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Departments of 1 Anesthesia and Critical Care, 2 Medicine (Pulmonary and Critical Care Unit), and 3 Radiology (Division of Nuclear Medicine), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; 4 Massachusetts Institute of Technology, Boston, Massachusetts 02139; and 5 Clinic of Anesthesiology and Intensive Care Medicine, University Clinic Carl Gustav Carus, Dresden University of Technology, Dresden 01307, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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Using positron emission tomography
(PET) and intravenously injected 13N2, we
assessed the topographical distribution of pulmonary perfusion (
) and ventilation (
) in six healthy, spontaneously
breathing subjects in the supine and prone position. In this technique, the intrapulmonary distribution of 13N2,
measured during a short apnea, is proportional to regional .
After resumption of breathing, regional specific alveolar
(sA, ventilation per unit of alveolar gas volume)
can be calculated from the tracer washout rate. The PET scanner imaged 15 contiguous, 6-mm-thick, slices of lung. Vertical gradients of
and sA were computed by linear regression,
and spatial heterogeneity was assessed from the squared coefficient of
variation (CV2). Both CV
and had vertical gradients favoring
dependent lung regions, 2) vertical gradients were similar in the supine and prone position and explained, on average, 24% of
heterogeneity and 8% of heterogeneity, 3)
CV, and 2) although does not seem to be
systematically more homogeneous in the prone position, differences in
individual behaviors may make the prone position advantageous, in terms
of -to- matching, in selected subjects.
functional lung imaging; positron emission tomography; gas exchange; heterogeneity; prone position
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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RECENTLY THERE HAS BEEN A renewed
interest in the effects of body position changes on the topographical
distribution of pulmonary perfusion () and ventilation ()
for two reasons. First, the prone position is increasingly used in the
treatment of patients with acute respiratory distress syndrome (ARDS),
and a recent clinical trial suggested that prone positioning may
improve survival in a subset of patients with ARDS (6).
Whether the prone position is associated with a more uniform
distribution of , , or both is unclear (16).
Although animal studies have shown , , and
/ to be more uniform in the prone position (15,
29), the results in normal humans are discordant. Whereas some
studies reported a more uniform distribution of (17,
18) and (1) in the prone position, other
studies reported no difference in (10, 11) and
(4, 11) gradients between the supine and prone
positions or even greater gradients in the prone position
(2). Second, animal studies have employed position changes
to draw inferences on the role of gravity in determining the
distribution of . Some of these studies suggested that gravity is a minor determinant of distribution in recumbent postures (7), whereas other studies found a much greater
contribution of gravity to the distribution of (9,
29). The extent to which these results in animals can be
extrapolated to humans is unclear.
Positron emission tomography (PET) imaging of the lung during a
constant rate intravenous infusion of [13N]nitrogen
(13N2) has been used to measure regional
/ in humans (24). We modified that technique
into a bolus infusion of 13N2 during a short
apnea. By measuring the concentration of 13N2
during apnea and the ensuing period of 13N2
washout, the topographical distributions of and can be assessed separately. The potential advantages of this method include its ability to assess both and with a single
administration of tracer, its minimal invasiveness, and the low
radiation exposure to the subject. These characteristics might make
this method suitable for future clinical applications in a variety of
lung diseases.
In the present study, we used the 13N2 bolus
infusion technique and PET to pursue two aims: 1) to assess
the topographical distribution of and in healthy,
spontaneously breathing humans in the supine and prone position and
2) to quantify the amount of spatial heterogeneity of
and explained by a vertical gradient, after accounting
for the estimated contribution of random imaging noise to the measured
heterogeneity of and .
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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Experimental Subjects
We studied six healthy adults (3 men, 3 women; ages 19-32 yr). All subjects were nonsmokers and nonobese and had normal pulmonary function tests. Informed consent was obtained from each subject before the study.13N2-Saline Bolus Infusion Technique
To assess regional lung function, we used the 13N2-saline bolus infusion technique (9, 14, 29, 32). Simultaneously with the start of a 13N2-saline bolus infusion, the collection of a PET scan of the thorax was initiated. Each PET scan consisted of a series of consecutive PET images, acquired during an apnea (40 s) and the ensuing period of tracer washout. As the injected tracer reached the lung, its concentration rose until it reached a plateau for the remainder of the apnea (~30 s). When the subject resumed breathing, the tracer concentration decreased as 13N2 was eliminated by ventilation (washout). From the tracer kinetics (Fig. 1), regional lung function was assessed for each volume element of lung in the tomogram (i.e., voxel) as follows.
