronchial hyperreactivity were studied. A standardized histamine inhalation test was performed," Inhalations were performed with tidal breathing from a Wright nebulizer operated with an airllow rate of 7 L/min which delivered an output of 0.130 mVmin of an aerosol with particle size mass median diameter of 1.0 p.. Following a two minute inhalation of normal saline solution as a control, doubling concentrations of histamine acid phosphate (0.125-8.0 mg/ml) were inhaled for two minutes, at five minute intervals, until the FEV 1 had fallen by 20 percent or until the top concentration had been administered. Prior to inhalations and following each inhalation, FRC, IC, FEV l' and FVC were determined in duplicate. Since all subjects inhaled at least three concentrations of histamine, the final three concentrations were analyzed. The FEF25751 from the spirogram with the largest FEV1 following each inhalation was calculated in the standard manner, and by the 2 volume adjusting techniques described above. Analyses
In order to demonstrate the contribution of changes in TLC to the volume adjustment of FEF25-75%, the percentage diHerence in FEF25-75~ volume adjustment techniques (100 X [Method 2-Method 1] I Method 1) was plotted against the percentage change in TLC for the 18 subjects in studies 2 and 3; the changes at 60 min after therapy with metaproterenol and following the final histamine concentration were used. Analyses were performed using the paired t test. S 9
Study 2 Ten subjects with bronchial asthma were selected from the chest clinic. Six were atopic and four were nonatopic. An subjects required regularly inhaled salbutamol (n = 8) or fenoterol (n = 2), and regularly inhaled beelomethasone to control symptoms. In addition, five subjects were using oral theophylline preparations and two were using prednisone. Subjects were studied at a time when symptoms were well controlled and there was no exposure to allergens or respiratory infection for at least four weelcs. Inhaled bronchodilator was withheld for eight hours and theophylline preparations and steroids were withheld for 12 hours. The patients were studied before, and at 5, 15, 30, 60, 120, 180, 240, 300, and 360 minutes after two actuations (1,500 p.g) of inhaled metaproterenol sulphate. At each time, functional residual capacity (FRC) was measured as the mean of three readings using a variable pressure constant volume body plethysmograph (Cardio Pulmonary Insbuments model 2000). Inspiratory capacity (IC), FEV!, and FVC were measured in duplicate with a Godart 9 liter water spirometer, with subjects seated. The spirogram at each time, with the greatest FEV l , was analyzed and FEF25-75% was determined by the standard technique, as well as by the volume-adjusting technique (using results of the pre-metaproterenol spirographic test as reference) outlined in Figure 1 (Method 1). In addition, TLC was determined, the spirograms were com-
598 COCKCROn, BERSCHEID
8 7
LUNG
6
VOLUME (litre. )
5
0.731/·ec
1.89
4
" 2 4
e
so'
I/sec
o.s31/sec
"2 4 6 8
10 12
TIME (seconds)
FIGUBE 2. Volume adjusbnent of FEF25-75% to absolute lung volume. The vertical axis represents lung volume (liters) and the horizontal axis time ( seconds). The same two spirograms shown in Figure 1 are shown. On the left, the prebronchodilator spirogram is plotted at measured TLC (8.5 L ). On the right, the post-bronchodilator spirogram is depicted with a reduction in measured TLC of 0.5 L (6.3 percent). The standard calculation of FEF25-75% gave the same results as in Figure 1, while volume adjustment to absolute lung volume (dotted lines) shows a marked increase to 1.89 Lisee.
CHEST, 78: 4, OCTOBER, 1980
justing methods resulted in significantly larger values for FEF25-75S (p < 0.05) at all times from 5 to 180 min. Method 2 resulted in significantly greater FEF25-75S·values than method 1 (p < 0.05) at all times, except 30 and 300 min. The maximum mean FEF25-7~ improvement occurred at 60 minutes, and was 44 + 35 percent for the standard method, 98 ± 71 percent for volume-adjusted method 1, and 192 + 136 percent for volume-adjusted method 2. At the same time (60 minutes following metaproterenol) there was a small but significant reduction in TLC (4.4 + 4.1 percent, p < 0.01) and significant increases in FEV1 (30 + 17 percent, p < 0.(01) and in FVC (19 + 13 percent, p < 0.01).
REsULTS
Study 1
From 330 consecutive routine pulmonary functiOn studies, 100 studies were found in which the FEV1 improved ~ 10 percent after therapy with 200 p.g salbutamol. In these 100 studies, the FEF25-75S improved ~ 10 percent in 79, was unchanged « 10 percent) in 16, and decreased by ~ 10 percent in five. In the 21 studies where the FEF25-75fJfailed to show improvement, volume adjustment by method 1 resulted in ~ 10 percent improvement in 18; the mean improvement in volume-adjusted FEF25-75% in these 21 subjects was 77 percent compared with a mean fall of 2.5 percent using the standard method of calculation (p <0.(01).
Study 3
Results of the mean FEF25-7~ determined by the three methods following use of saline solution and the final three histamine concentrations are shown in Figure 3. Both volume-adjusted methods resulted in larger reductions in FEF25-75S than the standard method (p < 0.05), and method 2 showed
Study 2 The results of the FEF25-75~ calculated by the standard method and the two volume-adjusted methods over six hours following metaproterenol inhalation are shown in Figure 3. Both volume-ad-
METAPROTERENOL 3
FEF 25.- 75 %
(L/sec)
2
"",'
..:,. .. :
,
3
....,,
-.... " '
"
" ~
1
.
