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Departments of 1 Medicine and 2 Physiology and Biophysics, University of Washington, Seattle, Washington 98195
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Changes in the spatial distribution of perfusion during acute lung injury and their impact on gas exchange are poorly understood. We tested whether endotoxemia caused topographical differences in perfusion and whether these differences caused meaningful changes in regional ventilation-to-perfusion ratios and gas exchange. Regional ventilation and perfusion were measured in anesthetized, mechanically ventilated pigs in the prone position before and during endotoxemia with the use of aerosolized and intravenous fluorescent microspheres. On average, relative perfusion halved in ventral and cranial lung regions, doubled in caudal lung regions, and increased 1.5-fold in dorsal lung regions during endotoxemia. In contrast, there were no topographical differences in perfusion before endotoxemia and no topographical differences in ventilation at any time point. Consequently, endotoxemia increased regional ventilation-to-perfusion ratios in the caudal-to-cranial and dorsal-to-ventral directions, resulting in end-capillary PO2 values that were significantly lower in dorsal-caudal than ventral-cranial regions. We conclude that there are topographical differences in the pulmonary vascular response to endotoxin that may have important consequences for gas exchange in acute lung injury.
endotoxin; blood flow; heterogeneity; pulmonary
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ENDOTOXIN, A
CELL WALL COMPONENT of gram-negative bacteria, may play an
important role in determining abnormalities in pulmonary perfusion,
ventilation-perfusion matching, and gas exchange in acute lung injury.
Endotoxemia increases ventilation-to-perfusion ratio
(
A/
) heterogeneity in humans
(25) and animals (6, 9, 15), causes pulmonary
vasoconstriction (5, 16), and impairs hypoxic pulmonary
vasoconstriction (27). Because endotoxemia frequently complicates the acute respiratory distress syndrome (ARDS)
(18), the pulmonary vascular response to endotoxin may, in
part, be responsible for the increased A/
heterogeneity and intrapulmonary shunt associated with ARDS (4,
21).
The global response of the pulmonary circulation to endotoxemia has
been extensively studied (5, 14, 16, 19), but regional
differences in the pulmonary vascular response to endotoxin have only
recently been reported and play an important role in determining the
efficiency of gas exchange (9). Topographical differences
in the pulmonary vascular response to endotoxin may be particularly
relevant to gas exchange when endotoxemia complicates ARDS. Because
lung involvement in ARDS is predominantly dependent (8),
ventilation is likely decreased in dependent regions. Thus a
stereotyped pulmonary vascular response to endotoxin might produce
characteristic changes in perfusion that potentially worsen development
of low A/ and shunt in dependent regions.
However, endotoxin's effect on the spatial distribution of perfusion
is unknown.
Because perfusion is greatest in dorsal-caudal lung regions at rest
(2, 11, 13), during exercise (3), and in
response to pharmacological stimuli (20) in several animal
models, we reasoned that endotoxemia might preferentially increase
perfusion to dorsal-caudal lung regions, thus decreasing
A/ and worsening gas exchange in these
regions. To test this hypothesis, we independently measured regional
alveolar ventilation and perfusion in pigs before and during
endotoxemia using intravenous and aerosolized fluorescent microspheres
and analyzed endotoxin's effects on the spatial distribution of
ventilation, perfusion, and A/.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study represents a new analysis of fluorescent data
collected in seven animals by Gerbino et al. (9) in which
we analyzed the contribution of changes in ventilation heterogeneity,
perfusion heterogeneity, and ventilation-perfusion correlation to
A/ heterogeneity during endotoxemia.
Measurements of respiratory mechanics, gas exchange, and hemodynamics
in these experiments have been reported previously (9) and
are, therefore, omitted from this manuscript.
Animal preparation.
