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Vol. 83, Issue 5, 1690-1696, 1997
1 Department of Immunological Diseases, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877; and 2 Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02115
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Madwed, Jeffrey B., and Andrew C. Jackson.
Determination of airway and tissue resistances after antigen and
methacholine in nonhuman primates. J. Appl.
Physiol. 83(5): 1690-1696, 1997.
Antigen challenge of Ascaris suum-sensitive
animals has been used as a model of asthma in humans. However, no
reports have separated total respiratory resistance into airway (Raw)
and tissue (Rti) components. We compared input impedance (Zin) and
transfer impedance (Ztr) to determine Raw and Rti in anesthetized
cynomolgus monkeys under control and bronchoconstricted conditions. Zin
data between 1 and 64 Hz are frequency dependent during baseline
conditions, and this frequency dependence shifts in response to
A. suum or methacholine. Thus it
cannot be modeled with the DuBois model, and estimates of Raw and Rti
cannot be determined. With Ztr, baseline data were much less variable
than Zin in all monkeys. After bronchial challenge with
A. suum or methacholine, the absolute
amplitude of the resistive component of Ztr increased and its zero
crossing shifted to higher frequencies. These data can estimate Raw and Rti with the six-element DuBois model. Therefore, in monkeys, Ztr has
advantages over other measures of lung function, since it provides a
methodology to separate estimates of Raw and Rti. In conclusion, Ztr
shows spectral features similar to those reported in healthy and
asthmatic humans.
input impedance; transfer impedance; forced oscillations; cynomolgus monkeys
INTRODUCTION NONINVASIVE MEASUREMENT of mechanical impedance of the
respiratory system using forced oscillations superimposed on normal spontaneous breathing in humans was proposed by DuBois et al. (3). They
described input impedance (Zin) derived from application of forced
oscillations at the airway opening and transfer impedance (Ztr) derived
from application of forced oscillations at the body surface. They
suggested a model of the respiratory system that includes six elements:
airway resistance (Raw), airway inertance (Iaw), gas compression (Cg),
tissue resistance (Rti), tissue inertance (Iti), and tissue compliance
(Cti). However, over the frequency range of their measurements (2 < f < 15 Hz), the system behaved as a
much more simple model, consisting of a single resistance (respiratory
system resistance, Rrs), inertance (respiratory system inertance, Irs),
and compliance (respiratory system compliance, Crs).
Investigators (16, 26) have used the six-element model to analyze Ztr
measurements from healthy adults to extract estimates of five of the
six parameters (i.e., all except Cg). However, it has been shown that
similar analysis of Zin in healthy adults is not possible (14).
Michaelson et al. (20) reported measurements of Zin data in adult
humans showing that the resistive part of Zin is relatively frequency
independent for f < 32 Hz in healthy individuals, whereas in patients with airway obstruction it decreases with increasing frequency at these frequencies. The frequency-dependent decrease in the resistive part of Zin in patients cannot be modeled by
the DuBois six-element model; thus it cannot be used to analyze Zin in
patients with airway obstruction. Thus, in healthy adult humans,
fitting of Ztr with the DuBois model allows for the estimation of Raw
and Rti, but similar estimates cannot be obtained from Zin in healthy
individuals or in patients with airway obstruction.
Several reports have demonstrated the usefulness of nonhuman primates
as an appropriate animal model for investigating normal respiratory
function (12, 13, 31, 32) and asthma (4-6, 11, 22-29, 32,
33). These experimental models of asthma have included an allergic
reaction to single or repeat exposures to antigen (4, 6, 22, 28, 33) or
airway hyperresponsiveness to a methacholine challenge (5, 7, 13, 29,
32). A variety of parameters have been used to quantify changes in
airway caliber, including pulmonary resistance at the breathing
frequency (4, 13), flows during maximum expiratory effort (13), and Zin
between 4 and 40 Hz (31, 32).
Zin in healthy nonhuman primates is similar to Zin in healthy humans,
except the resistive component is slightly frequency dependent and the
reactive component is shifted toward higher frequencies (30, 31).