,'
"..------& "<,...... ,
~
HISTAMINE
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..
2 ...
..
~.~.~.~:~:~~-. IAt:4
0 .......- .....- ....- .....- .......- ...............
1
0--....-..-.----......- .....
200
o 150 25
FEF 25 - 75 % 100
(% change)
50 50
75
o o
1
2
3
4
5
8
C
TIME (hours)
-0
-1
112
#3
HISTAMINE (cone.)
FIGURE 3. Changes in FEF25-75~ following inhalation of metaproterenol and histamine ca1culated by the standard and the two volume-adjusted techniques. The upper graphs show FEF25751 (Lisee) on the vertical axis and the lower graphs show the FEF25-751 (I change) on the vertical axis. The left side shows time (hours following metaproterenol 1,500 p,g at time 0) and on the right side C indicates control (before inhalations); 0 indicates the saline inhalation, and Nos 1 to 3 indicate the last three histamine concentrations; FEF25-75i calculated by the standard method, -'_'_._0_0FEF25-751 adjusted to the same volume below TLC (method 1); - - - - - FEF25-751 adjusted to the same absolute lung volume (method 2).
=
CHEST, 78: 4, OCTOBER, 1980
=
=
VOLUME ADJUSTMENT OF MAXIMAL MIDOPIRATORY
now
581
%b. TLC 25
20
•
15
•
-100
-75
10
-SO
-25 -5
-10
-15
FiGURE 4. Contributions of changes in TI..C to volume adjusbnent of FEF25-75S. The vertical axis is percentage of change in TLC, and the horizontal axis is the percentage of difference between the two methods of volume adjust%6, In Volume Adjustment of FEF 25 -75 % ment of .FEF25-75S, method 2 considering the change m TLC and method 1 not. The value 25 50 75 100 125 on the horizontal axis was calculated by the formula 100 X (volume-adjusted FEF25-75S method 2 - volume-adjusted FEF25-75S method 1)/volume-adjusted FEF25-75S method 1. The triangles represent the ten subjects studied 60 min after 1,500 p.g inhaled metaproterenol and the circles represent eight subjects studied after the final histamine concentration (No 3, Fig 3).
greater reductions than method 1 (p < 0.01) for the final two histamine concentrations. The mean maximum FEF25-75~ reduction was 34 ± 17 percent calculated by the standard method, 53 + 14 percent by method 1, and 75 + 16 percent by method 2. There was a significant increase in TLC (11 + 7.2 percent, p < 0.01) and significant reductions in FEV1 (24 + 11 percent, p < 0.001) and FVC (13 + 7.3 percent, p < 0.01) following the final histamine concentration. The effect of TLC changes on FEF25-75%volume adjustment is shown in Figure 4. Small changes in TLC resulted in large changes when applied to volume adjustment of FEF25-75~. A 50 percent increase in FEF25-75iJJ was seen at a 7 percent reduction in TLC, and a 50 percent decrease in FEF25-75~ at a 10 percent increase in TLC. DISCUSSION
This investigation has confirmed and expanded on the value of volume-adjusbnent of the FEF25-75~, not only for the demonstration of bronchodilatation on routine pulmonary function studies and in bronchodilator research, but also in bronchoprovocation studies. Furthermore, small changes in TLC, when taken into account, can result in large changes in the volume-adjusted FEF25-75iJJ and should be considered when volume-adjusting FEF25-75S. In routine pulmonary function tests, we have identified a 21 percent frequency of failure of improvement of FEF25-75S following therapy with a bronchodilator in 100 consecutive patients who demonstrated an increase in FEV1. This is comparable to the study of Olsen et al2,a who demonstrated no increase in FEF25-75S following use of a bron-
598 COCKCROFT, BERSCHEID
chodilator drug in 34 of 100 consecutive unselected bronchodilatation studies. Volume adjustment of the FEF25-75S to the same volume below the maximum inspiratory point (TLC) resulted in significant improvement in 18 of 21 in the present study, and 24 of 34 in Olsen's study. The experience in the clinical trial involving metaproterenol is similar to a recent report by Sherter et al," in which 25 subjects observed for six hours following administration of oral ephedrine 25 mg failed to show much change in FEF25-75~, but showed a mean 60 percent improvement after adjustment to the same volume below TLC. In another study of bronchodilator regimens, changes in FEF2575~ were shown to be larger than changes in FEV1, but were also shown to be less discriminating than FEV1 changes in separating different bronchodilator regimens. 7 Volume adjustment might have added to the significance of FEF25-75~ changes in this study. In the present study, metaproterenol aerosol produced a 44 percent increase in FEF2575i and a 98 percent increase in volume-adjusted FEF25-75~ by the same technique. It was observed, however, that the small reduction in TLC (4.4 + 4.1 percent, p < 0.01) had a great influence on volumeadjustment of FEF25-75~. When this small change was considered, and FEF25-75~ adjusted so it was consistently measured at the same absolute lung volume (above "zero" volume), the result was almost a doubling of the mean percentage of improvement when compared with the previous technique (192 percent vs 98 percent at 60 minutes). This confirms the previous demonstrationv' that increases in FVC result in underestimates of FEF2575S when calculated in the standard manner. HowCHEST, 78: 4, OCTOBER, 1980
