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Meeting Abstracts  |   October 1995
Fluorine-19 Nuclear Magnetic Resonance Imaging and Spectroscopy of Sevoflurane Uptake, Distribution, and Elimination in Rat Brain
Author Notes
  • (Xu) Assistant Professor of Anesthesiology/Critical Care Medicine and Pharmacology.
  • (Tang) Research Assistant Professor of Anesthesiology/Critical Care Medicine.
  • (Zhang) NMR Spectroscopist, Pittsburgh NMR Center for Biomedical Research and the Department of Biological Sciences, Carnegie Mellon University.
  • (Firestone) Associate Professor of Anesthesiology/Critical Care Medicine.
  • (Winter) Professor of Anesthesiology/Critical Care Medicine.
  • Received from the Departments of *Anesthesiology and Critical Care Medicine and of Pharmacology, University of Pittsburgh, and the Pittsburgh NMR Center for Biomedical Research and the Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania. Submitted for publication August 4, 1994. Accepted for publication May 9, 1995. Supported by a seed grant (to Y.X.) from the University Anesthesiology and Critical Care Medicine Foundation. The Pittsburgh NMR Center for Biomedical Research is supported by a grant from the National Institutes of Health (RR-03631). The Richard King Mellon Foundation, the Lucille Markey Charitable Trust, the Ralph M. Parsons Foundation, and the Ben Franklin Partnership Program of the Commonwealth of Pennsylvania provided financial support for the establishment of the Pittsburgh NMR Center for Biomedical Research. Presented in part at the annual meetings of the Society of Magnetic Resonance in Medicine, New York, New York, August 16-20, 1993, and the American Society of Anesthesiologists, Washington, D.C., October 10-13, 1993.
  • Address reprint requests to Dr. Xu: Department of Anesthesiology, University of Pittsburgh, W-1358 Biomedical Science Tower, Pittsburgh, Pennsylvania 15261. Address electronic mail to: y_xu@poplar.anes.upmc.edu.
Article Information
Meeting Abstracts   |   October 1995
Fluorine-19 Nuclear Magnetic Resonance Imaging and Spectroscopy of Sevoflurane Uptake, Distribution, and Elimination in Rat Brain
Anesthesiology 10 1995, Vol.83, 766-774.. doi:
Anesthesiology 10 1995, Vol.83, 766-774.. doi:
Methods:19F NMR imaging and spectroscopy were conducted at 4.7 Tesla using a specially developed NMR probe and new imaging methods. With the new techniques, it was possible to observe directly the uptake, distribution, and elimination in brain of sevoflurane, a fluorinated general anesthetic with special advantages for NMR investigations.
Results:19F NMR images, acquired at different times after sevoflurane administration, clearly showed the distribution of a fluorinated general anesthetic within the brain. Based on continuous transverse relaxation time measurements, sevoflurane signals could be separated into two components, attributable respectively to sevoflurane in a mobile or immobile microenvironment. During washin, there was a delayed accumulation of anesthetic in the mobile microenvironment. During washout, there was a rapid elimination from the immobile microenvironment.
Conclusions: At anesthetizing concentrations, sevoflurane distributes heterogeneously in the brain. Sevoflurane in the brain tissue contributes mostly to the immobile component of the19Fluorine signal, whereas that in the surrounding adipose and muscle tissues contributes mostly to the mobile component. Imaging and spectroscopic results suggest that the immobile component of sevoflurane is associated with the general anesthetic effects of the agent.
Key words: Anesthetic action. Anesthetics, volatile: sevoflurane. Measurement techniques: magnetic resonance imaging; spectroscopy. Pharmacokinetics.
THEORIES of mechanisms of general anesthesia have engendered considerable debate but limited agreement. [1-4] A systematic approach to elucidating these mechanisms would require investigations at three interrelated levels [5,6] : macroscopic studies of spatial or anatomic distribution of general anesthetics to identify central nervous system (CNS) sites of action; microscopic studies of cellular and subcellular distributions of general anesthetics to identify cellular sites of action; and molecular studies of interactions between anesthetic molecules and membrane constituents (lipids and proteins) to identify molecular sites of action.
Many inhalational general anesthetics are fluorinated. Fluorine-19 (sup 19 Fluorine) magnetic resonance spectroscopy (MRS) and imaging (MRI) can be used for investigations of such anesthetics at all three levels. (sup 19 Fluorine is the fluorine isotope that is 100% naturally abundant.) Because fluorinated compounds are present only at trace levels in living systems, the imaging of exogenously administered fluorinated anesthetics against a "silent background" permits direct visualization of the spatial distribution of anesthetics in the CNS. Similarly, MRS measurements of19Fluorine chemical shifts and relaxation time constants, T1and T2, permit detailed analyses of the microenvironments of these agents. (Definitions and details of MRI and MRS methodology are reviewed in the Appendix.) The feasibility of applying19Fluorine nuclear magnetic resonance (NMR) techniques in humans [7,8] was demonstrated after an earlier in vivo animal study. [9] These investigations created the hope that19F-NMR would become useful for noninvasive assessment of general anesthetic action. [10-18] 
Earlier attempts of imaging halothane distribution [12,19] produced only silhouettes of the brain. Brain tissue could not be detected with sufficient signal, because the transverse relaxation time, T2, of19Fluorine magnetization in brain tissue is extremely short (approximately 3 ms), and because there is substantial accumulation of halothane in extracranial muscle and fat, where T2is long.19F MRS studies of uptake and elimination of fluorinated anesthetics have been controversial [9-11,13,14,20,21] because of somewhat ambiguous spatial localization of the signals detected with a surface coil, the receiver most commonly used in vivo. To overcome limitations of previous studies, we made technologic improvements that allow for direct measurements of macroscopic and molecular distributions of fluorinated anesthetics in the brain. Studies were performed using sevoflurane (fluoromethyl 2,2,2-trifluoro-l-[trifluoromethyl] ethyl ether, CH2F-O-CH(CF3) sub 2), [22-26] a fluorinated anesthetic having especially favorable properties for NMR detection.