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Assessment of .
The theoretical basis for the measurement of from the
13N2 concentration during apnea was provided in
detail by Mijailovich et al. (14). Because of the low
solubility of 13N2 in blood and tissues
(partition coefficient 
water/air = 0.015 at
37°C), on arrival into the pulmonary capillaries, virtually all the
tracer diffuses into the alveolar air space at first pass (23,
24, 30), and regional tracer content during apnea is proportional to regional (14, 32). Mean-normalized
regional could thus be expressed as the ratio between tracer
concentration in each voxel and mean tracer concentration of all voxels
in the imaged lung field, measured during the plateau phase of the
apnea. This approach to the calculation of is justified by the
fact that 13N2 reabsorption into pulmonary
venous blood during the apnea is negligible in a normally aerated and
perfused lung (see APPENDIX and Fig. 1).
Assessment of .
As the subject resumed spontaneous breathing,
13N2 was eliminated from the lung almost
exclusively by ventilation (30). Specific alveolar
ventilation [sA, alveolar ventilation
(A) per unit of alveolar gas volume] was calculated
as the reciprocal of the time constant (
) of the tracer washout
curve (see APPENDIX). For a monoexponential washout, corresponds to the mean residence time (MRT) of the tracer
(31) defined as
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(1) |
A was calculated as the reciprocal of the MRT.
Assessment of /.
From the derivation above, it follows that the integral of the tracer
concentration during the washout is proportional to the
-to-sA ratio (/sA;
see APPENDIX). This can be intuitively appreciated from
Eq. 1, which shows that the integral of the tracer washout
curve is the product of Cw, which is proportional to
, and the MRT.
A and
/sA in the order of 1.5% in a normally
aerated and perfused lung.
PET Transmission Scan
A 10-min transmission scan was recorded for each subject in both body positions by using a uniform rotating pin-source of 68Ge (Fig. 2). The transmission scan was used to correct the emission scan for energy attenuation caused by body tissues and supporting structures, to demarcate the lung field, and to calculate fractional gas content (Fgas), as previously described (4, 9, 30). Fgas represents the fraction of the volume of a voxel occupied by gas.
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Experimental Setup
We used a PC-4096 PET scanner (Scanditronix) that imaged 15 contiguous, 6-mm-thick slices of thorax with an in-plane spatial resolution of 6 mm full width half maximum (FWHM). Impedance plethysmography (Respitrace, Non-Invasive Monitoring Systems, Miami Beach, FL) was used to monitor tidal volume and respiratory rate and to ensure that the subject held his or her breath at mean lung volume for the duration of the apnea.13N2 gas was dissolved into sterile saline solution. The specific activity of the injectate was 0.38 ± 0.05 (means ± SD) mCi/ml and a dose of 8.9 ± 2.3 mCi per scan was injected at a rate of 5 ml/s in a peripheral vein. This corresponded to a radiation exposure of 17.8 ± 4.6 mrem per scan.
Experimental Protocol
The study protocol was approved by the Human Research Committee of our Institutional Review Board. Subjects were randomized to start in the supine or prone position (subjects 1, 2, and 5 started supine, and subjects 3, 4, and 6 started prone). After placement of an intravenous catheter in one antecubital vein, subjects lay recumbent on the PET scanner table with arms abducted and thorax in the PET scanner field up to the level of the axilla. A 10-min transmission scan was then collected, after which the subject was instructed to take two large breaths to total lung capacity and then to resume normal breathing for five additional breaths. During the expiratory phase of the fifth breath, when mean lung volume was reached, as assessed by the Respitrace, the subject was instructed to stop exhalation and remain apneic for 40 s. The lung volume signal from the Respitrace was monitored continuously to ensure the absence of ventilation during the apnea. At the end of this period, spontaneous ventilation was resumed and the subject was encouraged to maintain a regular breathing pattern despite the increased respiratory drive that followed the apnea. The apnea was performed at mean lung volume to ensure that the lung volume during the apnea was the same as the mean lung volume during the washout. This should limit the effect of image registration artifacts on the measurement of sA.
