The Relationship Between Conductance and Functional Residual Capacity during Drug-induced Bronchoconstriction

The Relationship Between Conductance and Functional Residual Capacity during Drug-induced Bronchoconstriction* Valentin Popa, M.D., F.C.C.R;t Prenl C. Chandnani, M.D.; and Mark Reardon, B.S.

We wondered if the inverse changes in airway conductance (Gaw) and functional residual capacity (FRC) during histamine (H) and acetylcholine (ACH) challenge are interrelated or occur at random. In 14 normal and 14 asthmatic subjects, we determined FRC and Gaw changes corresponding to changes in specific airway conductance (SGaw) around -40 percent produced by an aerosol of H or ACH inhaled quantitatively and with measured lung deposition. We also assessed the elastic recoil following H inhalation (5A). We found that in 11 normal and nine asthmatic subjects, after H or nine normal and 11 asthmatic subjects after ACH, Gawand IIFRC were linearly and directly related (p<0.05). The steepness of this slope was directly related to the resting Gaw values. A similar relation was uncovered in the literature for asthmatic patients at rest or during recovery

from natural asthma. As the elastic recoil was normal and did not change after H, it could not explain ~ FRC at ~ SGawof -40 percent. In conclusion: (1) during H or ACH challenge, Gaw-FRC relationship in normal or asthmatic subjects tends to be hyperbolic and dependent on resting Gaw; (2) such a relationship is seemingly present in other bronchoconstrictor responses with a different pathogenesis; and (3) during bronchoconstriction, as Gaw vs FRC is no longer linear, SGaw becomes volume dependent. (Chest 1990; 97:831-39)

In a normal population, within each individual, there

examined in situ and after dissection, free of parenchyma,15 etc) have clarified many aspects of hyperinflation. An important aspect for airway pharlnacolo!-,'Y is that the bronchial \valls are pulled out\vard by inflated lung parenchynla. Pulling on the bronchial \\rall may contribute ,inter alia, to the limitation of the nlaximum contractility in vivo,16 the alteration of the longitudinal distribution of bronchoconstriction (since the smaller bronchi are more compliant than the larger ones),9 and the possible modulation of the drugreceptor response at the level of the bronchial IllUScle. 17 Thus, the same factor (ain\rays pulling) that exerts, \\ithin certain lilnits, a beneficial antibronchoconstrictor effect could interfere with the assesslnent of the conducting airn'ay response to drugs. If body plethysmography is used during brollchoprovocation, the observed specific ainvay conductance (SGaw) Inay actually result from either an orderly or a variable, unpredictable cOlnbination of Ga\\' and FRC changes. In the latter event, the same dSGa\\' recorded during acute bronchoconstriction in different subjects nlay reflect a variable response of conducting airways, as measured by Ca\\r, and a variable degree of terminal airnrays pulling, as lneasured by FR(:. In such a case SCa\\' could hardly be reconllnended as a mechanical measurement in ain\'ay pharmacology. The first goal of this study \vas to determine the changes in FRC corresponding to - aSCa\v of approximately 40 percent during histamine (H) and acetylcholine (ACH) bronchoprovocation in normal and asthmatic subjects.

is a linear relationship between airway conductance (Caw) and the various lung volumes at which it is recorded .. This linear slope can be conveniently expressed as the ratio between Caw measured at functional residual capacity (FRC) and FRC. Predictably, across subjects, Caw will also increase linearly as a function of FRC. 2 A linear correlation should not be expected during acute or chronic bronchoconstriction because in this situation Caw and FRC change in opposite directions, the former decreasing as the latter increases. 3 - 6 Whether this inverse variation of Caw and FRC could be described mathematically is still unknown. Human 7 or in vivo animalS experiments demonstrating changes in airway resistance dependent on lung inflation do not apply to the relationship Caw-FRC during bronchoconstriction because lung volumes other than FRC have been measured. Similarly, in a series of studies evaluating the collapsibility of the bronchi 9 - 11 or testing the interdependence l2- 14 between parenchymal and conducting airways, vital capacity, "maximum" lung volume, or bronchial diameter were measured rather than FRC. However, these and other data (eg, the difference in pressure-volume behavior of the bronchi *From the Medical College of Ohio at Toledo. tPresentlyat Department of Medicine, University of California at Davis, Sacramento. Supported in part by NIH Grant HL23679 and a ~rant from Knoll Pharmaceuticals. Manuscript received May 22; revision accepted Septemher 11.