In a sevoflurane molecule, six of seven19Fluorine nuclei, those in the two trifluoromethyl groups, are magnetically identical. This causes one molecule of sevoflurane to have an NMR resonance peak with twice the signal intensity that occurs in toto for a single molecule of halothane. Thus, if the same number of sevoflurane, halothane, or isoflurane molecules were present at a critical site in the brain, sevoflurane would give rise to twice as strong an NMR signal from the trifluoro-methyl chemical group. Moreover, animals appear to tolerate higher doses of sevoflurane better, without the severe depression of cardiac output that is found with halothane anesthesia.*,**,*** Because sevoflurane can give rise to twice as much enhancement in NMR intensities as halothane or isoflurane for the same increase in dosage (in terms of minimum alveolar concentration multiples), imaging with sevoflurane at higher doses facilitates the capture of rapidly decaying signals in brain tissue and thereby improves the signal-to-noise ratio.
This study used new spectroscopic and imaging techniques to minimize signal loss from the short T2of19Fluorine in the brain. Images obtained at various times after the onset of sevoflurane administration showed the spatial distributions of the anesthetic in brain tissue. T2measurements were made during sevoflurane uptake and elimination to separate washin and washout kinetics that were specific for each T2component. Because T2depends on the microenvironment of the anesthetic (see Appendix), T2-specific washin and washout kinetics can help differentiate each microenvironment. As suggested in an earlier study, [27,28] the short T2microenvironment was associated with the production of general anesthesia.
Methods and Materials
Animal Preparation
All animal protocols were approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh. Adult, male Sprague-Dawley rats weighing 250-300 g were anesthetized with 55 mg/kg sodium pentobarbital subcutaneously, after which the trachea was nontraumatically intubated. The lungs were ventilated with 100% Oxygen2using a rodent ventilator (Model 683, Harvard Apparatus, Boston, MA) at 60 strokes/min. When the first sign of awakening from pentobarbital anesthesia was observed, sevoflurane administration was started at a predetermined dose (4-10% in oxygen), and the time was arbitrarily designated as zero. A calibrated sevoflurane vaporizer (Ohmeda Sevotec 3, BOC Health Care, England) was used in conjunction with a Vetroson small animal anesthesia machine (Model 6610, Summit Hill Laboratories, Navesink, NJ). Pancuronium was given intraperitoneally for neuromuscular blockade, at a dose of 1 mg initially and at 0.25 mg every 2 h thereafter. Uptake of sevoflurane was terminated at a designated time (2.5-85 min), either by discontinuing anesthetic administration or by a 1-ml intracardiac bolus injection of 4 M KCl to induce cardiac arrest. The former method was used for continuous observation of sevoflurane washout, whereas the latter was used to image the anesthetic distribution at specific time. Animals were placed prone in all experiments. A heating pad maintained a body temperature of 37 degrees Celsius.
NMR Methods
All experiments were carried out at the Pittsburgh NMR Center for Biomedical Research, using a 4.7-Tesla, 40-cm horizontal bore Bruker BIOSPEC NMR spectrometer. The resonance frequency for19Fluorine was 188.316 MHz. Definitions and details of NMR methodology are contained in the Appendix. The NMR detection coil, a home-built, 12-element birdcage resonator tunable to1Hydrogen and19Fluorine, was used for most MRI and MRS experiments. A single-turn, 2 cm-diameter, surface-coil probe was used in selected experiments to confine the imaging volume to the brain. A three-dimensional (3D) Fourier transform (FT) imaging sequence and a two-dimensional (2D) FT imaging sequence, both with an echo time, TE, of 1.7 ms, were developed and used to minimize brain signal loss due to short T2. Continuous T2relaxation measurements were made during washin and washout. Each complete T2measurement, consisting of 16 or 18 TE values ranging from 200 micro second to 200 ms, was best fit using Equation 2to determine the washin and washout kinetics that were T2-specific.
Results
(Figure 1(left)) shows three representative19Fluorine head images, acquired at 2.5, 7.5, and 62 min, respectively, after the onset of sevoflurane administration. Corresponding1Hydrogen images (right) are also shown for anatomic reference. The19Fluorine image at 2.5 min was the sum of five coronal slices of a three-dimensional image, and the other two19Fluorine images were acquired using the two-dimensional sequence shown in Figure 1(A) in the Appendix. The B1inhomogeneity seen in the uppermost1Hydrogen image arose because the probe was not returned to the1Hydrogen frequency.
Figure 1. Representative19Fluorine head images (left) at 2.5 (top), 7.5 (middle), and 62 (bottom) min, respectively, after the onset of sevoflurane administration. Corresponding1Hydrogen images (right) are displayed for anatomic reference. The19Fluorine image at 2.5 min was the sum of five coronal slices of a three-dimensional data set, which had a final size of 128 x 128 x 32 and a field of view (FOV) of 4 x 4 x 4 cm3. The other two19Fluorine images were obtained using the two-dimensional sequence of Figure 5in the Appendix, with a slice thickness of 7 mm and an FOV of 6 x 6 cm2.
Figure 1. Representative19Fluorine head images (left) at 2.5 (top), 7.5 (middle), and 62 (bottom) min, respectively, after the onset of sevoflurane administration. Corresponding1Hydrogen images (right) are displayed for anatomic reference. The19Fluorine image at 2.5 min was the sum of five coronal slices of a three-dimensional data set, which had a final size of 128 x 128 x 32 and a field of view (FOV) of 4 x 4 x 4 cm3. The other two19Fluorine images were obtained using the two-dimensional sequence of Figure 5in the Appendix, with a slice thickness of 7 mm and an FOV of 6 x 6 cm2.
Figure 1. Representative19Fluorine head images (left) at 2.5 (top), 7.5 (middle), and 62 (bottom) min, respectively, after the onset of sevoflurane administration. Corresponding1Hydrogen images (right) are displayed for anatomic reference. The19Fluorine image at 2.5 min was the sum of five coronal slices of a three-dimensional data set, which had a final size of 128 x 128 x 32 and a field of view (FOV) of 4 x 4 x 4 cm3. The other two19Fluorine images were obtained using the two-dimensional sequence of Figure 5in the Appendix, with a slice thickness of 7 mm and an FOV of 6 x 6 cm2.
×
To visualize the intracranial, regional distribution of sevoflurane, a localizing surface-coil probe was placed closely above the head. The radiofrequency pulse length was preadjusted, using a spherical phantom, to have a maximum excitation profile about 7 mm from the center of the coil. Figure 2(a) shows a representative coronal slice from a three-dimensional image after a 10-min administration of 7% sevoflurane; an anatomic reference appears in Figure 2(b).
