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Canadian Journal of Anesthesia 47:579-584 (2000)
© Canadian Anesthesiologists' Society, 2000
Laboratory Investigation

Uptake and elimination of sevoflurane in rabbit tissues - an in vivo magnetic resonance spectroscopy study

Tomoko Takeda, MD, Koshi Makita, MD, Seiji Ishikawa, MD, Koh Kaneda, MD, Kuninori Yokoyama, Be and Keisuke Amaha, MD

From the Department of Anesthesiology and Critical Care Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

Address correspondence to: T. Tomoko MD. Phone: 81-3-5803-5323; Fax: 81-3-5803-0149; E-mail: makita.mane{at}med.tmd.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Purpose: Previous pharmacokinetic studies of fluorinated anesthetics using 19F-magnetic resonance spectroscopy (19F-MRS) have focused on the brain. Investigation of other tissues would give more precise information about the pharmacokinetics of inhalational anesthetics. In this study we investigated the pharmacokinetics of uptake and elimination of sevoflurane in brain, liver, muscle, venous blood and arterial blood of rabbits.

Methods: Twenty rabbits were examined by 19F-MRS conducted at 4.7 Tesla using a 1-cm-diameter surface coil for brain (n=4), liver (n=5) and muscle (n=5), and a 1.3-cm-diameter surface coil for arterial (n=3) and venous (n=3) blood. Sevoflurane, 4% in oxygen, was administered for 120 min, followed by 120 min elimination.

Results: Both the uptake and elimination kinetics were best fitted by a biexponential curve which was divided into fast and slow components. During the uptake experiment the time required to reach half of the maximum spectroscopic intensity in each tissue was 1.6 min in arterial blood, 4.7 min in liver, 12.2 min in venous blood, 14.4 min in brain and 20.9 min in muscle. During the elimination experiment the time required to reach half maximum intensity was 2.4 min in arterial blood, 6.3 min in liver, 13.4 min in venous blood, 19.6 min in brain and 28.7 min in muscle.

Conclusions: Sevoflurane uptake or elimination in the tissues examined followed biexponential kinetics. In this rabbit model, sevoflurane uptake and elimination were fastest in arterial blood, followed, in order, by liver, venous blood, brain and muscle.


   Introduction
TOP
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
THE introduction of 19F-magnetic resonance spectroscopy (19F-MRS) has made it possible to conduct in vivo pharmacokinetic studies of fluorinated inhalational anesthetics.1 Since the brain is a site of anesthetic action, most previous studies using MRS have examined pharmacokinetics in the brain,2–11 but the results obtained are controversial. Few studies have examined other tissues.12–14 and the pharmacokinetics of anesthetics in tissues other than brain are unclear. Therefore, investigation of other tissues would give more precise information about the pharmacokinetic behaviour of inhalational anesthetics in the whole body.

In this study, we investigated the pharmacokinetics of sevoflurane uptake and elimination in brain, liver, muscle, arterial blood and venous blood of rabbits using in vivo 19F-MRS. As the liver has a special blood supply consisting of the hepatic artery and portal vein, the uptake and elimination pattern in the liver may differ from that in the brain. Venous blood may reflect a composite of the kinetics of those of the individual tissues. We compared the pharmacokinetics of sevoflurane among various tissues, as well as comparing the uptake and elimination in each tissue.


