Vol. 84, Issue 3, 933-938, March 1998
Perfusion heterogeneity in the pulmonary acinus
Nobuhiro
Tanabe1,4,
Thomas M.
Todoran1,
Gerald M.
Zenk1,
Brenda R.
Bunton1,
Wiltz W.
Wagner Jr.1,2,3, and
Robert G.
Presson Jr.1
Departments of
1 Anesthesiology,
2 Physiology/Biophysics, and
3 Pediatrics,
Indiana University School of Medicine, Indianapolis, Indiana
46202-5120; and
4 Department of Chest Medicine,
Chiba University School of Medicine, Chiba 260, Japan
 |
ABSTRACT |
There is little information on the distribution of acinar
perfusion because it is difficult to resolve blood flow within such small regions. We hypothesized that the known heterogeneity of arteriolar blood flow and capillary blood flow would result in heterogeneous acinar perfusion. To test this hypothesis, the passage of
fluorescent dye boluses through the subpleural microcirculation of
isolated dog lobes was videotaped by using fluorescence microscopy. As
the videotapes were replayed, dye-dilution curves were recorded from
each of the tributary branches of Y-shaped venules that drained an
acinus. From the dye curves, we calculated the mean appearance time of
each curve. The difference in mean appearance times between venular
tributary branches was small in most cases. In 43% of the observed
venular branch pairs, the dye curves were essentially superimposable
(the mean appearance-time difference was <5%); and in another 42%,
the mean appearance-time difference between curves was 5-10%.
From these results, we conclude that acinar perfusion is unexpectedly
homogeneous.
pulmonary microcirculation; acinar perfusion; dogs
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INTRODUCTION |
THE ACINUS, the functional unit of pulmonary
ventilation, contains ~10,000 alveoli supplied by a single
respiratory bronchiole (17). Although acinar ventilation
has been studied in detail (5, 6, 9, 10), there is less information
about acinar perfusion. Several lines of evidence strongly suggest that
acinar perfusion is likely to be heterogeneous. First, a dye bolus
flowing from the main pulmonary artery to subpleural arterioles is
dispersed in a way that suggests the presence of stream tubes within
the arterial tree (2), a characteristic that could cause heterogeneity of blood flow into the acinus. A second potentially important contributor to acinar perfusion heterogeneity is the fact that local
regions may have inputs from multiple sources. These may come from
supernumerary arteries, the vessels of the pulmonary arterial tree that
branch more frequently than the airway tree (3). Third, stratification
of perfusion has been found in secondary pulmonary lobules, with the
lowest flow going to the distal part of the lobules (12, 19). Fourth,
there is clear evidence of a distribution of transit times through the
capillary network (4, 7, 8, 11). Thus the potential variability of
blood flow into the acinus, the likely stratification of perfusion
within the acinus, and the distribution of capillary-transit times all suggest that individual pulmonary acini are likely to be perfused heterogeneously. If that is true, heterogeneous perfusion not only
would have implications in terms of normal gas exchange but would also
have potential clinical importance when acinar volume increases, for
example, in panacinar emphysema. In that case, successful
matching of ventilation to perfusion, which is normally thought to
occur on an interacinar level, would have to occur on an intra-acinar
level.
Much of the problem in studying acinar perfusion comes from the
difficulty in measuring pulmonary blood flow within so small a volume
of tissue. In vivo microscopy alone has the required resolving power.
With that technique, it is possible to observe the flow patterns in
subpleural venules that directly drain capillary blood after it has
traversed the acinus and reached the surface of the lung. Using this
approach, we videotaped the passage of fluorescent dye boluses through
the tributary branches of Y-shaped subpleural venules. From these
observations, some deductions could be made about the uniformity of
acinar perfusion. For example, simultaneous passage of the dye through
each of the tributary branches would suggest either that acinar flow
was homogeneous or, alternatively, that intra-acinar variations in
blood flow cancelled each other. Dissimilar dye transits would favor
perfusion heterogeneity. Either result would test the hypothesis that
pulmonary acini are heterogeneously perfused.
| |
METHODS |
Animal preparation.