=

=

Gaw airway conductance; FRC functional residual capacity; SGaw specific airway conductance; H histamine;

=

ACH = acetylcholine; TLC = total lung capacity

=

CHEST I 97 I 4 I APRIL, 1990

831

Table I-Demographic, Physiologic, and Pharmacologic Measurements Normal Subjects

Parameter* No. of subjects years Sex, M/F Hei~ht, cm SGaw, % pred FRe, % pred FVC, % pred FEV), % precl FEV/FVC, abs val FEF25-75, % pred PD-If,-I1, m~ PD¥l-ACH, m~ A~e,

Asthmatic Subjects

14

24

8/6

175 141 ± 17 104±6 104±8 97±9 83±3 94± 10 0.58±O.45 1.81 ± 1.51

14 25

7n

Study Design

173 I15± 15t IIO±7 92±7 76±5t 74±3t

63± lot

0.07 ±O.It 0.12±0.It

* M/F = Inales/fenlales; % pred = percent of predicted; abs val = absolute value; m~ = m~ hase. tStatistical analysis: Asthmatics compared with normals: p<0.05. tStatistical analysis: Asthmatics eompared with normal: p
The second goal \vas to determine whether the changes in FRC at - aSGaw of 40 percent are similar for these two drugs. Such a similarity would further support the interchangeable use of H and cholinergic agonists for the assessment of unonspecific" bronchial responsiveness. MATERIALS AND METHOIJS

Subjects

The suhjet·ts, 14 asthmaties·~ and 14 normals, had the follo\\'in~ charaeteristics, seen many times in the subjects selected for airway pharmacolo~y studies or dia~nostic hronchoprovoeation for asthma: nonsmokers, a~e 18 or 40 years, baseline SGaw and FEV) hi~her than 75 percent of predicted, 2.• 9 baseline per(''ent FEV/forced vital than 70 percent, and ~o()d reproducibility of capacity (FVC) hi~her FEV. both within the day and from day to day (range/mean of5 and 10 percent, respet·tively) (Table I). Afethocl.fi

For dnl~ nebulization \\'e used a volume ventilator (Mona~han 22.5) (,'()nnected with a Bard-Parker nebulizer delivering on inspiration only 0.30 mV20 breaths. The ventilator \\'as set at 600 ml tidal volume, 1 Us plateau flow and (,'Onsequently 0.6 s duration of nebulization. ~22 On four different days we measured airway responses to H or AC II, the pulmonary deposition of a radiota~ed aerosol and the elastic re(,"()iI durin~ H challen~e. Specific airway conductance was measured in a eonstant volume phethysmograph (Jaeger, Rockford, IL). The subjects were prompted to pant at RtJ I Hz6· 20.;Z2 by the operator's (,"()mmand Uinout:' Since in Jae~er's body box the subject is breathing humidified the loop flow vs box air through a heated pneumotacho~raph, pressure was dosed despite the low breathing frequency. \Ve (,'onsidered the lung volume to approximate FRC for three reasons: (1) in this old Jaeger box, after pressing the shutter's control button durin~ expiration, the shutter \\ri)) clf,se at the next change in the direetion of flow, ie, at FRC; (2) the tracing allo\\'s the identification of the point where the shutter comes on demonstrating implieitly that it occurred at resting level; (3) the FRC measured during standard S(;a\\' re<.·ording was praetically identical to that measured hefore, in normals or asthmaties, \\rith a different pro~ram: on a volume-time tracing we t'ould appreciate the tidal breathin~, the panting maneuver, and the point of shutter closing. Follo\\ring body plethysmography, FVC, FEV. and FEF25-75 were ra'Orded with a