Figure 2. (a) A representative surface coil19Fluorine image showing detailed distribution of sevoflurane in a rat brain. (b) An anatomic schematic for (a). The frames and lines are added as reference marks only and are not the margins of FOV. CC = corpus callosum; CS = superior colliculus; FD = dentate gyrus (Fascia dentata); FH = hippocampal fissure; HPC = hippocampus; LM = medial lemniscus; NCP = bed nucleus of the posterior commissure; TCS = corticospinal tract.
Figure 2. (a) A representative surface coil19Fluorine image showing detailed distribution of sevoflurane in a rat brain. (b) An anatomic schematic for (a). The frames and lines are added as reference marks only and are not the margins of FOV. CC = corpus callosum; CS = superior colliculus; FD = dentate gyrus (Fascia dentata); FH = hippocampal fissure; HPC = hippocampus; LM = medial lemniscus; NCP = bed nucleus of the posterior commissure; TCS = corticospinal tract.
Figure 2. (a) A representative surface coil19Fluorine image showing detailed distribution of sevoflurane in a rat brain. (b) An anatomic schematic for (a). The frames and lines are added as reference marks only and are not the margins of FOV. CC = corpus callosum; CS = superior colliculus; FD = dentate gyrus (Fascia dentata); FH = hippocampal fissure; HPC = hippocampus; LM = medial lemniscus; NCP = bed nucleus of the posterior commissure; TCS = corticospinal tract.
×
The19Fluorine signals of sevoflurane in the rat head contained two T2components. Nonlinear regression of T2measurements using multiple-exponential decay functions of TE produced two different time constants, with T2fastin the range of 3-5 ms and T sub 2slow in the range of 105-130 ms. Typical examples of such regressions using Equation 2are given in Figure 3(A). The percentages of the two T2components in the total intensity depended on the receiver coil used and on the uptake time. The insert to Figure 3(A) compares the T sub 2 relaxation measured with the birdcage coil and with the surface coil on the same animal, which was killed 6.5 min after the sevoflurane administration. Clearly, the surface coil detected a higher percentage of the T2fastcomponent than did the birdcage coil. This remained true during the course of uptake.
Figure 3. (A) (Main plot) Representative T2relaxation measurements of whole head using the birdcage coil. The measurements were made at 2.5 (open triangle), 7.5 (open square), and 62 (open circle) min, respectively, after beginning sevoflurane uptake. The relative signal intensities, in arbitrary units, are plotted as a function of spin-echo time. The decays of the overall intensity are best fit by biexponential functions of Equation 2in the Appendix, yielding two time constants in the ranges of T2fast= 3 [nearly equal] 5 ms and T2slow= 105 approximately 130 ms. (Insert) Comparison of T2relaxation measured with birdcage head probe ([diamond]) and surface coil probe ([diamond]). Measurements were made on the same animal killed 6.5 min after the sevoflurane administration. (B) The percentage of T2fastcomponent in the total intensity is plotted as a function of uptake time. The 12 rats studied are denoted by the different symbols on the plot. Each point on the plot resulted from nonlinear regressions of 16 or 18 spin-echo measurements with different TE values, similar to those shown in A. Note the logarithmic scale on the ordinate and the difference in the two slopes. (C) A typical sevoflurane uptake curve in the head region measured with the birdcage coil. The total sevoflurane intensity (closed cirle) and the T2slowcomponent (open circle) did not plateau within the time range used in the study, but the T2fastcomponent (open square) did.
Figure 3. (A) (Main plot) Representative T2relaxation measurements of whole head using the birdcage coil. The measurements were made at 2.5 (open triangle), 7.5 (open square), and 62 (open circle) min, respectively, after beginning sevoflurane uptake. The relative signal intensities, in arbitrary units, are plotted as a function of spin-echo time. The decays of the overall intensity are best fit by biexponential functions of Equation 2in the Appendix, yielding two time constants in the ranges of T2fast= 3 [nearly equal] 5 ms and T2slow= 105 approximately 130 ms. (Insert) Comparison of T2relaxation measured with birdcage head probe ([diamond]) and surface coil probe ([diamond]). Measurements were made on the same animal killed 6.5 min after the sevoflurane administration. (B) The percentage of T2fastcomponent in the total intensity is plotted as a function of uptake time. The 12 rats studied are denoted by the different symbols on the plot. Each point on the plot resulted from nonlinear regressions of 16 or 18 spin-echo measurements with different TE values, similar to those shown in A. Note the logarithmic scale on the ordinate and the difference in the two slopes. (C) A typical sevoflurane uptake curve in the head region measured with the birdcage coil. The total sevoflurane intensity (closed cirle) and the T2slowcomponent (open circle) did not plateau within the time range used in the study, but the T2fastcomponent (open square) did.
Figure 3. (A) (Main plot) Representative T2relaxation measurements of whole head using the birdcage coil. The measurements were made at 2.5 (open triangle), 7.5 (open square), and 62 (open circle) min, respectively, after beginning sevoflurane uptake. The relative signal intensities, in arbitrary units, are plotted as a function of spin-echo time. The decays of the overall intensity are best fit by biexponential functions of Equation 2in the Appendix, yielding two time constants in the ranges of T2fast= 3 [nearly equal] 5 ms and T2slow= 105 approximately 130 ms. (Insert) Comparison of T2relaxation measured with birdcage head probe ([diamond]) and surface coil probe ([diamond]). Measurements were made on the same animal killed 6.5 min after the sevoflurane administration. (B) The percentage of T2fastcomponent in the total intensity is plotted as a function of uptake time. The 12 rats studied are denoted by the different symbols on the plot. Each point on the plot resulted from nonlinear regressions of 16 or 18 spin-echo measurements with different TE values, similar to those shown in A. Note the logarithmic scale on the ordinate and the difference in the two slopes. (C) A typical sevoflurane uptake curve in the head region measured with the birdcage coil. The total sevoflurane intensity (closed cirle) and the T2slowcomponent (open circle) did not plateau within the time range used in the study, but the T2fastcomponent (open square) did.
