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1 Department of Anesthesiology, 2 Department of Radiology, and 3 Institute of Physics, Johannes Gutenberg University, D-55131 Mainz, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Inhalation of hyperpolarized 3He allows magnetic resonance imaging (MRI) of ventilated airspaces. 3He hyperpolarization decays more rapidly when interacting with paramagnetic O2. We describe a method for in vivo determination of intrapulmonary O2 concentrations ([O2]) based on MRI analysis of the fate of measured amounts of inhaled hyperpolarized 3He in imaged regions of the lung. Anesthetized pigs underwent controlled normoventilation in a 1.5-T MRI unit. The inspired O2 fraction was varied to achieve different end-tidal [O2] fractions (FETO2). With the use of a specifically designed applicator, 3He (100 ml, 35-45% polarized) was administered at a predefined time within single tidal volumes. During subsequent inspiratory apnea, serial two-dimensional images of airways and lungs were acquired. At least once in each animal studied, the radio-frequency excitation used for imaging was doubled at constant FETO2. Signal intensity measurements in regions of interest of the animals' lungs (volume range, 54-294 cm3), taken at two different radio-frequency excitations, permitted calculation of [O2] in these regions of interest. The [O2] fractions in the regions of interest correlated closely with FETO2 (R = 0.879; P < 0.0001). O2-sensitive 3He-MRI may allow noninvasive study of regional distribution of ventilation and alveolar PO2 in the lung.
lung; ventilation; distribution; respiratory gas; instrumentation; oxygen; measurement; noble gases
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CONVENTIONAL MAGNETIC RESONANCE imaging (MRI) is based on signal acquisition from the magnetic resonance (MR) of spin-polarized hydrogen nuclei (protons) in water or organic molecules. Because of low proton spin density in air, 1H-MRI does not visualize aerated spaces within the body. MR signal intensity, however, may be enhanced considerably, i.e., by a factor of 105, by hyperpolarization of nuclear spins beyond the naturally prevailing Boltzmann equilibrium. This can be achieved most efficiently in noble-gas isotopes with an odd number of nucleons, i.e., 129Xe or 3He. It is accomplished technically by optical pumping of, for example, a 3He plasma with circularly polarized infrared laser light (7). In 1994, Albert et al. (1) were the first to image the spatial distribution of ventilated lung spaces by MR tomography of inhaled hyperpolarized 129Xe.
Several groups have since demonstrated that hyperpolarized noble gases, in particular 129Xe or 3He (13, 15), could also become useful as imaging agents for functional MRI of the lung. In patients with pulmonary disease, 3He-MRI was used first by Kauczor et al. (10, 11). In chronic obstructive pulmonary disease and pneumonia, they demonstrated very inhomogeneous signal distribution, whereas patients with healthy lungs showed more homogeneous patterns. One obstacle to 3He-MRI in patients with significant pulmonary disease and oxygenation failure was, however, that the paramagnetism of O2 accelerates relaxation, i.e., the decay of nuclear spin hyperpolarization. This decay is described by a time constant of longitudinal spin relaxation, T1. In air at atmospheric pressure, T1 is ~11 s, and it decreases reciprocally to O2 concentration ([O2]) (20). In effect, the presence of O2 destroys the MRI signal so rapidly that functional 3He-MRI studies, at least in diseased lungs, become technically demanding.
On the other hand, this problem led us to the idea that O2-induced destruction of 3He hyperpolarization may be utilized for in vivo measurement of regional intrapulmonary [O2]. Until now, noninvasive techniques to measure [O2] at or beyond the subsegment level are still lacking. The objective of this study was to examine, in a large-animal model, the feasibility of using O2 effects on loss of 3He polarization for the in vivo analysis of regional intrapulmonary [O2].
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal model.