832

dry-roll spirometer (CPI, Dayton, Oll) interfaced \\rith an Apple II computer (Chestech, Kin~ of Pnlssia, PA).20.2) For SGa\\' and FRC we averaged five to six technically acceptahle plethysmographic tracings, whereas for FVC and flow responses we selected the Uhest" values for three forced expiratory maneuvers.2.'l

(I) On t\\'O different days we carried out inhalation tests with H and ACH starting ,,'ith 20 breaths of saline solution and continuing with increasing dru~ concentrations. \Ve hegan II or ACH nebulization with 0.01 pert'ent in normals and 0.001 percent in asthmatics. The increasin~ concentrations of dnlg \\'ere delivered over 20 hreaths, at I5-minute interval2(~2.1 until provocation dose PD.ac, eould he measured hy interpolation. Previous experiments in normals and asthmatics have indicated that a - ~SGaw of 20-35 percent dissipates within 10 to 15 minutes (V Popa: unpublished observations). The tests \\'ere performed bern'een 9 AM and 5 PM, after 20 minutes 7 ae(,'()mmodation in the laboratory and, for the same subjeet, at the same time of the day. The asthmatic subjects were asked to refrain for 12 hours from taking p-agonists. regular theophylline preparations, or drinkin~ coffee. No subject \\'as treated "rith slow-release theophylline preparations, steroids, or antihistamines. (2) To define the lun~ deposition of Hand ACH responsible for the pattern of physiologie chan~es re(,'(uded, we nleasured in six normal and six asthlnatic subjects the deposition of a radiota~ed aerosol. After measuring baseline FEV. and FVC to document the similarity of these tests across experiments, \\'e performed a ).'l..lXe ventilation scan followed in 30 minutes hy a WroTc pertechnetate scan. \Ve used the methods of Ryan et al:M to caleulate the total and the centraVperipheral ratio of lung deposition except for the follo,,'in~ modifications: (a) the total dose of radionuclide administered was 0.0.1 mCi and this was inhaled over five ventilator breaths; (h) \\'e used a PDPIl-34 Di~ital computer interfaced with the ~amma counter to record on tape both the ventilation and the inhalation scan; (c) hecause of the 10\\' dose ofOOmTc perteehnetate, the total dose deposited in the right lung and the central-peripheral ratio \\'ere measured usin~ the first ten-minutes counts. The particle size ranged bern'een 0.8 and 6.0 J.'.nl for 80 percent of the aerosol particles. 2.'\ (3) In five asthmatie subjects displaying ~FRC of 10 to 14 percent at - ~SGa\\' of 40 per(''ent, we measured the elastie recoil befi>re and after H. Static pressure-volume curves \\'ere measured during inflation in the same body plethysmograph, \\rith the door open and usin~ an esophageal balloon. Z6 Similar to a previous report,6 the balloon (IO-cm len~h), tubing (90-em len~h, 2-mm internal diameter). and the transducer had a flat amplitude ( + 3.3 percent) and frequency response (+ 3.6 per(''ent) up to 10 Hz. Five to six measurements before or after H challen~e \\'ere used to caleulate the static-re<.'Oil pressure at 90, 80, 70, 60, and 50 percent of total lun~ capacity (TLC). Baseline values of FEV. and FVC had to be (,'()mparable to those measured during the radioaerosol, H, or ACH days (see criteria of selection). The lun~ volume was measured by inte~rating How rate and TLC by addin~ to the separately measured FRC the inspiratory capacity. The study was approved by the Committee on Human Rights in Research of our Institution. A written informed (,'Onsent was obtained from all subjects. Statistical Analysis

We (,'Ompared individual values or suhject groups by Student's t test for paired and unpaired observations, or X2 test with Yates' (,'Orrection, respectively. We related two sets of data by means of regression analysis and correlation coefficient. 27 Log values were used to l'ompare or correlate various provocation doses. The least squares method was used to determine whether Gaw-FRC responses are linear.