   Materials and methods
TOP
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Animal preparation
The study was approved by the Institutional Review Board for the care of laboratory animals. Twenty Japanese white rabbits weighing 2.9-3.4 kg were divided into five groups for investigation of brain (n=4), liver (n=5), muscle (n=5), arterial (n=3) and venous blood (n=3). The animals were initially anesthetised with ketamine/xylazine im. A catheter was placed in an ear vein for administration of fluid and intravenous anesthetics, and another in a femoral artery for blood gas sampling and blood pressure monitoring. Anesthesia was maintained using intravenous xylazine and ketamine until sevoflurane administration was initiated. A tracheotomy was performed and muscle paralysis was induced by 0.4 mg•hr–1 pancuronium iv. Ventilation was controlled mechanically to maintain PaCO2 at 40 ± 5 mmHg. Rectal temperature was monitored and a water-circulating heating pad was used to maintain body temperature at 38.0 ± 1.0°C. A craniotomy was performed on the rabbits in the brain group to expose a 2.5~3.0 cm diameter circle of dura. In the muscle group, the right femoral muscle was exposed widely enough to exclude contamination by skin tissue, and in the liver group, the liver was exposed by a laparotomy. In the venous and arterial blood groups, catheters were placed in the carotid artery and the right atrium through the carotid vein. The catheters from the vein and the artery were connected using a circuit tube system 130 cm in length with a 2.5-ml syringe midway in the circuit. As an accurate magnetic resonance (MR) signal cannot be obtained from a moving object, the pharmacokinetics in venous or arterial blood were measured in the 2.5-ml syringe. The arterial and venous blood group received 10 mg•kg–1 heparin iv, before the measurements were made. Either arterial or venous blood was injected into the syringe just before the measurement, and the blood was reinfused into the animal after the measurement.

Magnetic Resonance Spectrometry method
The 19F-MRS measurements were carried out using a 4.7-T MRS/I system (Unity plus-SIS 200/330, Varian, Palo Alto, Calif) with a magnet bore inner diameter of 33 cm. The resonant frequency of 19F of our MR system was 188.238 MHZ. In the brain, liver and muscle groups, a two-turn 1.0-cm-diameter surface coil was placed on the surface of each tissue, and the animals were placed in the MR chamber. In the blood groups, one 2.5-ml syringe was connected midway in the circuit described above, and two 5-ml syringes were connected to the arterial and venous sides of the tube. A two-turn 1.3-cm-diameter surface coil was wound around the 2.5-ml syringe and it was placed in the MR chamber, the other two syringes being outside the chamber. The magnetic field homogeneity was optimised using shimming coils until the water proton line width was < 35 Hz. Just before collecting the MR spectra, the ketamine infusion was discontinued and the inspired sevoflurane concentration was set at 4.0% using an anesthetic vaporiser (Sevotec3, Ohmeda). The sevoflurane concentration was measured at the Y-piece of a respiratory circuit using an anesthetic gas analyser (Ultima, Datex) calibrated with a calibration gas. 19F-MR spectra were obtained by averaging 128 acquisitions. The acquisition parameters used were a 50-kHz spectral width, 30 µsec pulse width, and a 0.2-sec repetition time. Acquisition of one data took 40 sec.

The inspired concentration of sevoflurane, 4%, was delivered in oxygen 100%. Spectroscopic data were obtained during 120 min of sevoflurane wash-in and during 120 min of sevoflurane wash-out.

In the uptake phase, data collection was performed at 0, 1, 2, 3, 4, 5, 6, 8, 10, 15, 20, 25, 30, 40, 50, 60, 80,100, and 120 min after commencement of sevoflurane. In the elimination phase, data were collected at the same intervals as those for the uptake phase after discontinuation of sevoflurane. For brain, liver and muscle data, the midpoint in the spectral acquisition duration was taken as the ‘time’ value. For arterial and venous blood, the time of sampling was used as the ‘time’ value. The end-tidal sevoflurane concentration and arterial blood pressure were recorded continuously.

Data analysis
The sevoflurane MR signal intensity obtained by numerical integration was normalised to the maximum intensity that was observed during the final 40 sec of sevoflurane administration. The naive pooled data method15–17 was used for data analysis. In this method, a descriptive structural model is fitted to data from all individuals by treating them as a single individual. The data for each tissue were then fitted to a mono-, bi-, or tri-exponential curve using commercial software (KaleidaGraph, Synergy Software, Reading, PA). The Akaike information criterion (AIC)18,19 was used to compare the goodness-of-fit among three curves. The AIC takes into account the number of parameters, and the model that gives the lowest AIC value is considered the best fit. In the same way, the alveolar concentrations of sevoflurane were expressed relative to the alveolar concentration at 120 min of sevoflurane exposure.