With institutional approval and in conformity with the
Guide for the Care and Use of Laboratory
Animals [DHEW Publication No. (NIH) 86-23,
Revised 1985, Office of Science and Health Reports, DRR/NIH, Bethesda,
MD 20892], six pigs (28 ± 1 kg) underwent anesthesia (8 mg/kg
im azaperone; 1.2 mg/kg iv piritramide; 10-15
mg · kg
1 · h1
iv thiopental), endotracheal intubation facilitated by a single dose of
pancuronium (4 mg iv), controlled ventilation with an O2-air mixture, and
instrumentation with intra-arterial and intravenous femoral catheters
for pressure monitoring and drug administration. O2 saturation of the blood was
monitored by pulse oximetry.
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3He administration. High-degree spin polarization of 3He is accomplished by optical pumping at the Institute of Physics, Johannes Gutenberg University, on campus. The gas is delivered in special low-iron-content glass vials (Schott Glaswerke, Mainz, Germany), which hold 300 ml of 3He, with a polarization degree of 35-45%, at 3 bar. This container material provides sufficiently long relaxation times of hyperpolarized 3He, ranging from 10 to 70 h. Loaded vials are transported within a 0.3-mT magnetic holding field to preserve spin polarization (22).
To administer hyperpolarized 3He from these vials to patients or animals, a gas control and delivery device has been developed by our group; its technical specifications are described by Lauer (12). In brief, a "bag-in-bottle" system is fed by the high-pressure 3He cell; the low-pressure bag is designed to apportion measured amounts of decompressed 3He at atmospheric pressure. When the bag within the rigid bottle is compressed from a pressurized air source, it empties, via a switch valve, its 3He content at a predefined volumetric position into the inspiratory tidal volume. The within-breath range of FIO2 produced by this gas-delivery apparatus has been measured, as part of the technical development of the device, at the mouth of the patient or tube connector. When used in a ventilator circuit with standard tubing during flow-constant, volume-controlled mode, and for bolus volumes between 80 and 400 ml, the applicator produces a He concentration profile that rises from 0 to 50% within 6 ± 1 ml of inspired volume and falls from 50 to 0% within 22 ± 2 ml, independent of bolus size or timing (12). All valves and switches are pneumatically driven and microprocessor controlled via a personal computer-based, self-developed application software written in Borland Delphi (version 1.0). To preserve spin polarization, the applicator is set up within the homogeneous field inside the scanner. Also, the omission of any magnetic or electronic components in its construction reduces loss of polarization during 3He administration. Flow and pressure transducers of the 3He applicator unit were calibrated with a 1-liter supersyringe; the applicator, positioned at the animal's head, was switched into the inspiratory limb of the nonrebreathing circuit next to its Y connector.MRI of hyperpolarized 3He.
With the technique described here, MR visualization of
3He amounts as small as 40 ml is
possible. Depending on bolus placement within the inspiratory tidal
volume, transverse supradiaphragmatic pulmonary cross-sectional, as
well as coronal, images of the lungs or of the characteristics of the
porcine tracheobronchial tree are obtainable (Fig.
2,
A-C).
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Image analysis.
Image analysis was performed by using the NMRWin software
[version 3.33; German Cancer Research Center (Deutsches
Krebsforschungszentrum), Institute for Radiological Diagnostics and
Therapy, Heidelberg, Germany]. For each individual animal and
image series, large regions of interest (ROI) with a minimum size of
>1,500 voxels (voxel size, 1.25 × 1.25 × 20 mm) were
defined as follows (Table 1): signal
intensity within a ROI had to be normally distributed, without overlap
to noise distribution in a ROI of similar dimensions sampled outside
the thoracic circumference. Nonventilated areas as well as major
airways were excluded. In effect, this selection yielded ROIs with
signal-to-noise ratios (SNR) >3. After additional correction for
background noise according to Ref. 8, the arithmetic mean of signal
intensity with normal distributions and SNR >3 was accepted for
analysis.
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Determination of [O2] by
T1 measurements from serial
3He images.