Simultaneously with the beginning of the apnea, a bolus of 13N2-saline was injected intravenously and a PET scan lasting 3 min and 40 s (40 s of apnea followed by 3 min of washout) was started. Each PET scan consisted of a series of sequential PET images. At the end of the scan, the subject turned to the opposite body position, and the imaging protocol was repeated. Care was taken to image the same cross section of thorax in both body positions by aligning the laser pointer of the PET scanner with skin marks on the chest of the subject.
Four subjects had an additional emission scan in the last of the two body positions (subjects 2 and 5 had two prone scans and 3 and 4 had two supine scans). This third scan, taken ~30 min after the second scan, was used to assess reproducibility of the measurements.
Image Processing and Analysis
The projection data were corrected for nonuniformity of detector response, dead time, random coincidences, attenuation, and scattered radiation. The PET scanner was cross-calibrated with a well scintillation counter by comparing the scanner response from a fluoride-18 solution in a 20-cm cylindrical phantom with the response of the well counter to an aliquot of the same solution. All emission scans were reconstructed by using a conventional filtered back-projection algorithm to an in-plane resolution of 7 mm FWHM.Selection of voxels for analysis.
Lung "masks" were defined by thresholding the transmission scan
(4, 24). These masks were then refined to exclude regions corresponding to the main bronchi and large pulmonary vessels. In
subject 1 in the supine position, small dependent areas of tracer retention were identified on the last PET image of the washout
and were excluded from the lung mask that was used to obtain the
and / measurements.
A is effectively calculated as the ratio of
two variables (i.e., the tracer concentration at the beginning of the washout and the integral of the washout curve; see Eq. 1),
the frequency distribution of sA is particularly
prone to have outliers. These outliers would profoundly affect the
estimate of heterogeneity, although they probably reflect the
uncertainty of our method in estimating sA in
regions of very low / rather than true extreme values of
sA. Outliers, defined as voxels with
sA < [Q1 
2(Q3 Q1)] or sA > [Q3 + 2(Q3 Q1)], where Q1 and Q3 are the 25th and 75th percentile of the
sA distribution (26), were excluded
from the analysis of .
PET scans.
Emission scans, corrected for tracer radioactive decay (half-life of
13N2: 9.96 min), were low-pass filtered to a
length scale of 12 mm and corrected for edge effects (32).
After scans were filtered, the size of the effective resolution element
corresponded to 12 × 12 × 6 mm. For each voxel within the
lung mask, , sA, and /sA were calculated from the tracer kinetics
of the PET scan and displayed on a color-coded scale to yield
functional images (Fig. 2).
Assessment of vertical ("gravitational") gradients.
For each voxel, , sA,
/sA, and Fgas were regressed vs.
the vertical distance from the most dependent point of the imaged lung
field. Gradients, measured from the slope of the corresponding regression line, were expressed in percent per centimeter, relative to
the mean (Fig. 3). Negative gradients
indicate a decrease of , sA,
/sA, or Fgas from the dependent
to the nondependent regions (i.e., higher values of ,
sA, /sA, or
Fgas in dependent than in nondependent regions, Fig. 3).
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Assessment of spatial heterogeneity.
Spatial heterogeneity of , sA, and
/sA was assessed from the squared coefficient
of variation [CV2 = (SD/mean)2] of the
respective functional images (29, 32).
.
To correct the measured heterogeneity for the contribution of
random imaging noise caused by finite count statistics, an approach
similar to the one reported by Venegas et al. (33) was
used. The assumption behind this approach is that, during the plateau
phase of the apnea, regional tracer concentration remains constant.
