Vascular Structure Determines Pulmonary Blood Flow
Distribution
Michael P. Hlastala and Robb W. Glenny
Physiology 14:182-186, 1999. ;
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Vascular Structure Determines
Pulmonary Blood Flow Distribution
Michael P. Hlastala and Robb W. Glenny
Scientific knowledge develops through the evolution of new concepts. This process is
usually driven by new methodologies that provide observations not previously
available. Understanding of pulmonary blood flow determinants advanced
significantly in the 1960s and is now changing rapidly again, because of
increased spatial resolution of regional pulmonary blood flow measurements.
U
“. . . oxygen and
carbon dioxide
exchange
differed. . . .”
nderstanding the mechanisms determining
pulmonary blood flow (PBF) distribution
provides insight into basic lung function and is
essential to providing treatment for a wide variety of pulmonary diseases. Our current understanding has followed from important research
carried out in the 1950s and 1960s that sought to
explain vertical differences in oxygen and carbon dioxide exchange.
Before the late 1950s, the lung was thought to
be uniform in its gas exchange properties. New
technologies, using radiolabeled gases, provided
M. P. Hlastala and R. W. Glenny are in the Department of
Physiology and Biophysics and the Department of Medicine,
Division of Pulmonary and Critical Care Medicine, University of Washington, Box 356522, Seattle, WA 98195-6522,
USA.
182
News Physiol. Sci. • Volume 14 • October 1999
higher-resolution information about the vertical
distribution of PBF. The observation was made
that oxygen and carbon dioxide exchange differed between upper and lower lung regions. The
zone model evolved as an explanation for the
observed vertical differences and provided a
framework that guided both research and clinical
medicine for over three decades.
New methods with even higher resolution
have led to equally surprising observations and
new insights. It is now apparent that although
gravity does have a measurable influence on PBF
distribution, the anatomic structure of the arterial
tree plays a prominent role in the distribution of
PBF. For more details of the factors that lead to
heterogeneity in the lungs, the reader is referred
to Complexity in Structure and Function of the
Lung (11).
0886-1714/99 5.00 © 1999 Int. Union Physiol. Sci./Am.Physiol. Soc.
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9. Pellerin, L., G. Pellegri, J. L. Martin, and P. J. Magistretti.
Gravity-dependent vascular mechanisms
“. . . a model was
proposed with three
zones.”
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Early work with the concept of vertical dependence of PBF began in the 1950s with the efforts
of Richard Riley and colleagues. These authors
first examined the changes in dead space by
measuring gas exchange in subjects placed in
various postures. Riley et al. (13) reported that in
the erect position, alveoli in the apex of the lung
were not perfused. They presented the idea that
alveolar and vascular pressures determine blood
flow changes with lung volume (alveolar pressure) in the whole lung.
This concept was advanced by the introduction of the waterfall concept by Permutt and colleagues at the Fifth Annual Conference on
Research in Emphysema (also called the Aspen
Conference) in 1962 (12). They pointed out that
pulmonary capillary flow was determined by the
relationship between alveolar pressure and
intravascular pressure. This comprehensive article outlined the equations to describe the relationships among alveolar, arterial, and venous
pressures. They considered the pulmonary circulation to be the equivalent of a series of Starling
resistors but did not discuss the possible vertical
distribution of these relationships.
Similar work was carried out at the same time in
Great Britain. Banister and Torrance (2) described
the influence of airway pressure in PBF and the
concept that height in the lung influences the
effective transmural pressure of the blood vessels.
They explained the effect by referring to a “sluice,”
a channel for flow of water with a gate at the head
of the channel to control flow. This is a very different concept than that of the Starling resistor.
The original description of the vertical dependence of PBF was put forth by West, Dollery, and
Naimark (15). This group used an isolated perfused dog lung, mounted in the upright position,
set up so that the arterial and venous pressures
could be controlled relative to alveolar pressure.
133
Xe was injected in the blood, and the vertical
distribution of average blood flow was measured
with scintillation counters. In this preparation,
blood flow was greater near the lower (caudal)
part of the lung and less near the upper (cranial)
part of the lung. Using the presumption that the
vertical distribution of arterial and venous pressure is determined primarily by hydrostatic mechanisms, these authors proposed the zone model
(Fig. 1) to explain the vertical distribution of blood
flow. Intravascular pressure is thought to decrease
linearly with vertical height. In zone 1 near the
top of the lung, alveolar pressure exceeds arterial
pressure and the collapsible blood vessels close,
stopping flow. In zone 2, arterial pressure exceeds
alveolar pressure, which exceeds venous pres-
sure. At any given height, the flow is determined
by the difference between arterial and alveolar
pressure. In zone 3, both arterial and venous pressures exceed alveolar pressure. Although the driving (arterial–venous) pressure is equal with vertical position, the increase in flow down the lung
was explained by vessel distension, decreasing
vascular resistance, going down the lung. In the
initial zone presentation (15), a model was proposed with three zones. A fourth zone was added
later to deal with the decreased flow near the bottom of the lung. This has been explained by
perivascular cuffing due to the excessive vascular
pressures and consequent edema formation.
