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Departments of Anesthesiology, Physiology, and Pathology, and Shock Trauma Center, University of Maryland, and Research Services, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Barnas, George M., Paul A. Delaney, Ileana Gheorghiu,
Srinivas Mandava, Robert G. Russell, Renée Kahn, and Colin F. Mackenzie. Respiratory impedances and acinar gas transfer in a
canine model for emphysema. J. Appl.
Physiol. 83(1): 179-188, 1997.
We examined how
the changes in the acini caused by emphysema affected gas transfer out
of the acinus (Taci) and lung
and chest wall mechanical properties. Measurements were taken from five
dogs before and 3 mo after induction of severe bilateral emphysema by
exposure to papain aerosol (170-350 mg/dose) for 4 consecutive wk.
With the dogs anesthetized, paralyzed, and mechanically ventilated at
0.2 Hz and 20 ml/kg, we measured
Taci by the rate of washout of
133Xe from an area of the lung
with occluded blood flow. Measurements were repeated at positive
end-expiratory pressures (PEEP) of 10, 5, 15, 0, and 20 cmH2O. We also measured dynamic
elastances and resistances of the lungs
(EL and
RL, respectively) and chest wall at the different PEEP and during sinusoidal forcing in the normal range
of breathing frequency and tidal volume. After final measurements, tissue sections from five randomly selected areas of the lung each
showed indications of emphysema.
Taci during emphysema was similar
to that in control dogs. EL
decreased by ~50% during emphysema (P < 0.05) but did not change its
dependence on frequency or tidal volume.
RL did not change
(P > 0.05) at the lowest frequency
studied (0.2 Hz), but in some dogs it increased compared with control at the higher frequencies. Chest wall properties were not changed by
emphysema (P > 0.05). We suggest
that although large changes in acinar structure and
EL occur during uncomplicated
bilateral emphysema, secondary complications must be present to cause
several of the characteristic dysfunctions seen in patients with
emphysema.
xenon-133 washout; alveoli; gas transport; resistance; elastance
INTRODUCTION PATIENTS WITH PULMONARY EMPHYSEMA usually have
complications, including heterogeneous lesions, bronchoconstriction,
mucous plugging, and/or airway inflammation (35). In addition
to decreases in static lung elastance, they usually display frequency
(f) dependence of dynamic elastance
(EL), airflow limitation on
expiration (35), and air trapping leading to intrinsic positive
end-expiratory pressure (PEEP; see Ref. 34). It has also been reported
that lung resistance (RL)
shows a large dependence on f (35). However, it is not clear how
emphysematous changes in acinar tissue alone may affect the mechanical
behavior of the airways without the presence of complications. Although
overall lung size is increased with emphysema, there should be less
radial force distending the airways. Therefore, it is difficult to
predict how airway size, and thus resistance to flow through the
airways, would be changed with emphysema alone. Also unclear is how the
large changes in the structure of the acinus that occur with emphysema
affect resistance to flow from the acinus. It has been suggested that
an increase in peripheral RL is
a major factor that determines dysfunction with emphysema (35).
However, overall RL may not be
affected by increases in resistance in the peripheral parts of the
lung, and peripheral function must be directly measured to understand emphysema.
We addressed these issues in a chronic canine model for uncomplicated,
bilateral pulmonary emphysema induced by repeated exposures to papain
aerosol. We measured lung and chest wall mechanical properties during
sinusoidal forcing in the normal range of f and tidal volume
(VT), as previously described
in healthy and edematous lungs (7). Such measurements can give
information concerning functionally relevant respiratory mechanical
behavior that may be lacking with other techniques (3). For example, a
large negative dependence of EL
on VT and of
RL on f occurs during pulmonary
edema (7). Also as previously described (1, 5, 23), we measured
133Xe washout (XeW) in a lung
region (~30% of 1 lung) during 90 s of mechanical ventilation while
pulmonary blood flow to the region was occluded. With this technique,
133Xe is injected into the
nonperfused lung region during apnea, and apnea is continued for 15 s
before ventilation is reinstated and washout is measured. Thus there is
sufficient time for the 133Xe to
diffuse throughout the acini by the beginning of washout. XeW is
affected by the gas transfer from the acini to the airways (Taci) caused by the ventilation
(1, 5) and is a more direct index than other current methods for
studying acinar gas transfer, such as measurement of exhaled gas in
single or multiple breaths or monitoring of dispersion of inhaled
aerosol boli. Taci is affected by
increases in resistance to flow from the acinus and has been shown to
be greatly decreased during pulmonary edema unless a high level of PEEP
is applied (1).