   Results
TOP
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
The AIC values of mono-, bi-, and tri-exponential curve-fitting during the uptake phase are shown in Table IGo. The alveolar concentration ratio was not curve-fitted to a triexponential curve in the uptake phase, as the third term became negative. The AIC values show that the obtained data were best fitted by a biexponential curve for each tissue, denoted by the formula: Y=ku1x{1-exp(-t/{tau}u1}+ku2x{1-exp(-t/{tau}u2)}, where Y is the relative intensity of the spectrum obtained at time point t, {tau}u1 and {tau}u2 are the time constants of the fast and slow components of uptake respectively, and ku1 and ku2 are constants that reflect the relative volumes of the fast and slow components in each tissue. The corresponding values of ku1, ku2, {tau}u1, and {tau}u2 are shown in Table IIGo. The biexponential curve-fit of sevoflurane uptake by five tissues and that of the end-tidal sevoflurane concentration are shown in Figure 1Go. The end-tidal sevoflurane concentration reached a plateau rapidly during the uptake phase. Less than 10 min after the start of inhalation, the end-tidal sevoflurane concentration reached 90% of the maximum concentration. In the brain, for example, 25% of sevoflurane uptake occurred rapidly at a time constant of 3.12 min, and 80% of sevoflurane uptake occurred slowly at a time constant of 38.0 min. Uptake of sevoflurane in arterial blood occurred predominantly (70%) in the rapid phase ({tau}u1=1.4 min).


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  		TABLE I Data of wash-in phase. AIC 1u is the AIC (Akaike Information Criterion) value obtained from monoexponential curve-fit data of each tissue. AIC 2u is the AIC value obtained from biexponential curve-fit data. AIC 3u is the AIC value obtained from triexponential curve-fit data. The lowest value of AIC is considered the best fit.
 

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  		TABLE II Constants of the biexponential equation expressed as Y=ku1x{1-exp(-t/{tau}u1}+ku2x{1-exp(-t/{tau}u2)} and derived values in uptake phase. {tau}u1 and {tau}u2 are the time constants of uptake. ku1 and ku2 are constants that reflect the relative volumes of the fast and slow components. tu1/2 is the time to reach half of the maximum intensity and t90% is the time to reach 90% of the maximum intensity.
 


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  		FIGURE 1 Biexponential curves for sevoflurne uptake in rabbit tissues. Each line shows curve which is best fitted to biexponential function denoted as Y=ku1x{1-exp(-t/{tau}u1}+ku2x{1-exp(-t/{tau}u2)}. Time value means time after starting sevoflurane inhalation. See text for details.

 
The AIC values of mono-, bi-, and tri-exponential curve-fitting in the elimination phase are shown in Table IIIGo. The AIC values show that the obtained data were best fitted to a biexponential curve best for each tissue, denoted by the formula Y=ke1xexp(-t/{tau}e1)+ke2xexp(-t/{tau}e2), where {tau}e1 and {tau}e2 represent the time constants of the fast and slow components of elimination, and ke1 and ke2 are constants representing the relative volumes of the fast and slow components of elimination in each tissue. The corresponding values of ke1, ke2, {tau}e1, and {tau}e2 are shown in Table IVGo. The biexponential curve-fit of sevoflurane elimination from rabbit tissues is shown in Figure 2Go. The end- tidal concentration of sevoflurane decreased rapidly from 100% to 10% of the maximum concentration in 18 min. Among the five tissues tested, sevoflurane elimination was fastest in arterial blood, followed in order by liver, venous blood, brain, and muscle.


