| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departments of
1 Anesthesiology, We used
fluorescent-labeled microspheres in pentobarbital-anesthetized dogs to
study the effects of unilateral alveolar hypoxia on the pulmonary blood
flow distribution. The left lung was ventilated with inspired
O2 fraction of 1.0, 0.09, or 0.03 in random order; the right lung was ventilated with inspired
O2 fraction of 1.0. The lungs were
removed, cleared of blood, dried at total lung capacity, then cubed to
obtain ~1,500 small pieces of lung (~1.7 cm3). The coefficient of
variation of flow increased (P < 0.001) in the hypoxic lung but was unchanged in the hyperoxic lung.
Most (70-80%) variance in flow in the hyperoxic lung was
attributable to structure, in contrast to only 30-40% of the
variance in flow in the hypoxic lung
(P < 0.001). When adjusted for the
change in total flow to each lung, 90-95% of the variance in the
hyperoxic lung was attributable to structure compared with 70-80%
in the hypoxic lung (P < 0.001). The
hilar-to-peripheral gradient, adjusted for change in total flow,
decreased in the hypoxic lung (P = 0.005) but did not change in the hyperoxic lung. We conclude that
hypoxic vasoconstriction alters the regional distribution of flow in
the hypoxic, but not in the hyperoxic, lung.
regional pulmonary blood flow; heterogeneity; gravitational
gradient; hypoxic pulmonary vasoconstriction; fluorescence; microspheres
THE PULMONARY CIRCULATION constricts in response to
alveolar hypoxia, resulting in a dual response: an increase in
pulmonary arterial pressure (Ppa) and diversion of blood flow away from hypoxic lung regions (18). The reduction of blood flow away from
hypoxic alveoli toward normoxic alveoli preserves the matching of
ventilation
( The overall dominance of the structure of the pulmonary arterial system
in distributing blood flow (3, 9, 10, 16, 21, 25) leads to the belief
that other factors, such as HPV, may also play a lesser role than had
been previously appreciated. This study assessed the role of hypoxia
administered to large lung regions (left lung) in changes in the
distribution of blood flow in small
(1.7-cm3) lung regions. The role
of hypoxia was evaluated by comparing changes in patterns of blood flow
distribution between the hypoxic and hyperoxic lungs. There are two
components to the shift in pulmonary blood flow with HPV:
1) the increase in total blood flow
to the hyperoxic right lung equal to the decrease in total blood flow
to the hypoxic left lung and 2) the
presence of alveolar hypoxia in the left lung and hyperoxia in the
right lung. The HPV stimulus-response curve is sigmoidal in shape, with
a maximal HPV response observed at <25 Torr alveolar
PO2
(PAO2) and a 50% response
at 55 Torr PAO2 (1, 19).
Given the normal
Anesthesia and surgical preparation.
The study was approved by the University of Washington Animal Care
Committee. Eight dogs (weight 23.6 ± 1.9 kg) of mixed gender were
anesthetized with pentobarbital sodium (30 mg/kg iv, supplemented with
30-90 mg every 20-30 min). The trachea was intubated, and the
lungs were ventilated with a tidal volume of 15 ml/kg. Femoral and
carotid arterial catheters, a pulmonary arterial catheter via the
external jugular vein, and a femoral venous catheter were placed via
peripheral cutdown. Mean systemic arterial pressure, mean Ppa,
pulmonary arterial occlusion pressure, and airway pressure were
measured continuously and recorded on a Western Graphtec Mach 12 data-management system (model DMS 1000) with Validyne amplifiers
(Irvine, CA). Body temperature was maintained at 38 ± 1°C with
use of heat lamps and heating pads. Thermodilution cardiac outputs were
obtained in triplicate (SAT-2 cardiac output computer, Edwards, Santa
Ana, CA).
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
A) and
perfusion (
) in the lung and minimizes hypoxemia (5).
In prior work, older techniques that measure average blood flow within
large regions of the lung were used to examine the distribution of
hypoxic pulmonary vasoconstriction (HPV)-induced flow diversion.
Recently, imaging techniques (12-15) and radioactive-labeled
(8-10, 21) or fluorescent-labeled microspheres (3, 9, 16, 23) have
been used to study the distribution of pulmonary blood flow in small
lung regions. These studies have questioned the overwhelming importance
of the classic gravitational model (17, 22, 23, 26) and suggest that
the resistive properties of the pulmonary vascular tree are primarily
responsible for determining the distribution of pulmonary blood flow.
A-
heterogeneity in the lung, there will be local variations in
PAO2 and the stimulus for
HPV with resting A/.
We therefore tested the hypothesis that hypoxia alters the regional
distribution of pulmonary blood flow beyond the effect of flow per se.