Thus differences in the tracer concentration measured in a given voxel
on the PET images collected during the plateau of the apnea are due to
random imaging noise. This assumption is valid if tracer reabsorption
into pulmonary venous blood is negligible, a condition that is met in
the normal human lung (see APPENDIX and Fig. 1). For each
injection of tracer, a number of sequential PET images corresponding to
the plateau phase of the apnea were identified by inspection. In the
analysis of the data, these images were averaged in different
combinations by calculating a voxel-by-voxel duration-weighted mean of
the tracer activities of the images included in each combination. For
example, if ai,j denotes the tracer activity of
the ith voxel (i = 1, ... , N, where N is the number of voxels
in the lung mask) in the jth image (j = 1, ... , M, where M is the number of images
corresponding to the plateau of the apnea) and
tj is the duration of the jth image, then the tracer activity of the ith voxel in the combination
image made of, for instance, the first, second and Mth image
is
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(2) |
image (Fig. 2). The CV2 of each
combination image (i.e., the CV2 of
{ai}i=1, ... , N) was then calculated and regressed vs. the reciprocal of the
duration-weighted sum of the mean voxel activity of the images included
in each combination. For the same example as above, in which we
considered the combination image made of the first, second and
Mth image, the duration-weighted sum of the mean voxel
activities is
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(3) |
, had a image with an infinite number of counts been
acquired. The intercept is therefore a measure of
heterogeneity, corrected for the contribution of random imaging noise
(33). We will denote the value of the intercept as
CV image (i.e., the CV2 of
{ai}i = 1, ... ,N when j = 1, ... , M in Eq. 2) as
CV
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CV image. The ratio
R heterogeneity explained by the
vertical gradient.
/ and .
For each PET scan, the duration-weighted sum of the mean activity of
the PET images taken during tracer washout was calculated as
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(4) |
/sA image. The CV2 due to
random imaging noise was then subtracted from the CV2 of
the /sA image
(CV
/sA heterogeneity
(CV
A, we used a Monte Carlo approach. Because
sA was computed as the ratio of the image
and the /sA image, a ratio that corresponds
to the reciprocal of the MRT (see Eq. 1), the parameters
describing the distribution of noise in the image and in the
/sA image were used for the Monte Carlo
simulation as follows. A normally distributed random variable (r.v.),
with mean equal to the mean activity of the image and
CV2 equal to the product of the reciprocal of the
activity-time integral of the image (Eq. 3 for
j = 1, ... , M) by the slope of the
CV2 vs. activity regression line, was generated. The
distribution of this r.v. characterizes the distribution of random
noise in the image, under the assumption that such noise can be
modeled as a normally distributed stochastic process. Similarly, a
second normally distributed r.v., with mean equal to the mean activity of the /sA image and CV2 equal to
the product of the reciprocal of the activity-time integral of the
/sA image (Eq. 4) by the slope of
the CV2 vs. activity regression line, was generated. The
distribution of this second r.v. represents the distribution of random
noise in a PET image with the same mean activity as the
/sA image. Because sA was
computed as the ratio of and /sA, a
third r.v. was generated as the ratio of the first and the second r.v. The distribution of this third r.v. represents the effect that random
noise in the and /sA images has on
the distribution of sA. One hundred thousand empiric
realizations of this r.v. were generated by computer simulation
(Matlab, The MathWorks, Natick, MA), and their CV2 was
calculated. This CV2 represents an estimate of the
sA heterogeneity that could be attributed to random
imaging noise. This was subtracted from the CV2 of the
sA image
(CV
A heterogeneity
(CV
Statistical Analysis
Least squares linear regression was used to estimate all regression relationships. When calculating the regression of the supine-to-prone difference in the Fgas gradient vs. the supine-to-prone difference in the gradient (see below), the
constraint of a zero intercept was imposed. This constraint reflected
the assumption that, if the gradients were equal in the supine
and prone position, then the Fgas gradients would also be
equal. This assumption was justified by the consideration that, if the
lung behaved as a passive structure under the influence of hydrostatic
forces, then the gradients of and lung density (and therefore
of Fgas) would not differ between the two body positions.
