Forced oscillatory respiratory parameters following papain exposure in dogs A. G. HADDAD, R. L. PIMMEL, D. D. SCAPEROTH, Department of Medicine, University of North Carolina,
HADDAD, A. G.,R. L. PIMMEL,D. D. SCAPEROTH, AND P. A. BROMBERG. Forced osciZZatory respiratory parameters following papain exposure in dogs. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 46 (1): 61-66, 1979. - Respiratory mechanics were studied in nine intubated dogs before and after exposure to aerosolized papain under conditions known to produce emphysemalike lesions. Forced oscillatory resistance (RF& compliance (CFO), and inertance (I,) were computed from impedance data obtained at transrespiratory pressures of -10, 0 (FRC), +lO, and +20 cmH,O. Dynamic compliance during tidal breathing (C,,) was also measured at FRC. After papain exposure C,, and C,, increased by 25% (P < 0.05) at FRC and at +lO cmH,O. There were no consistent changes in R FO or IF0 at FRC. However, RF0 showed a greater dependency on transrespiratory pressure, which suggests that the elastic properties of airways may also have been affected by papain. Measurements made in open-chested papain-exposed animals showed that about 17% of total RF0 and 20% of total elastance were attributable to the chest wall. Forced oscillatory impedance data are sensitive to experimental changes in lung mechanics and provide useful estimates of standard respiratory parameters.
AND P. A. BROMBERG Chapel Hill, North Carolina
27514
METHODS
Nine mongrel dogs were anesthetized with pentobarbital sodium (6 mg kg-l), intubated with - a cuffed endotracheal tube, placed in a supine position, and ventilated with a volume-controlled respirator (Harvard Apparatus model 607). Animals were studied three times During the first experimental study, physiological measurements were made and the animals then were exposed to an aerosolized solution containing papain. The physiological measurements consisted of forced oscillatory resistance (R,,), compliance (C,,), and inertance (I&) at functional residual capacity (FRC); RF0 and C FOat three other lung volumes defined pressures of -10, +lO, and +20 bY transrespiratory cmH,O; and dynamic compliance during tidal breathing (CTB). The latte r t wo sets of measurements were not obtained in the first two dogs. Seven days later the animals were reanesthetized and exposed to papain for a second time. Nineteen days after the first study the animals were anesthetized for the third time and a second set of physiological measurements were made. respiratory resistance, compliance, inertance; chest wall reAt this time, the animals’ chests were opened at the sistance and compliance; emphysema; lung mechanics; transmidline and widely retracted. A third set of forced respiratory pressure oscillatory data was obtained with a transpulmonary pressure -of +5 cmH,O. These measurements, which represent pulmonary resistance (Rp), compliance (Cp) , and inertance (Ip), were used with the closed-chested, IN A PREVIOUS REPORT, we showed that data describing postexposure values at FRC to obtain estimates of chest the frequency dependence of the forced oscillatory impedance can be obtained easily in normal dogs and wall resistance (Rcw), compliance (Ccw), and inertance that conventional respiratory mechanical parameters (Icw). can be computed from these data (18, 22). Resulting In each exposure, the an .imal received 3 ml 15% papain (Sterling-Winthrop Labs , Renssela .er, NY; resistance, compliance, and inertance values were re306,000 UJmg). A Bennett twin nebulizer driven by 3-4 peatable and consistent with measurements obtained psi 0, was connected to the respira torto admini ster this during tidal breathing and with published data. When the resistive, compliant, and inertial characteristics of solution. Aftir the in .itial exposure , all animals received 300,000 U Bicillin (150,000 U procaine penicillin G) the respiratory system were mechanically manipulated every other day until death. by adding resistance, varying gas density, or weighting The forced oscillatory parameters were obtained by the abdomen, the measured changes in these three parameters were consistent with predicted effects. In our previously described method (18, 22), in which the dependence of the total respiratory impedthe present study, we show that changes induced by an frequency the effects of the endotracheal tube, was emphysemalike lesion can also be characterized by ance, including measured and used to compute RF*, IFO, and CFO. In this resistance and compliance estimates obtained from the frequency dependence of forced oscillatory impedance method, an oscillator in a special electronics unit (18) (Acoustic Research model AR-3), data. Lesions were produced by exposing dogs to an excites a loudspeaker aerosolized solution containing papain as described by which is connected to the endotracheal tube. The resulting pressure and flow fluctuations are detected by that papain Marco et al. (11); it is well documented appropriate transducers (Validyne model MP-45, t 20 produces lesions with many of the physiological and Co. model 3700), and procanatomic features’of panlobular emphysema (9, 11, 19). cmH,O and Hans Rudolph 0161-7567/79/0000-0000$01.25
Copyright
0 1979 the American
Physiological
l
Society
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61
62
HADDAD,
essed by the electronics unit to provide readings of pressure and flow amplitude, phase angle between these two signals, and frequency of oscillation. Data were collected at 26 logarithmically spaced frequencies in the range 0.9-16 Hz. We have previously shown the amplitude and phase response of the system to be adequate over this bandwidth (18), and we verified that static pressures between - 10 and +20 cmH,O produced no deterioration in the response characteristics. Before obtaining data at each frequency, several tidal breaths and three inflations to a transrespiratory pressure of 20-30 cmH,O were used to produce a constant lung volume history. For measurements at FRC, the respiratory system was allowed to passively deflate until the airway pressure was atmospheric. For measurements at other lung volumes the procedure was identical except the endotracheal tube and loudspeaker were connected to a -10, +lO, or +20 cmH,O pressure source after the last hyperinflation. Impedance data were used with our linear regression algorithm to obtain optimum estimates of RFO, CFO, and I,, (22). To obtain estimates of C TB, airway pressure, respiratory flow at the mouth, and the integral of this flow were recorded while the animal was tidally ventilated with the respirator at 12 breaths/min. From these tracings, C TB was computed from the ratio of the tidal volume to the difference between end inspiratory pressure and end-expiratory pressure at instants of zero flow (22). RESULTS
Figure
0
1 shows pre- and postexposure
k
impedance
I3
data
PIMMEL,
SCAPEROTH,
AND
BROMBERG
(magnitude, phase angle, and real and imaginary parts) obtained in dog 6 in which the change in CT, induced by papain exposure was closest to the mean value for all animals. Figure 1 also shows the response of the model using the derived values for RFO, C&, and IF0 for this dog. There is some scatter of the data about these curves, but except for a small frequency dependence in the real part of the impedance, no consistent differences are apparent. The agreement between the imaginary part of the impedance value and the model’s response suggests no frequency dependence in compliance over the range of 0.9-16 Hz. The data in Fig. 1 show that papain exposure produced changes predominantly at the lower frequencies where compliant effects dominate the impedance. The observed changes in the magnitude, imaginary part, and phase angle of the impedance at low frequencies are consistent with an increase in compliance and relatively little change in resistance and inertance. Although the compliance change is in the opposite direction, the selective nature of the change is similar to the effects on impedance reported by Tsai et al. (22) with abdominal weighting. A summary of the values for C&B, CFO, RFO, and IF0 at FRC is presented in Table 1. Mean values of preexposure parameters are similar to those reported for another group of dogs (22). Following papain exposure, CT, and CFO increased in all animals and mean values were significantly different by paired t test (P 5 0.05 and P 5 0.01, respectively). Changes in RF0 and I,, after papain exposure were inconsistent and no significant differences between the means were noted. Figure 2 shows the relationship between pre- and
8 6
-I
80
B
'"
6-
xl?