If hypoxia shifts blood flow from the left lung to the right lung in
proportion to flow alone, the relative decrease in flow in each region
of the hypoxic lung will result in no change in the regional
distribution of pulmonary blood flow and the structural component of
flow determination. If the heterogeneity of hypoxic vasoconstriction
contributes differently to the change in flow in different regions,
then we would expect to find redistribution of blood flow and a smaller
structural component of flow determination. Animals were studied in the
supine and prone position, because posture-related differences are
important in the dorsal-to-ventral gradient in the distribution of
pulmonary blood flow (8, 9).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
Study protocol. Before the study was begun, the animals were "primed" with three or four hypoxic challenges. After demonstration of a stable HPV response by consistent increases in Ppa and stable arterial blood gases with left lung hypoxia, the study protocol began. The right lung was ventilated with fraction of inspired O2 (FIO2) of 1.0 throughout the study. This FIO2 was used to ensure the absence of systemic hypoxemia during left lung hypoxia. The left lung was ventilated with FIO2 of 1.0, 0.09, and 0.03 in random order. Inspired CO2 (FIO2 = 0.03) was added to the left lung inspired gas mixture during hypoxia; during hyperoxia, inspired CO2 (inspired fraction of CO2 = 0.01-0.02) was added to both lungs to prevent alveolar hypocapnia. Animals were studied in the supine and prone posture in random order. After 20 stable minutes in each phase, blood gases and hemodynamic measurements were obtained.
Fluorescent-microsphere techniques. Pulmonary blood flow was measured using fluorescent-labeled microspheres (7). One of six colors (blue, orange, scarlet, red, blue-green, and crimson) of 15-µm fluorescent latex microspheres (FluoSpheres 0.2% solids, Molecular Probes, Eugene, OR) was randomly selected, sonicated for 5 min, and vortexed immediately before slow injection (over 60 s) of 2-3 × 106 microspheres through the femoral venous cannula. The catheter was flushed with saline after the injection.
After the final microsphere injection, the animals were deeply anesthetized with pentobarbital sodium. A rapid infusion of saline was started. Papaverine (60 mg) was given intravenously to vasodilate the pulmonary vasculature and facilitate flushing of the lungs. The animals were heparinized (20,000 U) and exsanguinated via the arterial cannula. A median sternotomy was performed, and the pulmonary artery and left atrium were cannulated with wide-bore catheters. A 2% dextran solution was infused into the pulmonary circulation until the effluent from the left atrium was clear of blood. The lungs were excised, and the trachea was connected to a pressure source (~25 cmH2O) to inflate the lungs at total lung capacity while the lungs were suspended to dry. The apical and most ventral rims of the left and right lungs were glued together with a small amount of cyanoacrylate glue (Duro Superglue, Loctite, Cleveland, OH) to preserve the configuration of the lungs. The lungs were allowed to dry for 6-8 days and then coated with a 1-cm-thick layer of polyurethane foam (Kwik Foam, DAP, Dayton, OH). The foamed lungs were suspended in a plastic-lined square box so that isogravitational planes were parallel to the caudal-cranial axis. The box was filled with a rapidly setting foam (Polyol and isocynate, International Sales, Seattle, WA). The foam block was then sliced into 1.2-cm-thick slices with a band saw with a blade designed to eliminate tearing and loss of tissue, and the slices were cut into squares (1.2 × 1.2 cm) to yield cubes ~1.7 cm3 in volume, in a miter box. Samples with a weight <0.008 g were discarded. The remaining pieces were assigned unique x-, y-, and z-coordinates, where x represents distance in the left-to-right plane, y represents distance in the dorsal-to-ventral plane, and z represents distance in the caudal-to-cranial plane. The percentage of airway present in the sample was estimated. Fluorescent dye was extracted from the lung tissue samples by soaking in 1.5 ml of 2-ethoxyethyl acetate (Cellosolve, Aldrich Chemical, Milwaukee, WI) for 48 h. The supernatant was pipetted into cuvettes and read in a fluorescent spectrophotometer (model LS 50B, Perkin-Elmer, Norwalk, CT) at the dye-specific excitation and emission wavelengths. A sample of kidney from each animal was harvested and digested for 24-48 h in 4 N KOH and filtered through a 10-µm-pore polycarbonate filter (Poretics, Livermore, CA). The filter containing the microspheres was soaked in Cellosolve for 4 h, and the fluorescence from the supernatant was measured.Statistical methods.
Tissue samples with an airway content of 
25% were not included in
the final analysis (8, 9). Fluorescence was corrected for weight of
each piece by dividing the fluorescence of each color by weight.