ever, in addition to increases in FVC, reductions in TLC also lead to marked FEF25-75fJ underestimates. .:. '. The histamine bronchoprovocation study demon-· strated the same principle in reverse. In this study, reductions in FVC and increases in TLC resulted in overestimates of FEF25-75~. Thus, whereas the standard FEF25-75~ fell by 34 percent, adjusting the FEF25-75% to the same volume below TLC resulted in a 53 percent reduction, and adjustment of FEF25-75~ to the same absolute lung volume resulted in a 75 percent reduction. There are several reasons for the widespread usefulness of the FEF25-75~, as outlined by Olsen and Hale," First, it is easily calculated from the forced expired spirogram." second, there are data available on normal subjects for comparison." and it is derived from a segment of the spirogram thought to be relatively independent of subject effort.9,10 Furthermore it has been found to be a more sensitive measurement than FEV111 and is felt to be, at least in part, a reflection of obstruction to airflow in smaIl airways," For these reasons, the FEF25-75~ alone, or in conjunction with other variables, is commonly used to assess bronchodilatation on routine pulmonary function studies. In addition, it is frequently used in clinical investigations to evaluate new bronchodilator drugs 12-15 and in clinical research involving bronchoprovocation studies. I 6-20 In these situations, acute changes in maximal expiratory Howrates are assumed primarily to relate to changes in bronchomotor tone, and volume adjustment of FEF2575~, or of the effort-independent segment of the maximum expired How-volume curve, should be performed, In previous studies on the significance of volumeadjusting FEF25-75~,2-4 changes in TLC were not considered. Olsen et al2 reported a 1.7 percent reduction in TLC following inhaled isoproterenol, and Sherter et al4 reported no significant change in TLC 30 minutes after therapy with oral ephedrine; no TLC data were presented for three hours, the time of maximal bronchodilatation. Reduction of TLC has been shown to occur following several days of treatment in asthmatic patients. 21-23 Woolcock et al 21 reported a group of seven asthmatic subjects in whom reductions in lung volumes were the major changes upon treatment. In two of these seven, FEV1 did not improve substantially and note was made that the reduction in TLC obscured the real extent of improvement in FEV1. In the present study we document that the acute reduction in TLC following metaproterenol, although small, (4.4 -+- 4.1 percent, range 4 percent increase to 12 percent decrease), is highly significant (p < 0.01) and results
CHEST, 78: 4, OCTOBER, 1980
in large changes when applied to volume adjusbnent
of FEF25-75S. Acute increases in TLC following induced asthma have also been documented22 •24 and co~firmed in the present study. These studies suggest that acute changes in TLC are relevant when volume-adjusting FEF25-75%. Note has been made that the FEF25-75% is the most sensitive of the measurements calculated from the spirogram!' and that volume adjustment increases this sensitivity.' Although changes in volume adjusted FEF25-75~ are larger, these changes may not be more discriminating. Consequently, caution has been advocated when interpreting small changes in the volume-adjusted FEF25-75%, particularly with reference to errors induced by small changes in "starting volume/" When the FEF25-75% was volume-adjusted to the same absolute volume, as described in this study, the sensitivity increases even further. In addition, variations in the "starting volume" were less likely to be a source of error, since this "starting volume," ie TLC, was determined separately for each spirogram. As with any sensitive test, however, small changes should not be given undue attention. We agree with Olsen et al3 and Sherter et al4 that the FEF25-75~ should be volume adjusted following bronchodilator administration. Furthermore, the technique should also be applied when evaluating FEF25-75~ following bronchoprovocation. In studies where it is feasible, particularly clinical research in bronchodilators and in bronchoprovocation studies, TLC should be measured and changes therein applied to FEF25-75%volume adjustment. ACKNOWLEDGMENTS: We wish to thank Mrs. R. Day and Mr. A. Campbell for help in preparing the manuscript, and Mrs. B. P. C. Gore for technical assistance.