4-
& 2
2
z 2 5 2-
o-
E -0
I I
2
I
I
4
6
IIIIJ
8
FIG. 1. Data describing frequency dependence of impedance for dog 6 before (open circEes) and after (closed circles) exposure. Percent change in tidal breathing compliance, CTB, for this dog was closest to average value.
T z
-2-
1
IO 12 14 16
FREQUENCY
’
I
1
I
I
2
4
6
IIIIJ
8
IO I2 l4l6
(Hz)
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OSCILLATORY
MECHANICS
AFTER
63
PAPAIN
postexposure values for CFO and C,,. Linear regression analysis was performed on these data and the resulting equation was CFO = 5.3 + 0.78 C,, with an r value of 0.72. Figure 2 shows that in animals studied after exposure both C F() and C,, increased, although the increase in these two parameters was not identical in each animal. Table 2 lists values of RF0 obtained with transrespiratory pressures of -10, 0, +lO, and +20 cmH,O before and after exposure. For both the pre- and postexposure data, the mean values for RF0 at -10 cmH,O were significantly greater, and for RF0 at + 10 cmH,O were significantly less than the mean RF0 at FRC (paired t test, P 5 0.05). The mean value for RF0 at +20 cmH,O was significantly less than RF0 at FRC only postexposure. Figure 3 shows the variation in RF0 normalized by the values at FRC for individual dogs as a function of transrespiratory pressure. As the latter increased from - 10 to + 10 cmH,O, normalized RF0 invariably decreased, consistent with the established relationship between airway resistance and lung volume (2). Small
TABLE 2. Values ofRFo obtained at various transrespiratory pressures before and after exposure Preexposure
“N”,” . 4
-10 cmH,O
0 cmH,O
Postexposure 10 cmH,O
20
-10 cmH,O
cmHzO
0 cmHzO
10 cmHzO
20 cmHzO
8
2.77 3.13 2.53 2.54 1.77
2.25 2.26 2.25 2.11 1.55
2.21 2.19 2.10 1.96 1.44
2.39 2.17 2.08 1.95 1.43
3.34 4.13 2.78 2.68 2.08
2.32 2.52 2.12 1.97 1.42
1.95 2.22 1.91 1.59 1.42
1.80 2.15 1.81 1.64 1.50
Mean +SE
2.45 kO.23
2.08 50.14
1.98 to.14
2.00 to.16
3.00 kO.35
2.08 kO.18
1.82 20.14
1.78 kO.11
5 6
7
Units
on resistances
_
are cmH,O
.1-l. s.
PREEXPOSURE
POST EXPOSURE
TABLE 1. Values for CTB, CFO, RF*, and IF0 at FRC before and after exposure Preexposure
w kg
C TB
C
FO
Postexposure R FO
I FO
C
TB
C FO
I FO
R FO
--
17 14 20 14 14 14 13 19 13
29.3 23.0 33.2 29.9 28.6 35.5 16.8
25.3 17.0 26.2 24.5 20.8 22.5 28.2 41.0 19.3
2.50 3.06 2.05 2.25 2.26 2.25 2.11 1.55 2.81
60.2 76.3 69.2 63.3 68.4 71.4 68.7 57.6 68.6
31.2 38.5 31.9 30.2 42.8
26.8 23.9
2.35 2.89
70.2 66.6
28.3 28.6 32.8 33.6 42.3
2.32 2.52 2.12 1.97 1.47
64.4 71.2 66.2 55.5 56.6
/ 1 I
-10
I
I
0
+10
I 0
I LI +20 -10
TRANSRESPIRATORY
PRESSURE
3. Before and after exposure values value at FRC as a function of transrespiratory ual dogs identified by number. FIG.
Mean GE -C TB cnil&O ments papain
15.3 kO.87 ____
28.0 t2.5
25.0 2.32 22.3 20.15
67.1 kl.9
34.9 22.4
30.9 2.23 +2.3 ItO.
64.4 +2.3
have units of ml cmH,O-l; RF0 has units of and CFO * 1-l s; and IF0 has units of cmH,O *ml-l. s2. CT, measurewere not made on dogs 1 and 2. Dogs 3 and 9 died following exposure.
I +10
I +20
(cm H,O)
of RF0 normalized by pressure for individ-
l
changes of R F0 were associated with an additional increase in transrespiratory pressure to + 20 cmH,O. However, RF0 included the resistances of the chest wall, nominally 0.40 cmH,O -1-l s (See below), and of the endotracheal tube, 1.11 cmH,O 1-l s (22). Because these accounted for more than one-half of the total resistance and because neither varied with lung volume, the effect of lung volume on the measured resistance was greatly attenuated. In comparing the pre- and postexposure data in Fig. 3, it appears that the effect of transrespiratory pressure on RF0 was more marked after papain. At FRC, mean values of RF0 in the two conditions were equal (Table 2). At -10 cmH,O the mean value of RF0 postexposure was significantly (paired t test, P 5 0.05) larger than the preexposure mean value. Similarly, mean RF0 values at + 10 and +20 cmH,O were lower in the postexposure condition. This is more clearly illustrated in Fig. 4, which shows the postexposure values of RF0 normalized by the corresponding preexposure value at each transrespiratory pressure for each of the five dogs. The general negative slope of the relationship shown by these data indicates that resistance had a greater dependence on transrespiratory pressure in the range -10 l
50
r
l
40 T 0 I”
30
E 0 .
