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The Effects of Xenon Anesthesia on the Relationship Between Cerebral Glucose Metabolism and Blood Flow in Healthy Subjects: A Positron Emission Tomography Study

Laitio, Ruut M. MD*†; Långsjö, Jaakko W. MD*†; Aalto, Sargo MSc*‡; Kaisti, Kaike K. MD*†; Salmi, Elina MD; Maksimow, Anu MD*†; Aantaa, Riku MD; Oikonen, Vesa MSc*; Viljanen, Tapio MSc*; Parkkola, Riitta MD; Scheinin, Harry MD*

doi: 10.1213/ane.0b013e31818ffc9d
Neurosurgical Anesthesiology and Neuroscience: Research Reports
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BACKGROUND: General anesthetics can alter the relationship between regional cerebral glucose metabolism (rCMRglc) and blood flow (rCBF). In this positron emission tomography study, our aim was to assess both rCMRglc and rCBF in the same individuals during xenon anesthesia.

METHODS: 18F-labeled fluorodeoxyglucose and 15O-labeled water were used to determine rCMRglc and rCBF, respectively, in five healthy male subjects at baseline (awake) and during 1 minimum alveolar anesthetic concentration of xenon. Anesthesia was based solely on xenon. Changes in rCMRglc and rCBF were quantified using region-of-interest and voxel-based analyses.

RESULTS: The mean (sd) xenon concentration during anesthesia was 67.2 (0.8)%. Xenon anesthesia induced a uniform reduction in rCMRglc, whereas rCBF decreased in 7 of 13 brain regions. The mean decreases in the gray matter were 32.4 (4.0)% (P < 0.001) and 14.8 (5.9)% (P = 0.007) for rCMRglc and rCBF, respectively. rCMRglc decreased by 10.9 (6.4)% in the white matter (P = 0.030), whereas rCBF increased by 9.2 (7.3)% (P = 0.049). The rCBF/rCMRglc ratio was especially increased in the insula, anterior and posterior cingulate, and in the somatosensory cortex.

CONCLUSIONS: In general, the magnitude of the decreases in rCMRglc during 1 minimum alveolar anesthetic concentration xenon anesthesia exceeded the reductions in rCBF. As a result, the ratio between rCMRglc and rCBF was shifted to a higher level. Interestingly, xenon-induced changes in cerebral metabolism and blood flow resemble those induced by volatile anesthetics.

IMPLICATIONS: Xenon anesthesia reduced markedly regional cerebral glucose metabolism with a concomitant smaller reduction in regional cerebral blood flow.

From the *Turku PET Centre, University of Turku; †Departments of Anesthesiology and Intensive Care, §Otorhinolaryngology, and ∥Radiology, Turku University Hospital; and ‡Department of Psychology, Åbo Akademi University, Turku, Finland.

This article has supplementary material on the Web site:www.anesthesia-analgesia.org.

Accepted for publication October 1, 2008.

Supported by Turku University Hospital EVO grant no. 13323, Turku, Finland; Seinäjoki Central Hospital EVO grant, Seinäjoki, Finland; the AGA AB Medical Research Fund, Stockholm, Sweden; Instrumentarium Science Foundation, The Academy of Finland, Helsinki, Finland; and the Sigrid Juselius Foundation, Helsinki, Finland.

Please see supplementary material available at www.anesthesia-analgesia.org.

Address correspondence to Ruut Laitio, MD, PhD, Department of Anesthesiology and Intensive Care, Turku University Hospital, POB 52, FIN-20521 Turku, Finland. Address e-mail to ruut.laitio@tyks.fi.

Reprints will not be available from the authors.

Inhaled anesthesia based on the noble gas, xenon, has a unique profile of hemodynamic stability combined with fast induction and emergence from anesthesia.1–3 In addition to its analgesic potency,4 xenon has also been shown to possess significant cardioprotective and neuroprotective capacity.5–7 Because of these organ-protective characteristics, interest in xenon has been propagated.

Neuronal activation in the brain is coupled by parallel changes in regional metabolism and cerebral blood flow (CBF).8,9 The association between regional metabolism and blood flow can be altered in pathological conditions. Because anesthetics have their own vasoactive properties, they might disturb the coupling of regional CBF (rCBF) to regional cerebral glucose metabolism (rCMRglc).10,11 Inappropriate increases in rCBF or marked luxury perfusion should be avoided, particularly if the cerebral homeostasis is already compromised, and the margins of intracranial compliance are reached. In addition, increases in rCMRglc induced by anesthetics are considered harmful. Therefore, the in vitro neuroprotective propensity of an anesthetic may in vivo be compromised or even overridden by an unfavorable impact on the regional relationship between rCMRglc and rCBF.