If, in an O2-containing
atmosphere, consecutive images of hyperpolarized
3He are acquired with identical
MRI settings, the ratio of signal intensity (s) in a representative ROI
of an image
(sn+1) to
that of the identical ROI in the previous image
(sn), where
n is the number of image acquisition,
depends on the following: 1) image
acquisition per se, in particular on the flip angle 
of the
magnetization by a single radio-frequency (RF) pulse;
2) the time interval between
subsequent acquisitions, 
t = tn+1 
tn;
3) the molecular density of
O2
(
O2);
4) relaxation properties of the
tissue surfaces that come into contact with hyperpolarized
3He; and
5) diffusive and convective
transport of hyperpolarized 3He
into and out of the volume of signal acquisition.
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(1) |
is the flip angle in units of radian
imposed by each RF excitation on the nuclear spin polarization of
3He in the acquisition volume.
Simultaneously, 3He
hyperpolarization and, hence, signal intensity
(sn) decay exponentially, due
to relaxation between subsequent images, according to
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(2) |
O2, and
temperature (T) (for T 
200-400 K) in a gas mixture containing
hyperpolarized 3He has been
established by Saam et al. (20)
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(3) |
O2 is a
fraction of 1 amagat
(ag).1
At airway temperatures between 36.5 and 39.5°C, this yields
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(3a) |
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(4) |
and
O2 upon the
decay
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(5) |
(in degrees) can be determined from
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(6) |
O2, as the
second unknown, is eliminated from Eq. 6 by obtaining additional measurements at constant
O2 but at
different [or RF excitation voltage (U)]. Then the
relationship between U and is, in first approximation, linear for
small < 10° (U ~ sin ~ ).
Thus for instance, two acquisition series can be performed after two
separate 3He breaths, keeping
FETO2
and FIO2 as well as tidal
volume and 3He bolus volume
constant but varying U by a factor of, for example, 2 (i.e.,
U2 = 2 U1 and, hence,
2 = 2 1).
From the signal decays q1 and
q2, which are produced by U and 2 U at the same
O2, (in
degrees) can then be determined by simultaneous solution of
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(7) |
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(7a) |
t and
O2 are
constants, resulting in
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(8) |
yields
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(9) |
will be independent of the
[O2] to the degree
that O2
remains constant between the two imaging series. With known, it is
then possible to derive
O2 from a
series of signal intensity determinations, obtained in the same animal, in the same ROI and position, and with the same U, according to
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(10) |
O2 in a ROI
was calculated from signal decay of image pairs acquired at U = 10 V. Values for were entered that had been obtained from
double-acquisition series performed at U = 20 V and U = 10 V (radian
10 V 0.5 × radian 20 V), in a
paired fashion at constant oxygenation conditions, slice, and ROI position.
Because
FETO2
were measured by sidestream respiratory gas analysis in dry gas at room
temperature, the results obtained for
T1-derived
intrapulmonary
O2 in a ROI
(in ag at 37°C body temperature,
BTPS) were also converted to a
fractional [O2] (FROIO2)
at ambient temperature (21°C, 760 mmHg, dry) to facilitate comparison.
In this first feasibility study, the dilution of intrapulmonary gas
composition by 3He and the drop in
alveolar PO2
(PAO2) from the start of the
imaging breath hold until the first image (2 s) were not accounted for.
In contrast, the decrease of
PAO2 during
t of paired imaging (1.2 s) enters
into the measurement, which thus represents an average
O2 for the
period of image acquisition.
Protocol and measurements. FETO2 was preset by changing the FIO2 until a steady state was established. The size of the 3He bolus was set to 40 ml (animal 1 only) or 100 ml (animals 2-6) by using the application unit, and the bolus was delivered after the initial 60 ml (combined volume of applicator tubing distal to the 3He delivery valve and the attached inspiratory limb tubing) of an inspiratory tidal volume had been administered. Sequential MR images were acquired during breath hold after end-inspiration had been reached. Before and after each apneic episode, FETO2 was recorded, together with end-tidal CO2 fraction, expiratory minute volume, and vital parameters.