20
5 u
c
IO
Post exposure
l
I
1
I
I
1
IO
20
30
40
50
C,,( ml-cm H,O-’ ) FIG. 2. Before and after exposure individual dogs identified by number. 0.78 CTB, is also shown.
values of C,, VS. CTB for Regression line, CF, = 5.3 +
l
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64
HADDAD,
PIMMEL,
SCAPEROTH,
AND
BROMBERG
studied. The use of other elastases has been reported (7-9, 20). The resulting lesion closely resembles human panlobular emphysema morphologically (9,11,19). Similarly the changes in physiological measurements induced by papain exposure are consistent with the data obtained in spontaneous human emphysema and can be explained by the loss of alveolar tissue with the concomitant reduction in elastic recoil pressure. Specifically, lung volumes (8, 9, 12, 15, 19), static compliance (5, 8, 12, 17, l9), peripheral resistance (19), and frequency dependence of dynamic compliance (15) were increased; elastic recoil pressure (11, 17,19), CO diffusing capacity (11, 19), and maximum expiratory flow at all lung volumes (3, 5, 15, 17) were decreased. No significant
w oz 2 2 0.8 X
w
z
0 0.6 CL 1
I
t
-10 0 +10 +20 TRANSRESPIRATORY PRESSURE km H,Ol FIG. 4. Values of R,, after exposure, normalized by corresponding values obtained before exposure, as a function of transrespiratory pressures for individual dogs identified by number.
to +lO cmH,O following papain exposure. Table 3 lists the pre- and postexposure values of CFO obtained with transrespiratory pressures of - IO, 0, + 10, and +20 cmH,O. Both before and after exposure there was a marked decrease in mean CFO at the two extreme volumes defined by -10 and +20 cmH,O, and a smaller change at +lO cmH,O. When compared to the corresponding FRC values, differences in the values were significant (paired t test, P 5 0.025) except for preexposure at + 20 cmH,O and for postexposure at + 10 emH,O. These variations in total respiratory compliance with transrespiratory pressure are consistent with the established S-shape pressure-volume curve of the total respiratory system (1). Figure 5 shows postexposure CFO values normalized by the corresponding preexposure value. All these ratios are greater than one at transrespiratory pressures of 0 and +lO cmH,O but more variable at the pressure extremes. . Table 4 shows individual and mean values calculated for Rcw and Ccw at FRC. These data indicate that Rcw represented about 17% of the total respiratory resistance. Because the endotracheal tube had a resistance of 1.11 cmH,O 1-l s (22), the chest wall therefore accounted for about 40% of the total respiratory resistance after correction for the endotracheal tube. With regard to Ccw, there was one large value (dog 8), and when this value was neglected, the mean t SE became 116 230 ml cmH,O? This suggests that the chest wall is three to four times more compliant than the lungs, and that total respiratory compliance at FRC is determined primarily by the lungs. As open-chested and closedchested inertance values were very similar, the inertial properties of the chest wall are negligible and total respiratory inertance is determined by the airways. l
TABLE
various
3. Values of CFO obtained at transrespiratory pressure I I PreexDosure
4 5 6 7 8
20.1 15.3 16.7 18.0 32.0
24.5 25.8 20.8 25.2 22.5 24.4 28.2 , 29.6 41.0 37.3
Mean tSE
20.4 +6.7
27.4 +&.l
Units
on compliance
Postexposure
I 20 cmH&
-10 cmH@
0 cmH,O
10 cmH,O
20 cmH,O
are ml. cmH,O?
l
l
/I
I
1
1
1
-IO 0 +10 +20 TRANSRESPIRATORY PRESSURE km Hz01 FIG. 5. Values of CFo after exposure, normalized by corresponding values obtained before exposure, as a function of transrespiratory pressures for individual dogs identified by number. TABLE 4. Values of chest wall resistance and compliance Dog
No. Mean
DISCUSSION
Since Gross et al. (6) introduced the use of papain to induce emphysemalike lesions, dogs (II, 19, 23), hamsters (5, 6, 12, 15, 17), rabbits (3), and rats (4) have been
Rcw ccw Units tively.
2
4
5
6
7
a
0.59 107
0.68 127
0.46 75
0.34 116
0.05 155
0.25 479
on Rcw and Ccw are cmH,O
l
0.40 * 0.23 177 t 150
1-l . s and ml cmH20q1, l
+ SE
respec-
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OSCILLATORY
MECHANICS
AFTER
PAPAIN
changes have been noted in total (19>, pulmonary (11, E), or airway resistance (5), dynamic lung compliance (ll), or the conductance-volume relationship (19). In several studies, alterations of pulmonary function show close correlation with quantitative morphological data (12, 15, 19). In our study we used the exposure methodology who exposed intubated described by Marco et al. (1 dogs to aerosolized solutions 2, 4, 8, and 16% papain. With the latter two concentrations they found enlarged air sacs with irregular contours and broken strands representing remnants of alveolar walls and septa distributed throughout the lung. There were no major bronchial changes. Functionally, after exposure to the 16% solution, they found an increase in FRC, a decrease in elastic recoil pressure and CO diffusing capacity, and no significant changes in dynamic lung compliance at FRC, pulmonary resistance, and the conductance-volume relationship. We followed their method of exposure using a 15% solution of papain obtained from the same manufacturer. Since our postexposure measurements were made almost 2 wk after the last exposure and almost 3 wk after the first, the initial inflammatory reaction should have dissipated and the emphysematype lesions should have progressed to a fairly stable state (6, 8, 11, 15, 17, 19). In our study we measured dynamic compliance during tidal breathing, CTB, and during forced oscillation, C&. After papain exposure both measurements increased from control values in all animals and the differences in mean values obtained before and after exposure were statistically significant. Marco et al. (ll), with exposure to a 16% solution, found an increase in dynamic compliance that did not achieve statistical significance, probably due to a small number of animals. In our study CTB was measured during artificial ventilation with highly repeatable pressure and volume waveforms, and this may explain the consistency in our results. The forced oscillation measurement, CFO, represents the best estimate obtained from 26 measurements at frequencies ranging from 0.9 to 16 Hz (22). It seems to be at least as good as CTB in characterizing changes in elastic properties induced by the papain. The overall correlation of CFO with CTB (Fig. 2) is similar to that observed by Tsai et al. (22) in a variety of other experimental conditions. At FRC, measurements of total resistance after papain exposure were not significantly different from values obtained prior to exposure. This is consistent with the findings of others (6,15,18,22). However, after papain exposure, we did find larger changes in resistance as compared to the FRC value at both positive and negative transrespiratory pressures (Table 2, Figs. 3 and 4). This finding contrasts with the results of Pushpakom et al. (19) who found no consistent changes in lung resistance as a function of transpulmonary pressure. The effect observed in our study cannot be explained by increased lung compliance inasmuch as the transpulmonary, and hence transmural, pressure should comprise a smaller fraction of the applied transrespi ratory pressu re under these conditions. The effect in the bY papai .n-induced alterations may be explained elastic properties of the airways (i.e., the diameter-