Healthy adult male mongrel dogs (18-27 kg;
n = 17) were anesthetized by using
pentobarbital sodium (30-40 mg/kg iv), intubated, and mechanically
ventilated with room air via a constant-volume respirator (Harvard
Apparatus model 607D). After heparinization (1,000 U/kg), the animals
were rapidly exsanguinated through a cannula (3 mm ID) placed in the
left common carotid artery. The lungs were inflated to a constant
airway pressure of 5 mmHg, a left thoracotomy was performed,
and the left upper lobe was excised to provide access to the left lower
lobe. The left lower lobar artery was cannulated with a Teflon
fluorinated ethylene polypropylene cannula (6 mm ID), and
the left lower lobe bronchus was clamped to maintain constant
inflation. The left lower lobe was then excised, along with a cuff of
left atrium, and it was placed on a microscope stand. The left atrial
cuff was secured around another Teflon fluorinated ethylene
polypropylene cannula (10 mm ID), and the lobe was perfused with
autologous, heparinized whole blood (hematocrit = 30-41%). The
time interval from complete exsanguination to reperfusion of the lobe
was <30 min. Blood was pumped (Masterflex 7522-10 pump drive and
7024-20 pump head) through a windkessel to dampen pump vibrations
and trap bubbles, a filter (20-µm pore size; Fenwal 4C7700) to remove
microaggregates, a heat exchanger (Bentley HE-30) to warm the blood to
37-38°C, and finally a dye injection loop before entering the
lobe (Fig. 1). Venous blood drained
passively from the lobe into a reservoir. The height of the tubing
between the vein and the reservoir could be altered to change venous
pressure. The lobe was ventilated with 6%
CO2-17%
O2-77%
N2 at a tidal volume of 100 ml.
End-expiratory pressure was set to 5 mmHg by using a water overflow on
the expiratory limb of the ventilator. Arterial and venous pressures
were measured continuously with two transducers (model P23 XL; Statham)
zeroed at the site of microcirculatory observation and connected to
polyethylene tubing (PE-200), the tips of which were located at the
ends of the arterial and venous cannulas. Airway pressure was measured
intermittently (P23 XL transducer; Statham). All measurements were made
under zone 2 conditions: pulmonary arterial pressure, 10-15 mmHg;
airway pressure, 5 mmHg; and pulmonary venous pressure, 1 mmHg. Pump flow rate was 400 ml/min.
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Fig. 1.
Schematic diagram of experimental setup. ICCD, intensified
charge-coupled device; Ppa, pulmonary arterial pressure; Ppv, pulmonary venous pressure; PA, alveolar
pressure.
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Data collection.
The lobe was suspended by two small spring-backed paper clips attached
to opposite edges of the lobe (18) and raised until the uppermost
pleural surface (the diaphragmatic surface in this orientation) came
into contact with a transparent window. A 1.3 cm2 area on the surface of the
lobe was observed through the window, which was surrounded by a vacuum
ring to prevent lateral movement (13, 15). The subpleural
microcirculation under the window was observed with a modified Olympus
BH2 reflectance microscope coupled to a Leitz Ultropak illuminator and
a ×11 objective. Bright-field illumination through the Ultropak
illuminator was provided by a 200-W mercury arc lamp mounted on an
optical bench. This light source was heavily filtered with a
combination of dichroic infrared-reflecting filters, broad band-pass
ultraviolet-absorbing filters to prevent tissue damage, and a narrow
band-pass interference filter to illuminate the field only with the
mercury green line (546 nm). This wavelength was absorbed by
hemoglobin, thereby increasing the contrast between the erythrocytes
and surrounding tissue (14). Illumination for fluorescence microscopy
was provided by a 100-W mercury arc mounted on a sidearm of the Olympus
microscope. This light was also filtered by dichroic
infrared-reflecting filters and ultraviolet-absorbing filters. The
light from this arc passed through a blue band-pass exciter filter
(410-480 nm) and a high-pass dichroic mirror (cutoff wavelength = 480 nm) that reflected the exciting light down through the objective
onto the subpleural microcirculation beneath the window. Emitted light
from the lung passed back through the objective, the dichroic mirror,
and a yellow high-pass barrier filter (cutoff wavelength = 510 nm).
Video recordings of the subpleural microcirculation were made with a
Panasonic AU650 MII videorecorder and a Cohu (model 5510) intensified
charge-coupled device camera that was attached to the microscope with a
Nikon zoom adapter (model CCTV 79444).