1 Leuallen EC, Fowler WS. Maximal midexpiratory How. Am Rev Tuberc 1955; 72:783 2 Olsen CR, Hale FC, Newman M. Decreases of forced expiratory flow after a bronchodilator aerosol. The Physiologist 1966; 9:257 3 Olsen CR, Hale FC. A method for interpreting acute response to bronchodilators from the spirogram. Am Rev Respir Dis 1967; 98:301 4 Sherter CB, Connolly JJ, Schilder DP. The significance of volume-adjusting the maximal midexpiratory How in assessing the response to a bronchodilator drug. Chest 1978; 73:568 5 Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: A method and clinical survey. Clin Allergy 1977; 7:255 6 Steel RDG, Torrie JH. Principles and procedures of statistics with special reference to the biological sciences. New York: McGraw-Hill 1960:62 7 Light RW, Conrad SA, George RB. Clinical significance
VOLUME ADJUSTMENT OF MAXIMAL MIDEXPIRATORY FLOW •
of pulmonary function tests: The one best test for evaluating the effects of bronchodilator therapy. Chest 1977; 72:512. 8 Morris JF, Koski A, Johnson LC. Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis 1971; 103:57 9 Fry DL, Hyatt RE. Pulmonary mechanics: A unified analysis of the relationship between pressure, volume and gas flow in the lungs of normal and diseased human subjects. Am J Moo 1960; 29:612 10 Mead J, Turner JM, Macklem PT, Little JB. Significance of the relationship between lung recoil and maximum expiratory flow. J Appl Physiol 1967; 22: 95 11 McFadden ER Jr, Kiser R, de Groot WJ. Acute bronchial asthma: Relations between clinical and physiologic manifestations. N Eng} J Moo 1973; 288:221 12 Saleeby PR, Ziskind MM. Clinical study on carbuterol (SKF 40383) a new selective bronchodilator agent aerosol: Double-blind comparison with isoproterenol aerosol. J Current Ther Res 1975; 17:225 13 Cockcroft DW, Donevan RE, Copland GM. Carbuterol: a double-blind clinical trial comparing carbuterol and salbutamol. J Current Ther Res 1976; 19: 170 14 'Geumei AM, Miller WF, Miller J, Gast LR. Bronchodilator effect of a new oral beta adrenoreceptor stimulant, Th 1165a: A comparison with metaproterenol sulphate. Chest 1976; 70:460 15 Chervinsky P. Double-blind study of ipratopiwn bro-
•
COCKCRon, BERSCHEID
16 17
18
19 20
21 22 23 24
mide, a new anticholinergic bronchodilator. J Anergy Clin ImmunoI1977; 59:22 Sosman AJ, Schlueter DP, Fink IN, Barborialc JJ. Hypersensitivity toward dust. N Engl J Med 1969; 281:977 Weill H, Salvaggio J, Neilson A, Butcher B, Ziskind M. Respiratory effects in toluene diisocyanate manufacture: A multidisciplinary approach. Environ Health Perspectives 1975; 11:101 Butcher BT, Salvaggio JE, Weill H, Ziskind MM. Toluene diisocyanate (TDI) pulmonary disease: Immunologic and inhalation challenge studies. J Allergy Coo Immunol 1976; 58:89 Booth BH, LeFoldt RH, Moffitt EM. Wood dust hypersensitivity. J Allergy Clio Immunol1976; 57 :352 Butcher BT, Jones RS, O'Neil CE, Glindmeyer HW, Oein JE, Dharmarajan V, Wein H, Salvaggio JE. Longitudinal studies of workers employed in the manufacture of toluene-diisocyanate. Am Rev Respir Dis 1977; 116:411 Woolcock AJ, Read J. Improvement in bronchial asthma not reflected in forced expiratory volume. Lancet 1965; 2:1323 Woolcock A], Read J. Lung volumes in exacerbations of asthma. Am J Moo 1966; 41:259 Gold WM, Kaufman HS, Nadel JA. Elastic recoil of the lungs in chronic asthmatic patients before and after therapy. J Appl Physioll961; 23:433 Freedman S, Tatters6eld AE, Pride NB. Changes in lung mechanics during exercise. J Appl Physio11975; 38:974
CHEST, 78: 4, OCTOBER, 1980
In 21 of 100 consecutive subjects demonstrating
~ 10 percent increase in one second forced expired volume foRowing 200 pog inhaled salbutamol, the forced expired flow over the middle half of the vital capacity (FEF257S%) was unchanged (n 16) or feD ~ 10 percent (n S). Volume adjustment of FEF2S-7S%, to the same volume below total IUDg capacity (TLC) before and after administration of the bronchodilator resulted in significant increases in 18 of these 21 subjecfs. The volumeadjusted FEF2S-75 % increased more (98 percent) following IS00 Pg inhaled metaproterenol in ten ........tic subjects, and decreased more (53 percent) foRowing inhalation of histamine in eight subjects, than did the standard FEF2S-7S% (44 percent increase and 34 per-
cent decrease respectively). When the smaD changes in TLC wblcb were seen foDowing metaproterenol (4.4 ± 4.1 percent reduction, p < 0.01) and histamine (11.0 ± 7.2 percent increase, p < 0.001) were considered, and FEF2S-7S% volume adjusted so it was measured at the same absolute lung volume, greater changes were seen (198 percent increase after use of metaproterenol, and 75 percent decrease after use of histamine). When FEF2S7S % is being examined following administration of a bronchodilator or a bronchoprovocation cbaUenle, It should be volume-adjusted to absolute lung volume. When TLC cannot easily be determined repeatedly (e« routine pulmonary function studies), volume adjustment to the same volume below TLC is advised.