Because, in this specific experimental setting, measurements of functional residual capacity (FRC) and serial dead space were not available, we approximated the reduction of preapnoic FETO2, which occurs by dilution with 100 ml of 3He theoretically, using FIO2, expired tidal volume, and estimates for dead space volume (200 ml) and FRC [30 ml/kg (16)]. Under these conditions, 3He bolus administration was estimated to reduce FETO2 of a subsequent normal expiration, on average, by ~8%. Study interventions consisted of variations of the RF excitation and of FETO2: for flip angle determination, consecutive series with RF excitations of U = 20 V and U = 10 V were performed; pilot studies had shown that an U of 20 V was the prevailing source of signal loss at a known steady-state FETO2. The experiments designed to determine regionalO2 at
several levels of
FETO2 used the smaller RF excitation of U = 10 V; this lower voltage was
chosen such as to permit O2 to
exert more influence on signal decay in relation to RF excitation. In
the same ROIs, signal intensity ratio
q10 V = s2/s1
was then determined from paired images obtained at 2 s and 3.2 s after
inspiratory hold, giving a t of 1.2 s.
Applicator settings for 100-ml boluses of
3He in animals
2-6 resulted in the delivery of 100 ± 12 ml
(means ± 1 SD for a total of 41 bolus administrations). For reasons
of comparability, only those image series
(n = 29) that fulfilled the following
conditions were included in further analyses of flip angle and
O2 density: a measured bolus size
between 90 and 110 ml of 3He,
first image acquired 2 s after inspiratory hold, and resultant ROIs
with SNRs >3. Thus 12 paired series, performed with U = 20 V and U = 10 V at the same
FETO2,
could be used for calculation of flip angles in the defined ROIs.
Seventeen 10-V image series were useful for
FROIO2
determinations; the minimum SNRs of ROIs chosen from these images
ranged between 3.2 and 10.8.
Statistical analysis. Linear regression analysis was used to describe the strength of the relationship between the FETO2 measured with the respiratory gas analyzer and instantaneous fractional [O2] (FROIO2) as determined by the above method in two-dimensional 3He images of the lungs.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Qualitative evaluation of image series.
In Fig. 2A, a representative
two-dimensional 3He image of an
animal's lungs is shown, acquired, at a level 4 cm cephalad to the
xiphoid, in end-inspiratory hold after administration of a 95-ml bolus
of hyperpolarized 3He within the
initial one-half of a tidal volume. The effects of different
intrapulmonary
O2 and
doubling of RF voltage were already discernible in preliminary image
series, which were obtained in the first two animals
(animals 1 and
2) during inspiratory breath holds
after steady-state
FETO2
had been established and 3He
volumes of only 40 ml (animal 1, Fig.
3A) or 100 ml
(animal 2, Fig.
3B) had been administered. Figure
3A illustrates that O2 in the lungs accelerates
3He signal decay in a
dose-dependent fashion. Each four-image series taken at a different
FETO2
represents a period of 6 s of inspiratory breath hold. Because the
applied 3He amount in this
animal 1 (40 ml) differed considerably
from that of the next series, its image data were not included in the subsequent quantitative O2 study.
Figure 3B demonstrates, in images taken 3 s apart, that the signal of a 100-ml bolus given at similar levels of
FETO2
is also destroyed much quicker when the RF voltage is doubled.
Paired-image series like this one were used to extract flip angle ,
as described in METHODS and below. Sizes of ROIs that provided acceptable signal quality are shown exemplarily in Fig. 4,
A and
B. Table 1 gives an overview of their
number and their sizes in relation to the total cross-sectional lung
field.
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Determination of flip angle in ROIs of
3He representations.
In each of animals 2-6, identical
ROIs of 10- and 20-V image pairs acquired at the same
FETO2
were compared to extract the influence of RF excitation on signal
intensity. By using Eq. 9, flip angles
were determined for each ROI from the ratio
q2/q1 of signal intensity decays q2 at U = 20 V and q1 at U = 10 V. 10 V, as the flip angle
that corresponded to RF excitations with U = 10 V was found to be 3.11 ± 0.14 (SD)° (n = 12 pairs and
ROIs). Individual, i.e., ROI-specific, results for
10 V are listed in Table
1. 10 V showed no
correlation to the
FETO2
at which they were determined
(R2 = 0.001).