The neuroprotective capacity of xenon has been thought to be related to its mechanism of action via N-methyl-d-aspartate (NMDA) receptors.12 Another NMDA antagonist, ketamine, has also been shown to be neuroprotectant in vitro.13,14 Unfortunately, ketamine increases rCMRglc, and also CBF, in many brain locations far beyond metabolic needs.10,15 These characteristics make its use in neuroanesthesia debatable.

We have recently shown, with positron emission tomography (PET), that xenon reduces rCBF in humans.16 It has also been demonstrated in humans that xenon anesthesia induces a global reduction in rCMRglc.17 Accordingly, animal studies have indicated strongly suppressed rCMRglc in parallel with initially increased rCBF followed by decreased rCBF during xenon inhalation.18 A recent study about the effects of xenon on the relationship between rCMRglc and rCBF indicated minor effects on coupling.19 The aim of this PET study with healthy subjects was to determine the concomitant changes in rCBF and rCMRglc in the same individuals during 1 minimum alveolar anesthetic concentration (MAC) xenon anesthesia to estimate the preservation of their regional relationship.

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METHODS

Subjects and Study Design

The study protocol was approved by the Ethical Committee of the Hospital District of Southwest Finland. After written informed consent, eight healthy, right-handed, nonsmoking male volunteers were recruited in this open, nonrandomized study. The present study is based on a separate population than that of our previous PET study.16 None of the subjects had a history of lung disease or any signs of infection. Three subjects had to be excluded from the study because of technical problems and failure in tracer production and, thus, the results presented are based on five subjects whose ages were 21–25 yr and body mass index 24.1 (3.1) kg/m2 mean (sd). Physical examination with laboratory testing and a 12-lead electrocardiography were normal in all subjects, and all were considered to be ASA status I. Magnetic resonance images (1.5 T Scanner, Philips intera system, Philips Medical Systems, Best, The Netherlands) were obtained from each subject to exclude cerebral pathologies. Subjects fasted overnight and did not use alcohol or any medication for 48 h before anesthesia.

18F-labeled 2-fluoro-2-deoxy-d-glucose ([18F]FDG) and 15O-labeled (half-life 2 min) water were used as PET tracers to assess rCMRglc and rCBF, respectively, at baseline (awake) and during anesthesia with 1 MAC of xenon. PET assessments were made similarly at both awake and during anesthesia. Because of the long half-life of 18F-isotope (110 min), the baseline [18F]FDG scan was performed in a separate session. This was scheduled approximately 2 wk before the day of anesthesia (Fig. 1). In the second session, the baseline (awake) rCBF was first assessed twice awake while subjects were breathing room air. The time period between these rCBF measurements was 10 min (half-life of 15O is only 2 min). The mean value of the two measurements was used in the rCBF analysis. After 1 h denitrogenation with 100% oxygen, the subjects were anesthetized with xenon (Xenon Pro Anesthesia, Air Liquide Deutschland GmbH, Krefeld, Germany). A minimum 30-min stabilization period was allowed to pass after intubation before the PET assessments were initiated. At a concentration of approximately 1 MAC (63%),20 the PET assessment for rCBF was repeated twice with 10-min interval between assessments. Finally, the second rCMRglc assessment concluded the study.

Figure 1

Figure 1

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Anesthesia and Monitoring

No premedication was given. A peripheral vein was cannulated for the administration of 15O-labeled water and 0.9% saline infusion (100 mL/h). A radial artery cannula was placed for blood sampling and invasive arterial blood pressure monitoring. Ventilation variables and breathing gases (oxygen, carbon dioxide, xenon) were monitored throughout the anesthesia. The xenon concentration was measured using the thermo-conductive method. Vital variables and depth of hypnosis were monitored using GE Datex-Ohmeda S/5 anesthesia monitor (GE Healthcare, Helsinki, Finland) with plug-n modules continuously recording invasive arterial blood pressure, electrocardiogram, pulse oximetry (E-PRESTIN Module, GE Healthcare, Helsinki, Finland), bispectral index (E-BIS Module, GE Healthcare, Helsinki, Finland, algorithm version 4.0, XP-level), and nasopharyngeal temperature. A portable computer running S/5 Collect software (GE Healthcare, Helsinki Finland) was used for data recording. Hematocrit and partial pressures of oxygen and carbon dioxide were repeatedly analyzed from arterial blood samples using portable equipment (i-STAT, Abbott Laboratories, Birmingham, UK).