Conductance and FRC during Drug-induced Bronchoconstriction (Popa, Chandnani, Reardon)

2.20

11

10

2.00 1.80

o ~

N

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1.40

~ In

1.20

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1.00

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0.80

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14

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,,

•

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0.40 0.20 1.000

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2.000

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3.500

4.000

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5.000

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F~C(L) FIGURE 1. Conductance vs functional residual capacity (FRC) changes during bronchoprovocation with histamine in individual normal subjects. The straiJdIt lines connect haseline values with specific airway conductance (SGaw) values immediately below and immediately above - ~SGa\\r = 40 percent. The interrupted lines connect PD..,-high with a higher dose point (see text). RESULTS

(A) The average pulmonary deposition of99mTc pertechnetate, expressed as percenta~e of the dose inhaled, ",'as 8.2 ± 1 percent with a ratio centraVperipheral distribution of 3.12 ± 0.12. (B) For either agonist, a slight increase in f"RC

As sho\vn in Table 1, the asthmatic subjects had slightly lower SGa\\; FEV., FVC, and FEF25-75% than the normals (0.01
2.20 2.00

61.80

:r.

N

E C.)

en

1.60

19

1.40

1.20

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1.00

~ ca

0.80

25

23 24

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18

20 21 22\

1~ ~~;--_o~~

CJ 0.60 0.40

----0

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2.000

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3.000

~

~X4-

3.500

26

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27 2\

~~ x

4.000

4.500

5.000

5.500

FRC(L) FIGURE 2. Conductance vs functional residual capacity (FRC) chan~es durin~ bronchopn)vocation with hisulmine in individual asthlnatic subjects. For straight and interrupted lines, see Fi~re 1. x-x, Chan~es in the resolution of spontaneous (natural), severe attacks of asthma (plotted from data of McFadden et aIJll). CHEST I 97 I 4 I APRIL. 1990

833

occurred at the hi~hest dose-response level used to compute PD4()' This increase averaged 10.3 ± 0.8 percent after Hand 10±O.9 percent after ACH. The dose-related changes in Gaw and FRC are illustrated for H in Figure 1 and Figure 2 for normals and asthmatics, respectively. Above the dose-response level necessary to compute PD4(h FRC continued to increase. (In 15 of56 Hand ACH challenges, - dSGa\\T than the response level was unintentionally hi~her needed for the calculation of PD4()' This happened because bronchial challen~es were stopped according to the visual inspection of plethysmographic slopes rather than on the spot calculation of SGa\\r). Within this dose range, the decrease in Gaw became pro~res­ sively smaller and the increase in FRC became progressively larger (Fig 1 and 2). The pattern of Ga\v vs FR(~ changes showed a large interindividual variability, unrelated to subject group (ie normal or asthmatic), drug, magnitude of the concomitant change in FEV. or FEF25-75, or aerosol deposition (the latter is not sho\\rn). In ten normal subjects and nine asthmatics challenged with H and nine normal subjects and 11 asthmatics challenged with ACH, there was a linear

relationship between the individual changes and Gaw and l/FRC (p<0.05). However, for the entire group of subjects the common slope of these changes was not significant (p>0.05), neither for H (15.58 ± 24.20 L2/ s1cm H 20) nor for ACH (19.60±26.10 L2/s/cm H 20). The individual and common slopes, however, were similar for both drugs (p>0.05). The value of significant slopes was linearly related to the value of prechallenge Caw: the lower the resting airway caliber the higher the change in FRC during bronchoprovocation (a=O.15, b=36.95), r2= .66; Fig 3). Two-point common slopes of Gaw vs I/FRC calculated from the data of Stanescu et al5 were numerically similar (21.62 ± 22.68 L2/s1cm H 2 0) to those reported herein; however, because the linearity of the two-point slopes reported by the Belgian authors had an unknown statistical significance, those slopes were not plotted on Figure 3. Figure 4 shows that the intragroup relationship between Caw and FRC is linear (p<0.05) only in our normal (open circles) and asthmatic subjects (open triangles) with low normal values of these tests. The relationship becomes hyperbolic (p<0.05) in the group of asthmatic subjects with a higher degree ofbroncho-