The goal of this study was to quantify the effects of uncomplicated
pulmonary emphysema on the mechanical properties of the lungs and chest
wall in the normal range of breathing f and
VT, on the f and
VT dependencies of these
properties, and on the mechanical function of the most peripheral parts
of the lung. We hypothesized that some of these variables may be
unaffected by this model of emphysema because complications that
usually occur in patients with emphysema would not be present. If so,
this would suggest that the interaction of emphysema with these
complications may be important in determining dysfunction. We used a
chronic papain model that was designed to produce very extensive
emphysematous changes in the acini, and we waited a relatively long
time after the papain exposure to make measurements to ensure that
temporary lesions caused by the papain, unrelated to emphysematous
changes, were probably reversed.
METHODS
1 · h1)
and pancuronium bromide (0.08 mg · kg1 · h1)
in normal saline at 60 ml/h. In addition, we infused each dog with 6%
hetastarch in saline solution at 25 ml/kg to minimize cardiovascular
changes caused by increases in PEEP. We measured airway flow with a
pneumotachograph (Fleisch no. 1) attached to the end of the
endotracheal tube and a differential pressure transducer (Celesco
LCVR). Airway pressure (Paw) was measured (Celesco LCVR) through a
sampling port in the endotracheal tube that opened at its tip.
Esophageal pressure (Pes) was measured (Celesco LCVR) via a
polyethylene catheter attached to a 10-cm-long thin-walled latex balloon placed in the caudal part of the esophagus. The accuracy
of the esophageal balloon was verified with a method modified from
Baydur et al. (8), as previously discussed (7). A fourth Celesco LCVR
transducer measured transpulmonary pressure, the difference between Paw
and Pes. Arterial O2 saturation
(SaO2) was continuously monitored by a
pulse oximeter (Nellcor, N-100) attached to the tongue, and
SaO2 remained >95% at all times. Body temperature, monitored in the pulmonary artery, was
controlled between 36.5 and 37.5°C with a heat lamp and blanket.
T;
Oximetrix 3 thermodilution computer, Abbott). Arterial and mixed venous blood gases were sampled simultaneously and analyzed (Stat Profile, NOVA Biomedical), with temperature correction.
SaO2 and mixed venous
O2 saturations and contents were
measured with a CO-oximeter (Instrumentation Labs, model 282). Mean
expired CO2 concentration was
continuously measured in a mixing chamber (Marquette Gas Analyzer-A).
For the measurements of lung and chest wall impedances during
sinusoidal forcing in protocol 2,
inductance plethysmographic belts (Respitrace, Ambulatory Monitoring)
were placed around the rib cage and abdomen to measure mean lung volume
above functional residual capacity (FRC). For these measurements, the
Respitrace amplifier was used in DC mode, and the electrical gains of
the rib cage and abdominal signals were set to equal values. The summed signal from the belts was linearly related to changes in lung volume
made during the static elastance measurements. The difference between
the mean volume during forcing and the volume at the end of the period
of 0 cmH2O Paw immediately after
forcing was taken as the volume above FRC.
Protocol 1: XeW.
A few minutes before each set of measurements, the dog was
hyperinflated with six breaths of >550 ml at 10 cmH2O PEEP to provide a constant
volume history, and then VT was
returned to control for 15 min, at the level of PEEP to be measured.
Immediately before injection of
133Xe, we measured
EL and
RL, and, as indicated below,
cardiorespiratory variables as well as arterial and mixed venous gases.
We then inflated the balloon of the pulmonary artery catheter and
monitored the pressure at the tip of the catheter to ensure proper
occlusion (the balloon remained inflated until the end of each scanning period). Ventilation was stopped, and
133Xe (1-2 mCi dissolved in 4 ml of saline) was injected through the cannula in the occluded
pulmonary artery and flushed with 4 ml of saline. Scanning by a gamma
scintillation camera (Nucleonics) positioned 1-2 cm above the
sternum commenced 10 s after the injection at 1 frame/s for 90 s.
Ventilation was returned 15 s after the injection. After the image
acquisition was completed, we reduced PEEP to 0 for a single breath to
measure the change in lung volume above FRC, from integration of airway
flow, caused by the previous level of PEEP. The sequence of PEEP was
10, 5, 15, 10, 0, and 20 cmH2O.