Experiments were approved by the University of Washington Animal Care
Committee. Seven pathogen-free pigs weighing 21-25 kg were
chemically restrained with ketamine (20 mg/kg) and xylazine (2 mg/kg)
and anesthetized with a thiopental infusion (initially 10 mg · kg
1 · h1) titrated to
produce a surgical stage of anesthesia and suppress spontaneous
ventilation (~10-17
mg · kg1 · h1). Pigs
breathed air and were mechanically ventilated with a bag-in-box ventilator adapted to deliver aerosolized fluorescent microspheres (23) via tracheostomy. Tidal volume was set at 11-12
ml/kg without positive end-expiratory pressure. Respiratory rate was
set to achieve an arterial PCO2 between 30 and
35 Torr before endotoxin infusion (requiring 1 change in respiratory
rate in 1 animal) and was not changed after endotoxin infusion began.
Lungs were hyperinflated to twice tidal volume every 15 min to prevent
atelectasis. Central venous, arterial, and pulmonary artery catheters
were placed. Animals were placed in the prone posture for the remainder of the study to minimize the effect of the pleural pressure gradient on
the distribution of ventilation. Exhaled CO2 and expiratory flow were digitally sampled with an infrared CO2 detector
(model 1260, Novametrix Medical Systems, Wallingford, CT) and
pneumotach, respectively, for later determination of anatomic dead
space (7).
Study protocol.
Data were collected at two time points before endotoxemia (i.e.,
baselines 1 and 2) and after 30 min of endotoxin
infusion. The end of data collection for one time point and the start
of data collection for the subsequent time point were always separated by 40 min. Escherichia coli O55:B5 endotoxin (Sigma
Chemical, St. Louis, MO) was infused at 2.5 µg · kg1 · h1 through a
femoral venous catheter. Normal saline (500 ml) was given intravenously
if systemic blood pressure fell to 80% of its preendotoxin level. The
rate of endotoxin infusion was halved if systemic blood pressure did
not respond to fluids.
Data processing. For a given color microsphere, fluorescent intensity within a piece was converted to relative perfusion by dividing the weight-normalized fluorescent intensity in that piece by the mean of weight-normalized fluorescent intensities in all lung pieces. We used relative rather than absolute perfusion because our primary goal was to determine whether endotoxemia changed the way cardiac output was partitioned between lung regions. Relative perfusion changes only if there is a change in partitioning of cardiac output between regions, whereas the decrease in cardiac output during endotoxemia (9) causes absolute perfusion to change even if there is no change in how cardiac output is partitioned.
A/ within each piece was calculated from the
quotient of ventilation and perfusion expressed in milliliters per
minute. Fluorescent intensity within a piece was converted to flow in milliliters per minute by dividing the fluorescent intensity in that
piece by the sum of fluorescent intensities for that color in all
pieces and then multiplying by total alveolar ventilation (for
ventilation) or cardiac output (for perfusion). Alveolar ventilation
was calculated by estimating anatomic dead space in three consecutive
breaths from plots of exhaled CO2 concentration vs. exhaled
volume (7).
Statistical analysis. Data are reported as means ± SD. All logarithms are base 10. Differences between baselines 1 and 2 reflect the effects of time and method error and were, therefore, used as within-animal controls for evaluating effects of endotoxemia. Statistical significance was assumed if P < 0.05, unless otherwise stated.
Calculation of ventilation, perfusion, and
A/ gradients.
We analyzed the change in ventilation and perfusion within lung pieces
as a function of cranial-caudal and ventral-dorsal position and as a
function of distance from the ipsilateral hilum (i.e., hilar-peripheral
position). Lungs were corrected for tilt before these relationships
were calculated, so that x-, y-, and z-axes reflected the true anatomic right-left,
ventral-dorsal, and cranial-caudal directions (Fig.
1). Spatial gradients of ventilation or
perfusion can be characterized two different ways. Gradients can be
determined at two different time points, and the slopes describing each
time point can be compared. Alternatively, the ratio of ventilation or
perfusion measured at different times within the same piece [e.g., log
( at time 2/ at time 1)] can be
analyzed as a function of position. We chose the latter method because
it permits spatial analysis (i.e., calculation of spatial correlation
and spatial gradients) of changes in ventilation and perfusion as a
function of position and best reflects the impact that relative changes
in ventilation or perfusion have on A/ and,
therefore, gas exchange.