×
As the uptake time increased, the ratio of the two T2components changed. Figure 3(B) depicts, on a log scale, IT2fast(t)/Itotal(t) x 100% (see Appendix) as a function of sevoflurane uptake time (t). Twelve rats, denoted by different symbols in Figure 3(B), were measured with the birdcage or the surface coil or both. Although the total19F-NMR intensity in the rat head increases with increasing uptake time (Figure 3(C)), the percentage of the T2fastcomponent contributing to the total intensity decreases exponentially (linear on the semi-log plot seen in Figure 3(B)). For example, the T2fastcomponent contributes initially to almost 60% of the total19F NMR signal intensity in the head, as measured with the birdcage head coil (or 82%, as measured with the 2 cm-diameter surface coil). Ninety minutes later, this contribution decreased to less than 28% when measured with the birdcage coil (or to approximately 55% with the surface coil).
(Figure 4) depicts typical NMR washout data for three rats after 67-89 min of 4% sevoflurane general anesthesia. Total NMR signal intensities, normalized by initial values for each washout, were decomposed using Equation 2to provide the elimination kinetic constants for the T2fastand T2slowcomponents. Solid lines show best fits with single- or double-exponential functions. Note that the washout of the T2fastcomponent, which constitutes 25% of the total intensity at the beginning of the washout process, is single-exponential and occurs at a faster rate than that of the T2slowcomponent, which washes out at two different rates.
Figure 4. Anesthetic washout after 67-89 min of 4% sevoflurane general anesthesia. The total wash-out intensity (closed circle) at each time is weighted by the percentage of T2fastand T2slowcomponents at that time, resulting in separate elimination kinetics for the T2fast(open square) and T2slow(open circle) components. The solid lines are best fit to the data with single- or double-exponential functions, yielding elimination rate constants: kf= 0.053 plus/minus 0.004 min sup -1, ks1= 0.046 plus/minus 0.009 min sup -1, and ks2= 0.007 plus/minus 0.001 min sup -1.
Figure 4. Anesthetic washout after 67-89 min of 4% sevoflurane general anesthesia. The total wash-out intensity (closed circle) at each time is weighted by the percentage of T2fastand T2slowcomponents at that time, resulting in separate elimination kinetics for the T2fast(open square) and T2slow(open circle) components. The solid lines are best fit to the data with single- or double-exponential functions, yielding elimination rate constants: kf= 0.053 plus/minus 0.004 min sup -1, ks1= 0.046 plus/minus 0.009 min sup -1, and ks2= 0.007 plus/minus 0.001 min sup -1.
Figure 4. Anesthetic washout after 67-89 min of 4% sevoflurane general anesthesia. The total wash-out intensity (closed circle) at each time is weighted by the percentage of T2fastand T2slowcomponents at that time, resulting in separate elimination kinetics for the T2fast(open square) and T2slow(open circle) components. The solid lines are best fit to the data with single- or double-exponential functions, yielding elimination rate constants: kf= 0.053 plus/minus 0.004 min sup -1, ks1= 0.046 plus/minus 0.009 min sup -1, and ks2= 0.007 plus/minus 0.001 min sup -1.
×
Discussion
The19F NMR images in Figure 1and Figure 2are the first to show in vivo detection of anesthetic distributions in brain parenchyma. Almost immediately after beginning administration of the anesthetic, sevoflurane is seen mostly in the brain tissue (Figure 1, top left). As uptake time increases, sevoflurane can be seen to accumulate in the surrounding muscle and fat (Figure 1, middle and bottom left). Note that the decrease in relative intensity in the brain region with increasing uptake time does not represent an absolute reduction in the total amount of sevoflurane in brain. Rather it represents a relative reduction due to slower accumulation of sevoflurane in the surrounding tissues. The sequence of images is consistent with perfusion-limited models of anesthetic uptake, [5] wherein saturation of the vessel-rich group (e.g., CNS) occurs significantly earlier than that in the vessel-poor group (fat). The surface coil images (Figure 2), with better image quality and partial localization to the brain, show nonuniform distribution of sevoflurane in brain tissue 10 min after the onset of sevoflurane administration. Corpus callosum and dentate gyrus occur in this image as relatively hypointense regions (compare Figure 2(a and b)). Detailed anatomic identification and quantitation of concentrations, however, will require improved image resolution.
The ability to conduct19F MRI of the brain has significant implications. For example, if fluorinated anesthetics were administered by microdialysis, one might use these new19F MRI techniques to visualize affected regions, so as to correlate anesthetic intensity with neurophysiologic effects. Another potential application of the new technique is to evaluate anesthetic distribution in the presence of cerebral blood flow abnormalities, e.g., slowed uptake after stroke or head injury.
Similar to results with halothane and isoflurane, [9-13] our data indicate that sevoflurane resides in at least two distinct microenvironments in the rat head, as characterized by the two T2time constants. The T2fastcomponent results from relatively immobile sevoflurane molecules, possibly bound to macromolecules. [29] In contrast, the T2slowcomponent results from relatively mobile sevoflurane molecules. Taken together, the early abundance of imaging intensity in the brain, the later change of the intensity to adipose tissue, and the shift in total signal distribution from the T2fastcomponent to the T2slowcomponent during uptake indicate that sevoflurane in brain tissue contributes primarily to the T2fastcomponent, whereas that in adipose tissue contributes primarily to the T sub 2slow component. This conclusion is consistent with the observations that partial localization with surface coil to the brain region results in a much higher percentage of T2fastthan that from the entire head (Figure 3(A)) and that the relative decrease in T2fastcomponent as a function of uptake time is less steep with the surface coil than with the head coil (compare the two slopes in Figure 3(B)).
Elimination of sevoflurane can be described phenomenologically using apparent first-order kinetics. [10,11] Thus, the overall rate of elimination can be characterized by the half time, t1/2: Equation 1where k is the apparent first-order elimination rate constant. By decomposing the total washout intensities based on the T2values, distinct washout kinetics were revealed for sevoflurane in different microenvironments in the rat head. From regions where sevoflurane is relatively immobile, as characterized by T2fast, the washout is single-exponential and has a t1/2 of 13 min. In contrast, in the relatively mobile environments, sevoflurane exhibits two washout rates, with t1/2 being 15 and 100 min, respectively. Thus, after 1 h of washout, sevoflurane is almost completely eliminated from the immobile environments (Figure 4); and after 2 h of washout, 99.8% of the total sup 19 Fluorine signal remaining in the rat head originates from the T2slowcomponent.