65 transmural pressure relationship) analogous to those produced in alveolar tissue. Such changes would make the cross-sectional area of the airways, and thus airway resistance, more dependent on the transmural pressure. Morphological examination of the airways following papain exposure has been reported to show minor bronchial changes that are generally thought to be insignificant (3, 5, 11, 19). However, there is some evidence of morphological and physiological changes in the small airways. Caldwell (3) has reported that intratracheal administration of papain in rabbits significantly decreased the number of alveolar attachments to noncartilaginous airways. Similarly Pushpakom and associates (19), using the retrograde catheter technique, described large increases in peripheral resistance over values reported earlier by Macklem and Mead (10) for normal dogs. Thus, it seems possible that the mechanical properties of the airways may be altered by papain exposure. The parameters derived for the chest wall seem reasonable. After neglecting the one large value for Ccw (dog 8), the mean value is about twice that predicted with Spells’ regression formula (21) and the mean weight of our dogs. Such an overestimation would result if lung compliance is under estimated during open-chested measurements due to some remaining that effects of the chest wall posteriorly. The indication the inertance of the chest wall is negligible is consistent with our conclusion in an earlier report based on inertante measurements made with air and a He-O, gas mixture (22). Computation of the forced oscillatory parameters are based on a simple series model with linear elements. Papain-induced emphysemalike lesions might produce lungs with peripheral compartments with dissimilar time constants (15). Frequency dependence in effective compliance and resistance have been predicted for such lungs at frequencies less than 2 Hz (16). Our measurements were largely done at higher frequencies where effective compliance would not be expected to show significant frequency dependence. Thus, we believe that a series linear model with constant parameters should be adequate, and our results (Fig. 1) support this. The parameters C FOand RF0 were sensitive to changes in the mechanical properties of the lung induced by papain exposure. Because such exposure is known to produce emphysemalike lesions, it appears that these measurements are capable of characterizing deterioration in mechanical function produced by this disease. This supports the conclusion of our earlier study in which we showed that these measurements were sensitive to changes produced by mechanical interventions and that the magnitude of the changes were consistent with predicted alterations (22). The measured CFo is well correlated with tidal breathing dynamic compliance (Fig. 2) as previously reported (22). Also, preexposure values for RFO, CFO, and IF0 are similar to values previously reported for normal dogs (22). It is noteworthy that forced oscillation techniques have been most frequently used to measure resistance parameters. The present study indicates that relatively small changes in compliance in a dog model of emphysema can be suc-
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66 cessfully estimated as well. In summary, this approach seems to be a reliable method for quantitatively characterizing changes in mechanical parameters in anesthetized, intubated, apneic dogs. When this is coupled with the semiautomation of the measurements (18), it becomes a very attractive approach for studying experimental animals. Unfortunately, readings from the special electronics unit used to obtain the frequency dependence of respiratory impedance become unstable when spontaneous breathing patterns are superimposed on the forced oscillations. Michaelson et al. (14) described an alternate approach
HADDAD,
PIMMEL,
SCAPEROTH,
AND
BROMBERG
for collecting impedance data that used random noise excitation. It may be possible to couple this method for acquiring data with our analytical approach to produce reliable estimates of resistance, compliance, and inertante in spontaneously breathing subjects. We thank the Sterling-Winthrop Laboratory, Rensselaer, NY for supplying the papain used in this study. This work was supported by National Institutes of Health Research Grant HL-19118 and by Environmental Protection Agency Research Grant R-805184. R.L. Pimmel was the recipient of National Institutes of Health Research Career Development Award HL-00207. Received
10 February
1978; accepted in final form 17 August
1978.
REFERENCES 1. AGOSTONI, E., AND J. MEAD. Statics of the respiratory system. Handbook of PhysioZogy. Respiration. Washington, DC: Am. Physiol. Sot., 1974, sect. 3, vol. I, chapt. 13, p. 387-409. 2. BRISCOE, W. A., AND A. B. DUBOIS. The relationship between airway resistance, airway conductance and lung volume in subjects of different age and body size. J. CZin. Invest. 37: 12791285, 1958. 3. CALDWELL, J. Physiological and anatomic effects of papain on the rabbit lung. J. Appl. PhysioZ. 31: 458-465, 1971. 4. GILES, R. E., M. P. FINKEL, AND R. LEEDS. The production of an enphysemalike condition in rats by the administration of papain aerosol. Proc. Sot. Exp. BioZ. Med. 134: 157-162, 1970. 5. GOLDRING, I. P., S. S. PARK, C. S. SHIM, L. GREENBURG, AND I. M. RATNER. Histopathology and mechanical properties of the lung in experimental emphysema. PathoZ. Microbial. 35: 176180,. 1970. 6. GROSS, D., M. A. BABYAK, E. TOLKER, AND M. KASCHAK. Enzymatically produced pulmonary emphysema - a preliminary report. J. Occup. Med. 6: 481-484, 1964. 7. KAPLAN, P. D., C. KUHN, AND J. A. PIERCE. The induction of emphysema with elastase. I. The evolution of the lesion and the influence of serum. J. Lab. CZin. Med. 82: 249-365, 1973. 8. KARLINSKY, J. B., G. L. SNIDER, C. FRANZBLAU, P. J. STONE, AND F. G. HOPPIN, JR. In vitro effects of elastase and collagenase on mechanical properties of hamster lungs. Am. Rev. Respir. Dis. 113: 769-777, 1976. 9. KUHN, C . III, AND F. TAVASSOLI. The scanning electron microscopy of elastase-induced emphysema. Lab. Invest. 34: 2-9, 1976. of central and 10. MACKLEM, P. T., AND J. MEAD. Resistance peripheral airways measured by a retrograde catheter. J. AppZ. Physiol. 22: 395-401, 1967. 11. MARCO, V., D. R. MERANZE, M. YOSHIDA, AND P. KIMBEL. Papain-induced experimental emphysema in the dog. J. AppZ. PhysioZ. 33: 293-299, 1972. 12. MARTORANA, P. A., N. W. MCKEEL, J. W. RICHARD, AND N. N. SHARE. Function-structure correlation studies on excised hamster lungs in papain-induced emphysema. Can. J. PhysioZ. PharmacoZ. 51: 635-641, 1973. 13. MEAD, J. Contribution of compliance of airway to frequencydependent behavior of lungs. J. AppZ. Physiol. 26: 670-673,1969.