Two-tailed Student's t-test was used to assess any significant difference from zero and to compare the results in the supine and prone position (t-test for paired data). Statistical significance was set at P < 0.05. To control the "experiment-wise" type I error and limit the number of statistical comparisons, the following approach was used. It was decided a priori that the primary comparisons of interest were those involving the gradients and the total heterogeneity. Only if these were statistically significant, then comparisons involving the different components of the total heterogeneity were performed as secondary endpoints. Values are presented as means ± SD.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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Vertical Gradients
The gradient was different from zero in both body
positions, without a significant difference between supine and prone (Table 1). There was, however, large
intersubject variability in the gradients, ranging from
+0.5%/cm to 10.6%/cm (Fig. 5). Only
in one subject (subject 6 in prone position) was there a
slightly positive gradient; otherwise, was consistently greater in dependent than in nondependent lung regions (i.e.,
had a negative gradient).
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The Fgas gradient was positive in both body positions
(Table 1). The difference in Fgas gradient between the
supine and prone positions (
grad Fgas) was negatively
correlated (r = 0.778) with the difference in
gradient (grad ), as shown in Fig. 6. The slope of the regression line was
0.162 (95% confidence interval: 0.313 to 0.012).
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There was a significant, negative sA gradient in
both supine and prone positions (Table 1), and all subjects had greater sA in dependent regions (Fig. 5).
The average /sA gradient was not
significantly different from zero in either body position (Table 1).
However, two subjects in both body positions (2 and
6) and one subject in the supine position (3) had
positive /sA gradients, consistent with the finding that, in these cases, the gradient was less pronounced than the sA gradient (Fig. 5). Consequently, in
these cases, the /sA was higher in
nondependent than in dependent regions. In contrast, negative
/sA gradients (subjects 1,
3 in prone position, 4, and 5)
corresponded to cases in which the magnitude of the gradient
was greater than the magnitude of the sA gradient.
This implies that, in these cases, the fraction of going to
dependent lung regions was greater than the fraction of
sA in these regions (Fig. 5).
The difference in vertical gradients between the first and second scan
obtained in the same body position (n = 4) was 0.4 ± 1.1%/cm for , 0.9 ± 1.2%/cm for
sA, and 0.5 ± 2.3%/cm for /sA.
Heterogeneity
There was no statistically significant difference in
heterogeneity, CV heterogeneity explained by the vertical
gradient, R
gradients (subject 4 and subject 3 in prone
position) had higher values of CV heterogeneity, CV
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heterogeneity, CV heterogeneity explained by the vertical
gradient, R heterogeneity persisted after subtraction of the
component due to the vertical gradient (Table 2, Fig. 7).
There was no difference in /sA heterogeneity,
CV/sA gradients, we did not test
the components of
CV
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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Comparison to Other Methods and Critique of the Technique
Several methods have been employed to assess regional in animals and humans (5, 7, 8, 10, 15, 17-19,
27). Because 13N2 has a first-pass
retention of virtually 100% in aerated lung regions (23,
30), the 13N2-saline bolus infusion
technique is conceptually similar to methods that utilize tracers that
are retained in the pulmonary microvasculature, such as microspheres or
macroaggregated albumin. The advantage of using
13N2, though, is that N2, like
O2 and CO2, is a low-molecular-weight gas that
is dissolved in the blood. Its distribution through the pulmonary
capillary network should therefore resemble that of the respiratory
gases more closely than the bulkier (10-100 µm in diameter)
microspheres or albumin macroaggregates. Furthermore, compared with the
macroaggregated albumin method, the 13N2
infusion technique reduces radiation exposure for the subject because
13N2 has a shorter half-life and is eliminated
more rapidly than 99mTc.
For the 13N2 content during apnea to
accurately reflect regional , two basic conditions need to be
met. First, the apnea itself needs not to influence the regional
distribution of . Second, tracer removal by the bloodstream
during the apnea needs to be negligible. Because tracer distribution
into the lung is virtually complete within the first 10 s since
the start of the infusion, the effect of the apnea should be minimal.
To further limit the potential effect of the apnea on regional ,
the subjects took two inspirations to total lung capacity five breaths
before the beginning of the apnea. This maneuver should prevent the
development of alveolar atelectasis and reduce the level of hypercapnia
reached during the apnea. Because of the low solubility of
13N2 in blood, tracer reabsorption into
pulmonary venous blood during the apnea is minimal. In normally aerated
and perfused lungs, tracer reabsorption can be expected to result in a
<2% drop in tracer concentration during the apnea (see
APPENDIX).