3He-MRI-based determination of
FROIO2.
Instantaneous fractional
[O2] during the third
second of an inspiratory breath hold, determined from extrabronchial
ROIs of two-dimensional 3He images
of the lungs
(FROIO2),
correlated with the FETO2
measured immediately preceding the apnea
(R = 0.879; P < 0.0001). Figure
5 demonstrates the data points of
individual animals.
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, e.g., wall relaxation,
to signal destruction was very small.
The slope of the regression line of 0.90, on the other hand, indicates
that
FROIO2,
which had been determined after one
3He-containing breath, appeared
systematically lower than the
FETO2 measured during steady-state
3He-free ventilation (Fig. 5). The
reduction of alveolar gas concentrations by
3He admixture, estimated in
METHODS to be ~8%, would appear in the regression as an increase of the slope to 0.98 without changing the
y-intercept or the correlation coefficient.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study confirms the O2 dependence of longitudinal nuclear spin relaxation time T1 of 3He in vivo and shows that this effect can be used to determine instantaneous, regional [O2] within the respiratory tract. The results are based on the feasibility of administering measured amounts of hyperpolarized 3He reproducibly within single inspirations; this allowed us to follow quantitatively, by MRI, the temporal evolution of 3He hyperpolarization within the lungs.
Application of hyperpolarized 3He in MRI. Hyperpolarized 129Xe or 3He gas can be visualized by MR techniques. Static imaging of the bronchopulmonary airspace has already been demonstrated in animals (1, 15), human volunteers, and patients (10). At relatively low grades of hyperpolarization (5-20%), 3He has also been administered during controlled ventilation to be visualized by repetitive ventilator cycle-gated image acquisition (3). This was performed during 10-40 inspirations to increase overall signal intensity and to compensate for O2-dependent signal attrition in vivo.
We use, instead of the common Rb exchange polarization (4), so-called metastability exchange optical pumping of 3He (5), which is highly efficient in terms of rate, as well as grade, of hyperpolarization. Meanwhile, 35-45% hyperpolarized 3He is achieved routinely (7). We have developed special storage and transport techniques, which preserve longitudinal relaxation time T1 up to 120 h (9). High-grade hyperpolarization allows the imaging of single inspired 3He volumes with high SNR (2, 7, 10, 11). The relaxation time constant T1 of hyperpolarized 3He due to O2, which has been quantified in vitro by Saam et al. (20), will recover on an average of ~14 s within the lungs of volunteers breathing air to up to 36 s if two to four large tidal volumes of N2 or 4He are inhaled to wash out O2 before 3He inhalation (2). For clinical purposes, particularly in sick patients, however, anoxic flushing of the lungs followed by prolonged apnea is not feasible. A prerequisite for patient studies was, therefore, to develop a method of reproducible tracer-gas administration. It should allow a timed, quantitative 3He delivery into any portion of a vital capacity inspiration, be independent of the mode of respiration or ventilatory support, and cause minimal loss of hyperpolarization during administration, and O2 effects should be quantifiable. This has been accomplished with sufficient accuracy and precision by our prototype computer-controlled, nonrelaxing gas control and delivery device. Thus this technique of exactly timed, flow-controlled administration of high-grade hyperpolarized 3He, as it is described here, is a new addition to functional MR imaging per se. Despite the use of comparably small 3He amounts, a good SNR can be achieved from the upper airways to the alveolar space. This technique may better accommodate patients with pulmonary disease and may be less prone to motion artifacts than prolonged repetitive imaging, as required by the method of Black et al. (3). For instance, very fast imaging sequences may eventually allow the clinician to analyze the distribution of ventilation in patients with lung disease without radiation exposure, at a temporal resolution in the range of 100-150 ms/image and a spatial resolution of 2-3 mm.Intrapulmonary O2 measurement. O2 confounds morphological interpretation of MR images of airspaces, filled with partially hyperpolarized 3He. In a first step, we had designed a device for automated 3He application to reduce random O2 effects, because 3He volume, hyperpolarization grade, time of exposure to relaxing environments, and placement in the respiratory tract could be kept fairly reproducible. By producing the highest grade of hyperpolarization obtainable and preserving it as well as possible before administration, our goal was to reduce the inspired amount of indicator gas to minimize its disturbance of the observed system. The applicator device, together with high-grade 3He hyperpolarization and appropriate MRI sequences, enabled us to use the O2-T1 relationship for [O2] measurements in vivo.