In 11 lobes, microscopic fields were selected in which there was a
venule that had two tributary branches forming a Y shape (2-14
Y-shaped venules per lobe; 82 total). While these fields were observed
with fluorescence microscopy, test injections of dye [fluorescein
isothiocyanate conjugated to 70-kDa dextran (Sigma Chemical), 10 mg/ml
of 0.9% saline] were made by using a loop just proximal to the
lobar artery. Each limb of the loop contained a volume of ~25 ml and
was controlled by a solenoid pinch valve (Cole Parmer
NO/C-1367-92/93) on its downstream end. On one limb, the valve was
open when deenergized, whereas on the other limb, the valve was closed.
The normally closed limb was loaded with a 1-ml bolus of dye, and, when
the solenoids were energized, blood flow was diverted through the
dye-containing limb, thereby washing the dye into the lobar artery. In
this way, the bolus of dye was rapidly introduced into the arterial
circulation without the pressure increase or movement of the
microscopic field that occurred when high-pressure injections were made
directly into the lobar pulmonary artery.
The passage of dye through the field was videotaped, and elapsed time
in milliseconds was recorded on the videotape images by a Panasonic
WJ-810 time-date generator that was activated by the same switch that
energized the solenoids of the injection loop. The black level of the
camera and the gain of the camera and intensifier were adjusted
according to these test injections of dye to maximize the contrast
between the baseline brightness of the microscopic field before dye
entered the circulation and the peak brightness during passage of dye
through the microcirculation.
After the test injections, we recorded the passage of two separate dye
injections per venule during end expiration. Dye-dilution curves were
obtained by replaying the recordings and sampling image brightness at
30 Hz from rectangular areas over the venular lumens (referred to as
vessel windows) and from areas over the adjacent alveoli (background
windows) with a frame-grabber board (Data Translation DT-2851)
interfaced with a microcomputer (Dell 486, 50 MHz). The
windows were moveable and of adjustable size. To obtain a dye-dilution
curve for each of the two tributaries of the Y-shaped venules, the
recordings of each injection were replayed twice, sampling over a
different branch each time.
The three-dimensional structure of the lung caused detectors placed
over the venules to measure light emitted not only from dye within the
venular lumens but also from dye in the surrounding alveolar
capillaries. To obtain curves that accurately reflected the
concentration of dye in the venular lumens at each instant in time, it
was necessary to subtract light emitted by dye in the capillaries
(background window signal) from the vessel window signal, using the
method of Presson et al. (8). In each animal, the background-corrected
dye-dilution curves from the duplicate injections were aligned at the
injection time and then averaged to produce a single curve for each
branch. The baseline segment of each of these average curves, before
dye entered the vessel, was set to zero, and the tail of each curve
(~5% of the area under the curve) was extrapolated to baseline as a
monoexponential function. Finally, the area under each curve was set to
unity.
The mean appearance time (MT) from the time of injection was calculated
as
|
(Eq. 1)
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where
t1 was the time
when the intensity of the dye-dilution curve (I) became >0, and
tn was the time
when the curve returned to baseline. The percentage difference in MT
between the fast branch and the slow branch (
MT) of a venular pair
was calculated as
|
(Eq. 2)
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where
MTslow was the MT of the slow
tributary branch, and MTfast was
the MT of the fast tributary branch. We divided by the average of
MTslow and
MTfast, as if flow were
homogeneous. From Eq. 2, when
MTslow = MTfast (homogeneous perfusion),
MT = 0%.
Arteriolar heterogeneity.
To determine how heterogeneous the dye bolus was when it arrived in the
subpleural microcirculation, we recorded the passage of dye through all
arterioles (diameter 
50 µm) under the window (4-12
arterioles in each of 9 lobes; total, 53 arterioles). That information
permitted the estimation of the separate effect that arteriolar input
had on acinar perfusion homogeneity. Because the daughter branches of
an arteriole were fed by a single parent, they had the same
MT distribution as the parent. For this reason, we
calculated the difference in MT between pairs of different arterioles
to get an idea of the general variation of input to the subpleural
microcirculation being studied. We computed in each lobe the difference
for all possible pairs of arterioles under the window (total, 157 pairs
for all lobes). The data collection and methods of analysis were the
same as those used for the venules.