The forced expired flow from 25 percent to 75
inhalation of 200 p.g of saIbutamol, whereas the forced expired volume in one second (FEV1) and forced vital capacity (FVC) improved substantially. In order to standardize the driving pressure at which FEF25-75% is measured, it has recently been advised that FEF25-75~ be "volume-adjusted" following inhalation of a bronchodilator, so that measurement is made at constant lung volume.v' It has been suggested that the spirograms be compared at total lung capacity (TLC), making the assumption
=
=
percent of the forced vital capacity (FEF2575S) has been widely used as a measure of bronchial airflow obstruction since its description in For editorial comment, see page SS1
1955.1 It is easily obtained from the forced expired spirogram by calculation of the slope of the line connecting the points at 25 and 75 percent of the vital capacity. On repeated spirographic tests performed in the presence of different degrees of airHow obstruction, ie following inhalation of a bronchodilating or of a bronchoconstricting agent, the FEF25-75%, when calculated in the standard way, may be measured at a different lung volume. Flow may thus be measured over a range of different elastic recoil and consequently different driving pressure. It has recently been observed that because of this, FEF25-75i may actually decrease paradoxically following inhalation of a bronchodilator drng.2-4 An example of this is shown in Figure 1 where the FEF25-75% decreased from 0.73 to 0.53 following °From the Pulmonary Service, Department of Medicine, University Hospital, University of Saskatchewan, Saskatoon, Canada. Supported in part by a grant from the Medical Research Council of Canada. Manuscript received September 29; revision accepted November 12. Reprint requests: Dr. Cockcroit, University Hospital, Saskatoon, Sask, Canada S7H 486
CHEST, 78: 4, OCTOBER, 1980
o LUNG VOLUME
1
(litres 2 below TLC)
3
0.731/S8C 0.97
I/sec
4
,
024
8
o
,
,
2
4
,
e
,
8
,
,
10 12
TIME (seconds)
FIGURE 1. Forced expired spirograms before (lett) and after inhaling (right) 200 p.gsalbutamol. The vertical axis is volume below TLC in liters and the horizontal axis is time in seconds. The FEF25-751 was 0.73 Lisee before and 0.53 Lisee after bronchodilator inhalation (solid straight lines). When the FEF25-75i was adjusted to the same volume below TLC (dotted parallel lines), this volume-adjusted FEF25-751 (dotted line on right rome) increased to 0.97 Lisee.
VOLUME ADJUSTMENT OF MAXIMAL MIDEXPIRATORY FLOW 595
that TLC does not change in this short period of time. The "volume adjusted FEF25-75f:' can then be calculated from the postbronchodilator curve at the same lung volume below TLC at which it was calculated before administration of the bronchodilator (Fig 1). In this study, we have investigated the frequency of apparent paradoxic changes in FEF25-75% following inhalation of a bronchodilator drug during routine pulmonary function tests, and have evaluated this method of volume adjustment of FEF2575% on the routine function studies, as well as in ten asthmatic patients observed for six hours after inhaling 1,500p.g of metaproterenol sulphate, and in eight subjects receiving histamine bronchoprovocation challenges. Following use of metaproterenol and histamine, changes in TLC were determined, and an improved technique of volume adjustment of FEF25-75~, which takes into consideration changes in TLC, was also evaluated. METHODS
Study 1 Consecutive routine pulmonary function studies were reviewed until 100 studies were found in which the FEV 1 improved by 10 percent or more following inhalation of 200 p.g of salbutamol. The FEF25-751 following inhaled salbutamol was then reviewed for these 100 pulmonary function tests, and was recorded as improved (~ 10 percent increase), unchanged « 10 percent change), or reduced (~ 10 percent decrease) . In studies where the FEF25-75S improved less than 10 percent following inhalation of salbutamol, the post-salbutamol FEF25-75% was recalculated by volume adjustment to the same volume below TLC.
pared at absolute lung volume, and FEF25-751 was remeasured on the postmetaproterenol tracings, between the same points of absolute lung volume that were used in determining the premetaproterenol FEF25-75%. This technique (Method 2) is shown diagramatically in Figure 2. Studf/3 Eight subjects with known nonspecific bronchial hyperreactivity were studied. A standardized histamine inhalation test was performed," Inhalations were performed with tidal breathing from a Wright nebulizer operated with an airllow rate of 7 L/min which delivered an output of 0.130 mVmin of an aerosol with particle size mass median diameter of 1.0 p.. Following a two minute inhalation of normal saline solution as a control, doubling concentrations of histamine acid phosphate (0.125-8.0 mg/ml) were inhaled for two minutes, at five minute intervals, until the FEV 1 had fallen by 20 percent or until the top concentration had been administered. Prior to inhalations and following each inhalation, FRC, IC, FEV l' and FVC were determined in duplicate. Since all subjects inhaled at least three concentrations of histamine, the final three concentrations were analyzed. The FEF25751 from the spirogram with the largest FEV1 following each inhalation was calculated in the standard manner, and by the 2 volume adjusting techniques described above. Analyses
In order to demonstrate the contribution of changes in TLC to the volume adjustment of FEF25-75%, the percentage diHerence in FEF25-75~ volume adjustment techniques (100 X [Method 2-Method 1] I Method 1) was plotted against the percentage change in TLC for the 18 subjects in studies 2 and 3; the changes at 60 min after therapy with metaproterenol and following the final histamine concentration were used. Analyses were performed using the paired t test. S 9