At each level of PEEP, we also calculated
EL and
RL by using multiple regression
as previously described (1) from measurements of airway flow, Paw, and
Pes. During each of these measurements, inspiratory-to-expiratory time
ratio was temporarily changed to 1:1 with no inspiratory pause to
improve accuracy (3). In two of the dogs, we also measured FRC at 0 cmH2O PEEP by nitrogen washout
(20), with measurements of expiratory flow and nitrogen concentration
(Med Spect mass spectrometer, Allegheny International).
Protocol 2: Respiratory impedances.
In each dog, on the same day as protocol
1, static elastances of the total respiratory system,
lungs, and chest wall were plotted from Paw, Paw
Pes, and Pes,
respectively, at the end of a 6-s inspiratory pause after inflation to
different volumes. Then, lung and chest wall impedances were measured
during sinusoidal forcing. About 1 min before each measurement of lung
and chest wall impedances, VT
was increased to 550 ml for three successive breaths. To obtain
measurements, we used a three-way valve system to switch the dog from
the mechanical ventilator to a piston pump driven by a linear motor. A
series of sinusoidal volume oscillations at 300 ml (0.2, 0.4, 0.6, 0.8, and 1.0 Hz; five or seven cycles at each f ) was delivered while a
low flow of 60% O2 to the
pump-dog system was adjusted to keep end-expiratory Paw at 0 cmH2O. After the volume forcing,
Paw was allowed to fall to 0 cmH2O
for 4 s to measure changes in mean lung volume above FRC, and then the dog was switched to the mechanical ventilator. Next, the procedure was
repeated at VT of 100, 200, and
50 ml. At these lower VT values, the f sequence additionally included 2 Hz, and 60%
O2 flow into the system was
adjusted to keep mean Paw equal to that observed during forcing with
300 ml (7.5 ± 0.4 cmH2O). In
other words, at all f and VT
values, mean Paw was constant. Then measurements were made at each of
the VT and f combinations at a
constant mean Paw (15.0 ± 0.8 cmH2O) twice as high as that just
employed. The entire protocol was then repeated two more times to give
a total of three trials at each combination of mean Paw, f, and
VT.
Protocol 3: Induction of emphysema and final measurement.
After control measurements were made in each dog, we used a method
previously described (37) to produce lung injury. While the dogs were
anesthetized as described above, they were exposed to aerosolized
papain (170-350 mg in 15 ml 0.05 M sodium acetate) delivered to
both lungs through the endotracheal tube during mechanical ventilation,
using a nebulizer (Misty-Neb, Baxter) with 4 l/min O2 flow. Dogs were exposed
immediately after control measurements and once each week for the
following 3 wk. They were allowed to awaken after each exposure and
showed no untoward clinical signs. Protocols
1 and 2 were repeated
in each dog 3 mo after the last papain exposure and again during
anesthesia and paralysis as described for controls. The mean Paw used
for forcing during emphysema were 5.9 ± 0.4 and 11.8 ± 0.9 cmH2O. Determinations of FRC were
made at these times in the two dogs measured in the control state.
Histology.
After final measurements were made, five randomly selected areas of the
lung were fixed on 10% neutral-buffered Formalin. The
lungs were not inflated during fixation. Tissues were embedded in
paraffin, and 5-µm sections were stained with hematoxylin and eosin
for examination with light microscopy.
Data analysis: Protocol 1.
The XeW curves were analyzed with the use of Gamma II software, as
previously described (1, 5, 23), by identifying the regions of interest
within the lung by computer and performing monoexponential regression
analysis of the counts measured during the scan, beginning at the first
breath. There was no difference between the two measurements of XeW
made in each of the dogs at 10 cmH2O PEEP, during control and
during emphysema (P > 0.05, paired
t-tests), so values at 10 cmH2O PEEP in a given condition were averaged.
Physiological dead space (VDS)
was calculated from the Enghoff modification of Bohr equation
(equipment dead space = 40 ml) and shunt fraction
(S/T)
from the shunt equation (31). We also calculated alveolar ventilation
(
A) as 12 × (VT VDS 40 ml), where f was
12/min. FRC in the two dogs we measured was near that predicted by body
weight (13), and increases in FRC after induction of emphysema were in
the same range as that measured in other studies using papain in dogs
(14, 16, 17, 27, 36). Therefore, we assumed that FRC values before and
after induction of emphysema were the same in all of our dogs as the average of the two dogs measured. We then estimated alveolar volume at
each PEEP by adding the increment in volume above FRC caused by the
PEEP (measured in protocol 1) to the
estimated FRC and subtracting the
VDS.