A PhysioFlex closed-system ventilator (Dräger, Lübeck, Germany) was used for mask induction and mechanical ventilation. In order to be able to prime the circuit with 63% xenon, the subjects breathed 100% oxygen for 1 h through a 5-cm H2O continuous positive airway pressure mask before induction. Thereafter, the induction was performed with subjects breathing xenon spontaneously through a facemask. Induction was facilitated by several flushes of xenon to gain the target concentration of 63%. After loss of consciousness, a 0.8 mg/kg bolus of rocuronium (Esmeron, 10 mg/mL, Organon, Helsinki, Finland) was administered for muscle relaxation, and subjects were endotracheally intubated. Anesthesia was maintained with xenon, and additional doses of rocuronium were given to maintain relaxation at one twitch of the train-of-four. Ventilation was adjusted to maintain the arterial blood partial pressure of carbon dioxide at baseline level. After completing the scans, xenon was discontinued and muscle relaxation was reversed with a neostigmine-glycopyrrolate combination (Robinul Neostigmin; Wyeth Lederle, Vantaa, Finland). Subjects were tracheally extubated as they recovered spontaneous breathing and regained consciousness. They were monitored for stable vital signs for a minimum of 1 h. The subjects were discharged according to our hospital's standard criteria for ambulatory surgery patients.

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PET Assessments

PET scans were performed in a dim, quiet room. Positioning of the head was done by using a plastic holder, anatomical landmarks, and laser alignment lights. Detailed information about the PET scanner (GE Advance PET Scanner, GE Medical System; Milwaukee, WI) and the image reconstruction have been presented previously.21

[18F]FDG was produced with an automated synthesis device using a modified aminopolyether-supported nucleophilic substitution method.22 Radiochemical purity of [18F]FDG exceeded 95%, and the specific activity was more than 74 GBq/μmol at the end of the synthesis. A 110 MBq IV dose of [18F]FDG was administered manually as a 20 s bolus injection. Simultaneously with the tracer injection, a 60-min dynamic three-dimensional tissue activity image acquisition was initiated as described in our previous article.23 Plasma activity of manually drawn 22 arterial blood samples was measured using an automated cross-calibrated well counter (Wizard 1480; Wallac, Turku, Finland). Plasma glucose concentration was determined at baseline before tracer administration and 30 min and 60 min after the beginning of the scan. The mean value was used in the analysis.

A 300-MBq IV bolus dose of 15O-labeled water was administered in 15 s with automated infusion equipment, followed by 90-s static three-dimensional tissue activity image acquisitions. A roller pump and two-channel detector device were used for arterial blood activity measurement. A more detailed description of rCBF measurement has been presented previously.21

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Data Analysis

Quantification of Imaging Data

The tracer activity images were first computed into parametric images using tracer kinetic modeling and plasma activity data, as described previously.19,23–25

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Preprocessing of the PET Data

The preprocessing of imaging data was performed using Statistical Parametric Mapping26 software (Wellcome Department of Cognitive Neurology, University College London, England) version 99 (SPM99) and Matlab 6.5 for Windows (Math Works, Natick, MA) with a previously described procedure.21 Each subject's image series was realigned, and the mean image of the realigned images was used in the estimation of the spatial normalization parameters for each subject. The rCMRglc and rCBF images were spatially normalized by using tracer-specific PET-image templates for [18F]FDG and 15O-labeled water, respectively.21,23

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Automated ROI Analysis

To quantify rCMRglc and rCBF, an automated ROI analysis was performed using standardized ROIs defined on a magnetic resonance imaging template image representing brain anatomy in accordance with the Montreal Neurological Institute (MNI) space database. The method has been described earlier in detail.27 This method is based on common stereotactic space, i.e., spatial normalization that automatically fits individual parametric images to a template image. Spatial normalization was performed using standard procedure of SPM99, as described later. When using automated ROI analysis, operator-induced error in defining ROIs individually for each subject can be avoided and analysis can be automated. The ROIs were defined using Imadeus (version 1.20, Forima, Turku, Finland) to bilaterally outline the frontal, parietal, medial temporal, lateral temporal, and occipital cortices, the anterior and posterior cingulate cortices, the insular cortex, the thalamus, the caudate, the putamen, the cerebellum, and the white matter.