14. MICHAELSON, E. D., E. D. GRASSMAN, AND W. R. PETERS. Pulmonary mechanics by spectral analysis of forced random noise. J. CZin. Inuest. 56: 1210-1230, 1975. 15. NIEWOEHNER, D. E., AND J. KLEINERMAN. Effects of experimental emphysema and bronchiolitis on lung mechanics and morphometry. J. AppZ. Physiol. 35: 25-31, 1973. 16. OTIS, A. B., C. B. MCKERROW, R. A. BARTLETT, J. MEAD, M. B. MCILROY, N. J. SELVERSTONE , AND E . P. RADFORD, JR. Mechanical factors in distribution of pulmonary ventilation. J. AppZ. Physiol. 8: 427-443, 1956. 17. Park, S. S., I. P. Goldring, C. S. Shim, and M. H. Williams, Jr. Mechanical properties of the lung in experimental pulmonary emphysema. J. AppZ. PhysioZ. 26: 738-744, 1969. 18. PIMMEL, R. L., R. A. SUNDERLAND, D. J. ROBINSON, H. B. WILLIAMS, R. L. HAMLIN, AND P. A. BROMBERG. Instrumentation for measuring respiratory impedance by forced oscillations. IEEE Trans. Biomed. Eng. 24: 89-93, 1977. 19. PUSHPAKOM, R., J. C. HOGG, A. J. WOOLCOCK, A. E. ANGUS, P. T. MACKLEM, AND W. M. THURLBECK. Experimental papaininduced emphysema in dogs. Am. Rev. Respir. Dis. 102: 778-789, 1970. 20. SNIDER, G. L., C. B. SHERTER, K. W. Koo, J. B. KARLINSKY, J. A. HAYES, AND C . FRANZBLAU. Respiratory mechanics in hamsters following treatment with endotracheal elastase or collagenase. J. AppZ. PhysioZ.: Respirat. Environ. Exercise Physiol. 42: 206-215, 1977. 21. SPELLS, K. E. Comparative studies in lung mechanics based on a survey of literature data. Respir. Physiol. 8: 37-57, 1969. 22. TSAI, M. J., R. L. PIMMEL, E. J. STIFF, P. A. BROMBERG, AND R. L. HAMLIN. Respiratory parameter estimation using forced oscillatory impedance data. J. AppZ. PhysioZ.: Respirat. Environ. Exercise Physiol. 43: 322-330, 1977. 23. WEINBAUM, G., V. MARCO, T. IKEDA, B. MASS, D. R. MERANZE, AND P. KIMBEL. Enzymatic production of experimental emphysema in the dog: route of exposure. Am. Rev. Respir. Dis. 109: 351-357, 1974. 24. WOOLCOCK, A. J., N. J. VINCENT, AND P. T. MACKLEM. Frequency dependence of compliance as a test for obstruction in the small airways. J. CZin. Invest. 48: 1097-1106, 1969.
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HADDAD, A. G.,R. L. PIMMEL,D. D. SCAPEROTH, AND P. A. BROMBERG. Forced osciZZatory respiratory parameters following papain exposure in dogs. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 46 (1): 61-66, 1979. - Respiratory mechanics were studied in nine intubated dogs before and after exposure to aerosolized papain under conditions known to produce emphysemalike lesions. Forced oscillatory resistance (RF& compliance (CFO), and inertance (I,) were computed from impedance data obtained at transrespiratory pressures of -10, 0 (FRC), +lO, and +20 cmH,O. Dynamic compliance during tidal breathing (C,,) was also measured at FRC. After papain exposure C,, and C,, increased by 25% (P < 0.05) at FRC and at +lO cmH,O. There were no consistent changes in R FO or IF0 at FRC. However, RF0 showed a greater dependency on transrespiratory pressure, which suggests that the elastic properties of airways may also have been affected by papain. Measurements made in open-chested papain-exposed animals showed that about 17% of total RF0 and 20% of total elastance were attributable to the chest wall. Forced oscillatory impedance data are sensitive to experimental changes in lung mechanics and provide useful estimates of standard respiratory parameters.
AND P. A. BROMBERG Chapel Hill, North Carolina
27514
METHODS
Nine mongrel dogs were anesthetized with pentobarbital sodium (6 mg kg-l), intubated with - a cuffed endotracheal tube, placed in a supine position, and ventilated with a volume-controlled respirator (Harvard Apparatus model 607). Animals were studied three times During the first experimental study, physiological measurements were made and the animals then were exposed to an aerosolized solution containing papain. The physiological measurements consisted of forced oscillatory resistance (R,,), compliance (C,,), and inertance (I&) at functional residual capacity (FRC); RF0 and C FOat three other lung volumes defined pressures of -10, +lO, and +20 bY transrespiratory cmH,O; and dynamic compliance during tidal breathing (CTB). The latte r t wo sets of measurements were not obtained in the first two dogs. Seven days later the animals were reanesthetized and exposed to papain for a second time. Nineteen days after the first study the animals were anesthetized for the third time and a second set of physiological measurements were made. respiratory resistance, compliance, inertance; chest wall reAt this time, the animals’ chests were opened at the sistance and compliance; emphysema; lung mechanics; transmidline and widely retracted. A third set of forced respiratory pressure oscillatory data was obtained with a transpulmonary pressure -of +5 cmH,O. These measurements, which represent pulmonary resistance (Rp), compliance (Cp) , and inertance (Ip), were used with the closed-chested, IN A PREVIOUS REPORT, we showed that data describing postexposure values at FRC to obtain estimates of chest the frequency dependence of the forced oscillatory impedance can be obtained easily in normal dogs and wall resistance (Rcw), compliance (Ccw), and inertance that conventional respiratory mechanical parameters (Icw). can be computed from these data (18, 22). Resulting In each exposure, the an .imal received 3 ml 15% papain (Sterling-Winthrop Labs , Renssela .er, NY; resistance, compliance, and inertance values were re306,000 UJmg). A Bennett twin nebulizer driven by 3-4 peatable and consistent with measurements obtained psi 0, was connected to the respira torto admini ster this during tidal breathing and with published data. When the resistive, compliant, and inertial characteristics of solution. Aftir the in .itial exposure , all animals received 300,000 U Bicillin (150,000 U procaine penicillin G) the respiratory system were mechanically manipulated every other day until death. by adding resistance, varying gas density, or weighting The forced oscillatory parameters were obtained by the abdomen, the measured changes in these three parameters were consistent with predicted effects. In our previously described method (18, 22), in which the dependence of the total respiratory impedthe present study, we show that changes induced by an frequency the effects of the endotracheal tube, was emphysemalike lesion can also be characterized by ance, including measured and used to compute RF*, IFO, and CFO. In this resistance and compliance estimates obtained from the frequency dependence of forced oscillatory impedance method, an oscillator in a special electronics unit (18) (Acoustic Research model AR-3), data. Lesions were produced by exposing dogs to an excites a loudspeaker aerosolized solution containing papain as described by which is connected to the endotracheal tube. The resulting pressure and flow fluctuations are detected by that papain Marco et al. (11); it is well documented appropriate transducers (Validyne model MP-45, t 20 produces lesions with many of the physiological and Co. model 3700), and procanatomic features’of panlobular emphysema (9, 11, 19). cmH,O and Hans Rudolph 0161-7567/79/0000-0000$01.25