Taci was calculated, as previously
described (1), from the product of XeW and the estimated alveolar
volume. The effects of PEEP and emphysema on each variable were tested with two-way analysis of variance (ANOVA) for repeated measures with
Bonferroni correction. To test whether the slopes of the relationships
between lung volume and PEEP, XeW and PEEP, and VDS and mean transpulmonary
pressure were affected by emphysema, we used a general linear multiple
regression that accounts for repeated measures in the same dog (4).
Significant interaction terms indicated changes in slope caused by
emphysema. The accepted level of significance in all tests was
P < 0.05.
Data analysis: Protocol 2.
All pressure and flow signals were low-pass filtered at 5 Hz (series
730, Frequency Devices). The first two or three cycles at each f were
discarded to avoid transients that may occur on switching. The
remaining three cycles were digitized (sampling rate = 32 samples/cycle), computer averaged, and analyzed by
discrete Fourier transform (3). In the closed chest, resistances and dynamic elastances of the chest wall (Rcw, Ecw) and lungs
(RL, EL) were calculated from the
complex ratios of Pes and Paw Pes, respectively, to flow. Note that
dynamic elastances were calculated by multiplying the imaginary part of
the impedance by 2
f and therefore can contain effects
contributed by inertia. These effects should be small at the
frequencies measured in the present study (3).
We used the stepwise multiple linear regression that accounts for
repeated measurements in the same dog (4) first to test whether there
was a difference among values for resistances and for
elastances between control and emphysema at each mean
Paw, considering the entire range of f and
VT of forcing. Then we separated the data and repeated the stepwise multiple regression in each of the
groups at each mean Paw to test for the effects (i.e., regression
coefficients) of f and VT on
EL,
RL, Ecw, and Rcw. Significant
regression coefficients indicated that the dependent variable increases
(positive coefficient) or decreases (negative coefficient) with an
increase in the independent variable. We used ANOVA with Bonferroni
correction to test for differences in the regression coefficients among
the groups. Multiple regression was also used to test whether mean lung
volume during sinusoidal forcing was affected by mean Paw, emphysema,
and VT. Using linear regression,
we calculated static elastances as the slopes of the relationships
between appropriate pressures and volumes. These elastances were
calculated for two ranges of volumes: 350 ml and below (the range
during sinusoidal forcing at the lower mean Paw) and 350 ml and above.
ANOVA with Bonferroni correction was used to compare each elastance in
the different conditions. The accepted level of significance was
P < 0.05 for all analyses.
RESULTS
A decreased with increasing PEEP, but
neither was affected by emphysema (Fig. 1). XeW decreased with
increasing PEEP in both control and emphysema (Fig. 1), but the slope
of this decrease was less (P < 0.05)
with emphysema (0.06 ± 0.01 min/cmH2O) than with control
(0.11 ± 0.01 min/cmH2O). Estimated
Taci (Fig.
2) was not affected by emphysema
(P > 0.05).
A;
B), physiological dead space (VDS;
C) and washout of
133Xe from the acinus (XeW;
D) at different positive
end-expiratory pressure (PEEP) in 5 anesthetized and paralyzed dogs
before and after induction of bilateral emphysema. Bars, SE.
Differences (P < 0.05) within same
condition: a, compared with 0 cmH2O PEEP; b, compared with 5 cmH2O PEEP; c, compared with 10 cmH2O PEEP; d, compared with 15 cmH2O PEEP.
EL was decreased with emphysema compared with control (P < 0.05) and tended to increase at higher PEEP in both control and emphysema (Fig. 3). RL was not affected by emphysema (P > 0.05) and, in both control and emphysema, decreased only at 20 cmH2O PEEP compared with 0 cmH2O PEEP (Fig. 3).
Although PEEP affected
T,
S/T,
mean arterial pressure, and pulmonary arterial pressure (Ppa) (Fig.