Statistics.
We used the paired t-test to compare
the physiological variables at the beginning of the venular
measurements with those at the end of the venular measurements and the
variables at the beginning of the arteriolar measurements with those at
the end of the arteriolar measurements. We then compared the average
physiological variables during the venular measurements to the average
variables during the arteriolar measurements by using the
t-test for independent samples. The
2 test was used to compare the
distribution of arteriolar appearance-time differences to the
distribution of venular appearance-time differences. The mean and
variance of the venular appearance-time differences were compared with
the corresponding mean and variance of the arteriolar appearance-time
differences with a t-test for
independent samples. We accepted P < 0.05 as significant.
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RESULTS |
Of the 82 Y-shaped venules, the 164 tributaries were binned into either
the fast or slow tributary, which were not different in diameter [50.0 ± 1.6 (SE) and 50.2 ± 1.8 µm, respectively (P > 0.94)]. Their recipient vessel had an average diameter of 72.6 ± 24.8 µm. The MT difference between tributary venular
branches (Eq. 2) was divided into
five groups: 0-5, 5-10, 10-15, 15-20, and >20%
(Fig. 2). This distribution was right
skewed, with a mean difference of 6.5 ± 0.6% (SE) and a median
difference of 5.8%. In 42.7% of the sample, there was a minimal MT
difference (<5%) between the tributary branches. When the
electronically measured MT difference was this small, it
was not possible to observe with the unaided eye a difference between
tributary branches during videotape replay (Fig.
3, left). In 41.5% of the
cases, the MT difference was between 5 and 10%. When the
difference between branches was >10% (only 15.8% of the cases; Fig.
2), it was easy to detect the difference. In the more extreme cases, in
which the MT difference was >15% (7.3% of cases), the dye had
nearly drained from the faster branch before the dye arrived in the
slower branch (Fig. 3, right).
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Fig. 2.
Distribution of mean appearance-time differences between venular
tributary branches. In 42.7% of cases, there was minimal difference
(0-5%). In another 41.5%, there was a small but visually unimpressive difference (5-10%).
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Fig. 3.
Left: videomicrographs made from
single videotape images of a Y-shaped venule. At time
1 (middle), 7.50 s
after dye was injected, both branches 1 and 2 were filled with fluorescent dye. At time 2 (bottom), 2 s
later, the dye was draining from both tributary branches into the base
of the Y. Top: because the tributaries filled and emptied with dye simultaneously, the light intensity-time curves nearly overlie each other. Branch 1 has a mean
appearance time (MT) of 8.8 s and branch 2 has a MT of 9.0 s, a difference of 2.1%. Dashed lines, photo times
1 and 2 of
videomicrographs. Because dye appears visually to pass through these
vessels simultaneously, and because dye-dilution curves are nearly
superimposable, we conclude that the dye-drainage pattern into these
venules was homogeneous. Right: in
this example (as shown by the videomicrographs), dye in branch
1 (middle) arrived and drained
more rapidly than in branch 2 (bottom).
Top: MT difference of 15.2% indicates
heterogeneous pattern of drainage into venules.
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The distribution of venular appearance-time differences was different
from the arteriolar appearance-time difference distribution under the
same conditions (P < 0.01; Fig.
4). The average appearance-time difference
for the venules [0.67 ± 0.06 (SE) s] was significantly greater than the average appearance-time difference for the 53 arterioles studied (0.38 ± 0.02 s;
P < 0.01), indicating dispersion of
the dye by the capillary bed; i.e., the capillary bed added to
appearance-time differences already present among the arteriolar inputs
to the capillary bed. The variance of the venular appearance-time differences (0.27 s2) was also
greater than the variance of the arteriolar appearance-time differences
(0.08 s2). Thus the distribution
of venular appearance-time differences was more heterogeneous than the
distribution of arteriolar appearance-time differences. This indicated
a wider range of transit-time differences between regions of the
capillary network drained by different venular tributary branches than
there was among the arteriolar inputs to the capillary bed.
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Fig. 4.
Comparison of distribution of arteriolar MT differences to distribution
of venular MT differences. Both mean and variance of venular
distribution were greater than those of arteriolar distribution.