Weight-normalized relative pulmonary blood flow to each piece of lung
was calculated by dividing the color-specific fluorescence of each
piece by the mean color-specific fluorescence of all lung pieces in
both lungs together, yielding a normalized mean relative flow of 1.0. The data from the left and right lungs were then separated and analyzed
individually for pulmonary blood flow distribution. The percentage of
relative blood flow to the left
(L) and
right (R)
lungs was calculated. The coefficient of variation (CV, SD/mean) was
used to characterize the heterogeneity of blood flow within each lung.
These were compared by a two-factor (posture and
FIO2) repeated-measures
ANOVA. Significant differences in
FIO2 were further analyzed
by a paired t-test with Bonferroni's
correction. The change in blood flow [normoxia (N) 
hypoxia (H), N H] with
hypoxia (L/R FIO2 = 0.03/1.0, where L is left lung and R is right lung) in each lung was
characterized as a function of baseline blood flow
(N) during
hypoxia (L/R FIO2 = 1.0/1.0). The mean slopes for all animals for the left lung were
compared with the mean slope of the right lung by a two-tailed paired
t-test.
) was estimated as
|
i
is the mean relative flow for piece i
across the states considered, n is the
number of FIO2 states (e.g.,
3), and m is the number of pieces.
The variance component due to lung piece location
(
) was
estimated as
|
is the
grand mean flow across all pieces and
states; = 1.0 in these experiments. The relative contributions of
variation across pieces and variation across FIO2 levels (and other
changes) to total variation can be calculated as percent, because
variation across pieces and variation across
FIO2 levels, time, and
methodological noise are the only sources of variation in measured
flow. The percent variation (PV) across pieces is
PVstructure = 100 × 
2pieces/( + ). The PV across FIO2 levels
(and other sources of change) is
PVFIO2 = 100 PVstructure. The combination of
methodological noise and temporal variability is expected to be small
and contributes primarily to
and slightly to . The
PV attributable to structure and that attributable to the experimental
manipulation in each lung were compared by a two-factor repeated-measures ANOVA (position and lung).
Subsequent analyses were performed adjusting for the overall change in
blood flow to each lung with left lung hypoxia. Adjusted (e.g., for
change in amount of blood flow) left and right lung blood flow
distributions were obtained by dividing the fluorescence of each piece
in a given experimental condition by the mean fluorescence of all
pieces within the left or right lung separately in that experimental
condition. Thus the change in flow distribution under hypoxia was
assessed, while the total flow was adjusted to that comparable in the
hyperoxic state. The pulmonary hila were defined with spatial
coordinates as the points of entry of the left and right pulmonary
artery into the lungs (25). The radial distance to the ipsilateral
hilum (h) for a piece with
coordinates (x,y,z) was calculated
as the Euclidean distance
![<IT>h</IT> = 1.2 × [(<IT>x</IT> − <IT>x</IT><SUB>h</SUB>)<SUP>2</SUP> + ( <IT>y</IT> − <IT>y</IT><SUB>h</SUB>)<SUP>2</SUP> + (<IT>z</IT> − <IT>z</IT><SUB>h</SUB>)<SUP>2</SUP>]<SUP>0.5</SUP>](/content/vol84/issue6/fulltext/2010/img007.gif)
|
4.0%/cm, for example, means that flow
decreased 0.04 normalized flow units per centimeter. The slope was
expressed in terms of percent per centimeter, because the mean
normalized flow for each lung for each animal was 100%. The mean
slopes (e.g., flow vs. x) of all animals were compared with zero with a single-sample two-tailed t-test. The linear association
(Pearson's correlation coefficient, R) between relative pulmonary blood
flow and each spatial dimension (x, y,
z, or h) was determined. The PV in flow accounted for
by each of the dimensions was calculated as
R2. Slopes of the
linear gradients for all animals were analyzed by a two-factor (posture
and FIO2) repeated-measures ANOVA, with significant differences in
FIO2 evaluated by a paired
t-test with Bonferroni's correction.
The change in the hilar-to-peripheral slope with hypoxia
(SH) compared
with hyperoxia
(SN) was
calculated for each lung in the prone position. Flows normalized within
each lung were used for this analysis. The difference
(SN SH) is the
change in slope uniquely due to redistribution of flow under
hypoxia. Slopes for the two hypoxic states (left lung
FIO2 = 0.09 and 0.03) were
very similar and were averaged for this analysis. To determine whether
the redistribution of flow varied with the fraction of flow
allocated to left and right lungs, we compared the
redistribution difference,
SN SH, with
H/N,
the ratio of flow to the specific lung during hypoxia to flow to
that lung during hyperoxia. We calculated the Pearson correlation of
SN SH with
H/N
across animals. Using linear regression analysis, we tested whether
SN SH varied in a
different way with flow fraction on the hypoxic (left) vs. hyperoxic
(right) side of the lung. The dependent variable was the
difference (SN SH)left (SN SH)right,
and the independent variable was
(H/N)left (H/N)right.