t

90.0

o

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Gaw at rest (Us/em H20) 3. Scatter dia~ram of prechallen~e airway conductance (Caw) vs the statistically si~nificant slope of (;aw a~ainst lIFRC chan~es durin~ bronchoprovocatioll. There is a linear relationship shown as internlpted line, between the restin~ airway caliber, measured as Caw and the magnitude of (;a\\' vs 1/ FRC chan~es. (a = .15, h = 36.95, r = .66). FRC indicates functional residual capacity. N, normal suhject; A, asthmatk' subject; H, histamine; and ACII, acetylcholine. FIGtJRE

834

Conductance and FRC during Drug-induced Bronchoconstriction (Popa, Chandnani, Reardon)

2.4

o N before ACH • N after ACH ~ A before ACH • A after ACH o A before ACH} (Ref 5 6 ) • A after ACH '

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~/

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?---• • .--._.-..-...._._._.-

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FI(;t1HE 4. Conductance vs functional residual capacity (FRC) changes in groups of nonnal (N) and asthrnatic (A) subjects rc)lIo\\'ing acetylcholine (ACII) challenge. The plot USt»S the results of this and h,'o other studies. H ' The figure shows that a hyperholic relationship can he docunlented not only \\'ithin suhjects during drug-induced hronchoconstriction (Fig 1 and 2) hut also across suhjects with hronchoconstriction at rest (open squares, dotted regression line) or rc)lIowing ACII (clost»d trianglt»s and squares, internlpted regression line). However, the relationship het\\'t"en airway conductance (;aw) and FRC is linear (full line) if the n»stin~ values of these tests are normal (open circlt»s) or low nonnal (open triangles), As reported before,! the lower the normal resting value of Gaw, the HaUt»r tht» linear slope relating (;aw to FRC. Note that similar to Figure 2, the restin~ Caw in our subje<.'ts was larger than 0.40 [ls/erll 11 2 (»), which represents a normal value. I

constriction at rest (open squares5 .6). As mentioned above, most intraindividual values of Ga\\' and FRC during dru~-induced bronchoconstriction are best described by a hyperbolic relationship; this is not readily apparent in this figure since unlike Figures 1 and 2, it depicts the intragroup rather than the intraindividual relationship between Ga\\' and FRe. All post-ACH challenge values of Gaw and FRC recorded in our group and the group of Stanescu et al5 ,6 of asthmatic subjects (closed triangles and closed squares, respectively) follow a hyperbolic curve (p<0.05). Figure 5 depicts the volunle dependence of SGa\v Ineasurelllents in bronchoconstricted patients, Illost ofthern included in Figure 4. It presents the constant, volume-independent relationship benveen Ga\\-' and FRC in normal and asthmatic subjects \\'ith normal or low norlnal SGa\\' at rest; and the volume-dependent relationship bern'een these tests in asthmatic subjects with bronchoconstriction at rest'l·6 or recovering from a natural attack of asthma.:]o The chan~es in FRC and FEF25-75 at - dSGaw of 40 percent were unrelated (r2 = 0.01; p>0.05). The

changes in FE\l. and FEF25-75 at - aSGa\\' of 40 percent \vere siInilar in normal subjects and asthrnatics. Pooling the subjects together, they averaged H.2 ± 7 percent for FEV. and 14.3± 1.1 percent f()r FEF2575 after Hand 8.3±0.8 percent and 14.5± 1.2 percent, respectively for A(~H (p>O.05 for corresponding tests during Hand ACH challenge). (C) The elastic recoil pressures bef{u-e and after H \\'ere sirnilar challenge (at different percent of TI~(~) (p>0.05) and \vithin normal range 2h : 21.5±O.7 and 21.0 ± 0.8 COl H 2 0, respectively (at 90 percent ofTL(~), 8.5 ± 0.3 and 8.8 ± 0.4 (80 percent), 6.7 ± 0.4 and 6.6 ± 0.4 (70 percent), 5.4 ± 0.3 and 5.4 ± 0.4 (60 percent), and 3.7 ± 0.3 and 3.5 ± 0.6 (50 percent). Discuss)()~