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Ae/A2)] were compared with slopes describing changes in ventilation due to time
and method error [log
(A2/A1)]
using paired t-tests, where the subscripts 1,
2, and e refer to measurements during baselines 1 and 2 and endotoxemia, respectively. Slopes describing
changes in perfusion due to endotoxemia [log
(e/2)] were also
compared with slopes describing changes in perfusion due to time and
method error [log
(2/1)] using paired t-tests. Log ratios greater than 2 or less than
2 were set to 2 and 2, respectively, before linear regression. Hilar-peripheral distance was defined as the Euclidean distance between
the center of a piece and the ipsilateral hilum.
Regional A/ was described as a function of
ventral-dorsal, cranial-caudal, and hilar-peripheral position using
slopes of least squares regression lines. Values for log
(A/) greater than 3 or less than 3 were set
to 3 and 3, respectively, before linear regression. Slopes
from baselines 1 [log
(A1/1)] and 2 [log
(A2/2)]
and slopes from baseline 2 and
endotoxemia [log
(Ae/e)] were
compared using paired t-tests.
Due to the orientation of the lung in the thorax, ventral-dorsal,
cranial-caudal, and hilar-peripheral coordinates are interdependent. Caudal regions are more dorsal and peripheral, and cranial regions are
more ventral and closer to the hilum (Fig. 1). To eliminate the
interdependence of ventral-dorsal and cranial-caudal coordinates, we
entered right-left position and either ventral-dorsal or cranial-caudal position in a multiple linear-regression model against the
dependent variable A/ or changes in
perfusion and analyzed the residuals as a function of the remaining
orthogonal direction. For example, regression of ventral-dorsal and
right-left position against A/ yielded
residuals that were then analyzed as a function of cranial-caudal position. The slope of this relationship represents the effect of
cranial-caudal position, independent of the confounding influence of
ventral-dorsal position. Because hilar-peripheral position is a
function of both ventral-dorsal and cranial-caudal position, this
variable was not included in the multiple regression model, and
hilar-peripheral slopes were, therefore, not corrected for spatial
interdependence. Slopes for different time points were compared with
paired t-tests.
Nonlogarithmic values for changes between ventral and dorsal, cranial
and caudal, and hilar and peripheral regions were calculated by taking
inverse logarithms of values predicted by linear regression for these
regions. For example, if log (A/) equals 0 and 1 in ventralmost and dorsalmost regions, respectively, then
A/ increased from 1 to 10, or 10-fold, in the
ventral-to-dorsal direction.
Effect of A/ gradients on gas exchange.
Even if statistically significant, the magnitude of perfusion and
A/ gradients may not be physiologically
meaningful. Therefore, we reported the effects of these gradients on
regional gas exchange. Regional end-capillary
PO2 was predicted in each lung piece as
described by Altemeier et al. (1). Regression lines
describing end-capillary PO2 as a function of
cranial-caudal, ventral-dorsal, and hilar-peripheral position were used
to predict end-capillary PO2 values in regions
3 cm from the cranial, caudal, ventral, dorsal, hilar, and peripheral
extremes of the lung. By choosing regions 3 cm from the edge of the
lung, we avoided describing PO2 values in the
lung periphery where, on average, <4% of total pieces in the lung
were located. Differences between cranial and caudal, ventral and
dorsal, and hilar and peripheral PO2 values were evaluated with paired t-tests.
Spatial correlation.
The tendency for similar changes in ventilation or perfusion to be
clustered in neighboring lung regions was quantified by calculating
spatial correlation, 
(d), as described by Glenny (10). Briefly, pairs of lung pieces in the same lobe
separated by distance d were identified, and the correlation
between paired measurements was characterized with a linear correlation
coefficient. This process was repeated for all distances between
pieces, generating a series of linear correlation coefficients that
describes spatial correlation as a function of distance
d between pieces.