The calculation of variance in flow attributable to structure vs.
nonstructure was repeated using the blood flow data normalized separately for each lung. This analysis adjusted for the overall change
in blood flow to each lung with hypoxia while preserving the
nonstructural component in variance due to redistribution.
The data on hemodynamic and blood gas distribution were analyzed by a
two-factor (posture and
FIO2) repeated-measures ANOVA. Significant differences in
FIO2 were compared using a
paired t-test with Bonferroni's
correction. P < 0.05 was deemed
statistically significant. For post hoc tests of
FIO2 (3 levels),
P < 0.05 after Bonferroni's
correction was considered significant. Only this threshold value is
used in Tables 1-5 and Figs. 1-4 for indication of
significance to improve the clarity of presentation; specific
P values are presented in the text.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
Hemodynamic and blood gas data are presented in Table
1. The baseline conditions, including body
temperature, right and left airway pressure, arterial
PCO2, pH, and hematocrit, were fairly
constant throughout the study. In both positions, left lung hypoxia
increased Ppa (P < 0.001 by
ANOVA) and decreased arterial PO2 and
mixed venous PO2
(
; P < 0.001 by ANOVA). Total flow
shifted markedly from the left to the right lung in both positions
under hypoxia (P < 0.001 by ANOVA). Cardiac output (P < 0.05 by ANOVA), systemic arterial pressure
(P < 0.001 by ANOVA), and heart rate
(P < 0.05 by ANOVA) were increased
in the prone compared with the supine position.
|
For each animal, 1,586 ± 158 lung pieces were obtained; 13 ± 2% of the samples were deleted from analysis because of the presence of 25% airways, resulting in 589 ± 67 pieces in the left lung and 789 ± 97 pieces in the right lung in the final data analysis. The lungs were divided into an average of 24 ± 1 caudal-to-cranial planes, 16 ± 1 dorsal-to-ventral planes, and 16 ± 2 left-to-right planes. Kidney samples had no fluorescence, indicating
that all the microspheres were trapped in the lungs.
Pulmonary blood flow distribution during hyperoxia. The distribution of pulmonary blood flow during hyperoxia was characterized by marked heterogeneity in the distribution of pulmonary blood flow. The CV of pulmonary blood flow was greater in the supine than in the prone position for left (P < 0.05) and right (P < 0.01) lungs (Fig. 1). In the prone position the dorsal-to-ventral gradient in both lungs was close to zero, whereas in the supine position a significant negative dorsal-to-ventral gradient was present (Tables 2 and 3; P < 0.001 compared with zero). In this position, pulmonary blood flow was greater in the dorsal areas of the lung and decreased by ~4%/cm toward ventral areas of each lung. The dorsal-to-ventral gradient was not altered by exclusion of lung pieces representing 3 cm of lung most dependent in either position. A small, but significant, caudal-to-cranial gradient (P < 0.05 compared with zero) was present in the left lung (Table 2) and the right lung (Table 3) in the supine position. Blood flow decreased 2-3%/cm from the caudal to the cranial direction. Pulmonary blood flow decreased by 3-5%/cm (P < 0.001 compared with zero) in both lungs linearly with increasing distance from the ipsilateral hilum in both positions (Tables 2 and 3, Fig. 2). The hilar-to-peripheral gradient persisted with elimination of 3 cm of lung most distant from the hilum. The hilar predominance of pulmonary blood flow was also reflected in the left-to-right gradients, especially in the left lung, where there was a significant negative gradient (Tables 2 and 3).
|
|
|
|
Redistribution of pulmonary blood flow during hypoxia.
Hypoxic ventilation of the left lung increased
R and reduced
L in both
positions (P < 0.001 by ANOVA; Table
1). In the prone position, flow diversion away from the left lung was
46 ± 8% with FIO2 of
0.09 and 60 ± 8% with
FIO2 of 0.03. Similar values
were observed in the supine position. The CV of the left lung blood
flow increased with hypoxia (P < 0.001 by ANOVA; Fig. 1). However, the increase occurred in the prone
(P < 0.01), but not in the supine,
position (Fig. 1). In each position the CV of the right lung blood flow
was not affected by flow diversion occurring with left lung hypoxia.
N H) as
a function of blood flow during hyperoxia (N) is
illustrated in a representative animal in the prone position in Fig.
3. The decrease in blood flow in the
hypoxic left lung was greatest in high-flow lung pieces and lowest in
low-flow lung pieces. For all animals the mean slope of
(N H) vs.
N in
the hypoxic lung (FIO2 = 0.03) was 0.68 ± 0.18 (P < 0.001 compared with zero). Blood flow increased in the right lung more to pieces with high baseline flow than to pieces with low
flow (Fig. 3). However, in the right lung there was more dispersion around the trend line, and the high-flow pieces gained less than the
high-flow pieces in the left lung lost. The mean right lung slope of
(N H) vs.