Copyright
0 1979 the American
Physiological
l
Society
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61
62
HADDAD,
essed by the electronics unit to provide readings of pressure and flow amplitude, phase angle between these two signals, and frequency of oscillation. Data were collected at 26 logarithmically spaced frequencies in the range 0.9-16 Hz. We have previously shown the amplitude and phase response of the system to be adequate over this bandwidth (18), and we verified that static pressures between - 10 and +20 cmH,O produced no deterioration in the response characteristics. Before obtaining data at each frequency, several tidal breaths and three inflations to a transrespiratory pressure of 20-30 cmH,O were used to produce a constant lung volume history. For measurements at FRC, the respiratory system was allowed to passively deflate until the airway pressure was atmospheric. For measurements at other lung volumes the procedure was identical except the endotracheal tube and loudspeaker were connected to a -10, +lO, or +20 cmH,O pressure source after the last hyperinflation. Impedance data were used with our linear regression algorithm to obtain optimum estimates of RFO, CFO, and I,, (22). To obtain estimates of C TB, airway pressure, respiratory flow at the mouth, and the integral of this flow were recorded while the animal was tidally ventilated with the respirator at 12 breaths/min. From these tracings, C TB was computed from the ratio of the tidal volume to the difference between end inspiratory pressure and end-expiratory pressure at instants of zero flow (22). RESULTS
Figure
0
1 shows pre- and postexposure
k
impedance
I3
data
PIMMEL,
SCAPEROTH,
AND
BROMBERG
(magnitude, phase angle, and real and imaginary parts) obtained in dog 6 in which the change in CT, induced by papain exposure was closest to the mean value for all animals. Figure 1 also shows the response of the model using the derived values for RFO, C&, and IF0 for this dog. There is some scatter of the data about these curves, but except for a small frequency dependence in the real part of the impedance, no consistent differences are apparent. The agreement between the imaginary part of the impedance value and the model’s response suggests no frequency dependence in compliance over the range of 0.9-16 Hz. The data in Fig. 1 show that papain exposure produced changes predominantly at the lower frequencies where compliant effects dominate the impedance. The observed changes in the magnitude, imaginary part, and phase angle of the impedance at low frequencies are consistent with an increase in compliance and relatively little change in resistance and inertance. Although the compliance change is in the opposite direction, the selective nature of the change is similar to the effects on impedance reported by Tsai et al. (22) with abdominal weighting. A summary of the values for C&B, CFO, RFO, and IF0 at FRC is presented in Table 1. Mean values of preexposure parameters are similar to those reported for another group of dogs (22). Following papain exposure, CT, and CFO increased in all animals and mean values were significantly different by paired t test (P 5 0.05 and P 5 0.01, respectively). Changes in RF0 and I,, after papain exposure were inconsistent and no significant differences between the means were noted. Figure 2 shows the relationship between pre- and
8 6
-I
80
B
'"
6-
xl?
4-
& 2
2
z 2 5 2-
o-
E -0
I I
2
I
I
4
6
IIIIJ
8
FIG. 1. Data describing frequency dependence of impedance for dog 6 before (open circEes) and after (closed circles) exposure. Percent change in tidal breathing compliance, CTB, for this dog was closest to average value.
T z
-2-
1
IO 12 14 16
FREQUENCY
’
I
1
I
I
2
4
6
IIIIJ
8
IO I2 l4l6
(Hz)
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OSCILLATORY
MECHANICS
AFTER
63
PAPAIN
postexposure values for CFO and C,,. Linear regression analysis was performed on these data and the resulting equation was CFO = 5.3 + 0.78 C,, with an r value of 0.72. Figure 2 shows that in animals studied after exposure both C F() and C,, increased, although the increase in these two parameters was not identical in each animal. Table 2 lists values of RF0 obtained with transrespiratory pressures of -10, 0, +lO, and +20 cmH,O before and after exposure. For both the pre- and postexposure data, the mean values for RF0 at -10 cmH,O were significantly greater, and for RF0 at + 10 cmH,O were significantly less than the mean RF0 at FRC (paired t test, P 5 0.05). The mean value for RF0 at +20 cmH,O was significantly less than RF0 at FRC only postexposure. Figure 3 shows the variation in RF0 normalized by the values at FRC for individual dogs as a function of transrespiratory pressure. As the latter increased from - 10 to + 10 cmH,O, normalized RF0 invariably decreased, consistent with the established relationship between airway resistance and lung volume (2). Small
TABLE 2. Values ofRFo obtained at various transrespiratory pressures before and after exposure Preexposure
“N”,” . 4
-10 cmH,O
0 cmH,O
Postexposure 10 cmH,O
20
-10 cmH,O
cmHzO
0 cmHzO
10 cmHzO
20 cmHzO
8
2.77 3.13 2.53 2.54 1.77
2.25 2.26 2.25 2.11 1.55
2.21 2.19 2.10 1.96 1.44
2.39 2.17 2.08 1.95 1.43
3.34 4.13 2.78 2.68 2.08
2.32 2.52 2.12 1.97 1.42
1.95 2.22 1.91 1.59 1.42
1.80 2.15 1.81 1.64 1.50
Mean +SE
2.45 kO.23
2.08 50.14
1.98 to.14
2.00 to.16
3.00 kO.35
2.08 kO.18
1.82 20.14
1.78 kO.11
5 6
7
Units
on resistances
_
are cmH,O
.1-l. s.