However, the presence of similar values of flow in
the same region when the animal is inverted to
the opposing posture argues against this gravitydependent mechanism.
The zone model has been used to characterize
behavior of the pulmonary circulation to establish experimental protocols and help in the interpretation of experimental observations. Several
predictions can be made from the zone model.
1) Because the arterial and venous pressures are
determined by vertical height, PBF should be
uniform at any location within an isogravitational
plane. 2) At any location in the lung, PBF in any
posture should be negatively correlated with PBF
in the opposing posture (prone vs. supine, erect
vs. head down, left lateral decubitus vs. right lateral decubitus). 3) A vast majority of the variability of PBF among all regions of the lung should
be explained by vertical position of the region. 4)
Increasing pulmonary arterial pressure during
exercise should lead to a more uniform PBF distribution. 5) Increasing gravitational force should
increase the vertical height dependence of PBF
in a proportional manner.
Resolution of methods
Resolution limitations of methodology depend
on the available technology. The initial experiments defining the gravitational dependence of
blood flow relied on the use of radioactive gases
(133Xe or labeled CO2; Refs. 1, 14) and external
counters of radioactivity. Radiolabeled gases
were dissolved in venous blood. Appearance of
label in the lung indicated the relative amount of
blood flow in that lung slice. Collimated counters were placed horizontally adjacent to the
chest at different vertical positions. Each counter
integrated information across the lungs and
chest, giving a single average value for the entire
horizontal (isogravitational) slice of the lung. All
potential horizontal heterogeneity was, therefore, lumped into a single averaged value. In
these earlier experiments, one PBF value was
News Physiol. Sci. • Volume 14 • October 1999
183
“. . . changes also
occur in chest wall
and diaphragm
position. . . .”
used to represent the blood flow to any piece of
lung at a given vertical height.
Labeled 15-µm-diameter microspheres and personal computers are the new technologies that
provide for a markedly increased spatial resolution of PBF. Vascularly injected microspheres
lodge in pulmonary capillaries within lung regions
in proportion to the amount of blood flow to that
region. The lungs are processed by drying during
inflation to near total lung capacity and then cut
into small (1.0–2.0 cm3) pieces, depending on the
animal and degree of resolution desired. Radioactive counts or fluorescence labels are measured in
each piece and recorded along with its spatial
location. Thus the distribution of relative PBF is
measured in small pieces.
Isogravitational heterogeneity
A strong test of the zone model was performed
by Glenny et al. (7), who measured the PBF distribution using radiolabeled microspheres in anesthetized dogs placed in both the prone and supine
positions (Fig. 2). In the supine animal, a clear dorsal (down) dominance of PBF is demonstrated
(consistent with the zone model), but a considerable isogravitational heterogeneity is seen within
each isogravitational plane (inconsistent with the
zone model). In the prone animal, the degree of
isogravitational heterogeneity remains, but now
with an average blood flow that dominates in the
upward direction. This dorsal dominance, regardless of posture, was also identified by Beck and
Rehder (3) and is not predicted by the zone model.
A plot comparing prone and supine blood flow
shows a positive slope with a high correlation. If
the zone model dominates, a dependent region
should have relatively high blood flow in the
supine posture, and it should become a low-flow
184
News Physiol. Sci. • Volume 14 • October 1999
region when repositioned to the prone posture.
Thus the zone model would predict a negative
slope for a prone-supine flow comparison. The
data of Glenny et al. (7) indicate a positive correlation between flow in a prone and a supine posture, with an R2 of 0.725. Changing from the
supine posture to the prone posture or vice versa,
high-flow regions remain as high flow and lowflow regions remain as low flow. Simultaneous
injections of two microsphere colors reveal a
methodological measurement error of <1%.
Statistical analysis comparing flow in each
piece as posture is changed shows that gravity
accounts for only 4% of the variance (7). It should
be remembered that not only do changes in posture affect the direction of the gravity vector, but
changes also occur in chest wall and diaphragm
position and local parenchymal stresses. Thus the
calculated effects of gravity through the hydrodynamics stress, as outlined by the zone model, are
actually overestimated by this approach.
The zone model would predict a positive relationship between PBF and height up the lung. This
relationship should be greatest in animals with a
large vertical lung size. However, data in resting
thoroughbred horses, with a vertical lung size of
~50 cm, show no significant vertical gradient with
a large degree of isogravitational heterogeneity
comparable to other mammals (9). This finding is
not consistent with the zone model.
Exercising horses (at 90% VO2max) increase pulmonary artery pressure from rest by approximately
threefold (from 35 ± 6 to 107 ± 12 cmH2O). The
zone model would predict a marked increase in
zone 2, resulting in a smaller vertical gradient in
PBF and a more uniform PBF distribution. Bernard
et al. (4) found that exercise resulted in a proportional increase in flow to all regions of the lungs
with little change in coefficient of variation of het-
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FIGURE 1. The zone model. Flow is a function of vertical height and is dependent on the relationship between alveolar and vascular pressures. PA, alveolar pressure; Pa, arterial pressure; Pv, venous pressure.
erogeneity, with no change in gravity dependence
with exercise, despite the considerable increase in
pulmonary artery pressure.