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  		TABLE III Data of wash-out phase. AIC 1e is the AIC (Akaike Information Criterion) value obtained from monoexponential curve-fit data of each tissue. AIC 2e is the AIC value obtained from biexponential curve-fit data. AIC 3e is the AIC value obtained from triexponential curve-fit data. The lowest value of AIC is considered the best fit.
 

View this table:
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  		TABLE IV Constants of the biexponential equation expressed as Y=ke1xexp(-t/{tau}e1)+ke2xexp(-t/{tau}e2). and derived values in elimination phase. {tau}e1 and {tau}e2 are the time constants of the fast and slow components of elimination. ke1 and ke2 are constants that reflect the relative volumes of the fast and slow components in each tissue. te1/2 is the time to reach half of the maximum intensity and t10% is the time to reach 10% of the maximum intensity.
 


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  		FIGURE 2 Biexponential curves for sevoflurne elimination in rabbit tissues. Each line shows curve which is best fitted to biexponential function denoted as Y=ke1xexp(-t/{tau}e1)+ke2xexp(-t/{tau}e2). Time value means time after discontinuing sevoflurane inhalation. See text for details.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The uptake and elimination curves both gave best fits for biexponential curves. Namely, the uptake and elimination of the inhaled anesthetics by each tissue were each divided into a fast component and a slow component. The time constants of the fast and the slow components and the relative volumes (ku1, ku2, ke1 and ke2) of each component differed between the tissues, and also between the uptake and elimination phases in individual tissues.

Uptake of sevoflurane in brain was distinctly slower than in arterial blood and liver, and it took longer to reach equilibrium. However, it was still much faster than the rate of halothane uptake reported by Venkatasubramanian et al.10 Their NMR method was similar to ours in that a surface coil was positioned over the brain. In our study the time required to reach 90% of maximum intensity was 63.6 min, whereas for halothane it was 194~266 min (calculated from their data). The concentration and duration of inhalation differed between their study and ours, but it appears that long duration anesthesia with sevoflurane does not cause accumulation of sevoflurane in the brain, and does not cause delayed recovery, compared with halothane. Elimination of sevoflurane from the brain was slower than its uptake. Our kinetic data for sevoflurane uptake (tu1/2 and tu90%) and elimination in the rabbit brain are similar to the results of Xu et al.,11 who reported tu1/2 and tu90% values of approximately 18 and 53 min respectively (from their graph) and te1/2 and te10% values of 32.4 min and 230 min respectively (calculated from their results). In our study the time required to reach half of the maximum intensity (te1/2) was 19.6 min, and this value was smaller than that for isoflurane (36 ± 5 min) measured by a similar method.7 It took 233 min to eliminate 90% of the sevoflurane from brain according to our results, although this seems unlikely to be the case in the human brain based on our clinical experience. Concerning these results, we must consider the phamacokinetic differences between rabbits and adult humans. The uptake or elimination time constant may be defined as =(tissue volume x tissue/blood partition coefficient)/tissue blood flow.20 The tissue volume detected by the surface coil does not change, so only two of these parameters change: the tissue blood flow (inhomogeneity in the same tissue) and/or the tissue/blood partition coefficient (for example grey and white matter in the brain). Mutch et al.21 reported that CBF in rabbits is 68-86 ml•100 g–1•min–1, which is similar to that in humans (45-60 ml•100 g–1•min–1). On the other hand, the ratio of white matter and grey matter components differs between humans and rabbits, and this may be responsible for the difference between the two species in the brain/blood coefficient of sevoflurane. Therefore, we cannot apply this result to our clinical experience because of the pharmacokinetic differences between rabbits and humans.