PREEXPOSURE
POST EXPOSURE
TABLE 1. Values for CTB, CFO, RF*, and IF0 at FRC before and after exposure Preexposure
w kg
C TB
C
FO
Postexposure R FO
I FO
C
TB
C FO
I FO
R FO
--
17 14 20 14 14 14 13 19 13
29.3 23.0 33.2 29.9 28.6 35.5 16.8
25.3 17.0 26.2 24.5 20.8 22.5 28.2 41.0 19.3
2.50 3.06 2.05 2.25 2.26 2.25 2.11 1.55 2.81
60.2 76.3 69.2 63.3 68.4 71.4 68.7 57.6 68.6
31.2 38.5 31.9 30.2 42.8
26.8 23.9
2.35 2.89
70.2 66.6
28.3 28.6 32.8 33.6 42.3
2.32 2.52 2.12 1.97 1.47
64.4 71.2 66.2 55.5 56.6
/ 1 I
-10
I
I
0
+10
I 0
I LI +20 -10
TRANSRESPIRATORY
PRESSURE
3. Before and after exposure values value at FRC as a function of transrespiratory ual dogs identified by number. FIG.
Mean GE -C TB cnil&O ments papain
15.3 kO.87 ____
28.0 t2.5
25.0 2.32 22.3 20.15
67.1 kl.9
34.9 22.4
30.9 2.23 +2.3 ItO.
64.4 +2.3
have units of ml cmH,O-l; RF0 has units of and CFO * 1-l s; and IF0 has units of cmH,O *ml-l. s2. CT, measurewere not made on dogs 1 and 2. Dogs 3 and 9 died following exposure.
I +10
I +20
(cm H,O)
of RF0 normalized by pressure for individ-
l
changes of R F0 were associated with an additional increase in transrespiratory pressure to + 20 cmH,O. However, RF0 included the resistances of the chest wall, nominally 0.40 cmH,O -1-l s (See below), and of the endotracheal tube, 1.11 cmH,O 1-l s (22). Because these accounted for more than one-half of the total resistance and because neither varied with lung volume, the effect of lung volume on the measured resistance was greatly attenuated. In comparing the pre- and postexposure data in Fig. 3, it appears that the effect of transrespiratory pressure on RF0 was more marked after papain. At FRC, mean values of RF0 in the two conditions were equal (Table 2). At -10 cmH,O the mean value of RF0 postexposure was significantly (paired t test, P 5 0.05) larger than the preexposure mean value. Similarly, mean RF0 values at + 10 and +20 cmH,O were lower in the postexposure condition. This is more clearly illustrated in Fig. 4, which shows the postexposure values of RF0 normalized by the corresponding preexposure value at each transrespiratory pressure for each of the five dogs. The general negative slope of the relationship shown by these data indicates that resistance had a greater dependence on transrespiratory pressure in the range -10 l
50
r
l
40 T 0 I”
30
E 0 .
20
5 u
c
IO
Post exposure
l
I
1
I
I
1
IO
20
30
40
50
C,,( ml-cm H,O-’ ) FIG. 2. Before and after exposure individual dogs identified by number. 0.78 CTB, is also shown.
values of C,, VS. CTB for Regression line, CF, = 5.3 +
l
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64
HADDAD,
PIMMEL,
SCAPEROTH,
AND
BROMBERG
studied. The use of other elastases has been reported (7-9, 20). The resulting lesion closely resembles human panlobular emphysema morphologically (9,11,19). Similarly the changes in physiological measurements induced by papain exposure are consistent with the data obtained in spontaneous human emphysema and can be explained by the loss of alveolar tissue with the concomitant reduction in elastic recoil pressure. Specifically, lung volumes (8, 9, 12, 15, 19), static compliance (5, 8, 12, 17, l9), peripheral resistance (19), and frequency dependence of dynamic compliance (15) were increased; elastic recoil pressure (11, 17,19), CO diffusing capacity (11, 19), and maximum expiratory flow at all lung volumes (3, 5, 15, 17) were decreased. No significant
w oz 2 2 0.8 X
w
z
0 0.6 CL 1
I
t
-10 0 +10 +20 TRANSRESPIRATORY PRESSURE km H,Ol FIG. 4. Values of R,, after exposure, normalized by corresponding values obtained before exposure, as a function of transrespiratory pressures for individual dogs identified by number.
to +lO cmH,O following papain exposure. Table 3 lists the pre- and postexposure values of CFO obtained with transrespiratory pressures of - IO, 0, + 10, and +20 cmH,O. Both before and after exposure there was a marked decrease in mean CFO at the two extreme volumes defined by -10 and +20 cmH,O, and a smaller change at +lO cmH,O. When compared to the corresponding FRC values, differences in the values were significant (paired t test, P 5 0.025) except for preexposure at + 20 cmH,O and for postexposure at + 10 emH,O. These variations in total respiratory compliance with transrespiratory pressure are consistent with the established S-shape pressure-volume curve of the total respiratory system (1). Figure 5 shows postexposure CFO values normalized by the corresponding preexposure value. All these ratios are greater than one at transrespiratory pressures of 0 and +lO cmH,O but more variable at the pressure extremes. . Table 4 shows individual and mean values calculated for Rcw and Ccw at FRC. These data indicate that Rcw represented about 17% of the total respiratory resistance. Because the endotracheal tube had a resistance of 1.11 cmH,O 1-l s (22), the chest wall therefore accounted for about 40% of the total respiratory resistance after correction for the endotracheal tube. With regard to Ccw, there was one large value (dog 8), and when this value was neglected, the mean t SE became 116 230 ml cmH,O? This suggests that the chest wall is three to four times more compliant than the lungs, and that total respiratory compliance at FRC is determined primarily by the lungs. As open-chested and closedchested inertance values were very similar, the inertial properties of the chest wall are negligible and total respiratory inertance is determined by the airways. l
TABLE
various
3. Values of CFO obtained at transrespiratory pressure I I PreexDosure
4 5 6 7 8
20.1 15.3 16.7 18.0 32.0
24.5 25.8 20.8 25.2 22.5 24.4 28.2 , 29.6 41.0 37.3
Mean tSE
20.4 +6.7
27.4 +&.l
Units
on compliance
Postexposure
I 20 cmH&
-10 cmH@
0 cmH,O
10 cmH,O
20 cmH,O
are ml. cmH,O?
l
l
/I
I
1
1
1
-IO 0 +10 +20 TRANSRESPIRATORY PRESSURE km Hz01 FIG. 5. Values of CFo after exposure, normalized by corresponding values obtained before exposure, as a function of transrespiratory pressures for individual dogs identified by number. TABLE 4. Values of chest wall resistance and compliance Dog
No. Mean
DISCUSSION
Since Gross et al. (6) introduced the use of papain to induce emphysemalike lesions, dogs (II, 19, 23), hamsters (5, 6, 12, 15, 17), rabbits (3), and rats (4) have been
Rcw ccw Units tively.