(d = 1.2 cm), and the shortest
distance d for which (d) was not significantly
different than zero, d: (d) = 0 [i.e.,
the shortest distance at which (d) falls within 95%
confidence intervals around zero]. The 95% confidence
intervals around zero (i.e., confidence intervals describing a random
spatial distribution) were generated by using a permutation test
(10). Briefly, a hypothetical data set with a random
spatial distribution was generated from the experimental data set by
shuffling spatial coordinates so that each lung piece was assigned to a
randomly selected spatial location. This process was repeated 1,000 times, and (d) was calculated in each hypothetical data
set, yielding a distribution of values for (d) at each
distance d. The 95% confidence limits were defined as
values marking the upper and lower 2.5% of these distributions.
The (d = 1.2 cm) and d: (d) = 0 were calculated for changes in ventilation [log
(Ae/A2)]
and perfusion [log (e/2)] due to
endotoxemia and changes in ventilation [log
(A2/A1)]
and perfusion [log
(2/1)] due
to time and method error, and differences were evaluated with paired
t-tests. Spatial correlation was also characterized by fitting data to the equation (d) = Ad
, where A and 
are constants
determined using least squares weighted regression, with the number of
pairs at each distance d divided by the total number of
pairs in the entire data set used as the weighting factor. To
determine whether spatial correlation of perfusion changes due to
endotoxin was anisotropic, we also calculated (d = 1.2 cm) for perfusion changes in the right-left, ventral-dorsal, and
cranial-caudal directions (10) and evaluated differences with ANOVA.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Perfusion and ventilation gradients.
Relative perfusion decreased in the caudal-to-cranial direction during
endotoxemia. On average, relative perfusion doubled in caudal lung
regions and halved in cranial regions (Fig.
2E, Table
1). This gradient remained significant
(P = 0.001) even after correction for the influence of
ventral-dorsal position with multiple linear regression.
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A/ gradients and gas exchange.
A/ increased 10-fold in the caudal-to-cranial
direction (Fig. 2G), sixfold in the dorsal-to-ventral
direction, and sixfold in the peripheral-to-hilar direction during
endotoxemia. In contrast, there were no topographical differences in
A/ before endotoxemia (Fig. 2C,
Table 2). The cranial-caudal
A/ gradient during endotoxemia was
significantly different than that before endotoxemia, even after
correction for the influence of ventral-dorsal position (P = 0.001). However, ventral-dorsal (P = 0.06) A/ gradients during endotoxemia were
no longer significantly different than those before endotoxemia after
correction for the influence of cranial-caudal position.
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A/ gradients during endotoxemia significantly
impacted regional gas exchange, resulting in end-capillary
PO2 values that were 36 ± 15 Torr lower
in caudal than cranial regions (Fig. 2H), 25 ± 13 Torr
lower in dorsal than ventral regions, and 21 ± 15 Torr lower in
peripheral than hilar regions. In contrast, there were no topographical
differences in end-capillary PO2 before endotoxemia (Fig. 2D, Table
3).
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Spatial correlation.
Endotoxemia increased the spatial correlation of perfusion changes.
Perfusion changes in adjacent lung regions were more alike, and
perfusion changes were correlated over greater distances during than
before endotoxemia (Fig. 3, Table
4). The spatial correlation of perfusion
changes during endotoxemia was similar in right-left, ventral-dorsal,
and cranial-caudal directions (P = 0.58). In contrast, endotoxemia did not change the spatial correlation of ventilation changes (Fig. 3B, Table 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although the global response of the pulmonary circulation to
endotoxemia has been extensively studied (5, 14, 16, 19), this study is the first to describe topographically organized spatial
heterogeneity in the pulmonary vascular response to endotoxin. Endotoxemia decreased perfusion and increased
A/ in the caudal-to-cranial and
dorsal-to-ventral directions and increased the spatial correlation of
changes in perfusion, resulting in topographical differences in gas exchange.
Perfusion and A/ gradients.
Relative perfusion increased in dorsal, caudal, and peripheral lung
regions and decreased in ventral, cranial, and hilar lung regions
during endotoxemia. Because topographical differences in ventilation
were not significant, cranial-caudal, ventral-dorsal, and
hilar-peripheral A/ gradients were primarily
mediated by changes in perfusion. These A/
gradients were physiologically significant, resulting in marked
topographical differences in gas exchange (Fig. 2, Table 4).