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Voxel-Based Image Analysis

Voxel-based statistical image analysis was performed with SPM99, as described earlier.28 After the preprocessing described earlier, to improve the signal-to-noise ratio and to reduce the residual interindividual neuroanatomical variation, the parametric images were smoothed using a Gaussian filter of 12 mm full width at half maximum. Within-subject subtraction analysis with T-contrasts was used to test xenon-induced changes in rCMRglc and rCBF between the conditions. The visualizations were performed with height threshold T-value at least 6.0 for rGMR and 3.75 for rCBF. In addition, to directly explore regional changes in the ratio between these variables, a similar within-subject subtraction analysis with T-contrasts was performed for calculated rCBF/rCMRglc ratio images. As the values of parametric images are quantitative, SPM analyses were performed without global normalization, i.e., using absolute rCMRglc and rCBF values. The analyses were performed without any a priori hypothesis or spatial constrictions concerning the location of possible differences. A P value <0.05 (corrected for multiple comparisons) was considered significant. The visualization of the changes in the rCBF/rCMRglc ratio were performed with height threshold T-value at least 7.17. The nonsignificant clusters were discarded from the visualizations by adjusting the minimum cluster size (extend threshold, k). The localization of the results of the SPM analyses were made using the MNI space utility, which first converts the MNI coordinates given by SPM to Talairach coordinates using nonlinear transformation28 and then identifies each voxel by the anatomical labels presented in the Talairach Daemon database.29

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Statistical Analysis of ROI and Monitoring Data

Descriptive statistics (mean and sd) were calculated from each brain ROI. For both rCBF and vital monitoring variables, the mean values of two repeated measurements at baseline (awake) and during xenon anesthesia were calculated. The effects of xenon anesthesia on rCMRglc, rCBF, and vital monitoring variables were analyzed with a repeated measures analysis of variance (RMANOVA) model with the condition (awake/anesthesia) as a within factor. Comparisons between the baseline measurement (awake) and measurement during xenon anesthesia were performed by estimating and testing linear contrasts from the RMANOVA model (i.e., paired t-tests).

The effect of xenon anesthesia on the relationship between rCMRglc and rCBF was investigated by fitting a RMANOVA model with mean rCBF as the response variable and mean rCMRglc, condition (awake/anesthesia) and the interaction of these two as explanatory variables. In addition, brain ROI was included in the model to consider the differences between the regions. The effect was evaluated by testing the significance of rCMRglc-by-condition interaction. A two-sided P value of <0.05 was considered statistically significant. Statistical analysis was conducted with SAS (version 8.2; SAS Institute, Cary, NC).

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RESULTS

All subjects were successfully anesthetized. The mean (sd) xenon concentration during the anesthesia was 67.2 (0.8)%. One subject received a 25 μg bolus dose of remifentanil because of an evident pain reaction to intubation. Subjects' vital variables are summarized in Tables 1 and 2. Peripheral oxygen saturation, arterial partial pressure for oxygen, hematocrit, and temperature remained unchanged during the rCBF assessments. There was a decrease in arterial partial pressure for carbon dioxide and an increase in mean arterial blood pressure during anesthesia.

Table 1

Table 1

Table 2

Table 2

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Automated ROI Analysis: rCMRglc

The absolute rCMRglc values at baseline and during anesthesia, and the mean percentual changes in each brain region are presented in Table 3. The baseline rCMRglc varied between 13.2 and 36.3 μmol · 100 g−1 32 · min−1 in the studied regions. Xenon anesthesia decreased rCMRglc significantly in all studied regions. The most profound decreases were observed in the cerebellum, the posterior cingulate, and in the parietal and frontal cortices. The mean decrease in rCMRglc in the gray matter areas was 34.4 (4.0)% (P < 0.001). In cortical areas, a 35.4 (3.6)% (P < 0.001) decrease in rCMRglc was seen. rCMRglc decreased also in the white matter.