Estimates of Rrs derived from Zin have been used in several nonhuman
primate studies to quantify changes in airway caliber after bronchial
challenge (4-6, 28, 29, 32). In each case, Rrs was determined by
averaging the resistive component of Zin over the frequency ranges
studied: 4-40 Hz (4-6, 32) or 10-20 Hz (28, 29).
However, in these studies, the authors implicitly based their analyses
on a simple three-element (resistance-inertance-capacitance, R-I-C)
model of the respiratory system. Zin data were not shown, nor was it
indicated whether the resistive components of Zin were frequency
independent. Thus the appropriateness of Rrs inferred from these
measurements may be in question.
The techniques for measuring impedance have been improved since the
original work of DuBois. These original measurements were very time
consuming, since they were made using a discrete frequency technique
over the range of frequencies of interest. More recently, impedance
measurements have been made by forcing the system with a single burst
of pseudorandom noise that contains all frequencies of interest (1, 8).
The pseudorandom technique significantly improves the time resolution,
making it possible to track the dynamic response after a challenge.
Therefore, the goals of this study were to measure Zin and Ztr in
monkeys under control and bronchoconstricted conditions with improved
time resolution to determine the transient response to
Ascaris suum and methacholine
challenge. We also sought to determine the appropriate model for
analyzing these data, the appropriate frequency range to apply, and
whether Raw and Rti can be estimated separately from Zin and Ztr.
METHODS Experimental Procedure
4 U) in the chest
area and after showing a 
200% increase of Rrs (historically
calculated as the mean of the resistive component of the Zin over the
frequency range of 4-40 Hz) above baseline levels. Each monkey
selected was housed individually in a open-mesh cage with a squeeze
back and was provided food once a day and water ad libitum.
Monkeys were initially anesthetized with an intramuscular injection of ketamine hydrochloride (20 mg/kg) and xylazine (4 mg/kg), removed from their cages, and intubated with a cuffed endotracheal (ET) tube (5.5 mm ID). Monkeys were seated upright in a support chair (Zin, see below) or in a head-out body chamber (Ztr, see below). Anesthesia was maintained with ketamine (5 mg/kg im) when needed, which included any swallowing or eye reflexes. At the end of an experiment, monkeys were returned to their cages and observed until they were upright.
Impedance Measurements
Input impedance. A single speaker (series IV, Bose), connected to the ET tube, was driven with a pseudorandom signal. This signal was passed through a digital-to-analog converter, amplified, and low-pass filtered at 160 Hz (model 4112, Ithaco, Ithaca, NY). Flow was measured at the entrance of the ET tube using a Microswitch transducer (model 763PC) mounted across a pneumotachometer (Fleisch no. 2). Pressure was measured from a catheter located at the tip of the ET tube also using a Microswitch transducer (model 743PC). Therefore, because the pressure was measured at the tip of the ET tube, the Zin measurements did not include the impedance of the ET tube. The pressure and flow signals were band-pass filtered from 1 to 160 Hz to remove the breathing signal and its harmonics. The fundamental breathing frequency of our ketamine-anesthetized monkeys was ~0.25 Hz or 15 breaths/min. Transfer impedance. A head-out body chamber (9 in. wide × 10.5 in. long × 24 in. high) was used to seal the head from the rest of the body. Two loudspeakers (model 5N411L, Focal) were mounted on each side of the chamber. The speakers were driven with a pseudorandom signal (forcing function) as described above. Pressure in the chamber was measured with a Microswitch transducer (model 743PC). Flow was measured, and the pressure and flow signals were filtered as described above. Also, because the pressure at the body surface (i.e., pressure in the chamber) was referenced to atmospheric pressure, our Ztr measurements include the impedance of the ET tube. In the systems identification methods (i.e., using the DuBois model to fit the data) applied to Ztr measurements, the implicit assumption is made that the pressures applied to the thorax are relatively homogeneous. One can predict the level of the spatial nonhomogeneity of pressure on the basis of the speed of sound (c) and frequency (f) of the oscillation from
= c/f, where is wavelength. Using
this relationship, we can see that, given an approximate major
dimension of the monkey's thorax (i.e., height) of 20 cm, an
oscillation of 1,700 Hz would have a wavelength equal to that
dimension. Thus, because our highest frequency (128 Hz) would have a wavelength that is ~10 times the size of the chest, we
assume that the pressures applied to the thorax are relatively homogeneous. We also determined this experimentally by measuring the
pressures at several different locations within the box and found
differences in the Ztr estimates of <2%.