N was
0.42 ± 0.26 (P = 0.02 compared with zero). The mean absolute value of this slope was
significantly different between lungs
(P = 0.016 by paired
t-test). Similar results were obtained
in the supine position.
|
|
|
SH and the ratio
of hypoxic to hyperoxic blood flow
(H/N)
in the hypoxic left lung for the eight animals
(y = 0.062 ± 0.08x,
R = 0.68, P = 0.04). In contrast, the right lung
relationship was considerably weaker and was not significantly
different from zero (P = 0.5). The left and right lung linear trends in Fig. 4 were
significantly different (P = 0.006).
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
We studied the effects of unilateral alveolar hypoxia on the distribution of pulmonary blood flow in the hyperoxic and hypoxic lungs in supine and prone anesthetized dogs. Redistribution of blood flow in the hypoxic left lung was different from that in the hyperoxic right lung. The heterogeneity of flow increased, the component of variation in flow due to structure was smaller, and the hilar-to-peripheral gradient, adjusted for the decrease in blood flow, was reduced in the hypoxic lung. In contrast, no changes were observed in the hyperoxic lung. We conclude that HPV-flow diversion alters the distribution of pulmonary blood flow in the hypoxic, but not the hyperoxic, lung.
Methodological issues. Fluorescent-labeled microspheres were used to determine the distribution of pulmonary blood flow (7). The spheres were completely extracted by the pulmonary microcirculation, as demonstrated by the absence of fluorescence in a sample of kidney. The lungs were inflated and dried at total lung capacity. Although some distortion of the pulmonary parenchyma is possible when the lungs are inflated to 25 cmH2O, the influence on the major findings of the study should be small. Lung volume may be slightly greater than in the intact lung, which will increase the linear dimensions slightly. In addition, the weight of the heart in vivo may result in some compression of the lung below it. Lung shape and size were carefully maintained in anatomic position during drying. We visually ensured that the lungs were oriented properly in the rigid box when foamed, to ensure sectioning of the lungs into isogravitational planes. Lung pieces belonging to the left and right lungs were confirmed by close inspection of visual maps.
Lung pieces with >25% airway tissue were excluded, inasmuch as airway tissue has a higher density than alveolar tissue and results in an erroneously low weight-corrected signal. Thirteen percent of all lung samples were excluded. Inasmuch as a greater number of these pieces were located near the hilum than in the lung periphery, exclusion of these pieces may result in alterations in the estimated hilar-to-peripheral gradient compared with imaging methods, such as single-photon emission computed tomography (SPECT) scanning. We have evaluated the impact of exclusion of pieces with >25% airways in pilot work and found no significant change in results whether the specimens were included or excluded.Pulmonary blood flow distribution during hyperoxia. The present study confirms the results of previous studies in which marked heterogeneity was observed in the distribution of pulmonary blood flow independent of linear vectors (3, 8, 9, 16, 25). Small, but significant, hilar-to-peripheral flow gradients were present in both postures, and a vertical dorsal-to-ventral gradient and caudal-to-cranial gradient were found in the supine posture during hyperoxia (Tables 2 and 3). However, most of the flow variation was not explained by linear trends with distance. Although the distribution of pulmonary blood flow was evaluated during hyperoxia instead of normoxia, the findings on gradients are identical to those obtained in animals with normal lungs when FIO2 is 0.21 (3, 8, 9, 14, 16, 21, 24). The lack of dependence of the pulmonary blood flow distribution on vertical height in the prone position is consistent with previous studies in which similar methodology was used in dogs (8, 9), sheep (25), and horses (3, 16) and in which imaging techniques were used in humans (14) and dogs (13, 21, 24). The presence of a central-to-peripheral gradient in pulmonary blood flow is also consistent with previous results in sheep (25), in which the same methodology was used, and in dogs and humans, in which different center points and/or methodology were used (8, 9, 11, 12-15, 21). The central-to-peripheral gradient measured in the present study is based on the distance from the ipsilateral pulmonary artery located in the hilum. This center point is more peripherally located than that in the studies of Hakim et al. (12-15), where the correlation was relative to the center of mass of each lung or lobe. Despite the differences in center point and methodology, the results of the present study are remarkably similar to those of previous studies (8, 9, 11, 12-15, 21). The hilar predominance of pulmonary blood flow is most likely a function of vascular anatomy because of branching vessels in a fractal pattern (10).
Pulmonary blood flow distribution during unilateral hypoxia.
Left lung hypoxia decreased
L, increased
R, and increased
Ppa (Table 1). The amount of flow diversion was consistent with the
known properties of the HPV stimulus-response curve (1, 19) and similar
in magnitude to that observed in prior studies (5, 18). The effect of
left lung hypoxia on the distributions of pulmonary blood flow was
essentially similar in the prone and supine positions.