This study confirrns that the decrease in SGa\\' produced by H or ACH results fnun a dose-dependent change, variable from subject to subject, in the t\\'o terms of these Ineasurernents, Ga\\' and FR(:.:Hl \Ve find that the first active dose of agonist decreases Ga\\' \vithout a substantial change in FRC. As the hronchoprovocation continues, Ga\v decreases proportionally less but FRC sho\\'s a progressively larger increase CHEST / 97 / 4 / APRIL, 1990

835

0.35 Resting Normal subjects

0.30

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(p < 0.05)

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O~--~------,r-----~------,r------r-------.,~--.........-------r---

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c /Asthmatics c.

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(Ref. 5,6) (p < 0.05)

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---

FRC (L) FIGl1RE 5. Volume dependence of specific airway conductance (SGaw) during bronchoconstriction in different groups of subjects. The plot is inspired by Sobol et al. 31 For possible volume dependence introduced by the calculation ofSGaw, see Appendix.

(Fig 1 and 2). At - 4SGa\\' of 40 percent the changes in FRC are very small, PD40 reflecting essentially a conductance change. This intraindividual pattern is observed in both normal subjects and asthmatics, regardless of the drug used, but it displays a large intersubject variability. In the majority of subjects, this reciprocal change in Caw and FRC can be described as hyperbolic or as a straight line relating Caw to l/FRC (Fig 1 and 2). It is not clear why the inverse changes in Gawand FRC during acute bronchoprovocation are most of the time but not always related (insufficient data points? irregular relationship?31); and when related \\rhy the curve is hyperbolic in form rather than linear, exponential, etc. A hyperbolic relationship may serve two physiolo~c purposes: (1) to amplify the antibronchoconstrictor effect of hyperinflation (ie, the pulling on the airn'ays \vall,"·12 and (2) to prevent the complete occlusion of the airways at high degree of bronchoconstriction assumin~ that the decreasing Caw will plateau above zero value (infinite resistance [Fig 2 and 4]). The intraindividual slope of Caw vs FRC depends on the prechallen~e value of Caw: because of their lower prechallenge Ga\\r values, our asthmatic subjects have a correspondingly larger increase in FRC (ie, a flatter slope) than the normal subjects (p
tion. The steeper slope of Gaw vs FRC in normal subjects (Fig 1) than in asthmatic subjects (Fig 2) makes the hyperbolic relationship between these measurements less recognizable in the former than in the latter. The continuous increase in FRC as Caw decreases may tentatively be ascribed to a progressive narrowing of the peripheral airways during acute bronchoconstriction. 32 Other mechanical events that could hyperinflate the lungs during mild H- or ACH-induced bronchoconstriction probably play a minimal, if any role. For instance, large airway constriction may decrease the anatomic dead space33 and thereby cannot be held responsible for 4FRC. A persistent contraction of inspiratory muscles 34 increases FRC only when - aFEV I exceeds 15 percent. Finally, at the changes in Ga\\' and FRC recorded in this study a sudden decrease in elastic recoil did not seem to hyperinflate the lungs of our subjects; indeed, the pressure-volume curve failed to change after H inhalation. The hypothesis concerning the role of peripheral airways in the hyperinflation observed during H- or ACH-induced bronchoconstriction is in agreement with the progressive changes in large and peripheral airways resistance recorded in animals following challenge with similar drugs. 7 This hypothesis is not invalidated by the lack of relationship between 4FRC