In vivo NMR measurements of halothane [10] and isoflurane [11] washout using surface coils showed that t1/2 depended on the size of coil used. This dependence was attributed to unequal sampling and weighting of various tissues by different coils. By reducing the coil size to focus on brain tissue, Litt et al. [10] and Mills et al. [11] estimated elimination rates of 34 min for halothane from rat brain and 36 min for isoflurane from rabbit brain, respectively. As pointed out by the same authors, these times are considerably longer than those (t1/2 [nearly equal] 18 min) estimated from meticulous but invasive studies using gas chromatography, [20] autoradiography, and radiochromatography. [30-32] In our washout studies, however, a homogeneous birdcage coil was used to sample the entire rat head, with equal weighting of all tissue types. Although the retention time of sevoflurane in the rat head may differ slightly from that of halothane or isoflurane, the general agreement between the elimination rate of the T sub 2fast component and that found invasively from brain tissue is striking. This agreement further confirms our earlier assessment that sevoflurane in brain tissue contributes mostly to the T2fastcomponent.
Based on the Meyer-Overton rule and minimum alveolar concentration additivity, [5] at equal minimum alveolar concentration doses, similar molar concentrations of anesthetic molecules must be present at crucial sites in the CNS where clinical anesthesia is produced. By a similar argument, recovery from general anesthesia would require elimination of general anesthetics from these sites. Our ability to separate "short-life" (T2fast) from "long-life" (T2slow) sevoflurane signals during uptake and elimination points to a new, noninvasive way to study the pharmacokinetics of anesthetic action. The parallel relationship between rapid awakening from sevoflurane anesthesia (data not shown) and the rapid elimination of the short-life (T2fast) component suggest that sevoflurane general anesthesia results from sevoflurane binding to certain macromolecules in the brain (although the T2measurements in this study cannot distinguish specific from nonspecific binding). Inter-molecular dynamic polarization transfer* between nuclei in anesthetic molecules and in brain tissue has the potential to reveal the specificity of binding.
In conclusion, this19F NMR study used newer techniques at a higher magnetic field to demonstrate the intracerebral spatial distribution of sevoflurane. Sevoflurane distribution in the brain is heterogeneous under the experimental conditions described. There are two anesthetic microenvironments, characterized respectively by T2fastand T2slow, which exhibit different elimination kinetics. Both MRI and MRS data suggest that the T2fastcomponent of sevoflurane is related to general anesthesia.
The authors thank Dr. Etsuro K. Motoyama, for providing a sevoflurane vaporizer for this study; Ken Lee Foon, for machining the parts of the tunable birdcage probe; Maryann Butowicz, for assisting in animal preparation; and Dr. Chien Ho and Dr. Alan Koretsky, for suggestions and discussion.
Appendix: Definitions and Details of NMR Methods
MRI and MRS exploit an intrinsic nuclear property called nuclear spin. In an external magnetic field, nuclei with non-zero spins are polarized to build up spin energy. This energy is usually too weak to detect individually. Signals measured in MRI and MRS result from the so-called resonance phenomenon, which requires that an ensemble of spins act coherently to absorb excitation energy established by a radiofrequency coil. In modern NMR technology, the coherence occurs in response to radiofrequency impulses and is often a complicated function of resonance frequency and the "lifetime" of the coherence. For a given nucleus, the resonance frequency (often expressed as "chemical shifts" relative to a standard frequency) is directly proportional to the magnetic field strength, B0. In an MRI experiment, B0can be systematically varied by magnetic field gradients (i.e., changes in field strength per unit distance) to register the spatial information. The lifetime of the coherence is characterized by two relaxation times: a longitudinal relaxation time (T1) measuring how fast the nuclear spin energy is converted into non-spin energies, collectively referred to as lattice energy, and a transverse relaxation time (T2) measuring how fast the excitation energy is interchanged among nuclear spins. The resonance frequencies and relaxation times characterize the molecular environments of the nuclei. In general, a long T2indicates a relatively free (or more mobile) microenvironment, whereas a short T2indicates a relatively bound (or less mobile) microenvironment.
Spin Echoes and Gradient Echoes
In addition to T2relaxation, external factors such as magnetic field inhomogeneity and magnetic field gradients can contribute to loss of coherence. As long as these external factors do not change randomly with time, the additional loss of coherence can be regained by reversing the effects of such factors. In a spin-echo, an inversion radiofrequency pulse (also called a 180 degrees pulse) is applied to reverse the sense of spin precession about the magnetic field. The resultant regain of coherence is called a spin-echo. The time duration from the beginning of coherence loss to the maximum refocusing is called the echo time, TE. If additional loss of coherence occurs because of the application of a magnetic gradient, a second gradient, of exactly the same amplitude but opposite in direction, is applied to cancel the effects of the first gradient. The resultant regain of coherence is called a gradient-recalled echo. The total time from the beginning of coherence to the refocusing is again denoted as TE. Spin-echo and gradient-recalled echo are sometimes combined to maximize the gain.
Pulse Sequence
An NMR pulse sequence is a series of magnetic field gradient pulses, radiofrequency pulses, delays, and data acquisitions (Figure 1(A)). The effect of radiofrequency pulses is to bring nuclear spins into detectable coherence. Delays between and after pulses allow spins to evolve under the influence of their microenvironments. Such influence is reflected in the spectra or images as changes in chemical shifts and relaxation times.
Magnetic field strength can strongly affect the nuclear environment. In MRI, the static field is systematically modulated by magnetic field gradients. Because the resonance frequency of a nucleus is proportional to the magnetic field sensed by that nucleus, a linear change in the field strength along a given direction will result in a proportional change in the resonance frequencies of the nuclei along the same direction. Thus, by applying field gradients, spatial information is converted (or encoded) into frequency information, which can be displayed as images by an NMR spectrometer.