SH) and the
strength of the HPV response
(H/N)
for the hypoxic left lung, but not the hyperoxic right lung (Fig. 4).
The greater the decrease in
H/N,
the greater is the change in the hilar-to-peripheral gradient
(SN SH) in the
hypoxic lung. These results suggest that pulmonary vasoconstriction
alters the distribution of blood flow in the hypoxic lung in proportion
to the intensity of the HPV response. Because the findings persist
after statistical adjustment for the change in overall blood flow to
each lung, they also suggest that the redistribution of flow with HPV
is distinct from the change in total pulmonary blood flow.
A large percentage of pulmonary blood flow variation with hypoxia was
determined by a fixed spatial pattern. Piece structures determined
70-80% of the variance in blood flow to the right lung (Table 4).
Increases in blood flow to the right lung with HPV-flow diversion and
other nonstructural factors accounted for only 20-30% of the
pulmonary blood flow variation. This result is similar to that obtained
with increased flow in exercising horses (3). In contrast, only
30-40% of the variance in flow in the hypoxic left lung was
attributable to piece structure (Table 4). The remainder of the
variation in flow was attributable to HPV and other nonstructural
factors (such as time and methodological noise). This low percentage
was predominantly secondary to the decrease in flow rather than
redistribution, inasmuch as the proportion of variance due to
structural factors increased to 70-80% with statistical
adjustment for the decrease in flow (Table 5). However, structural
factors still played a greater role in determining the distribution of
flow in the hyperoxic right lung (90-95% with adjustment for flow
change) than in the left lung. The differences in the proportion of
variation in flow due to the fixed spatial pattern between the lungs
emphasize that, although the pulmonary vascular structure has an
important role in determination of the distribution of pulmonary blood
flow, factors such as HPV also play a major role in determining the
distribution of flow in the lung in which hypoxia is present.
The fact that hypoxic ventilation of a lung leads to a change in the
regional distribution of blood flow within that lung may be explained
by local differences in the stimulus for HPV. Given the normal
A-
heterogeneity present in the lung, it is likely that there will be
local variations in
PAO2 in
different lung regions dependent on the resting
A/.
Inasmuch as the stimulus for HPV is a reduction of
PO2 in the vicinity of the vascular
smooth muscle (19), the stimulus in high-A/
regions is likely to be different from that in
low-A/ regions. In
low-A/
regions the stimulus for HPV would approach (~60 Torr),
as it does in the presence of atelectasis (6). In addition, the hypoxic
stimulus would be expected to elicit a more intense vasoconstrictor
response in
high-A/
regions because of the lower
PAO2. However, this
explanation is speculative and requires further testing, inasmuch as
local PAO2 levels were not
measured.
The local HPV response may also be conditioned by the basal flow in the
local lung region, perhaps dependent on basal level of pulmonary
vascular tone. The HPV response is attenuated in the presence of high
pulmonary vascular tone (2). HPV may already be present in
low-flow,
low-A/
regions in the basal state, so little change in blood flow would be
observed during hypoxia. This is consistent with the finding that the
HPV response of each lung piece is directly proportional to its
baseline blood flow (Fig. 3). A greater decrease in blood flow occurred
during hypoxia in high-flow pieces, with smaller decreases in low-flow
pieces. However, our finding that a grossly similar relationship
(although quantitatively different, Fig. 3) was observed in the
hyperoxic right lung, in which the high-flow pieces increased in the
amount of flow more than the low-flow pieces, suggests that anatomic factors may also be important. This finding is partially consistent with those of Hakim et al. (13, 15), who found, using SPECT imaging,
that changes in cardiac output changed blood flow in proportion to
baseline blood flow. Greater absolute increases or decreases in blood
flow were observed in high-flow regions. These findings further
emphasize the importance of pulmonary vascular branching patterns in
determination of the distribution of pulmonary blood flow.
We previously demonstrated an increase in
A-
heterogeneity in hypoxic lung (5) and with reductions in lobar blood
flow, even without alteration in the predominant zonal conditions (4, 20). The present finding of increased heterogeneity in the perfusion distribution in the hypoxic lung suggests that alterations in the
perfusion distributions may contribute to the observed heterogeneities in gas exchange.
The present experiment cannot distinguish between whether pulmonary
vasoconstriction or changes in blood flow are responsible for the
observed differences between the hypoxic and hyperoxic lungs. Blood
flow decreases to the hypoxic lung while increasing to the hyperoxic
lung. Statistical adjustment for changes in the amount of blood flow
reduces the influence of the amount of blood flow on the results. It is
possible that decreases in blood flow may be associated with greater
redistribution of blood flow than increases in flow, especially when
zonal conditions vary, even in the absence of hypoxia. However, in the
present study it is unlikely that zone 1 occurred in the hypoxic lung.