4), emphysema did not
(P > 0.05). Similarly, emphysema did
not affect (P > 0.05) heart rate or
stroke volume (not shown). Arterial
O2 tension was 342 ± 6.62 Torr
at 0 cmH2O PEEP during control and
was not changed by PEEP or emphysema
(P > 0.05). Arterial
CO2 tension during control decreased (P < 0.05) from 36.2 ± 1.0 Torr at 0 cmH2O PEEP during control to 41.6 ± 2.3 Torr at 20 cmH2O PEEP. With emphysema, it was
not different from control at any PEEP
(P > 0.05).
T;
B), pulmonary arterial pressure
(Ppa; C), and pulmonary shunt
fraction (S/T;
D) in 5 anesthetized and paralyzed
dogs at different PEEP values before and after induction of bilateral
emphysema. a-d, Same as in Fig. 1.
FRC during control measurements was 399 and 323 ml in the 2 dogs in which it was measured. FRC was 510 and 493 ml, respectively, in the same dogs after induction of emphysema. Protocol 2. Static elastances (Fig. 5) of the respiratory system and of the lungs increased above 350 ml (P < 0.05) during control only (Table 1). Both elastances decreased with emphysema in either volume range (P < 0.05). Static elastance of the chest wall decreased (P < 0.05) above 350 ml during both control and emphysema (Table 1). Static chest wall elastance during emphysema was slightly higher than control (P < 0.05) above 350 ml only.
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1 · s1
and was not changed by emphysema or mean Paw
(P > 0.05). There was no dependence
on VT
(P > 0.05) in any condition.
With control, RL was not affected (P > 0.05) by mean Paw (Fig. 6). At low mean Paw, the regression coefficient for the dependence of RL on 1/f was 0.34 ± 0.10 cmH2O /l and was not changed at the higher mean Paw (P > 0.05). At 0.2 Hz, RL was not different with emphysema (P > 0.05). However, changes in RL throughout the entire range of f with emphysema were somewhat variable among dogs. At the lower mean Paw, RL increased throughout most of the range of f compared with controls in three of the dogs; in those cases, RL was also less dependent on f. At the higher mean Paw, RL returned to values similar to control in two of those dogs. With the average data including all f, RL was increased with emphysema compared with control (P < 0.05) at the low mean Paw only, and RL decreased (P < 0.05) as mean Paw was increased (Fig. 6). With the average data during emphysema, there was no dependence of RL on 1/f (P > 0.05). There was no dependence of RL on VT in any condition (P > 0.05). There were no effects (P > 0.05) of mean Paw or of emphysema on Ecw or Rcw (Fig. 7). In all conditions, Ecw and Rcw decreased with increasing VT (P < 0.05); Ecw increased slightly with increasing f (P < 0.05), whereas Rcw decreased with increasing f (P < 0.05).
Histology. Histological examination showed emphysema in all lung sections in all five dogs. Alveolar emphysema was characterized by large alveolar spaces with wide openings (Fig. 8A). Alveolar walls exhibited rounded, thickened knobs and hyperplastic epithelium that projected into the lumen of the alveolar space (Fig. 8B). The emphysematous areas were patchy, alternating with areas of normal lung. Terminal bronchioles and bronchioles were essentially unremarkable. There was no evidence of airway narrowing or inflammation.
DISCUSSION
The main findings of this study were large decreases in EL with emphysema that were not dependent on f and no changes in transfer of gas from the acinus. RL was increased at the higher f with emphysema in some dogs. Chest wall mechanical properties were not affected by the emphysema.