A/. For that reason, we used
absolute rather than relative perfusion to calculate
A/ gradients and predict regional gas exchange.
Topographical changes in perfusion during endotoxemia are unlikely to
reflect mechanisms related to hypoxic pulmonary vasoconstriction. Our
laboratory (9) has previously shown that perfusion changes during endotoxemia were unlikely to have been mediated by hypoxic pulmonary vasoconstriction. Relative perfusion increased in regions that developed alveolar hypoxia during endotoxemia, and changes in
regional ventilation and perfusion within each piece due to endotoxin
were poorly correlated.
Attenuation of hypoxic pulmonary vasoconstriction by endotoxin is also
unlikely to explain perfusion changes. Development of pulmonary
hypertension during endotoxemia suggests that vascular tone was
influenced by mechanisms other than blunting of hypoxic pulmonary
vasoconstriction. In addition, attenuation of hypoxic pulmonary
vasoconstriction would have redistributed perfusion only if
topographical differences in hypoxic vasoconstriction were present
before endotoxemia. However, these differences were unlikely to have
been present because pulmonary artery pressures were normal, alveolar
hypoxia (i.e., regional end-capillary PO2; Fig.
2D) minimal, and topographical differences in alveolar
PO2 lacking (Fig. 2D) before endotoxemia.
The mechanisms responsible for topographical changes in regional
perfusion during endotoxemia are unknown. One determinant of regional
perfusion is the balance between vasodilatory and vasoconstrictive
influences in one region compared with that in other regions. The
development of marked pulmonary hypertension during endotoxemia
(9) suggests that changes in vascular tone played a
dominant role in determining perfusion distributions. However,
increased microvascular (5, 19) or airway (9) pressures during endotoxemia could have resulted in topographical differences in microvascular recruitment and dilation, thereby also
contributing to topographical differences in perfusion.
Previous investigators have reported preferential perfusion to
dorsal-caudal regions in uninjured lungs at rest (2, 11, 13,
22), during exercise (3), and after oleic
acid-induced lung injury (26). In addition, horses show
greater vasodilation to pharmacological stimuli in dorsal-caudal than
ventral-cranial lung regions (20). Although the mechanisms
responsible for these perfusion changes have not been determined, the
similarity in perfusion distributions in several species and
experimental preparations suggests that the dorsal-caudal perfusion
bias in porcine endotoxemia may reflect a more general property of the
pulmonary circulation.
Whether increased perfusion of dorsal-caudal regions in other studies
reflects a ventral-dorsal or cranial-caudal bias is unclear, because
previous studies have generally not accounted for the interdependence
of the ventral-dorsal and cranial-caudal position. Our spatial analysis
accounts for this interdependence and suggests that the dorsal-caudal
perfusion bias during endotoxemia is primarily due to cranial-caudal
rather than ventral-dorsal position.
Although the spatial distribution of perfusion during human endotoxemia
is unknown, we speculate that a dorsal-caudal perfusion bias would have
important implications for gas exchange when endotoxemia complicates
ARDS. Radiographic opacities in ARDS are typically greatest in
dependent lung regions (8), and ARDS patients are typically supine, suggesting that alveolar ventilation is decreased in
dorsal lung regions. Perfusion to poorly ventilated regions is
typically limited by hypoxic pulmonary vasoconstriction, but endotoxin
blunts this compensatory mechanism (27). Thus a
dorsal-caudal perfusion bias due to endotoxemia would result in
excessive perfusion of poorly ventilated dorsal-caudal regions,
amplifying low A/ and shunt. Although
clinical measurement of regional pulmonary perfusion is not widely
available (24), detection of a dorsal-caudal perfusion
bias in ARDS may help identify patients likely to benefit from
treatments that redistribute perfusion (e.g., inhaled nitric oxide)
(12) or restore ventilation to dorsal regions (e.g., the
prone position) (8).
Spatial correlation. Increased spatial correlation during endotoxemia indicates that changes in perfusion are more alike in neighboring lung regions during than before endotoxemia. Because spatial correlation was not significantly different in cranial-caudal, ventral-dorsal, and right-left directions, the increase in spatial correlation of perfusion during endotoxemia does not merely reflect the significant cranial-caudal perfusion gradient (which by itself will increase spatial correlation). Rather, increased spatial correlation of perfusion changes represents additional spatial organization superimposed on the cranial-caudal perfusion gradient.