Further experiments are required to separate the influences of
vasoconstriction from decreases in flow.
In conclusion, redistribution of blood flow with unilateral alveolar
hypoxia was different in hypoxic and hyperoxic lungs. Significant
changes in the distribution of flow occurred in the hypoxic lung, in
contrast to the hyperoxic lung. We conclude that hypoxic
vasoconstriction alters the regional distribution of flow in the
hypoxic, but not in the hyperoxic, lung.
| |
ACKNOWLEDGEMENTS |
|---|
The authors thank Mical Middaugh, Dowon An, Susan Bernard, and Jeff Parker for expert technical help and Dawn Bolgioni for secretarial assistance.
| |
FOOTNOTES |
|---|
This study was supported by National Heart, Lung, and Blood Institute Grants HL-12174, HL-24163, and HL-02507; The Swedish Society of Medicine (Carin Tryggers Minnesford); and the Swedish Medical Research Council.
Address for reprint requests: K. B. Domino, Dept. of Anesthesiology, Box 356540, University of Washington, Seattle, WA 98195.
Received 10 October 1996; accepted in final form 28 January 1998.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
1.
Barer, G. R.,
P. Howard,
and
J. W. Shaw.
Stimulus-response curves for the pulmonary vascular bed to hypoxia and hypercapnia.
J. Appl. Physiol.
22:
139-155,
1970.
2.
Benumof, J. L.,
and
E. A. Wahrenbrock.
Blunted hypoxic pulmonary vasoconstriction by increased lung vascular pressures.
J. Appl. Physiol.
38:
846-850,
1975
3.
Bernard, S. L.,
R. W. Glenny,
H. H. Erickson,
M. R. Fedde,
N. Polissar,
R. J. Basaraba,
and
M. P. Hlastala.
Minimal redistribution of pulmonary blood flow with exercise in racehorses.
J. Appl. Physiol.
81:
1062-1070,
1996
4.
Domino, K. B.,
B. L. Eisenstein,
F. W. Cheney,
and
M. P. Hlastala.
Pulmonary blood flow and ventilation-perfusion heterogeneity.
J. Appl. Physiol.
71:
252-258,
1991
5.
Domino, K. B.,
M. P. Hlastala,
B. L. Eisenstein,
and
F. W. Cheney.
Effect of regional alveolar hypoxia on gas exchange in dogs.
J. Appl. Physiol.
67:
750-735,
1989.
6.
Domino, K. B.,
L. Wetstein,
S. A. Glasser,
L. Lindgren,
C. Marshall,
A. H. Harken,
and
B. E. Marshall.
Influence of on blood flow to atelectatic lung.
Anesthesiology
59:
428-434,
1983[Medline].
7.
Glenny, R. W.,
S. Bernard,
and
M. Brinkley.
Validation of fluorescent-labeled microspheres of regional organ perfusion.
J. Appl. Physiol.
74:
2585-2597,
1993
8.
Glenny, R. W.,
W. J. E. Lamm,
R. K. Albert,
and
H. T. Robertson.
Gravity is a minor determinant of pulmonary blood flow distribution.
J. Appl. Physiol.
71:
620-629,
1991
9.
Glenny, R. W.,
N. L. Polissar,
and
H. T. Robertson.
Relative contribution of gravity to pulmonary perfusion heterogeneity.
J. Appl. Physiol.
71:
2449-2452,
1991
10.
Glenny, R. W.,
and
H. T. Robertson.
Fractal modeling of pulmonary blood flow heterogeneity.
J. Appl. Physiol.
70:
1024-1030,
1991
11.
Greenleaf, J. F.,
E. L. Ritman,
D. J. Sass,
and
E. H. Wood.
Spatial distribution of pulmonary blood flow in dogs in left decubitus position.
Am. J. Physiol.
227:
230-244,
1974.
12.
Hakim, T. S.,
G. W. Dean,
and
R. Lisbona.
Effect of body posture on spatial distribution of pulmonary blood flow.
J. Appl. Physiol.
64:
1160-1170,
1988
13.
Hakim, T. S.,
R. Lisbona,
and
G. W. Dean.
Effect of cardiac output on gravity-dependent and nondependent inequality in pulmonary blood flow.
J. Appl. Physiol.
66:
1570-1578,
1989
14.
Hakim, T. S.,
R. Lisbona,
and
G. W. Dean.
Gravity-independent inequality in pulmonary blood flow in humans.
J. Appl. Physiol.
63:
1114-1121,
1987
15.
Hakim, T. S.,
R. Lisbona,
and
G. W. Dean.
Role of vasoconstriction in gravity-nondependent central-peripheral gradient in pulmonary blood flow.
J. Appl. Physiol.
74:
897-904,
1993
16.