Because it was decided to use MR and respirator equipment already certified for human studies, we chose a large-animal model that could be accommodated by a similar setup and, in particular, the transmit-receive coil. Adolescent pigs were selected for several reasons. Anatomic dimensions and respiratory characteristics are closer to human conditions than those of small animals. Distribution of ventilation is well studied in pigs, its temporal heterogeneity is known to be small (18), and there is lack of collateral ventilation (19). Numerous technical and physiological factors may be responsible for the residual variance of FROIO2, which is not explained by FETO2 in our study. In this first series, we compared respiratory gas samples expired from the entire alveolar space with the MRI data derived from one imaged coronal slice. At this stage, we did not aim for maximum resolution but sought to demonstrate, in principle, the feasibility of image-based O2 measurement within the lungs. Comparability of the data sets from the two measurement techniques is limited, first and foremost, by our present two-dimensional imaging technique, which provides only one slice for analysis. The required large SNR restricted analysis further, i.e., to ROI instead of total lung cross sections. We, therefore, selected rather large ROI with normally distributed signal intensity histograms, which allowed us then to average signal intensities of all pixels within these ROI and to determine a mean FROIO2. Because high SNRs will represent predominantly areas with good local ventilation (high 3He content), a selection bias toward well-ventilated regions may be expected; possibly, it is reflected in the residual 2-3% overestimation of FETO2 by our MR-derived mean FROIO2. On the other hand, exclusion of low-signal regions gives also some preference to zones containing low PAO2, where signal intensity in the second image of a pair is preserved somewhat better. The net effect of this selection bias remains unclear at present and may differ depending on FIO2. Mixing of the steady-state PAO2 that existed in a ROI before the 3He breath with the inspired 3He bolus introduces systematic error that is unavoidable with our present application technique. The size of this systematic error depends on the relation of the indicator gas volume to its intrapulmonary volume of distribution. From our results, we estimate it to be 8-10% in our study. Within a single inspiration, regional distribution of the inspired air-O2 mixture, as well as an interposed indicator gas bolus, should all be governed by the regional distribution of flow resistances. The within-breath range of FIO2 resulting in peripheral airways from the bolus technique of 3He administration, however, has not been determined with our system, but we assume that the relative admixture of 3He into regional alveolar gas does not vary so widely as to explain the entire variance observed. Indicator gas and respiratory gas distribution and mixing may differ, however, if transitions to turbulent flow occur in different regions for 3He and the air-O2 mixture. Such variation may increase with regional inhomogeneity of ventilation and may explain part of the variance of FROIO2 found in our series, which is much larger than that possible from ventilation-perfusion (
A/
) heterogeneity alone. On the other hand, in healthy supine beagle dogs ventilated with
He-O2 or air or
SF6-O2,
gas-composition-related flow characteristics have not been found to be
major determinants of intrapulmonary gas transport (21), and diffusive
gas transport appeared to overwhelm small differences in convective gas
transport. Also, in our study, images were obtained during breath holds
of 
1 s. In pilot experiments, we have performed ultrafast MR imaging
of an 80-ml 3He bolus followed by
air tidal volumes into a lung phantom (500-ml silicone bag); at the end
of a 0.8-s inspiration, MR signal distribution within the bag was
already homogeneous (unpublished data). This suggests that gas mixing
in the alveolar space may have also been complete during imaging.