The pressure and flow signals were displayed on a dual-channel
oscilloscope, digitized by the analog-to-digital board (ComputerBoard, Mansfield, MA), sampled at 512 Hz, and stored in the computer during
Zin and Ztr measurements. For Zin the forcing function contained
frequency components from 1 to 64 Hz in 1-Hz increments, and for Ztr
frequency components from 2 to 128 Hz in 2-Hz increments. The duration
of each burst was 1.0 s or 0.5 Hz for the Zin or Ztr measurement,
respectively. The energy of the loudspeaker oscillations was enhanced
below 32 Hz. The phase was adjusted such that the crest factor was
minimized; the crest factor is equal to the peak-to-peak pressure
oscillation divided by the root mean square of the signal (8). Pressure
and flow measurements were digitally compensated using the method of
Renzi et al. (27). Impedance was calculated as
|
) and 
ao() represent the Fourier transform
of the pressure and airway opening flow waveforms, respectively. The time domain signal and the Fourier transform measurement of the pressure signals were determined to be homogeneous throughout the body
chamber.
Experimental Protocol
Eight monkeys were used. All monkeys underwent bronchoconstrictor challenges with methacholine and A. suum. For each challenge, one experiment used Zin and a repeat experiment used Ztr. Thus four experiments were performed on each monkey. Monkeys were rested for at least 4 wk between challenges. Baseline conditions. Monkeys were allowed to stabilize for 15 min before baseline measurements were made. Impedance measurements were then made by application of five pseudorandom noise bursts, as described above, to the ET tube or the chamber (the whole trunk of the animal, including thorax and abdomen, was in the chamber and subjected to oscillation pressures). Bronchoconstrictor challenge. We administered A. suum or methacholine for 15 breaths via aerosol inhalation by compressed air nebulization and intermittent positive-pressure breathing with a Bird mark 7A respirator and micronebulizer (model 8158). We chose challenge doses of either agent to correspond with the dose that historically had elicited at least a twofold increase in Rrs in these animals (averaged between 4 and 40 Hz). Within 5 s after the cessation of either challenge, impedance measurements were initiated by application of five pseudorandom noise bursts to the ET tube or body chamber and were repeated every 30 s for up to 10 min. Modeling analyses. Parameters for the six-element model were estimated using a gradient optimization technique (2). The equations to define the transfer and input impedances are
|
|
![PI = <LIM><OP>∑</OP><LL><IT>i</IT> = 1</LL><UL>128</UL></LIM> ({Re<SUB>d</SUB>[Z(<IT>i</IT>)] − Re<SUB>m</SUB>[Z(<IT>i</IT>)]}<SUP>2</SUP> + {Im<SUB>d</SUB>[Z(<IT>i</IT>)] − Im<SUB>m</SUB>[Z(<IT>i</IT>)]})<SUP>2</SUP>](/content/vol83/issue5/fulltext/1690/img004.gif)
|
RESULTS
Input Impedance
Baseline measurements. In seven of eight monkeys, baseline Zin between 1 and 64 Hz showed a 3- to 10-fold frequency-dependent increase in the resistive component of Zin. In most monkeys, Zin was relatively constant from 1 to 24 Hz and began to increase at frequencies32 Hz. Representative monkeys are
shown in Fig. 1. The one animal that did
not show this frequency dependence exhibited much variability in the
resistive component between 1 and 64 Hz. Characteristic Zin data in
each animal were reproducible on five repeated measurements over 10 days.