Conductance and FRC during Drug-induced Bronchoconstriction (Popa, Chandnani, Reardon)

and either - LlFEF25-75 or - LlFEV. (data not shown) corresponding to - LlSCaw of 40 percent: (1) Unlike FRC, FEV. and FEF25-75 are affected by the maneuver used for their recording. Since deep inspirationexpiration has a large intersubject variability35 a relationship between LlFRC and the caliber of the airways measured by FEF25-75 or FEV. may not be apparent. (2) The distribution of acute bronchoconstriction is unhomogenous;8 the airways accounting for a decrease in FEF25-75 might include airways with a different role in hyperinflation. (3) The airways measured by FEF25-75 may not be necessarily the same with the peripheral airways producing hyperinflation. Both the slope of Caw vs FRC and the changes in FRC at - LlSCaw of 40 percent are similar for H and ACH. This further supports the interchangeable use of these drugs in bronchoprovocation, but this observation is not easy to explain. It is possible that the airways that possess a similar sensitivity for Hand ACH (2 to 6 mm36-38) are also those that affect the most Gawand FRC. Alternatively, the sensitivity gradient for H and ACH may be different in vivo and in vitro, or large airway constriction could trigger reflexly the constriction of the small airways responsible for LlFRC. Our findings contribute to the bronchoprovocation technique and also to the physiology and pharmacology of bronchoconstriction. For the bronchoprovocation technique, this study indicates that an ideal SCaw end point should be located on the relatively steep portion of this slope. Thus PD 35 or PD 40 initially proposed rather arbitrarily,28.29 appear to be more suitable than other SGaw end points based on larger changes in this parameter but located on the flat segment of the hyperbole. That Gaw and FRC are not random, but in most subjects seem mathematically related, validates the use of SCaw in bronchoprovocation. Then, this study emphasizes the advantages of using subjects with relatively normal airway caliber for H or cholinergic agent challenge. Indeed, hyperinflation may overestimate LlSCaw because of calculation problems (see Appendix) or panting maneuverS· 6 ,.2 and as shown no\\; may increase the part played by volume change (ie, FRC) in SCaw response (Fig 1 through 4). From a pharmacologic standpoint, the longitudinal gradient of bronchoconstriction, as assessed by the relationship between Caw and FRC, appears to be fairly comparable in three widely different conditions associated with bronchoconstriction: H or cholinergic agonist challenge (Fig 1 and 2), resolution of natural asthma attack (Fig 530), and intercritical period of asthma (Fig 45 ,6). From our current perspective, the similarity between natural and drug-induced asthma appears to be coincidental rather than mechanistic. Even if purely formal, this similarity has two major

implications for bronchoprovocation. First, it suggests that drug-induced bronchoconstriction may serve as a convenient model, contracted in time, for the pattern of mechanical changes during natural attacks and residual bronchoconstriction. Second, the bronchial responses to H or cholinergic agents and spontaneous asthma seem to involve the same combination of participatin~ airways. It is well established that all functional tests of bronchoconstriction give '"positive" reponses in drug-induced and natural asthma. Ho\\'ever, a similar relationship between predominantly large airway responses, as measured by Ga\\·~ and the result of small airways responses, as measured by FRC, has apparently not been described before in Hor ACH-induced asthma, natural asthma attacks, or (natural) intercritical periods. Physiologically, a hyperbolic relationship behveen Caw and FRC during acute or chronic bronchoconstriction, within subjects (Fig 1 and 2) and across subjects (Fig 4), implies that the determination of SGaw is volume dependent. As shown in Figure 5, in a group of normal and asthmatic subjects with lo\v normal SCaw (our subjects in Fig 4 and Fig 5) the resting value of this measurement is constant, independent of the lung volume. 1,2 However, in the group of asthmatic subjects with airways obstruction at rest,5,6 or in the group of asthmatic subjects recovering from a severe attackJO (see also Fig 2), SGa\v becomes volume dependent. Similarly, within the same subject, three or more sets ofGaw and FRC values (this study) recorded during H- or ACH-induced bronchoconstriction often produce a hyperbolic curve, making SGa\\' volume dependent (closed squares, Fig 5). Note that the simple calculation of SGa\\r according to the current equation indicates that this measurement is volume dependent;39 (Appendix and Fig 5). The conclusions of this work are limited by subjects' characteristics, including results of their pulmonary function tests at rest and method of drug nebulization. However, the latter is very similar to a popular nonquantitative, vital capacity Inethod in terms of inspiratory flow, sublaryngeal deposition of aerosol, and ratio of centraVperipheral lung deposition. 24 The differences bernreen these h\lO nebulization nlethods and a third, the tidal volume method, are snlall and as far as the results of bronchoprovocation are concerned, possibly irrelevant. 24 The population selected for this study is fairly representative for that currently submitted to diagnostic22 or investigational challenge with H or cholinergic agents. Thus, although inherently limited, our study seems to possess a satisfactory area of applicability in bronchoprovocation. Additional data are needed to assess across and \\rithin subjects the changes in large and small air\\'ays at different degrees of lung inflation occurring during spontaneous or drug-induced asthma. CHEST I 97 I 4 I APRIL, 1990