Study 2 Ten subjects with bronchial asthma were selected from the chest clinic. Six were atopic and four were nonatopic. An subjects required regularly inhaled salbutamol (n = 8) or fenoterol (n = 2), and regularly inhaled beelomethasone to control symptoms. In addition, five subjects were using oral theophylline preparations and two were using prednisone. Subjects were studied at a time when symptoms were well controlled and there was no exposure to allergens or respiratory infection for at least four weelcs. Inhaled bronchodilator was withheld for eight hours and theophylline preparations and steroids were withheld for 12 hours. The patients were studied before, and at 5, 15, 30, 60, 120, 180, 240, 300, and 360 minutes after two actuations (1,500 p.g) of inhaled metaproterenol sulphate. At each time, functional residual capacity (FRC) was measured as the mean of three readings using a variable pressure constant volume body plethysmograph (Cardio Pulmonary Insbuments model 2000). Inspiratory capacity (IC), FEV!, and FVC were measured in duplicate with a Godart 9 liter water spirometer, with subjects seated. The spirogram at each time, with the greatest FEV l , was analyzed and FEF25-75% was determined by the standard technique, as well as by the volume-adjusting technique (using results of the pre-metaproterenol spirographic test as reference) outlined in Figure 1 (Method 1). In addition, TLC was determined, the spirograms were com-
598 COCKCROn, BERSCHEID
8 7
LUNG
6
VOLUME (litre. )
5
0.731/·ec
1.89
4
" 2 4
e
so'
I/sec
o.s31/sec
"2 4 6 8
10 12
TIME (seconds)
FIGUBE 2. Volume adjusbnent of FEF25-75% to absolute lung volume. The vertical axis represents lung volume (liters) and the horizontal axis time ( seconds). The same two spirograms shown in Figure 1 are shown. On the left, the prebronchodilator spirogram is plotted at measured TLC (8.5 L ). On the right, the post-bronchodilator spirogram is depicted with a reduction in measured TLC of 0.5 L (6.3 percent). The standard calculation of FEF25-75% gave the same results as in Figure 1, while volume adjustment to absolute lung volume (dotted lines) shows a marked increase to 1.89 Lisee.
CHEST, 78: 4, OCTOBER, 1980
justing methods resulted in significantly larger values for FEF25-75S (p < 0.05) at all times from 5 to 180 min. Method 2 resulted in significantly greater FEF25-75S·values than method 1 (p < 0.05) at all times, except 30 and 300 min. The maximum mean FEF25-7~ improvement occurred at 60 minutes, and was 44 + 35 percent for the standard method, 98 ± 71 percent for volume-adjusted method 1, and 192 + 136 percent for volume-adjusted method 2. At the same time (60 minutes following metaproterenol) there was a small but significant reduction in TLC (4.4 + 4.1 percent, p < 0.01) and significant increases in FEV1 (30 + 17 percent, p < 0.(01) and in FVC (19 + 13 percent, p < 0.01).
REsULTS
Study 1
From 330 consecutive routine pulmonary functiOn studies, 100 studies were found in which the FEV1 improved ~ 10 percent after therapy with 200 p.g salbutamol. In these 100 studies, the FEF25-75S improved ~ 10 percent in 79, was unchanged « 10 percent) in 16, and decreased by ~ 10 percent in five. In the 21 studies where the FEF25-75fJfailed to show improvement, volume adjustment by method 1 resulted in ~ 10 percent improvement in 18; the mean improvement in volume-adjusted FEF25-75% in these 21 subjects was 77 percent compared with a mean fall of 2.5 percent using the standard method of calculation (p <0.(01).
Study 3
Results of the mean FEF25-7~ determined by the three methods following use of saline solution and the final three histamine concentrations are shown in Figure 3. Both volume-adjusted methods resulted in larger reductions in FEF25-75S than the standard method (p < 0.05), and method 2 showed
Study 2 The results of the FEF25-75~ calculated by the standard method and the two volume-adjusted methods over six hours following metaproterenol inhalation are shown in Figure 3. Both volume-ad-
METAPROTERENOL 3
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2
3
4
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HISTAMINE (cone.)
FIGURE 3. Changes in FEF25-75~ following inhalation of metaproterenol and histamine ca1culated by the standard and the two volume-adjusted techniques. The upper graphs show FEF25751 (Lisee) on the vertical axis and the lower graphs show the FEF25-751 (I change) on the vertical axis. The left side shows time (hours following metaproterenol 1,500 p,g at time 0) and on the right side C indicates control (before inhalations); 0 indicates the saline inhalation, and Nos 1 to 3 indicate the last three histamine concentrations; FEF25-75i calculated by the standard method, -'_'_._0_0FEF25-751 adjusted to the same volume below TLC (method 1); - - - - - FEF25-751 adjusted to the same absolute lung volume (method 2).
=
CHEST, 78: 4, OCTOBER, 1980
=
=
VOLUME ADJUSTMENT OF MAXIMAL MIDOPIRATORY
now
581
%b. TLC 25
20
•
15
•
-100
-75
10
-SO
-25 -5
-10
-15
FiGURE 4. Contributions of changes in TI..C to volume adjusbnent of FEF25-75S. The vertical axis is percentage of change in TLC, and the horizontal axis is the percentage of difference between the two methods of volume adjust%6, In Volume Adjustment of FEF 25 -75 % ment of .FEF25-75S, method 2 considering the change m TLC and method 1 not. The value 25 50 75 100 125 on the horizontal axis was calculated by the formula 100 X (volume-adjusted FEF25-75S method 2 - volume-adjusted FEF25-75S method 1)/volume-adjusted FEF25-75S method 1. The triangles represent the ten subjects studied 60 min after 1,500 p.g inhaled metaproterenol and the circles represent eight subjects studied after the final histamine concentration (No 3, Fig 3).