The dimension of an image refers to the number of independent directions in which encoding takes place. A two-dimensional imaging sequence usually contains two independent encoding gradients: a phase-encoding and a frequency-encoding gradient. The selection of a two-dimensional slice for imaging is achieved conventionally by using a long-duration selective excitation pulse during a third gradient. This method works only when the lifetime of the coherence (T2) is significantly longer than the selective pulse duration. Otherwise, loss of coherence during the selective pulse leads to no signal for imaging. In this study, we used a new two-dimensional sequence (see below), which is insensitive to short T2losses. The new method differs from conventional ones in that the selective pulse is not for excitation but for inversion of the thermal equilibrium population. Images are constructed from spectral differences with and without the selective inversion, so that only the inverted slice is imaged. Another alternative to reducing the T2loss is to avoid the use of selective pulses entirely. A three-dimensional imaging sequence can achieve this by adding a third encoding direction into an otherwise two-dimensional sequence. Obviously, adding a dimension will increase the scan time significantly.
Probes
NMR probes are radiofrequency devices that operate analogously to the transceivers in radio communication. Probes are designed in several different configurations; the most frequently used in vivo are birdcage resonators and surface coils. A birdcage resonator is made of capacitors and wire segments (often called elements) arranged as a cylindrical cage with open ends. The radiofrequency magnetic field generated by a birdcage resonator, often denoted as B1, is perpendicular to the cylinder axis and is highly uniform inside the cylinder. A surface coil, on the other hand, uses a loop of wire for transmission and receiving. Its B1field is perpendicular to the plane of the loop and is confined to the region close to the coil. This partial localization increases the detection sensitivity of the surface coil. Its drawback is poor B1homogeneity.
Specific NMR Details for This Study
In this study, a three-dimensional gradient-recalled echo imaging sequence with a short TE was used to minimize signal loss due to the short T2of19Fluorine signals in the brain. In the three-dimensional sequence, a short but strong radiofrequency pulse was applied, followed by two phase-encoding gradients and a third frequency-encoding gradient. Because no long-duration shaped pulses were involved, the shortest TE achievable was governed by the switching time of the gradient units and by eddy-current effects in the volume of interest. A 15-cm diameter gradient insert for the 40-cm bore magnet was used to reduce TE to values as short as 1.7 ms. In a typical three-dimensional experiment, time-domain data were digitized into a three-dimensional matrix (of size 128 x 32 x 16 or 8), which was then zero-filled twice in the second dimension and once in the third dimension before Fourier transformation to reconstruct the three-dimensional images. The fields of view in the three dimensions were 4 x 4 x 4 cm3. For the three-dimensional imaging experiments with the birdcage probe, a variable number of data averaging (NA), having a Gaussian distribution with respect to the second gradient dimension, was used to reduce the total imaging time. Thus, a typical NA list used was 4, 6, 8, 12, 18, 26, 34, 44, 56, 70, 82, 96, 108, 116, 124, and 128, respectively, for blocks 1 through 16 of the second dimension and symmetrically for blocks 17 through 32. The repetition delay (RD) between scans was 1 s with four initial dummy scans.
The major drawback of the three-dimensional method is the long imaging time. Thus, the possibility of imaging anesthetic distribution in a single slice in the rat head was investigated. Conventional two-dimensional methods based on a selective slice excitation scheme have proved inadequate [12] because the long-duration selective excitation pulses are part of the TE period and the T2relaxation occurs inevitably during these pulses, leaving only diminishing signal for imaging. To minimize such T2losses, a new two-dimensional sequence, as shown in Figure 5, was developed and used. In this new sequence, a hyperbolic secant-shaped [33] selective inversion pulse was applied in alternating scans during a slice-selective gradient (Gslice) to prepare the magnetization for imaging. A nonselective short 90 degrees pulse was applied to create the coherence, followed by a regular two-dimensional gradient-recalled echo imaging acquisition. Images were reconstructed using the spectral differences with and without the selective inversion pulses, so that signals from regions not being inverted were canceled. Because the slice selection occurred during the longitudinal rather than the transverse relaxation, and also because the shaped pulse was not part of the TE, the shortest TE achievable in this two-dimensional sequence was the same as that in the three-dimensional sequence. The efficiency for the sequence ranges from 100% in the cases of perfect inversion to 50% in the cases when the inversion pulse acts effectively as a saturation pulse. For a typical two-dimensional image, the slice thickness was 7 mm, the field of view was 6 x 6 cm2with a time-domain data matrix of 128 x 32, which was zero-filled twice in the second dimension before Fourier transformation. An NA list, having a symmetric Gaussian distribution with respect to the phase-encoding steps and ranging from 4 (for the first and the last blocks) to 2,048 (for center blocks), was used. The RD was 1 s with four initial dummy scans.
Figure 5. Basic pulse sequence for two-dimensional19Fluorine imaging with a slice selection scheme based on selective inversion [33] Gslice= slice-selecting gradient; Gphase= phase-encoding gradient; and Gread= frequency-encoding gradient. Images are constructed using the spectral differences with and without the 180 degrees secant-shaped selective inversion pulses. Note that the shaped pulse is not part of the TE. Therefore, the minimum echo time in this sequence is the same as that in a three-dimensional gradient-recalled echo sequence and limited only by the gradient switching time and eddy-current effects in the volume of interest.
Figure 5. Basic pulse sequence for two-dimensional19Fluorine imaging with a slice selection scheme based on selective inversion [33]Gslice= slice-selecting gradient; Gphase= phase-encoding gradient; and Gread= frequency-encoding gradient. Images are constructed using the spectral differences with and without the 180 degrees secant-shaped selective inversion pulses. Note that the shaped pulse is not part of the TE. Therefore, the minimum echo time in this sequence is the same as that in a three-dimensional gradient-recalled echo sequence and limited only by the gradient switching time and eddy-current effects in the volume of interest.
Figure 5. Basic pulse sequence for two-dimensional19Fluorine imaging with a slice selection scheme based on selective inversion [33] Gslice= slice-selecting gradient; Gphase= phase-encoding gradient; and Gread= frequency-encoding gradient. Images are constructed using the spectral differences with and without the 180 degrees secant-shaped selective inversion pulses. Note that the shaped pulse is not part of the TE. Therefore, the minimum echo time in this sequence is the same as that in a three-dimensional gradient-recalled echo sequence and limited only by the gradient switching time and eddy-current effects in the volume of interest.