In a previous study by Venkatasubramanian et al.,10 halothane uptake kinetics for both rabbit brain and arterial blood were reported to be fitted best to a biexponential curve. They suggested that the likely sources of the two components was the grey matter and white matter of the brain, and the plasma and erythrocytes of the arterial blood. Their suggestion may have been based partly on their observation that the ratio of the uptake volumes of the fast and slow components in arterial blood was 1:1 in their experiment. However, in our experiment, the same ratio in arterial blood was 7:3 (ku1: ku2), moreover, the ratio in venous blood was 2:8 changing to approximately 1:1 during elimination. In brain, the relative volume of the fast and slow components during the uptake phase (ku1 and ku2) also changed during elimination. These results mean that the two components do not arise only from the plasma and erythrocytes or the white and grey matter. From our study, we could not clearly identify the sources of the two components. However we hypothesise that blood flow in a certain tissue is not homogeneous and that it can be divided into a part with relatively abundant flow and a part with relatively scarce flow. The former represent fast uptake and elimination and the latter relatively slow uptake and elimination. The inhomogeneity of blood flow distribution in each tissue22 and recirculation of arterial blood may be sources of multi-exponential kinetics, but the overall result may still follow biexponential kinetics.

The methods used to obtain NMR signals have differed among previous studies. Wyrwicz et al.1 and others3–5 used a surface coil over the calvaria and elimination was slow, as the surrounding brain tissue was contaminated. Mills et al.7 compared isoflurane elimination over the exposed dura using a 3-cm-diameter surface coil and a 1-cm surface coil and obtained rapid elimination from the small 1-cm coil. They thought that the 19F-NMR signal arose from other tissues using the large coil. Therefore, we anticipated that sufficient exposure of the dura might yield a more accurate signal from the brain.

One-dimensional chemical shift imaging (CSI) provides a localisation method for observing signals from different locations in a subject.9,10 Venkatasubramanian9 compared the uptake of halothane between the surface coil-localised one pulse experiment and a CSI experiment, and found that the rates of uptake in the two methods were similar. The CSI localisation technique required 17 min per data set, so it was thought that a surface coil would reflect the signal more accurately in the early experimental period.

Alveolar uptake and elimination were assessed by Stephen et al.8 and compared with data for the brain. They assumed that the cerebral concentration of anesthetics was proportional to the cerebral partial pressure, and that end-tidal, arterial and cerebral partial pressures were equal after 30 min of equilibration. We also assumed that each tissue would reach equilibration after 120 min exposure to sevoflurane. This was one of the restrictions in our experiment because, as shown in Figure 1Go, sevoflurane uptake in muscle did not reach equilibration after 120 min exposure.

Stern et al.12 compared NMR methods with non-NMR methods in which they measured tissue sevoflurane concentration by gas chromatography concurrently. They found that the anesthetic concentration in adipose tissue measured by gas chromatography was consistently higher for sevoflurane than that measured by NMR, although this did not affect the absolute value of the time constants of elimination.

In conclusion, the uptake and elimination kinetics of sevoflurane in rabbit brain, liver, muscle, arterial blood and venous blood gave best fits to biexponential curves with fast and slow components. The relative volumes of the fast and slow components changed between uptake and elimination. Sevoflurane uptake and elimination kinetics in arterial blood were rapid and similar to the end-tidal sevoflurane kinetics. Sevoflurane uptake and elimination were fastest in arterial blood, followed in order by liver, venous blood, brain and muscle. Further studies will be necessary to obtain more detailed data on the uptake and elimination pharmacokinetics of fluorinated anesthetics, making comparison between different NMR methods, and also between NMR and non-NMR methods.


   Acknowledgments
 
This study was supported by a Grant-in-Aid for Scientific Research (c)(No.07671646) from the Ministry of Education, Science and Culture of Japan.


   Footnotes
 
Supported in part by Grant-in-Aid for Scientific Research (c)(no.07671646) from the Ministry of Education, Science and Culture of Japan.