Comparisons with other studies. Papain has been used in many studies as a model for emphysema, and several different protocols have been employed. Studies differ in the type of exposure (aerosol vs. intratracheal or intrabronchial instillation), dose, length and number of repetitions of exposure, and the period from last exposure to measurements. There is evidence that the model does not become stable until ~1 mo after the last exposure (21, 25, 33). The most common findings in studies using papain are increases in static or dynamic lung compliance (14, 16, 17, 25, 27, 30, 36) and FRC (9, 14, 17, 18, 21, 26, 27, 36), although in some studies these were not significant (10, 25). Our protocol of four repeated aerosol exposures was among the highest total doses given, and we expected that almost all acinar regions would be affected. Because we found definite evidence of emphysematous changes in tissue samples from throughout the lung, it is likely that the protocol produced a uniform distribution of extensive, although patchy, emphysema. In addition, lack of changes in EL with f also indicates uniform lung mechanical behavior (32). Although this is unlike the condition expected in most patients, it enabled evaluation of the effects of emphysema without complicating factors, and it allowed for the assumption that XeW from the area of the lung studied would be characteristic of the lung as a whole. Although we found that cardiovascular variables and arterial blood gases in our model for emphysema were not changed from control, increases in Ppa have been reported in a similar model elsewhere (28, 37). The high FIO2 used in our study probably prevented any increases in Ppa that might have caused hypoxic vasoconstriction in those studies. Therefore, possible indirect effects that were due to cardiovascular changes with emphysema probably did not contribute to the results in our model. EL. In various studies in patients with emphysema, static elastance near FRC has been reported to decrease from 32 to 60% compared with normal subjects (11, 12, 15, 22), although one early study reported no difference (38). Thus the 39% decrease in static elastance near FRC we found in the present dog model is within the range generally found in human patients. However, dynamically determined elastance (i.e., EL) decreased by ~50% in the dog model, whereas EL in patients with emphysema has been reported to not change (11) or to increase (29) compared with normal patients. The discrepancy is probably due to the complications of airway abnormalities and heterogeneity of lesion that are usually found in patients. With such conditions, EL increases as respiratory f increases (11, 29) and may be less than, equal to, or higher than control values, depending on the f at which it is measured. In fact, it has been suggested that one of the primary indications of onset of emphysema is frequency dependence of EL (35). We found no increase in the frequency dependence of EL after induction of emphysema in the papain-treated dogs, indicating that emphysema was homogeneously induced throughout the lung. As mentioned above, tissue samples corroborate this. Previous studies in excised hamster lungs (30) and intact dogs (14) after exposure to papain did find f dependence of EL. However, those studies used less extensive dosing and a shorter recovery period than the present study. Acinar gas transfer. As previously discussed, our measurements of XeW reflect transfer of gas, mostly by diffusion, from the acini to the convective gas front, which in turn will be limited by convective gas transfer from the mouth to the entrance of the acini (1). The most important factor for the decrease in XeW with increasing PEEP is probably the resulting increase in alveolar volume, because washout of a substance from a chamber is generally inversely proportional to the volume of the chamber (1). The rate of Taci (in l/min) equals the product of XeW and alveolar volume (1). Calculated Taci (Fig. 2) is nearly identical for the two conditions at all PEEP. Although papain-induced emphysema causes large structural changes in the acini (10, 16, 21, 25-28, 30, 33), none of these changes increases resistance to gas transfer. Pushpakom et al. (36) did find increases in peripheral airway resistance in excised dog lungs after papain treatment, and this resistance could possibly be influenced by changes in the acini. However, as pointed out by Klassen et al. (21), measurements were made when some transient lesions in response to papain may have still been present. RL. At the lowest breathing f studied (all measurements in protocol 1 and 0.2-Hz measurements in protocol 2), we found no consistent changes in RL between control and emphysematous lungs. Other studies using the papain model have also found no changes in morphology and diameter of the bronchi or small airways (10, 21, 25, 27, 30) and no changes in RL at routine ventilator f (9, 16-18, 25, 36), including studies that changed lung volume (14, 21, 30). Thus the structural changes in the papain-induced model of emphysema occur at the acinar level, and there seem to be no structural changes of the airways. However, specific morphometric studies of the peripheral airways have not yet been done, and subtle changes may occur. Furthermore, the structural changes in the acinus do not interfere with Taci because, as discussed above, acinar resistance does not appear to be increased. At the higher f, RL was much higher than control in some conditions in some dogs. The mechanism for these increases in RL are difficult to identify because we could discern no correlation of the occurrence of these increases with any measured factor. One possibility is that flow limitation occurred during some of the higher expiratory flow rates. Maximum expiratory flows at mid-lung volume have been reported to be between 0.5 and 1.0 l/s (21) in emphysematous lungs from dogs in the same range of body weight as the dogs in the present study. Our protocols infringed on this range only at 0.6 Hz at 300 ml