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The T2of19Fluorine in rat head was measured in a series of time segments throughout the uptake and elimination of sevoflurane. In each segment, the spin-echo sequence (90x-TE/2-180 sub y -TE/2-ACQ), with 16 or 18 TE values ranging from 200 micro second to 200 ms, was used. For every TE value, four scans were summed with an interscan delay of 4 s. Thus, a complete run of a T2measurement was about 4.3 min, the midpoint of which was used to time the uptake and elimination processes.
For each 4.3-min run, T2values were determined from unweighted nonlinear regression of 16 or 18 points of total spectral intensities as a function of TE. Fitting was performed on a Macintosh computer using KaleidaGraph, a commercial program from Synergy Software (Reading, PA). Because of the decay nature of the spin-echo train, a biexponential decay function of TE was used as the theoretical model in the nonlinear regression [34] : Equation 2where IT2fast(t) and IT2slow(t), to be determined from the fitting, are the relative intensities of the two exponential components, characterized by the time constants T2fastand T2slow, respectively, and t is a time index for the uptake or elimination process, with t = 0 being assigned arbitrarily to the onset of sevoflurane administration for the uptake and to the termination of sevoflurane for the elimination, respectively. For the uptake process, the percentage of the T2fastcomponent is normalized against the total intensities at each individual time point (i.e., IT2fast(t)/Itotal(t) x 100% for each sampling time t), whereas for the elimination process, the relative intensities of IT2fast(t) and IT2slow(t) are normalized against the total intensity at the beginning of the washout, I sub total (t = 0). After normalization, the overall washout intensities are decomposed to differentiate the elimination kinetics of the two T2components. All IT2fast(t) and IT2slow(t) are presented as the best estimates plus/minus SE of the estimates [34] using Equation 2.
* Kubota Y: Comparative study of sevoflurane with other inhalation agents. Anesth Prog 39:118-124, 1992.
** Shimada M: Hemodynamic effects of isoflurane, sevoflurane, enflurane, and halothane in man: An echo cardiography analysis. J Jpn Soc Clin Anesth 9:204-213, 1989.
*** Kazama T, Ikeda K: The comparative cardiovascular effects of sevoflurane with halothane and isoflurane. J Anesth 2:63-68, 1988.
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Figure 1. Representative19Fluorine head images (left) at 2.5 (top), 7.5 (middle), and 62 (bottom) min, respectively, after the onset of sevoflurane administration. Corresponding1Hydrogen images (right) are displayed for anatomic reference. The19Fluorine image at 2.5 min was the sum of five coronal slices of a three-dimensional data set, which had a final size of 128 x 128 x 32 and a field of view (FOV) of 4 x 4 x 4 cm3. The other two19Fluorine images were obtained using the two-dimensional sequence of Figure 5in the Appendix, with a slice thickness of 7 mm and an FOV of 6 x 6 cm2.
Figure 1. Representative19Fluorine head images (left) at 2.5 (top), 7.5 (middle), and 62 (bottom) min, respectively, after the onset of sevoflurane administration. Corresponding1Hydrogen images (right) are displayed for anatomic reference. The19Fluorine image at 2.5 min was the sum of five coronal slices of a three-dimensional data set, which had a final size of 128 x 128 x 32 and a field of view (FOV) of 4 x 4 x 4 cm3. The other two19Fluorine images were obtained using the two-dimensional sequence of Figure 5in the Appendix, with a slice thickness of 7 mm and an FOV of 6 x 6 cm2.
Figure 1. Representative19Fluorine head images (left) at 2.5 (top), 7.5 (middle), and 62 (bottom) min, respectively, after the onset of sevoflurane administration. Corresponding1Hydrogen images (right) are displayed for anatomic reference. The19Fluorine image at 2.5 min was the sum of five coronal slices of a three-dimensional data set, which had a final size of 128 x 128 x 32 and a field of view (FOV) of 4 x 4 x 4 cm3. The other two19Fluorine images were obtained using the two-dimensional sequence of Figure 5in the Appendix, with a slice thickness of 7 mm and an FOV of 6 x 6 cm2.
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Figure 2. (a) A representative surface coil19Fluorine image showing detailed distribution of sevoflurane in a rat brain. (b) An anatomic schematic for (a). The frames and lines are added as reference marks only and are not the margins of FOV. CC = corpus callosum; CS = superior colliculus; FD = dentate gyrus (Fascia dentata); FH = hippocampal fissure; HPC = hippocampus; LM = medial lemniscus; NCP = bed nucleus of the posterior commissure; TCS = corticospinal tract.
Figure 2. (a) A representative surface coil19Fluorine image showing detailed distribution of sevoflurane in a rat brain. (b) An anatomic schematic for (a). The frames and lines are added as reference marks only and are not the margins of FOV. CC = corpus callosum; CS = superior colliculus; FD = dentate gyrus (Fascia dentata); FH = hippocampal fissure; HPC = hippocampus; LM = medial lemniscus; NCP = bed nucleus of the posterior commissure; TCS = corticospinal tract.
Figure 2. (a) A representative surface coil19Fluorine image showing detailed distribution of sevoflurane in a rat brain. (b) An anatomic schematic for (a). The frames and lines are added as reference marks only and are not the margins of FOV. CC = corpus callosum; CS = superior colliculus; FD = dentate gyrus (Fascia dentata); FH = hippocampal fissure; HPC = hippocampus; LM = medial lemniscus; NCP = bed nucleus of the posterior commissure; TCS = corticospinal tract.
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Figure 3. (A) (Main plot) Representative T2relaxation measurements of whole head using the birdcage coil. The measurements were made at 2.5 (open triangle), 7.5 (open square), and 62 (open circle) min, respectively, after beginning sevoflurane uptake. The relative signal intensities, in arbitrary units, are plotted as a function of spin-echo time. The decays of the overall intensity are best fit by biexponential functions of Equation 2in the Appendix, yielding two time constants in the ranges of T2fast= 3 [nearly equal] 5 ms and T2slow= 105 approximately 130 ms. (Insert) Comparison of T2relaxation measured with birdcage head probe ([diamond]) and surface coil probe ([diamond]). Measurements were made on the same animal killed 6.5 min after the sevoflurane administration. (B) The percentage of T2fastcomponent in the total intensity is plotted as a function of uptake time. The 12 rats studied are denoted by the different symbols on the plot. Each point on the plot resulted from nonlinear regressions of 16 or 18 spin-echo measurements with different TE values, similar to those shown in A. Note the logarithmic scale on the ordinate and the difference in the two slopes. (C) A typical sevoflurane uptake curve in the head region measured with the birdcage coil. The total sevoflurane intensity (closed cirle) and the T2slowcomponent (open circle) did not plateau within the time range used in the study, but the T2fastcomponent (open square) did.