greater reductions than method 1 (p < 0.01) for the final two histamine concentrations. The mean maximum FEF25-75~ reduction was 34 ± 17 percent calculated by the standard method, 53 + 14 percent by method 1, and 75 + 16 percent by method 2. There was a significant increase in TLC (11 + 7.2 percent, p < 0.01) and significant reductions in FEV1 (24 + 11 percent, p < 0.001) and FVC (13 + 7.3 percent, p < 0.01) following the final histamine concentration. The effect of TLC changes on FEF25-75%volume adjustment is shown in Figure 4. Small changes in TLC resulted in large changes when applied to volume adjustment of FEF25-75~. A 50 percent increase in FEF25-75iJJ was seen at a 7 percent reduction in TLC, and a 50 percent decrease in FEF25-75~ at a 10 percent increase in TLC. DISCUSSION
This investigation has confirmed and expanded on the value of volume-adjusbnent of the FEF25-75~, not only for the demonstration of bronchodilatation on routine pulmonary function studies and in bronchodilator research, but also in bronchoprovocation studies. Furthermore, small changes in TLC, when taken into account, can result in large changes in the volume-adjusted FEF25-75iJJ and should be considered when volume-adjusting FEF25-75S. In routine pulmonary function tests, we have identified a 21 percent frequency of failure of improvement of FEF25-75S following therapy with a bronchodilator in 100 consecutive patients who demonstrated an increase in FEV1. This is comparable to the study of Olsen et al2,a who demonstrated no increase in FEF25-75S following use of a bron-
598 COCKCROFT, BERSCHEID
chodilator drug in 34 of 100 consecutive unselected bronchodilatation studies. Volume adjustment of the FEF25-75S to the same volume below the maximum inspiratory point (TLC) resulted in significant improvement in 18 of 21 in the present study, and 24 of 34 in Olsen's study. The experience in the clinical trial involving metaproterenol is similar to a recent report by Sherter et al," in which 25 subjects observed for six hours following administration of oral ephedrine 25 mg failed to show much change in FEF25-75~, but showed a mean 60 percent improvement after adjustment to the same volume below TLC. In another study of bronchodilator regimens, changes in FEF2575~ were shown to be larger than changes in FEV1, but were also shown to be less discriminating than FEV1 changes in separating different bronchodilator regimens. 7 Volume adjustment might have added to the significance of FEF25-75~ changes in this study. In the present study, metaproterenol aerosol produced a 44 percent increase in FEF2575i and a 98 percent increase in volume-adjusted FEF25-75~ by the same technique. It was observed, however, that the small reduction in TLC (4.4 + 4.1 percent, p < 0.01) had a great influence on volumeadjustment of FEF25-75~. When this small change was considered, and FEF25-75~ adjusted so it was consistently measured at the same absolute lung volume (above "zero" volume), the result was almost a doubling of the mean percentage of improvement when compared with the previous technique (192 percent vs 98 percent at 60 minutes). This confirms the previous demonstrationv' that increases in FVC result in underestimates of FEF2575S when calculated in the standard manner. HowCHEST, 78: 4, OCTOBER, 1980
ever, in addition to increases in FVC, reductions in TLC also lead to marked FEF25-75fJ underestimates. .:. '. The histamine bronchoprovocation study demon-· strated the same principle in reverse. In this study, reductions in FVC and increases in TLC resulted in overestimates of FEF25-75~. Thus, whereas the standard FEF25-75~ fell by 34 percent, adjusting the FEF25-75% to the same volume below TLC resulted in a 53 percent reduction, and adjustment of FEF25-75~ to the same absolute lung volume resulted in a 75 percent reduction. There are several reasons for the widespread usefulness of the FEF25-75~, as outlined by Olsen and Hale," First, it is easily calculated from the forced expired spirogram." second, there are data available on normal subjects for comparison." and it is derived from a segment of the spirogram thought to be relatively independent of subject effort.9,10 Furthermore it has been found to be a more sensitive measurement than FEV111 and is felt to be, at least in part, a reflection of obstruction to airflow in smaIl airways," For these reasons, the FEF25-75~ alone, or in conjunction with other variables, is commonly used to assess bronchodilatation on routine pulmonary function studies. In addition, it is frequently used in clinical investigations to evaluate new bronchodilator drugs 12-15 and in clinical research involving bronchoprovocation studies. I 6-20 In these situations, acute changes in maximal expiratory Howrates are assumed primarily to relate to changes in bronchomotor tone, and volume adjustment of FEF2575~, or of the effort-independent segment of the maximum expired How-volume curve, should be performed, In previous studies on the significance of volumeadjusting FEF25-75~,2-4 changes in TLC were not considered. Olsen et al2 reported a 1.7 percent reduction in TLC following inhaled isoproterenol, and Sherter et al4 reported no significant change in TLC 30 minutes after therapy with oral ephedrine; no TLC data were presented for three hours, the time of maximal bronchodilatation. Reduction of TLC has been shown to occur following several days of treatment in asthmatic patients. 21-23 Woolcock et al 21 reported a group of seven asthmatic subjects in whom reductions in lung volumes were the major changes upon treatment. In two of these seven, FEV1 did not improve substantially and note was made that the reduction in TLC obscured the real extent of improvement in FEV1. In the present study we document that the acute reduction in TLC following metaproterenol, although small, (4.4 -+- 4.1 percent, range 4 percent increase to 12 percent decrease), is highly significant (p < 0.01) and results