At any rate, because of its lower mass density and higher diffusivity,
He will be the least affected of all indicator gases by regional
differences in the distribution of ventilation. Theoretically, dilution
of "true" PAO2 could
be prevented by ventilation to a steady state of gas exchange with a
mixture of He, O2, and air and
then performing inspirations containing hyperpolarized 3He with unchanged
FIO2. Rapid relaxation of
hyperpolarization during the time spent in an
O2-containing mixing chamber makes this approach technically difficult, and ventilation with a
He-containing gas mixture would also constitute some deviation from
normal physiological conditions.
The decrease in PAO2 during
the imaging breath hold also enters the measurements, as outlined in
METHODS. Thus variability in
instantaneous O2 uptake among
imaging series as well as among the ROIs may also have influenced our
results, although this source of error may be minor in anesthetized
animals during breath-hold periods of only 2-4 s. It illustrates,
however, that instantaneous FROIO2
at the beginning of an inspiratory breath hold, even if measured
with perfect accuracy and precision, will be different from
PAO2 in a lung region or
compartment, as determined by techniques measuring in a steady state of
ventilation and perfusion (e.g., multiple inert-gas-elimination technique).
Several other determinants of regional
A/ ratio, e.g.,
topography, anteroposterior gradients of perfusion and ventilation, and
oxygenation itself, may have varied with each acquisition and region.
For instance, the supine position used in this series may have slightly
reduced the uniformity of
A/ distribution; on the
other hand, the two-dimensional, coronally oriented ROI contained both
ventral and dorsal areas and their respective, more or less uniform
contributions to measured end-expiratory O2. Although we studied healthy
animals, additional influences known to increase
A/ mismatch, like
anesthesia, positive-pressure ventilation, and neuromuscular paralysis,
were also present in our experiment. Under these circumstances,
FETO2
is never devoid of contributions from under- or nonperfused alveoli and will, therefore, fail to reflect "ideal"
PAO2 (17) as well as
PAO2 of an arbitrarily
selected ROI.
It was thus to be expected that
FROIO2,
when determined in ROIs of variable size and location, varies intra-
and interindividually but should maintain a fair overall correlation to
global
FETO2.
Our data from these experiments confirm, however, that
[O2] in lung regions
of a large animal model can, in principle, be determined from the decay
of 3He hyperpolarization.
Variability of regional intrapulmonary
[O2] due to regional
heterogeneity in pulmonary ventilation and perfusion may well
contribute to the rather large variance observed, but one would expect
its range to be smaller than that seen in our experiment. In resting
healthy subjects, in whom contamination by low
A/ alveoli or gas from
alveolar dead space is likely to be minimal, end-expiratory
PO2 can be assumed to approximate mean alveolar values, whereas a widened scatter of
A/ ratios, and hence
local PAO2 (16), is
characteristic of pathological conditions like chronic obstructive lung
disease, emphysema, or asthma (23). To date, there is no reference
laboratory method or clinically applicable technique to measure true
PAO2 regionally and to
resolve its scatter. Further development of the method described in
this paper into a technique of high-resolution PO2 mapping might have the potential
for application to a broad range of human pulmonary diseases.
At the present stage, however, interpretation of our results still has
to take several physical and technical limitations into account. The
in-plane spatial resolution physically attainable with our present
imaging system is in the order of 1-2
mm2. The minimum ROI size for
O2 determination, on the other
hand, depends critically on the SNR obtained. Sufficient
3He entry, i.e., at least a
minimum of regional ventilation, is of course a prerequisite. SNR then
improves for a given voxel size with the degree of
3He hyperpolarization, i.e., with
higher spin density. High hyperpolarization allows the reduction of the
amount of inhaled 3He, thus
improving the accuracy of
PAO2 determination, and the
voxel size, thus improving spatial resolution. Presently, 50%
hyperpolarization is attainable on a regular basis with our system.