The role of increased inertial (gravitational)
force on PBF distribution using high-resolution
methods has been studied by our group on the
human/animal centrifuge at Brooks Air Force
Base (10). Increasing force from –1 Gx (dorsal to
ventral direction) to –3 Gx resulted in an increase
of the coefficient of variation of PBF from 0.38 to
0.72, a substantial decrease in PBF in both the
ventral and dorsal regions of the lung, and an
increase in PBF (mean and variation) in the midlung or hilar regions. Statistical analysis revealed
that >81% of the variance in flow among the lung
pieces is due to vascular structure, whereas <19%
of the variance is due to changes in inertial force
via acceleration. These latter findings are inconsistent with the predictions of the zone model.
The importance of posture in normally erect
mammals has been evaluated in baboons
placed in four postures (upright, head down,
supine, and prone; Ref. 5). Baboons reveal a
considerable degree of nonrandom isogravitational heterogeneity of PBF distribution. The
variance of PBF due to vascular structure was
75, 93, and 95% for the upright, supine, and
prone postures, respectively.
Spatial and temporal correlation
Like many organs and tissues, the lungs exhibit
a remarkable degree of heterogeneity of structure
with a high degree of similarity of function. It has
been speculated that this heterogeneity of structure is an important advantage that allows easy
compensation in the face of disease and local
perturbation of function. Even though a significant heterogeneity exists across isogravitational
planes in the mammalian lung, there is a strong
correlation among adjacent pieces (6) and a negative correlation among pieces that are very far
apart (Fig. 3). High-flow pieces are next to highflow pieces and low-flow regions neighbor other
low-flow areas. The spatial pattern of PBF is not
random and remains very stable over days (6).
The ordered, nonrandom isogravitational heterogeneity of flow distribution is not consistent with
the zone model.
“. . . the lungs exhibit a
remarkable degree of
heterogeneity. . . .”
Fractal geometry
FIGURE 3. Correlogram of regional blood flow as a function
of distance between the pieces. Pieces separated by 1.2 cm
have similar flows (ρ = 0.676), and flows become less similar
and eventually negatively correlated at larger distances. Filled
circles indicate points with spatial correlation significantly
different from 0.0 (P < 0.05). Modified from Ref. 6.
Figure 4 demonstrates the relationship between
the apparent heterogeneity of perfusion, expressed
as the coefficient of variation, and size of pieces
used to examine this heterogeneity. Apparent
coefficient of variation increases as lung piece size
decreases. The linear relationship shows that the
observed heterogeneity depends on the resolution
News Physiol. Sci. • Volume 14 • October 1999
185
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FIGURE 2. Weight-normalized pulmonary blood flow (PBF) vs. vertical height up the lung in dogs in either the prone or the
supine posture. Modified from Ref. 7.
fractal vascular trees and perfusion heterogeneity;
they offer a new perspective from which to
explore determinants of regional blood flow. The
fractal model does not preclude the waterfall relationships proposed by Riley and Permutt. Rather,
it predicts that multiple sets of conditions exist
within isogravitational planes rather than being
vertically stacked. New models are important to
the scientific community; they influence interpretation of data and put forth new experimental
idea that may challenge or support commonly
held beliefs.
References
of the method. As the lung is examined with
smaller and smaller pieces, the heterogeneity
increases. This process continues until the heterogeneity does not increase. This occurs when the
“functional unit” is reached where further reduction in size yields pieces with identical properties.
A fractal system (8) is one in which the properties
of the system at different scales are self-similar. In
the pulmonary vasculature, the nature of a bifurcation is the same as either the parent or the
daughter generation. The spatial correlation of
flow and scale-dependent heterogeneity are consistent with pulmonary vascular anatomy being a
dominant factor in causing the observed patterns
of PBF distribution in mammals.
Conclusion
“. . . pulmonary
vascular structure as
the dominant
factor. . .”
186
The gravitational hypothesis that attributes the
distribution of both blood flow and ventilation to
hydrostatic forces in the lung has been a cornerstone of pulmonary physiology. The gravitational
model was advanced because higher spatial resolution methods revealed nonuniform blood flow.
Our current understanding of PBF distribution has
been further advanced with the development of
methods allowing even higher resolution in the
measurement of local PBF. These new observations are inconsistent with the zone model and
have led to a new conceptual framework emphasizing the pulmonary vascular structure as the
dominant factor in determining PBF distribution.
We continue to believe that gravity plays a role in
PBF distribution. We wish to advance the concept
that gravity alone cannot adequately account for
recent experimental observations of pulmonary
perfusion; additional factors must be considered.
These proposals are based on new concepts of
News Physiol. Sci. • Volume 14 • October 1999
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FIGURE 4. PBF heterogeneity vs. lung piece size. Measured
coefficient of variation (CV) depends on piece size and is
always lower than the maximal CV for the smallest pieces.