837

Table 1 Appendix -Influence of PmlVbox on Plethysmographic Tests Angle ofPmNbox (%)* Body Plethymo~raphic Test Gaw [UslcmHzO] FRC[L] SGa\\' [COl H z() I,

S

I]

43 2°

39 2°

35 2°

31 2°

0.94 3.6 0.26

1.20 (24) 4.2 (16) 0.27 (4)

1.41 (50) 4.9 (36) 0.29 (11)

1.80 (91) 5.7 (58) 0.32 (23)

*Numhers in parentheses indicate the percent change in each measurement. The table shows that when the an~le of PmNbox varies, Caw and FRC do not change proportionally and consequently SGaw does not remain the same; the latter becomes volume dependent.

ApPENDIX

In the SCaw equation, the term pressure at the mouth vs volume of the box does not cancel out if the combined resistance of the pneumotachograph and shutter is subtracted.4() Consider the following equation:-·" Pb-P PmlVbox-R (1) SGa\\'=. b x mlVb H 20 VmIV OX P ox where Ym and Pm are Rowand pressure at the mouth, respectively, Ph and PH 20 the barometric and water pressure, Vbox the box pressure, and R the instrument's resistance. SGaw is expressed in units of pressure and time (ie, cmH 2 0 1 X s - I) and the slope SGaw may pass close to or even through the origin. These two arguments led many authors to disconsider the role of lung volume at which SGaw is measured. However, as shown in Table 1 if the angle PmlVbox varies while the angle VmlVbox remains constant, Caw (predictably) and SGaw ('unexpectedly") will change. Such a change will overestimate SGaw in obese or hyperinflated individuals (Table 1, Appendix) and underestimate this change in lean or normal subjects (in this case the initially steep slopes ofPmlVbox become progressively Ratter during bronchoconstriction, approaching 45°. REFERENCES

2

3

4

5 6

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5th European Congress on Intensive Care Medicine This joint Ineetin~ of the European Shock Society, European Society of Pediatric Inh.·nsi\"t" Care and International Conference on Endotoxins Amsterdalll II I \vill be held in Alnstt'rdalll, The Netherlands, June 5-8. For infornlation, contact tilt' Holland ()rganizing C:t'ntrt', I.Klngt' \()orhout 16,2514 EE The Hague, The Netherlands.

Annual Meeting, International College of Angiology The 32nd Annual Meeting of tlu' (~A \vill be hl~ld at tilt· 1()ronto Princt~ floh'l, 1()ronto, Canada, June 24-29. For infonllation, contact ~fs. ()enist' ~1. Rossignol, I(:A, 1044 Nortllt'rn Blvd, Suitt~ 103, Roslyn, Ne\\' York 11576 (514:4H4-fif)H()).

CHEST I 97 I 4 I APRIL, 1990

839