Loss of hyperpolarization by RF excitation and
O2 relaxation will be accompanied
by simultaneous signal intensity changes of other origin: diffusion of
He into and out of the volume of acquisition will occur but may be
restricted in peripheral lung parenchyma because of the absence of
large conductive airways and also, in the porcine species, of
collateral ventilation (19). Resolution will be affected further by
both [O2] and
3He diffusion, because effective
T1 depends on all
local [O2], which are
encountered by hyperpolarized 3He
atoms during the observation period. Relaxation by bronchoalveolar surface contact, on the other hand, has not appeared as a significant contributor to T1
reduction, suggested by the very small
y-intercept in our correlation (Fig.
5), as well as by findings in
O2-depleted pig lungs (6).
Inspired 3He dilutes alveolar
[O2] depending on the
3He amount, distribution of
ventilation, and lung volumes. The latter are known to change during
anesthesia and artificial ventilation and during inspiratory hold.
Because FRC was not measured, reduction of
FETO2
by dilution with the tracer gas was estimated only. The numerical
effect of this correction on the slope of regression lines in Fig. 5
suggests that dilutional effects are likely and that the
FETO2
measured before breath hold overestimated the
3He-diluted
FETO2,
which would have been expired at the time of imaging. Ongoing
O2 uptake and inert-gas
concentration due to alveolo-capillary
O2 transfer during the 2-4 s
of apnea may have added to this bias. In the phantom experiment
mentioned above, MR analysis of the
air-3He mixture in the respirator
bag yielded a PO2 of
0.195 bar, with a PO2 of 0.193 bar
determined by gas analyzer (6).
Another source of artifact, suggested by observations during
fast-inspiratory imaging sequences, is inadvertent replenishment of
hyperpolarized 3He from outside
the target volume during acquisition. This may occur either by
3He convection along airways or by
movement of 3He-containing lung
tissue into the imaged slice with cardiac oscillation or with
relaxation of compressed respirator tubing. Particularly during imaging
of thin two-dimensional partitions, convective and diffusive movement
of gas or the lung itself into and out of the imaged slice, despite the
inspiratory hold, appears as an important source of error. In
two-dimensional studies as this, this effect may limit the reduction of
slice thickness and, hence, spatial resolution. This effect has also
been studied by our group (6). Multislice two-dimensional imaging or
three-dimensional imaging with simultaneous excitation of all spins may
solve this problem in the future and may permit regional
O2 determinations in lung volumes
of 1-2 cm3.
Finally, some signal intensity variation from RF coil inhomogeneity
constitutes another possible source of error. To eliminate these
shortcomings, a detailed MR physical error analysis is presently under
way, an improved transmit-receive coil has already been constructed and
tested, and appropriate three-dimensional imaging sequences are being developed.
In summary and perspective, our study shows that
3He-MRI holds promise as a
functional imaging technique to analyze the regional distribution not
only of ventilation but also of
[O2] within the lungs.
Its potential spatial and temporal resolution in the range of cubic
millimeters and seconds, its noninvasiveness, and the almost
unrestricted repeatability of the measurements appear as possible
advantages over present techniques based on radiography, radioisotopes,
microspheres, or aerosols. The method may eventually contribute to the
resolution of O2 kinetics within
functional lung units and help to identify regions of
A/ mismatch in diseased lungs.
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ACKNOWLEDGEMENTS |
|---|
This work was funded by Deutsche Forschungsgemeinschaft Grant TH 315/8-1; by Innovationsstiftung Rheinland-Pfalz, Mainz, Germany; and by Institut für Diagnostikforschung, Berlin, Germany.
| |
FOOTNOTES |
|---|
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. §1734 solely to indicate this fact.
1 One amagat (1 ag) = gas density/(2.68675 × 1019 molecules/cm3).
Address for reprint requests and other correspondence: B. Eberle, Dept. of Anesthesiology, Johannes Gutenberg Univ., School of Medicine, Langenbeckstr. 1, D-55131 Mainz, Germany (E-mail: eberle{at}anaesthesie.klinik.uni-mainz.de).
Received 2 October 1998; accepted in final form 3 August 1999.
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TOP
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METHODS
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DISCUSSION
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