CHEST, 78: 4, OCTOBER, 1980
in large changes when applied to volume adjusbnent
of FEF25-75S. Acute increases in TLC following induced asthma have also been documented22 •24 and co~firmed in the present study. These studies suggest that acute changes in TLC are relevant when volume-adjusting FEF25-75%. Note has been made that the FEF25-75% is the most sensitive of the measurements calculated from the spirogram!' and that volume adjustment increases this sensitivity.' Although changes in volume adjusted FEF25-75~ are larger, these changes may not be more discriminating. Consequently, caution has been advocated when interpreting small changes in the volume-adjusted FEF25-75%, particularly with reference to errors induced by small changes in "starting volume/" When the FEF25-75% was volume-adjusted to the same absolute volume, as described in this study, the sensitivity increases even further. In addition, variations in the "starting volume" were less likely to be a source of error, since this "starting volume," ie TLC, was determined separately for each spirogram. As with any sensitive test, however, small changes should not be given undue attention. We agree with Olsen et al3 and Sherter et al4 that the FEF25-75~ should be volume adjusted following bronchodilator administration. Furthermore, the technique should also be applied when evaluating FEF25-75~ following bronchoprovocation. In studies where it is feasible, particularly clinical research in bronchodilators and in bronchoprovocation studies, TLC should be measured and changes therein applied to FEF25-75%volume adjustment. ACKNOWLEDGMENTS: We wish to thank Mrs. R. Day and Mr. A. Campbell for help in preparing the manuscript, and Mrs. B. P. C. Gore for technical assistance.
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VOLUME ADJUSTMENT OF MAXIMAL MIDEXPIRATORY FLOW •
of pulmonary function tests: The one best test for evaluating the effects of bronchodilator therapy. Chest 1977; 72:512. 8 Morris JF, Koski A, Johnson LC. Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis 1971; 103:57 9 Fry DL, Hyatt RE. Pulmonary mechanics: A unified analysis of the relationship between pressure, volume and gas flow in the lungs of normal and diseased human subjects. Am J Moo 1960; 29:612 10 Mead J, Turner JM, Macklem PT, Little JB. Significance of the relationship between lung recoil and maximum expiratory flow. J Appl Physiol 1967; 22: 95 11 McFadden ER Jr, Kiser R, de Groot WJ. Acute bronchial asthma: Relations between clinical and physiologic manifestations. N Eng} J Moo 1973; 288:221 12 Saleeby PR, Ziskind MM. Clinical study on carbuterol (SKF 40383) a new selective bronchodilator agent aerosol: Double-blind comparison with isoproterenol aerosol. J Current Ther Res 1975; 17:225 13 Cockcroft DW, Donevan RE, Copland GM. Carbuterol: a double-blind clinical trial comparing carbuterol and salbutamol. J Current Ther Res 1976; 19: 170 14 'Geumei AM, Miller WF, Miller J, Gast LR. Bronchodilator effect of a new oral beta adrenoreceptor stimulant, Th 1165a: A comparison with metaproterenol sulphate. Chest 1976; 70:460 15 Chervinsky P. Double-blind study of ipratopiwn bro-
•
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21 22 23 24
mide, a new anticholinergic bronchodilator. J Anergy Clin ImmunoI1977; 59:22 Sosman AJ, Schlueter DP, Fink IN, Barborialc JJ. Hypersensitivity toward dust. N Engl J Med 1969; 281:977 Weill H, Salvaggio J, Neilson A, Butcher B, Ziskind M. Respiratory effects in toluene diisocyanate manufacture: A multidisciplinary approach. Environ Health Perspectives 1975; 11:101 Butcher BT, Salvaggio JE, Weill H, Ziskind MM. Toluene diisocyanate (TDI) pulmonary disease: Immunologic and inhalation challenge studies. J Allergy Coo Immunol 1976; 58:89 Booth BH, LeFoldt RH, Moffitt EM. Wood dust hypersensitivity. J Allergy Clio Immunol1976; 57 :352 Butcher BT, Jones RS, O'Neil CE, Glindmeyer HW, Oein JE, Dharmarajan V, Wein H, Salvaggio JE. Longitudinal studies of workers employed in the manufacture of toluene-diisocyanate. Am Rev Respir Dis 1977; 116:411 Woolcock AJ, Read J. Improvement in bronchial asthma not reflected in forced expiratory volume. Lancet 1965; 2:1323 Woolcock A], Read J. Lung volumes in exacerbations of asthma. Am J Moo 1966; 41:259 Gold WM, Kaufman HS, Nadel JA. Elastic recoil of the lungs in chronic asthmatic patients before and after therapy. J Appl Physioll961; 23:433 Freedman S, Tatters6eld AE, Pride NB. Changes in lung mechanics during exercise. J Appl Physio11975; 38:974
CHEST, 78: 4, OCTOBER, 1980