, Monkey 1; 
,
monkey 2; 
, monkey
3. Monkey 2 demonstrated a 3-fold frequency-dependent increase;
monkey 3 showed a 10-fold frequency-dependent increase.
Bronchial challenge. Bronchial challenge with methacholine or A. suum resulted in a frequency-dependent change in the resistive component of Zin that evolved over a period of 3-4 min. Figure 2 shows one representative monkey during the first 2 min after challenge. Peak response occurred within the first 2 min, with a frequency-dependent decrease in the resistive component of Zin between 1 and 24 Hz during this time. After 3-4 min the monkeys normally reached a relatively steady state. Finally, the peaks in Re(Zin) at ~8 Hz were curious, and we assumed they were due to some low-level physiological signal (cardiac) or measurement system resonance.
,
Baseline; , 30 s postadministration; , 60 s postadministration;
, 120 s postadministration.
Transfer Impedance
Baseline measurements. Baseline Ztr responses were much less variable than Zin in all monkeys. Therefore, we represent the data as a composite summary of baseline Ztr between 2 and 128 Hz in eight cynomolgus monkeys in Fig. 3. The resistive component was relatively frequency independent up to ~32 Hz, crossed the zero axis between 45 and 66 Hz, and decreased thereafter. The reactive components of Ztr were negative below 8 Hz, became increasingly positive up to 80 and 112 Hz, and then decreased.
Bronchial challenge. Figure 4 shows a representative example of Ztr after methacholine challenge. Results were similar for methacholine and A. suum challenges. In contrast to the changes relative to baseline in patterns of frequency dependence of Zin after bronchial challenges, methacholine and A. suum challenge did not change the overall frequency dependence of resistive or reactive parts of Ztr relative to baseline conditions. Absolute amplitude of the resistive component to Ztr increased after challenge, and the zero crossing shifted to higher frequencies.
, Baseline;
, 0 s; , 30 s postadministration; 
, 60 s postadministration.
Model fit. Figure 5 displays the measured Ztr data during control conditions and maximum response to A. suum and the six-element model fits to these data. Results from methacholine challenge were similar (data not shown). Because these measurements were made over a frequency range where the resistive part became negative and the reactive part reached a relative maximum, we were able to obtain statistically reliable estimates of Raw and Rti (14). Baseline values of Raw, Iaw, Rti, Iti, and Cti (the 5 elements of the DuBois model) were 19.9 ± 1.1 cmH2O · l
1 · s,
0.18 ± 0.02 cmH2O · l1 · s2,
2.7 ± 0.1 cmH2O · l1 · s,
0.004 ± 0.0001 cmH2O · l1 · s2,
and 0.006 ± 0.0005 l/cmH2O,
respectively. We found that after A. suum challenge, Raw increased rapidly and peaked at
~90 s but then rapidly decreased, reaching a new steady state after
~3 min, and stayed at this level for an extended period of time (Fig. 6A).
After A. suum challenge the peak
values of Raw, Iaw, Rti, Iti, and Cti were 67.7 ± 10.8 cmH2O · l1 · s,
0.15 ± 0.03 cmH2O · l1 · s2,
2.8 ± 0.2 cmH2O · l1 · s,
0.006 ± 0.0006 cmH2O · l1 · s2,
and 0.007 ± 0.002 l/cmH2O,
respectively. After methacholine challenge, Raw also
rapidly increased and peaked at ~90 s, then slowly decreased toward
baseline over the next 10 min (Fig.
6B).
) and model-fit data () of baseline
conditions (A and
C) and Ascaris
suum challenge (B and
D) data from 8 monkeys.
A and
B: resistive part of Ztr;
C and
D: reactive part of Ztr.