2
4
5
6
7
a
0.59 107
0.68 127
0.46 75
0.34 116
0.05 155
0.25 479
on Rcw and Ccw are cmH,O
l
0.40 * 0.23 177 t 150
1-l . s and ml cmH20q1, l
+ SE
respec-
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OSCILLATORY
MECHANICS
AFTER
PAPAIN
changes have been noted in total (19>, pulmonary (11, E), or airway resistance (5), dynamic lung compliance (ll), or the conductance-volume relationship (19). In several studies, alterations of pulmonary function show close correlation with quantitative morphological data (12, 15, 19). In our study we used the exposure methodology who exposed intubated described by Marco et al. (1 dogs to aerosolized solutions 2, 4, 8, and 16% papain. With the latter two concentrations they found enlarged air sacs with irregular contours and broken strands representing remnants of alveolar walls and septa distributed throughout the lung. There were no major bronchial changes. Functionally, after exposure to the 16% solution, they found an increase in FRC, a decrease in elastic recoil pressure and CO diffusing capacity, and no significant changes in dynamic lung compliance at FRC, pulmonary resistance, and the conductance-volume relationship. We followed their method of exposure using a 15% solution of papain obtained from the same manufacturer. Since our postexposure measurements were made almost 2 wk after the last exposure and almost 3 wk after the first, the initial inflammatory reaction should have dissipated and the emphysematype lesions should have progressed to a fairly stable state (6, 8, 11, 15, 17, 19). In our study we measured dynamic compliance during tidal breathing, CTB, and during forced oscillation, C&. After papain exposure both measurements increased from control values in all animals and the differences in mean values obtained before and after exposure were statistically significant. Marco et al. (ll), with exposure to a 16% solution, found an increase in dynamic compliance that did not achieve statistical significance, probably due to a small number of animals. In our study CTB was measured during artificial ventilation with highly repeatable pressure and volume waveforms, and this may explain the consistency in our results. The forced oscillation measurement, CFO, represents the best estimate obtained from 26 measurements at frequencies ranging from 0.9 to 16 Hz (22). It seems to be at least as good as CTB in characterizing changes in elastic properties induced by the papain. The overall correlation of CFO with CTB (Fig. 2) is similar to that observed by Tsai et al. (22) in a variety of other experimental conditions. At FRC, measurements of total resistance after papain exposure were not significantly different from values obtained prior to exposure. This is consistent with the findings of others (6,15,18,22). However, after papain exposure, we did find larger changes in resistance as compared to the FRC value at both positive and negative transrespiratory pressures (Table 2, Figs. 3 and 4). This finding contrasts with the results of Pushpakom et al. (19) who found no consistent changes in lung resistance as a function of transpulmonary pressure. The effect observed in our study cannot be explained by increased lung compliance inasmuch as the transpulmonary, and hence transmural, pressure should comprise a smaller fraction of the applied transrespi ratory pressu re under these conditions. The effect in the bY papai .n-induced alterations may be explained elastic properties of the airways (i.e., the diameter-
65 transmural pressure relationship) analogous to those produced in alveolar tissue. Such changes would make the cross-sectional area of the airways, and thus airway resistance, more dependent on the transmural pressure. Morphological examination of the airways following papain exposure has been reported to show minor bronchial changes that are generally thought to be insignificant (3, 5, 11, 19). However, there is some evidence of morphological and physiological changes in the small airways. Caldwell (3) has reported that intratracheal administration of papain in rabbits significantly decreased the number of alveolar attachments to noncartilaginous airways. Similarly Pushpakom and associates (19), using the retrograde catheter technique, described large increases in peripheral resistance over values reported earlier by Macklem and Mead (10) for normal dogs. Thus, it seems possible that the mechanical properties of the airways may be altered by papain exposure. The parameters derived for the chest wall seem reasonable. After neglecting the one large value for Ccw (dog 8), the mean value is about twice that predicted with Spells’ regression formula (21) and the mean weight of our dogs. Such an overestimation would result if lung compliance is under estimated during open-chested measurements due to some remaining that effects of the chest wall posteriorly. The indication the inertance of the chest wall is negligible is consistent with our conclusion in an earlier report based on inertante measurements made with air and a He-O, gas mixture (22). Computation of the forced oscillatory parameters are based on a simple series model with linear elements. Papain-induced emphysemalike lesions might produce lungs with peripheral compartments with dissimilar time constants (15). Frequency dependence in effective compliance and resistance have been predicted for such lungs at frequencies less than 2 Hz (16). Our measurements were largely done at higher frequencies where effective compliance would not be expected to show significant frequency dependence. Thus, we believe that a series linear model with constant parameters should be adequate, and our results (Fig. 1) support this. The parameters C FOand RF0 were sensitive to changes in the mechanical properties of the lung induced by papain exposure. Because such exposure is known to produce emphysemalike lesions, it appears that these measurements are capable of characterizing deterioration in mechanical function produced by this disease. This supports the conclusion of our earlier study in which we showed that these measurements were sensitive to changes produced by mechanical interventions and that the magnitude of the changes were consistent with predicted alterations (22). The measured CFo is well correlated with tidal breathing dynamic compliance (Fig. 2) as previously reported (22). Also, preexposure values for RFO, CFO, and IF0 are similar to values previously reported for normal dogs (22). It is noteworthy that forced oscillation techniques have been most frequently used to measure resistance parameters. The present study indicates that relatively small changes in compliance in a dog model of emphysema can be suc-
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66 cessfully estimated as well. In summary, this approach seems to be a reliable method for quantitatively characterizing changes in mechanical parameters in anesthetized, intubated, apneic dogs. When this is coupled with the semiautomation of the measurements (18), it becomes a very attractive approach for studying experimental animals. Unfortunately, readings from the special electronics unit used to obtain the frequency dependence of respiratory impedance become unstable when spontaneous breathing patterns are superimposed on the forced oscillations. Michaelson et al. (14) described an alternate approach
HADDAD,
PIMMEL,
SCAPEROTH,
AND
BROMBERG
for collecting impedance data that used random noise excitation. It may be possible to couple this method for acquiring data with our analytical approach to produce reliable estimates of resistance, compliance, and inertante in spontaneously breathing subjects. We thank the Sterling-Winthrop Laboratory, Rensselaer, NY for supplying the papain used in this study. This work was supported by National Institutes of Health Research Grant HL-19118 and by Environmental Protection Agency Research Grant R-805184. R.L. Pimmel was the recipient of National Institutes of Health Research Career Development Award HL-00207. Received
10 February
1978; accepted in final form 17 August
1978.
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