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Cardiorespiratory variables at the beginning of the study of venular
appearance times were not significantly different from those at the end
of the study (P > 0.10). Similarly,
cardiorespiratory variables at the beginning and end of the arteriolar
appearance-time study were not significantly different from each other
(P > 0.26). The averages of the
cardiorespiratory variables during the venular appearance-time study
were not different from the averages during the arteriolar study (Table
1).
| |
DISCUSSION |
The MT differences between venular tributary branches were
small in almost all cases. In 42.7% of the observed venular pairs, the
difference (Eq. 2) was <5% (Fig.
2). We classified perfusion of venular pairs with differences <5% as
homogeneous because it was not possible to visually detect a difference
between flow through tributary branches during videotape replay, and
the dye curves were essentially superimposable (Fig. 3,
left). In another 41.5% of cases
(Fig. 2), there was a small but visually unimpressive difference in dye
passage between tributary branches, reflected by a 5-10%
difference in MT. Only when the difference between branches was >10%
was it easy to detect the difference visually. This group was
classified as clearly heterogeneous, but it was a minority of cases
(<15.8%). Only 1.2% of venular tributaries had MT differences of
>20%.
The finding of small appearance-time differences between venular
tributary branches indicating homogeneous acinar perfusion was
unexpected because several lines of evidence have suggested that acinar
perfusion would be heterogeneous. Dawson et al. (2) showed that blood
arriving in the acinus via different arterioles could have different
appearance times. In addition to this variation in input to the acinus,
stratification of perfusion has been shown to occur in the secondary
pulmonary lobule (12, 19). Additionally, there are anatomical grounds
to expect a distribution of transit times through the capillary
network, because there are a range of capillary path lengths (4, 11),
an expectation confirmed by videomicroscopy (1, 7, 8, 16). On the basis
of these findings, we hypothesized that there would be significant
heterogeneity of perfusion within a single acinus.
Our interpretation of the results assumes that, in each case, the
tributary branches of a Y-shaped venule drained the same acinus. To
test this assumption, we compared the MT differences of the largest
venules with those of the smallest venules, reasoning that the largest
venules would be most likely to drain more than one acinus. The MT
difference of the largest branches [65-90 µm, 5.6 ± 1.0% (SE), n = 15] was not
different (P = 0.36, unpaired t-test) from that of the smallest
branches (20-35 µm, 7.2 ± 1.5%, n = 14). This result strongly implies
that all the branches studied drained single acini.
We also assumed that the results obtained from the isolated lobe are
similar to results in the intact dog. In pilot studies of intact dogs,
we found it more difficult to maintain a stable catheter position at
the site of injection (main pulmonary artery) and a constant cardiac
output between injections. However, there was a similar distribution of
venular appearance-time differences between tributary branches. The MT
difference was 0-5% in ~40% of venular branch pairs and was
5-10% in ~35% of pairs (n = 20 pairs), results similar to data reported here for the isolated lobes. Therefore, we think our results are reasonably representative of
the intact animal. Our results are also consistent with previous values
obtained from the isolated canine lobe preparation. In the present
study, the MT in arterioles was 6.8 s, and the MT from injection to
venules was 10.6 s, a difference of 3.8 s, which is the mean
capillary-transit time. This value is close to the 3.5 s reported
earlier at the same flow rate in the isolated dog lobe (8).
In conclusion, despite several lines of evidence suggesting that acinar
perfusion would be heterogeneous, our findings based on venular
drainage patterns demonstrate that acinar perfusion is homogeneous.
Acinar perfusion is homogeneous in the majority of cases and therefore
matches acinar ventilation, which is also thought to be homogeneous (5,
6, 9, 10).
| |
ACKNOWLEDGEMENTS |
The authors wish to thank Drs. T. M. Wagner, H. G. Bohlen, T. C. Lloyd, Jr., W. A. Baumgartner, Jr., and A. J. Peterson for helpful
criticism of the manuscript.
| |
FOOTNOTES |
This work was supported by National Heart, Lung, and Blood Institute
Grant HL-36033.
Address for reprint requests: W. W. Wagner, Jr., 635 Barnhill Dr., Rm.
MS 374, Indianapolis, IN 46202-5120.
Received 13 March 1997; accepted in final form 19 November 1997.
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Abstract
Introduction