As stated above, the six parameters in the DuBois model cannot be extracted independently from Ztr. Therefore, Cg was computed from the estimated FRC from the monkey's weight using a regression equation in the literature (22). Because the actual FRC could be different from the FRC estimated in this way, assigning it an erroneous value could influence the accuracy of the other parameter estimates. To investigate this issue, we determined the sensitivity of the other five parameters to errors in the Cg estimate. This was accomplished by using the means of the six parameters to generate a set of simulated data. We then used the systems identification routine to estimate the five parameters other than Cg, while Cg was fixed to values that varied between +50% and
50% of the value used to generate the simulated Zin data.
This analysis indicated that Rti and Iti were quite sensitive to errors
in Cg; i.e., the percent error in these parameters was roughly
equivalent to the error in the Cg estimate. Cti and Iaw were very
insensitive to errors in Cg; for a 20% error in Cg, Cti and Iaw were
accurately estimated to within 1% of their actual values. When Cg was
overestimated by 40%, Raw was overestimated by <2% of its actual
value. When Cg was underestimated by 40%, Raw was underestimated by
slightly more than 7% of its actual value.
DISCUSSION
Zin measurements have been used by several investigators (4-6, 28-33) to determine Rrs in nonhuman primates. These investigators measured Zin between 10 and 20 Hz (28, 29), 4 and 40 Hz (4-6, 32), and 2 and 32 Hz (30, 31). Each of these studies reports Rrs data, which are determined by averaging the resistive part of the Zin spectrum over the selected frequency range of interest. If Rrs is viewed as a feature of the Zin spectra that is sensitive to changes in airway caliber, then it becomes important to prove that this feature is indeed correlated with changes in airway caliber as determined by some other independent technique. However, if a single value of Rrs is taken to represent an overall, lumped-system parameter, this carries the implicit assumption that a simple three-element R-I-C model provides an adequate description of the respiratory system. The simple three-element R-I-C model is based on the assumption that resistance is relatively independent of oscillation frequency, which is not the case in baseline or postchallenge Zin data in the present study. A careful examination of the frequency dependence or independence has never been reported in baseline conditions, simulated disease states, or postbronchoconstriction challenges. Wegner et al. (30, 31) demonstrated in the monkey that during baseline conditions the resistive component of Zin decreased with frequency from 2 to 8 Hz and then increased with frequency from 8 to 32 Hz. Our baseline conditions between 2 and 32 Hz also showed that the resistive component of Zin is frequency dependent. In addition, we also demonstrated that the shape of the resistive component of Zin differed depending on the time after challenge. Therefore, the estimated Rrs would depend on the frequency range of the measurements, e.g., 2-32 Hz, 4-40 Hz, or 10-20 Hz.
Because the resistive part of Zin is frequency dependent, most evident after bronchoconstrictor challenge, a simple R-I-C circuit may not necessarily be an appropriate model for the respiratory system. Therefore, Rrs estimated by the mean of the resistive part of Zin may also not be an appropriate estimate of changes in airway caliber. The frequency-dependent drop in the resistive component of Zin after bronchoconstriction is thought to be due to parallel heterogeneity (8, 9, 14) or increased peripheral Raw, with a concomitant increase in the influence of nonrigid behavior of the central airway walls (19). One could incorporate parallel heterogeneity and airway wall compliance into the model, but with such a considerable increase in model complexity that reliable estimates of its parameters would be unlikely (21). These findings suggest that the respiratory system of the monkey behaves like that of the adult human, where Zin cannot be used to estimate Raw and Rti. In most cases, during baseline conditions, Zin between 2 and 32 Hz can be modeled with a simple three-element R-I-C circuit, which provides estimates of Rrs, Irs, and Crs. However, after bronchial challenge, Zin can no longer be analyzed with the simple three-element model, presumably because of heterogeneity of the bronchoconstriction or the increased influence of nonrigid airway walls.