The MRT of a gas tracer has been previously used to characterize the
regional distribution of (31). We assessed
from the reciprocal of the MRT during the washout. This approach has the following implications. First, because 13N2
is removed from the lung also by the pulmonary venous blood, the MRT is
shorter than if 13N2 had been eliminated
exclusively by ventilation. However, in a normally aerated and perfused
lung, this should lead to an overestimation of specific ventilation
(i.e., ventilation per unit of compartment volume) by only 1.5% (see
APPENDIX). Therefore, the reciprocal of the MRT appears to
be a reasonable estimate of specific ventilation. Second, the
reciprocal of the MRT represents the rate at which the concentration of
13N2 within the voxel decreases. If the voxel
behaves as a well-mixed single compartment, the rate of decrease of the
concentration of 13N2 within the voxel equals
the rate of decrease of the alveolar concentration of
13N2 (although the alveolar and the voxel
concentration of 13N2 may differ because
water/air = 0.015 for
13N2). Therefore, the reciprocal of the MRT
effectively represents specific alveolar ventilation,
sA, and the fact that we do not measure the alveolar
concentration of 13N2 but only its
concentration within the voxel is immaterial. Third, because
sA reflects the net rate of regional gas transfer and intrinsically accounts for the effect of reinspiration of gas from
the common dead space, the topographical distribution of
sA should be closely related to regional gas exchange.
Gradients and Heterogeneity
.
In this study, we found vertical gradients favoring
dependent lung regions in both supine and prone positions. These
gradients are similar to those reported previously in spontaneously
breathing humans with magnetic resonance imaging (28) and
single-photon-emission computed tomography (19) and
corroborate the results of earlier studies that employed low-resolution
planar imaging techniques (11, 12). Whereas it is
generally accepted that is highest in dependent lung regions in
the supine position, the vertical dependence of in the prone
position is more controversial. Animal data, mostly from quadrupeds,
indicate that there may be structural factors (3) or
biochemical modulators (20) of the pulmonary vasculature
that favor perfusion in dorsal lung regions. This is consistent with
the results of Treppo et al. (29), who found a marked
vertical gradient in supine (where both structural/biochemical factors
and gravity would tend to increase in dependent, dorsal,
regions) but not in prone dogs. These factors, by contrasting the
action of gravity in the prone position, would serve the purpose of
rendering the distribution of more homogeneous in quadrupeds.
Recent studies, employing single-photon-emission computed tomography,
suggested that also in humans the vertical gradient is either
less or nil in the prone position (17, 18). Our data do
not corroborate these findings, and caution on the extent to which
results of studies that showed greater dorsal in prone
quadrupeds (7) can be extended to biped humans. Our
results are in line with those of Amis et al. (2) and
Jones at al. (10), which also showed higher in
dependent (ventral) than in nondependent (dorsal) regions in prone
humans. Our results do, however, show a wide variability in individual
behaviors that may partly explain the discrepant findings in the
literature. The fact that vertical gradients were reproducible on
repeated measurements in the same body position argues against the
possibility that this variability was a measurement artifact. The fact
that the change in gradient between the supine and prone positions was
not dictated by the order of randomization (i.e., gradients were not
systematically higher, or lower, in the first than in the second
position, Fig. 5) virtually excludes the possibility that the
intersubject variability in the change in gradient was merely the
result of a systematic difference between the gradients in the first
and the second body position. Whereas supine gradients were very
similar in five of the six subjects, prone gradients were more disperse
(Fig. 5). This suggests that, on turning prone, redistributed
toward ventral, dependent lung regions in all subjects, but the extent to which this occurred was much greater in some subjects (e.g., subject 4) than in others (e.g., subject 6).