Hlastala, M. P.,
S. L. Bernard,
H. H. Erickson,
M. R. Fedde,
E. M. Gaughan,
R. McMurphy,
M. J. Emery,
N. Polissar,
and
R. W. Glenny.
Pulmonary blood flow distribution in standing horses is not dominated by gravity.
J. Appl. Physiol.
81:
1051-1061,
1996
17.
Lopez-Muniz, R.,
N. L. Stephens,
B. Bromberger-Barnea,
S. Permutt,
and
R. L. Riley.
Critical closure of pulmonary vessels analyzed in terms of Starling resistor model.
J. Appl. Physiol.
24:
625-635,
1968
18.
Marshall, B. E.,
and
C. Marshall.
Continuity of response to hypoxic pulmonary vasoconstriction.
J. Appl. Physiol.
49:
189-196,
1980
19.
Marshall, C.,
and
B. E. Marshall.
Site and sensitivity for stimulation of hypoxic pulmonary vasoconstriction.
J. Appl. Physiol.
55:
711-716,
1983
20.
Ohlsson, J.,
M. Middaugh,
and
M. P. Hlastala.
Reduction in lung perfusion increases A/ heterogeneity.
J. Appl. Physiol.
66:
2423-2430,
1989
21.
Parker, J. C.,
J. L. Ardell,
C. R. Hamm,
S. A. Barman,
and
P. J. Coker.
Regional pulmonary blood flow during rest, tilt, and exercise in unanesthetized dogs.
J. Appl. Physiol.
78:
838-846,
1995
22.
Permutt, S.,
J. B. L. Howell,
D. F. Proctor,
and
R. L. Riley.
Effect of lung inflation on static pressure-volume characteristics of pulmonary vessels.
J. Appl. Physiol.
16:
64-70,
1961
23.
Permutt, S.,
and
R. L. Riley.
Hemodynamics of collapsible vessels with tone: the vascular waterfall.
J. Appl. Physiol.
18:
924-932,
1963
24.
Treppo, S.,
S. M. Mijailovich,
C. A. Hales,
and
J. G. Venegas.
Contributions of pulmonary perfusion and ventilation to heterogeneity in A/ measured by PET.
J. Appl. Physiol.
82:
1163-1176,
1997
25.
Walther, S. M.,
K. B. Domino,
R. W. Glenny,
N. L. Polissar,
and
M. P. Hlastala.
Pulmonary blood flow distribution has a central-to-peripheral gradient in awake, prone sheep.
J. Appl. Physiol.
82:
678-685,
1997
26.
West, J. B.,
C. T. Dollery,
and
A. Naimark.
Distribution of blood flow in isolated lung: relation to vascular and alveolar pressures.
J. Appl. Physiol.
19:
713-724,
1964
This article has been cited by other articles:
|
|
 |
|
  Y. Yatsu, T. Tsubo, H. Ishihara, H. Nakamura, and K. Hirota A New Method to Estimate Regional Pulmonary Blood Flow Using Transesophageal Echocardiography Anesth. Analg., February 1, 2008; 106(2): 530 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. A. Lundblad, J. Thompson-Figueroa, G. B. Allen, L. Rinaldi, R. J. Norton, C. G. Irvin, and J. H. T. Bates Airway Hyperresponsiveness in Allergically Inflamed Mice: The Role of Airway Closure Am. J. Respir. Crit. Care Med., April 15, 2007; 175(8): 768 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J. Lee, J.-G. Im, J. M. Goo, Y. I. Kim, M. W. Lee, H.-G. Ryu, J.-H. Bahk, and C.-G. Yoo Acute Lung Injury: Effects of Prone Positioning on Cephalocaudal Distribution of Lung Inflation--CT Assessment in Dogs Radiology, January 1, 2005; 234(1): 151 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. R. Swenson, M. Maggiorini, S. Mongovin, J. S. R. Gibbs, I. Greve, H. Mairbaurl, and P. Bartsch Pathogenesis of High-Altitude Pulmonary Edema: Inflammation Is Not an Etiologic Factor JAMA, May 1, 2002; 287(17): 2228 - 2235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chang, S. J. Lai-Fook, K. B. Domino, C. Schimmel, J. Hildebrandt, H. T. Robertson, R. W. Glenny, and M. P. Hlastala Spatial distribution of ventilation and perfusion in anesthetized dogs in lateral postures J Appl Physiol, February 1, 2002; 92(2): 745 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Slama, M. Gesch, J. C. Bock, S. M. Pietschmann, W. Schaffartzik, and U. Pison Unilateral lung edema: effects on pulmonary gas exchange, hemodynamics, and pulmonary perfusion distribution J Appl Physiol, October 1, 2000; 89(4): 1513 - 1521. [Abstract] [Full Text] [PDF]
|
|
| ||||