Ztr has several advantages over Zin. First, the specific features of the Ztr spectra in baseline as well as bronchoconstricted conditions can be appropriately modeled with the six-element model of DuBois. Thus, as in adult humans, analysis of Ztr over the appropriate frequency range provides statistically reliable estimates of the separate Raw and Rti (K. L. Lutchen, A. Sullivan, F. T. Arbogast, B. R. Celli, and A. C. Jackson, unpublished observations). The frequency-dependent decrease in the resistive component of Zin that occurs with bronchoconstriction could not be modeled by the six-element model, but this does not occur in the Ztr. As discussed above, this frequency-dependent decrease in the resistive component of Zin is thought to be due to parallel heterogeneity in the bronchoconstriction or the increased influence of airway wall nonrigid behavior with increased peripheral Raw. Although parallel heterogeneity would theoretically influence Ztr and Zin to a similar degree, this is not the case with nonrigid airways. The impact of nonrigid airways is a function of the impedance of this pathway (Zaw) relative to the impedance of what is in parallel with it. In Zin measurements, Zaw is in parallel with the impedance of that portion of the Zrs that is distal to the effective location of Zaw (i.e., toward the lung periphery). In Ztr measurements, Zaw is in parallel with everything distal to the effective location of Zaw, i.e., the impedance of the upper airways, ET tube, and pneumotachometer. Because the impedance of the upper airways, ET tube, and pneumotachometer is much less than the impedance of the lower airways and lung and chest wall tissues, Zaw has a greater influence on Zin than on Ztr. As a consequence, Ztr can be analyzed with the six-element model, even during bronchoconstriction. Therefore, we were able to examine in more detail the usefulness in separating airways and tissues from the total Rrs during control and postbronchoconstrictive conditions.
Second, the Ztr measurements in the present study show spectral features similar to those reported elsewhere in healthy and asthmatic humans (15; Lutchen et al., unpublished observations). In addition, among monkeys, the data were very similar, and in any given monkey the data were very reproducible. Most importantly, the shape of the Ztr spectra after bronchial challenge was not changed relative to baseline conditions. The main spectral features that differed were the amplitude, which consistently increased, and the zero-crossing point, which was shifted to the right. To our knowledge, these data are the first to implement Ztr in nonhuman primates.
In the present study the six-element model of DuBois yielded very realistic estimates of Raw and Rti to the experimental data during baseline conditions and after bronchial challenge. These results indicate that Raw accounts for >80% of total Rrs. These results differ from those of Wegner et al. (30, 31), who reported that Raw was 50% of Rrs. The explanation for these differences is that to reliably separate airway and tissue properties from Zin data, measurements must be obtained over a wide enough frequency range to include a resonance and an antiresonance (15). Because Wegner et al. (32) did not measure to high enough frequencies to include an antiresonance, their estimates of separate Raw and Rti are open to question.
The present study has shown slightly different responses to A. suum and methacholine challenges. Whereas the degree and rate of the rise in Raw were similar with both, the subsequent decline or return to baseline differed. The decline from peak response after methacholine gradually returned toward baseline over the 10 min of observation. In contrast, the fall in Raw from its peak levels was sudden but did not reach its original baseline, maintaining an elevated steady state for the observation time. We believe that ours is the first study to report these differences in dynamic response to bronchial challenge, made possible by the pseudorandom bursts of oscillatory noise as in the present study.
We conclude that the six-element DuBois model fits the Ztr data well in baseline conditions and after bronchial challenge in anesthetized cynomolgus monkeys. The model allows separation of airway and tissue properties. Ztr data between 2 and 128 Hz provide a consistent method of quantifying the response to bronchoprovocation, and the appropriateness of the DuBois model permits interpretation of the data in terms of changes in airway caliber. Finally, improved time resolution provided by application of brief bursts of pseudorandom noise permits more complete description of the dynamic response after bronchial challenge.
ACKNOWLEDGEMENTS
The authors thank Carol Torcellini for assisting with the animal experiments, Peter Mulready for patience and advice, and Karl Noffke for electronic help.
FOOTNOTES
Address for reprint requests: J. B. Madwed, Dept. of Immunological Diseases, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877.
Received 9 July 1996; accepted in final form 8 July 1997.
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