Future studies will be needed to address whether a lesser degree of
redistribution toward dependent, ventral regions is associated
with a favorable response to prone positioning in patients with ARDS,
in whom lung densities have been shown to shift to ventral regions in
the prone position (13).
grad Fgas) was negatively correlated with the
supine-to-prone difference in gradient (grad ), but
the 95% confidence interval of the slope of the regression line did
not include 1. If perfusion per unit of lung tissue, and therefore
perfusion per alveolus, were constant and the redistribution of
between the supine and prone positions were merely a consequence of
redistribution of lung tissue, then the change in the mean-normalized
gradient would equal the change in the mean-normalized lung
density gradient. As a result, grad would be equal in
magnitude but opposite in sign to grad Fgas, and the
slope of the regression line in Fig. 6 would be 1. Our finding
instead suggests that redistribution of lung tissue cannot be the only
explanation for the redistribution of that is associated with
body position changes and that perfusion per unit of lung tissue, and
therefore perfusion per alveolus, increases when a nondependent region
of lung becomes dependent as a result of the position change. This is
consistent with a decreased vascular resistance of dependent lung
regions compared with nondependent regions.
Over the past decade, animal data obtained with the intravenous
injection of microspheres have suggested that vertical gradients explain only a minor fraction (i.e., ~5%) of heterogeneity in the supine or prone position (7). To avoid an
underestimation of the relative importance of vertical gradients,
because of an overestimation of the total heterogeneity, we applied a
method that allows estimation of the heterogeneity due to finite count statistics, which can then be used to correct the total measured heterogeneity (33). It is important to acknowledge,
though, that this method does not correct for systematic sources of
imaging noise such as reconstruction and registration artifacts. On
average, the vertical gradient explained ~24% of
heterogeneity in both positions. Both the total heterogeneity and the
residual heterogeneity were similar in the supine and prone position
(Table 2), suggesting that, in humans, is not systematically
more uniform in the prone position. There were marked differences,
though, in individual behaviors, and in four subjects
heterogeneity was lower in the prone position (Fig. 7). For
subject 4, vertical gradients explained the majority of
heterogeneity (57% in both positions), whereas for
subject 6 the contribution of the vertical gradient to
heterogeneity in the prone position was insignificant. These differences may reflect a variable contribution of structural factors
and active regulation of the pulmonary vasculature to the topographical
distribution of .
.
In both the supine and prone positions, we found vertical
sA gradients that favored dependent lung regions
(Table 1, Fig. 5). These results are consistent with early reports
(11, 22) and with more recent PET studies (4)
but differ from the observations of other authors that reported
to be uniform (1) or even greater in nondependent (dorsal)
than in dependent (ventral) regions in the prone position (17,
19, 21). This discrepancy of results in the literature is not
surprising in view of the different factors that can affect the
topographical distribution of in awake, spontaneously breathing
humans. These include the pleural pressure gradient and the pattern of
contraction of the respiratory muscles. The vertical gradient of
pleural pressure has been suggested to be less in the prone position
(34). This would favor a more uniform distribution of
when prone. Although the difference was not statistically
significant, we did find, on average, lower sA
gradients in prone subjects (Table 1), and sA
heterogeneity was significantly smaller in the prone than in the supine
position (Table 2, Fig. 7). These findings are consistent with a more uniform distribution of in the prone position.
(25) and explain part of the discrepancies in the literature. This is consistent with our results, which show that only a small fraction of heterogeneity is
explained by the vertical gradient and that residual,
"nongravitational," heterogeneity is significant.
Finally, our findings show that estimates of the regional
distribution of are profoundly affected by the occurrence of gas trapping. Dependent, crescent-shaped areas of very low
/ were reported, in healthy humans, by Rhodes et al.
(24) and attributed to low . We detected areas of
tracer retention during the washout (i.e., areas of gas trapping) in
the dependent lung regions of subject 1 in the supine
position. This finding suggests that airway closure may occur in
dependent lung regions during tidal breathing. Despite the fact that
these areas represented only 9% of the imaged lung field, the
sA gradient decreased from 0.9 to 1.5%/cm and the
sA heterogeneity decreased from 0.26 to 0.16 after
these areas were removed from the lung mask of this subject. In
contrast to methods like ours that use the intravenous infusion of
inert insoluble gases, methods that image by inhalation of
tracer will not reveal areas of gas trapping, because inhaled tracer
cannot reach the airspace distal to closed airways. These implications
of different methods may represent a further explanation for the
discordant data on the regional distribution of reported in the literature.