The most plausible explanation for increased spatial correlation during endotoxemia is that endotoxin affects vascular tone in large pulmonary arteries (16) and that these effects are spatially heterogeneous. Topographical differences in the vascular response of large pulmonary arteries increase spatial correlation because neighboring lung regions share a common vascular heritage. Thus changes in tone of a large pulmonary artery will have a similar influence on perfusion in all lung regions supplied by that parent vessel. This interpretation provides further support for our hypothesis that topographical differences in perfusion during endotoxemia are caused primarily by regional differences in vascular tone.Ventilation gradients. Lack of change in the spatial distribution of ventilation during endotoxemia is consistent with our previous observation that ventilation redistribution during endotoxemia is small (9) and suggests that this redistribution is not spatially organized. Although endotoxemia significantly increased peak and end-inspiratory hold airway pressures (9), global changes in airway pressures do not imply change in the spatial distribution of ventilation. The spatial distribution of ventilation will change only if mechanisms responsible for increased airway pressures, such as increased airway resistance or decreased lung compliance, are heterogeneously distributed in a spatially organized fashion.
Several factors may have minimized the effects of fluid administration and edema formation on the spatial distribution of ventilation. Use of the prone posture may have decreased ventral-dorsal differences in ventilation by minimizing the vertical pleural pressure gradient (17). Endotoxin's minimal effect on alveolar epithelial permeability (28) also potentially limited changes in the spatial distribution of ventilation. Although a spatially heterogeneous pattern of interstitial edema may redistribute ventilation by affecting lung compliance, we speculate that interstitial edema redistributes ventilation less than alveolar edema with associated alveolar filling. Finally, topographical differences in ventilation may have become apparent had we lengthened the period of endotoxemia.Study limitations. Perfusion changes in this study may be relevant to ARDS because ARDS is frequently complicated by endotoxemia (18). However, porcine endotoxemia is not a model of ARDS.
Several important differences between porcine endotoxemia and human sepsis suggest that caution be used when these results are applied to humans. Pulmonary hypertension in these experiments was severe (9), suggesting that regional differences in the pulmonary vascular response to endotoxin may have also been exaggerated. In addition, the decrease in cardiac output during porcine endotoxemia is uncharacteristic of sepsis in humans. Thus we cannot be sure that changes in relative perfusion in this study would be observed in species with a hyperdynamic cardiovascular response. A more detailed discussion of methodological limitations has been published previously (9). In brief, the microsphere method reliably measures regional alveolar ventilation and perfusion with a spatial resolution of 2.0 cm3.A/
heterogeneity beneath this level of spatial resolution cannot be
measured with our technique and may account for overestimation of
arterial PO2 during endotoxemia. However, this
source of error is unlikely to affect regional differences in
ventilation, perfusion, and A/ over distances
that span the entire lung.
Conclusions.
This study demonstrates significant topographical differences in the
response of the pig's pulmonary circulation to endotoxin. Relative
perfusion decreased and A/ and end-capillary
PO2 increased in the
caudal-to-cranial, dorsal-to-ventral, and peripheral-to-hilar directions during endotoxemia. Endotoxemia increased spatial
clustering of perfusion, suggesting that topographically organized
changes in perfusion are mediated by effects on large pulmonary
vessels. These changes may have important consequences for gas exchange in acute lung injury.
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grants HL-10284, HL-56239, and HL-30542.
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FOOTNOTES |
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We thank Dowon An, Susan Bernard, and Shen-Sheng Wang for excellent technical assistance.
Address for reprint requests and other correspondence: A. J. Gerbino, Division of Pulmonary/Critical Care Medicine, BB-1253 Health Sciences Bldg., Box 356522, Univ. of Washington, Seattle, WA 98195-6522 (E-mail: gerbino{at}u.washington.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 19 September 2000; accepted in final form 8 November 2000.
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REFERENCES |
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|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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