Accepted for publication March 9, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 Wyrwicz AM, Pszenny MH, Schofield JC. Noninvasive observations of fluorinated anesthetics in rabbit brain by fluorine-19 nuclear magnetic resonance. Science 1983; 222: 428–30.[Abstract/Free Full Text]

2 Strum DP, Johnson BH, Eger EI II. Elimination of anesthetics from rabbit brain. Science 1986; 234: 1586–8.[Free Full Text]

3 Wyrwicz AM, Conboy CB, Nichols BG, Ryback KR, Eisele P. In vivo 19F-NMR study of halothane distribution in brain. Biochim Biophys Acta 1987; 929: 271–7.[Medline]

4 Wyrwicz AM, Conboy CB, Ryback KR, Nichols BG, Eisele P. In vivo 19F-NMR study of isoflurane elimination from brain. Biochim Biophys Acta 1987; 927: 86–91.[Medline]

5 Litt L, Gonzáles Méndez R, James TL, et al. An in vivo study of halothane uptake and elimination in the rat brain with fluorine nuclear magnetic resonance spectroscopy. Anesthesiology 1987; 67: 161–8.[Medline]

6 Evers AS, Berkowitz BA, d'Avignon DA. Correlation between the anaesthetic effect of halothane and saturable binding in brain. Nature 1987; 328: 157–60.[Medline]

7 Mills P, Sessler DI, Moseley M, et al. An in vivo 19F nuclear magnetic resonance study of isoflurane elimination from the rabbit brain. Anesthesiology 1987; 67: 169–73.[Medline]

8 Lockhart SH, Cohen Y, Yasuda N, et al. Cerebral uptake and elimination of desflurane, isoflurane, and halothane from rabbit brain: an in vivo NMR study. Anesthesiology 1991; 74: 575–80.[Medline]

9 Venkatasubramanian PN, Shen YJ, Wyrwicz AM. In vivo 19F one-dimensional chemical shift imaging study of isoflurane uptake in rabbit brain. NMR Biomed 1993; 6: 377–82.[Medline]

10 Venkatasubramanian PN, Shen Y-J, Wyrwicz AM. In vivo 19F-NMR spectroscopic study of halothane uptake in rabbit brain. Biochim Biophys Acta 1995; 1245: 262–8.[Medline]

11 Xu Y, Tang P, Zhang W, Firestone L, Winter PM. Fluorine-19 nuclear magnetic resonance imaging and spectroscopy of sevoflurane uptake, distribution, and elimination in rat brain. Anesthesiology 1995; 83: 766–74.[Medline]

12 Stern RC, Towler SC, White PF, Evers AS. Elimination kinetics of sevoflurane and halothane from blood, brain, and adipose tissue in the rat. Anesth Analg 1990; 71: 658–64.[Abstract/Free Full Text]

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15 Wright PMC. Population based pharmacokinetic analysis: why do we need it; what is it; and what has it told us about anaesthetics? Br J Anaesth 1998; 80: 488–501.[Free Full Text]

16 Sheiner LB. The population approach to pharmacokinetic data analysis: rationale and standard data analysis methods. Drug Metab Rev 1984; 15: 153–71.[Medline]

17 Somma J, Donner A, Zomorodi K et al. Population pharmadynamics of midazolam administration by target controlled infusion in SICU patients after CABG surgery. Anesthesiology 1998; 89: 1430–43.[Medline]

18 Perrella FW. EZ-FIT: a practical curve-fitting microcomputer program for the analysis of enzyme kinetic data on IBM-PC compatible computers. Anal Biochem 1988; 174: 437–47.[Medline]

19 Yamaoka K, Nakagawa T, Uno T. Application of Akaike's Information Criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 1978; 6: 165–75.[Medline]

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21 Mutch WAC, Patel PM, Ruta TS. A comparison of the cerebral pressure-flow relationship for halothane and isoflurane at haemodynamically equivalent end-tidal concentrations in the rabbit. Can J Anaesth 1990; 37: 223–30.[Abstract/Free Full Text]

22 Gustafsson U, Sollevi A, Sirsjö A, Sjöberg F. Effects on skeletal muscle oxygenation and capillary blood flow by adenosine-, sodium nitroprusside- and acetylcholine-induced hypotension. Acta Anesthesiol Scand 1996; 40: 832–7.[Medline]





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