Figure 3. (A) (Main plot) Representative T2relaxation measurements of whole head using the birdcage coil. The measurements were made at 2.5 (open triangle), 7.5 (open square), and 62 (open circle) min, respectively, after beginning sevoflurane uptake. The relative signal intensities, in arbitrary units, are plotted as a function of spin-echo time. The decays of the overall intensity are best fit by biexponential functions of Equation 2in the Appendix, yielding two time constants in the ranges of T2fast= 3 [nearly equal] 5 ms and T2slow= 105 approximately 130 ms. (Insert) Comparison of T2relaxation measured with birdcage head probe ([diamond]) and surface coil probe ([diamond]). Measurements were made on the same animal killed 6.5 min after the sevoflurane administration. (B) The percentage of T2fastcomponent in the total intensity is plotted as a function of uptake time. The 12 rats studied are denoted by the different symbols on the plot. Each point on the plot resulted from nonlinear regressions of 16 or 18 spin-echo measurements with different TE values, similar to those shown in A. Note the logarithmic scale on the ordinate and the difference in the two slopes. (C) A typical sevoflurane uptake curve in the head region measured with the birdcage coil. The total sevoflurane intensity (closed cirle) and the T2slowcomponent (open circle) did not plateau within the time range used in the study, but the T2fastcomponent (open square) did.
Figure 3. (A) (Main plot) Representative T2relaxation measurements of whole head using the birdcage coil. The measurements were made at 2.5 (open triangle), 7.5 (open square), and 62 (open circle) min, respectively, after beginning sevoflurane uptake. The relative signal intensities, in arbitrary units, are plotted as a function of spin-echo time. The decays of the overall intensity are best fit by biexponential functions of Equation 2in the Appendix, yielding two time constants in the ranges of T2fast= 3 [nearly equal] 5 ms and T2slow= 105 approximately 130 ms. (Insert) Comparison of T2relaxation measured with birdcage head probe ([diamond]) and surface coil probe ([diamond]). Measurements were made on the same animal killed 6.5 min after the sevoflurane administration. (B) The percentage of T2fastcomponent in the total intensity is plotted as a function of uptake time. The 12 rats studied are denoted by the different symbols on the plot. Each point on the plot resulted from nonlinear regressions of 16 or 18 spin-echo measurements with different TE values, similar to those shown in A. Note the logarithmic scale on the ordinate and the difference in the two slopes. (C) A typical sevoflurane uptake curve in the head region measured with the birdcage coil. The total sevoflurane intensity (closed cirle) and the T2slowcomponent (open circle) did not plateau within the time range used in the study, but the T2fastcomponent (open square) did.
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Figure 4. Anesthetic washout after 67-89 min of 4% sevoflurane general anesthesia. The total wash-out intensity (closed circle) at each time is weighted by the percentage of T2fastand T2slowcomponents at that time, resulting in separate elimination kinetics for the T2fast(open square) and T2slow(open circle) components. The solid lines are best fit to the data with single- or double-exponential functions, yielding elimination rate constants: kf= 0.053 plus/minus 0.004 min sup -1, ks1= 0.046 plus/minus 0.009 min sup -1, and ks2= 0.007 plus/minus 0.001 min sup -1.
Figure 4. Anesthetic washout after 67-89 min of 4% sevoflurane general anesthesia. The total wash-out intensity (closed circle) at each time is weighted by the percentage of T2fastand T2slowcomponents at that time, resulting in separate elimination kinetics for the T2fast(open square) and T2slow(open circle) components. The solid lines are best fit to the data with single- or double-exponential functions, yielding elimination rate constants: kf= 0.053 plus/minus 0.004 min sup -1, ks1= 0.046 plus/minus 0.009 min sup -1, and ks2= 0.007 plus/minus 0.001 min sup -1.
Figure 4. Anesthetic washout after 67-89 min of 4% sevoflurane general anesthesia. The total wash-out intensity (closed circle) at each time is weighted by the percentage of T2fastand T2slowcomponents at that time, resulting in separate elimination kinetics for the T2fast(open square) and T2slow(open circle) components. The solid lines are best fit to the data with single- or double-exponential functions, yielding elimination rate constants: kf= 0.053 plus/minus 0.004 min sup -1, ks1= 0.046 plus/minus 0.009 min sup -1, and ks2= 0.007 plus/minus 0.001 min sup -1.
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Figure 5. Basic pulse sequence for two-dimensional19Fluorine imaging with a slice selection scheme based on selective inversion [33] Gslice= slice-selecting gradient; Gphase= phase-encoding gradient; and Gread= frequency-encoding gradient. Images are constructed using the spectral differences with and without the 180 degrees secant-shaped selective inversion pulses. Note that the shaped pulse is not part of the TE. Therefore, the minimum echo time in this sequence is the same as that in a three-dimensional gradient-recalled echo sequence and limited only by the gradient switching time and eddy-current effects in the volume of interest.
Figure 5. Basic pulse sequence for two-dimensional19Fluorine imaging with a slice selection scheme based on selective inversion [33]Gslice= slice-selecting gradient; Gphase= phase-encoding gradient; and Gread= frequency-encoding gradient. Images are constructed using the spectral differences with and without the 180 degrees secant-shaped selective inversion pulses. Note that the shaped pulse is not part of the TE. Therefore, the minimum echo time in this sequence is the same as that in a three-dimensional gradient-recalled echo sequence and limited only by the gradient switching time and eddy-current effects in the volume of interest.
Figure 5. Basic pulse sequence for two-dimensional19Fluorine imaging with a slice selection scheme based on selective inversion [33] Gslice= slice-selecting gradient; Gphase= phase-encoding gradient; and Gread= frequency-encoding gradient. Images are constructed using the spectral differences with and without the 180 degrees secant-shaped selective inversion pulses. Note that the shaped pulse is not part of the TE. Therefore, the minimum echo time in this sequence is the same as that in a three-dimensional gradient-recalled echo sequence and limited only by the gradient switching time and eddy-current effects in the volume of interest.
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