/.
We did not find significant /sA
gradients in either body position (Table 1), and the spatial
heterogeneity of /sA was similar in the
supine and prone position (Table 2). This is consistent with the rest
of our results and suggests that, on average, the vertical gradient of
match the gradient of . These findings contrast with the
results of animal studies that have shown both the vertical gradient
and the heterogeneity of the / ratio to be substantially
reduced in the prone position (15, 29). Interspecies
differences and the fact that animals were studied during anesthesia
and mechanical ventilation may account for this discrepancy.
and
can be assessed noninvasively, in humans, with the
13N2-saline bolus infusion technique and PET.
Our results suggest that both and are distributed
preferentially to dependent lung regions in the supine as well as in
the prone position and that, in awake spontaneously breathing humans,
the prone position does not offer any systematic advantage, in terms of
-to- matching, compared with the supine position.
However, individual differences, especially in the distribution of
, may explain why the prone position is effective in improving
gas exchange in some subjects. The next step is to identify patterns of
distribution of and that may be predictive of a
favorable response to prone positioning.
| |
APPENDIX |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
|
|---|
The purpose of this appendix is to present a one-compartment
model for a voxel of lung to 1) elucidate the rationale of
the measurements of sA and
/sA obtained with the
13N2-saline bolus infusion method, and
2) quantify the effect of 13N2
reabsorption into pulmonary venous blood on ,
sA, and /sA measurements.
Glossary
| VA | Alveolar gas volume |
| A |
Alveolar ventilation |
| sA |
Specific alveolar ventilation (sA = A/VA)
|
| |
Pulmonary perfusion |
| Co | Alveolar concentration (activity) of 13N2
immediately after arrival of the bolus of tracer (proportional to
; Ref. 14)
|
| c(t) | Alveolar concentration (activity) of 13N2 at time t |
| Cw | Alveolar concentration (activity) of 13N2 at the beginning of the washout |
| water/air |
partition coefficient for 13N2 ( = 0.015 at 37°C)
|
The rate of change of c(t) is given by the following
first-order differential equation (14)
|
(A1) |
|
(A2) |
|
(A3) |
, sA, and
/sA, we will use global values of
sA and /VA of normal human
lungs in which = A = 5 l/min and VA = 2.5 liters. This yields sA = /VA = 0.033/s.
During the apnea, sA = 0. According to
Eq. A2, the tracer concentration is expected to decrease by
1.5% over the 30 s of apnea that follow the arrival of the bolus
of tracer. This warrants the assumption that c(t) is
virtually constant during the plateau phase of the apnea and that
Co 
Cw. Because Co
(14) and Co Cw, then
Cw (Eq. A3).
During the washout, ventilation is resumed. Equation A2 shows that the reciprocal of the time constant of the tracer
washout curve is related to sA. Equation A3 shows that the integral of the tracer washout curve is related
to /sA.
The error in the estimation of sA and
/sA due to the fact that we neglect tracer
reabsorption by the pulmonary venous blood and estimate
sA from [sA + (/VA)] is
|
| |
ACKNOWLEDGEMENTS |
|---|
We thank M. Martinez for contributing to the analysis of the data; S. Barrow, S. Weise, A. Bruce, and the "MGH Cyclotron Group" for technical assistance; Dr. T. Richter and K. O'Neill for insightful comments; and Dr. W. M. Zapol for continued support with this project.
| |
FOOTNOTES |
|---|
This study was supported by National Heart, Lung, and Blood Institute Grants GM-07592, HL-38267, and HL-68011.
Address for reprint requests and other correspondence: G. Musch, Dept. of Anesthesia and Critical Care, CLN 309, Massachusetts General Hospital, 32 Fruit St., Boston, MA 02114 (E-mail: gmusch{at}partners.org).
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.
10.1152/japplphysiol.00223.2002
Received 15 March 2002; accepted in final form 3 July 2002.
| |
REFERENCES |
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DISCUSSION
APPENDIX
REFERENCES
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