VT, at 0.8 and 1.0 Hz at 200 and 300 ml VT, and at 2.0 Hz at 100 and 200 ml VT. However, changes in Paw and Pes during the sinusoidal forcing were always sinusoidal and symmetrical. That is, we did not observe any large, sudden decreases in Paw to the negative range that we have sometimes seen during the expiratory limb of the forcing at very high sinusoidal flow rates (i.e., flows at 2.0 Hz with 300 ml VT or higher) that indicate flow limitation. Because of the above evidence, we do not believe expiratory flow limitation occurred. As we have discussed (7), RL is complexly determined by airway resistance and lung tissue resistance (Rti). In the normal range of breathing, each of the components of RL depends differently on f, VT, and mean lung volume. Increases in RL, when they occurred during emphysema, may have been due to increases in Rti. In fact, Rti in excised, emphysematous human lungs, measured during low-amplitude oscillations from 2 to 32 Hz, was higher than in control lungs (42). The mechanisms governing Rti are not clear. We have previously discussed that, based on a model introduced by Wilson and Bachofen (43), Rti will be determined by the force-length relationships of the peripheral connective tissue and the axial tissue fibers surrounding the alveolar duct, the surface tension-surface area relationship of the alveolar surface film, and the interaction between the latter two relationships (39). If the hysteretic properties of each of these determinants are not closely matched, increases in Rti could occur. We found increases in Rti in rabbit lungs despite decreases in EL caused by lavage with a silicon fluid with a constant tension-area relationship (39). Therefore, it is possible for Rti to increase in emphysema despite decreases in EL. Why this increase was so inconsistent in the present data remains unknown. It is interesting to note, however, that we have observed similar patterns of RL in the normal range of f and VT in anesthetized and/or paralyzed, mechanically ventilated patients with chronic obstructive pulmonary disease (2). In those studies, RL was evaluated during the inspiratory half of the ventilatory cycle only, and values were thus independent of flow limitation that occurred during expiration. Analogous to the average response of the dogs during emphysema compared with control, RL in the patients decreased less with increasing f than did the RL in patients with healthy lungs; therefore, the difference compared with healthy lungs was enhanced at the higher f. These results contradict previous reports that dependence of RL on f increases with emphysema in patients (35). However, measurements of RL in those previous reports were made at f much higher than the normal range of breathing, and VT was not regulated to be in the normal range. Thus although we suggest that increases in Rti can sometimes occur with emphysema, further studies are needed to examine why this happens. Whether such presumed increases in Rti are important in patients with emphysema also needs to be considered. Ecw and Rcw. The relative constancy of static elastance and dynamic properties of the chest wall with emphysema in these dogs compared with controls agrees with lack of changes in static Ecw in dogs with unilateral (26) or bilateral (14) emphysema induced by papain and in hamsters with bilateral emphysema induced by elastase (41). The dependencies of Ecw and Rcw on f and VT were also not affected by emphysema. These dependencies seem to be a fundamental aspect of chest wall mechanical behavior, because we have found similar dependencies in human, chicken, and previous dog studies (40). We have attributed these characteristic dependencies to a combination of viscoelastic and viscoplastic behavior (40). Although FRC was increased with papain-induced emphysema, we have also shown that increases in lung volume have no effect on dynamic chest wall properties (6). It is possible that configurations of the rib cage and/or diaphragm-abdomen may have been affected by emphysema, but this was not examined in the present study. Therefore, we do not make any inferences of how respiratory muscle function may have been compromised in this canine model for emphysema. Summary. The data suggest that increases in overall lung volume and decreases in radial traction caused by emphysematous changes in the acini have no effect on airways function in uncomplicated, severe emphysema at the lower end of normal range of breathing f in the dog. Complicating factors such as localized heterogeneous lesions, bronchoconstriction, and airway inflammation may be needed for increased airways resistance, flow limitation and/or air trapping [i.e., intrinsic PEEP (34)] to occur during normal breathing. For example, Hogg et al. (19) found that excised lungs from patients with emphysema showed mucus plugging as well as narrowing and obliteration of the small airways, complications that do not seem to occur in the papain animal model. Increased f dependence of EL does not occur without the presence of complications, but RL can greatly increase compared with healthy lungs at higher flow rates. The mechanism for this increase in resistance is still unknown. Finally, it should be noted that differences in anatomy between human and canine lungs (e.g., dogs have relatively stiffer tracheae and larger airways) may cause functional mechanical differences [e.g., maximum flow per gram lung weight is greater in the dog and less dependent on lung volume (24)]. It is possible, therefore, that species differences may also contribute to some of the discrepancies between patients with emphysema and the canine papain model.ACKNOWLEDGEMENTS
This research was supported by National Heart, Lung, and Blood Institute Grant HL-33009.
FOOTNOTES
Address for reprint requests: G. M. Barnas, Anesthesiology Research Laboratories, Univ. of Maryland, Rm. 534 MSTF Bldg., 10 South Pine St., Baltimore, MD 21201.
Received 1 October 1996; accepted in final form 12 March 1997.
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