Table 3

Table 3

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Automated ROI Analysis: rCBF

The absolute rCBF values at baseline and during anesthesia and the mean percentual changes are presented in Table 4. The baseline CBF varied between 17.4 and 59.2 mL · 100 g−1 · min−1 in the studied regions. The rCBF values were highly reproducible. The coefficients of variation (sd/mean × 100%) within subjects in the gray and the white matter were 1.9% and 7.8% at baseline (awake) and 6.8% and 3.9% during anesthesia, respectively. On the average, rCBF decreased by 14.8 (5.9)% (P = 0.007) in all gray matter and by 14.7 (6.3)% (P = 0.01) in the cortical regions. rCBF increased by 9.2 (7.3)% in the white matter. The ratio of rCMR and rCBF was shifted to a higher level. (Fig. 2) The regression between rCMRglc and rCBF was statistically significant (P < 0.0001 for regression parameter). The interaction between rCMRglc and condition was statistically significant (P = 0.0259), implying that the slopes were different between the conditions (Fig. 2).

Table 4

Table 4

Figure 2

Figure 2

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SPM Analysis

SPM analysis indicated globally decreased CMRglc. The clusters representing CMRglc decreases reached all cortical regions, the cerebellum, the limbic lobe, the thalamus, the brainstem, and the lentiform nucleus. No CMRglc increases were detected (Fig. 3). The clusters representing CBF decreases were widely spread reaching the frontal, temporal, parietal, and the occipital cortices and the limbic lobes, the cerebellum, the thalamus, the brainstem, and the lentiform nucleus. No CBF increases were observed (Fig. 3). The detailed localizations of CBF decreases are presented in supplementary Table 1 (available at anesthesia-analgesia.org). The clusters demonstrating significant changes in the rCBF/rCMRglc ratio in SPM analysis are visualized in Figure 3. SPM analysis revealed that the rCBF/rCMRglc ratio was particularly increased in the pre- and postcentral gyri, i.e., in the somatosensory cortex in addition to the increases in the insula and the anterior and posterior cingulate.

Figure 3

Figure 3

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DISCUSSION

The main finding of the present study was that xenon anesthesia induced a global reduction in rCMRglc and widespread concomitant decreases in rCBF in many regions. In general, the decreases in rCMRglc exceeded the reductions in rCBF, resulting in signs of moderate luxury perfusion in some brain areas. As a result, the correlation of rCMRglc and rCBF was shifted to a higher level.

Earlier studies with rats and monkeys have demonstrated that subanesthetic xenon inhalation induces a reduction in rCMRglc.18,30 It has also been shown, with PET, that xenon anesthesia, after induction with propofol, is associated with markedly decreased glucose metabolism in humans.17 Thus, our results using awake control confirm the findings of Rex et al.17 Our earlier observations have demonstrated that an anesthetic concentration of xenon in humans also significantly reduces rCBF in many brain areas.16 These findings are supported by our present results demonstrating a uniform decrease in rCMRglc coupled with widespread reduction in rCBF. Even though xenon is thought to exert its effects via NMDA antagonism, interestingly, these xenon-induced effects on cerebral metabolism and blood flow are clearly different from other NMDA-antagonists, which have a propensity to increase both rCMRglc and rCBF in many locations.10,31,32

The preservation of the regional ratio between CMRglc and CBF is important in neurosurgical patients who benefit from neuroprotective properties of an anesthetic regimen. An earlier autoradiography study with rats inhaling 70% xenon demonstrated unchanged rCBF at steady-state inhalation along with cortical rCMRglc reduction. However, during the first minutes of inhalation, rCBF was initially elevated above the baseline. Due to the method was based on killing, rCMRglc and rCBF were assessed in different populations.18 In monkeys, 33% xenon induced a parallel reduction in whole brain CMRglc and CBF,33 whereas 80% xenon decreased CMRglc by 50% with a concomitant 50% increase in global CBF.30 However, the latter results may have been compromised by significant changes in arterial carbon dioxide levels during the experiment.

Recent observations support the present evidence that xenon anesthesia induces reductions in both rCMRglc and rCBF. Rex et al.19 found minor effects on coupling between rCMRglc and rCBF during xenon anesthesia. Their study was, however, compromised by induction with another anesthetic (propofol) and by the fact that rCMRglc and rCBF were assessed in two separate groups of subjects. Nevertheless, xenon anesthesia does not entirely disrupt the association between rCMRglc and rCBF. The decreases in rCMRglc seem to exceed the decreases in rCBF, and the changes in rCBF also demonstrate wider variability between different regions. Especially in the insula, the anterior and posterior cingulate and in the somatosensory area, the minimal reductions in rCBF resulted in an increased rCBF/rCMRglc ratio in the present study, possibly indicating luxury perfusion. We can only speculate on the basis for this phenomenon. For example, by their anatomical distribution, these areas might represent anatomical regions that are predisposed to greater perfusion being situated in the vicinity of major vessels. Interestingly, in our earlier study,16 a significant increase in rCBF was seen in the somatosensory cortex during xenon anesthesia. The present study could not confirm this finding but, notably, the ratio of rCBF and rCMRglc was markedly increased in this location. On the contrary, in the thalamus the rCBF/rCMRglc ratio remained relatively close to baseline. Metabolic depression coupled with significantly reduced rCBF in the thalamic region may represent neuronal deactivation, because it has been suggested that the anesthetic state itself is a consequence of the disorganization of the informative processing in the thalamo-cortical axis.34

At surgical concentrations many anesthetics, particularly those presumably acting through the Type-A γ-aminobutyric receptor, reduce both rCMRglc35,36 and rCBF.19,35,36 However, the anesthesia-induced reduction in rCBF because of decreased metabolism may in some occasions be overridden by the direct vasodilatory effects of the anesthetic, especially at high concentrations.11 This results in an altered relationship between rCMRglc and rCBF. Volatile anesthetics are particularly suspected to have vasodilatory effects on the cerebral vasculature. Sevoflurane, for example, has been shown to induce a reduction in rCBF, especially in the cerebellum, the thalamus, and in some cortical areas with concomitantly measured widespread greater reduction in regional cerebral metabolism.32 Accordingly, in this study, the largest absolute reductions in rCMRglc and rCBF during 1 MAC xenon anesthesia were observed in the cerebellum, thalamus, and the parietal and frontal cortices. Thus, xenon-induced changes in brain metabolism and blood flow seem to resemble those observed earlier with volatile anesthetics. Our finding of reduced rCMRglc in the white matter with a concomitant increase in rCBF may also support the conception of direct cerebral vasodilatory effects of xenon, because the increase in rCBF is not a consequence of increased metabolism. However, a possible time-related initial increase in rCBF cannot be excluded, because steady-state is reached much slower in the white matter than in gray matter.37 Even if the ROIs were drawn to avoid the margins of each separate brain region, the influence of partial volume effect cannot be totally excluded in the present study. In case of signal spilling from the gray matter regions, the true increase in the rCBF in the white matter could even be somewhat larger than those reported.

In the present study, the physiological factors known to affect rCBF were carefully standardized. There were no significant changes detected in arterial partial pressure for oxygen, temperature, hematocrit, or end-tidal carbon dioxide levels. Despite the carefully adjusted ventilation, there was, however, a minor decrease in measured values of arterial partial pressure for carbon dioxide. Within the range of 20–80 mm Hg of arterial carbon dioxide, CBF is changed approximately 2%–4% for each mm Hg.38 Thus, the effect of subtle hyperventilation on rCBF can be estimated to be only approximately 2%–4%. Also, the mean arterial blood pressure was slightly elevated but remained well within the range of intact cerebral autoregulation during the study. Based on a study with pigs, it can be assumed that xenon administration does not disrupt cerebral autoregulation.39

In conclusion, 1 MAC xenon anesthesia induced a widespread reduction in rCMRglc and a decrease in rCBF in many brain areas in our healthy subjects. In general, the magnitude of the decreases in rCMRglc exceeded the reductions in rCBF. The largest increases in the ratio between rCBF/rCMRglc were detected in the insula, the anterior and posterior cingulate, and in the somatosensory cortex, suggesting moderate luxury perfusion, especially in these areas. Interestingly, xenon-induced changes in cerebral metabolism and blood flow more closely resemble those induced by volatile anesthetics than those induced by classical NMDA-antagonists.

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ACKNOWLEDGMENTS

The authors thank the personnel of Turku PET Centre for technical assistance, Mika Särkelä and Jyrki Ruotsalainen (GE Healthcare, Helsinki, Finland) for providing monitoring equipment and for technical support, Mika Leinonen, MSc and Tanja Huovinen, MSc (4Pharma, Turku, Finland) for the statistical analyses.

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