BJA Advance Access published online on March 15, 2008
British Journal of Anaesthesia, doi:10.1093/bja/aen036
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Positron emission tomography study of regional cerebral blood flow and flow–metabolism coupling during general anaesthesia with xenon in humans 
1 Department of Anaesthesiology
2 Department of Nuclear Medicine, University Hospital, Technical University Aachen, Aachen, Germany
3 UMC St Radboud, Nijmegen, The Netherlands
* Corresponding author: Klinik für Anästhesiologie und Fachübergreifende Klinik Operative Intensivmedizin Erwachsene, Universitätsklinikum der RWTH Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany. E-mail: srex{at}ukaachen.de
Accepted for publication January 4, 2008.
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Abstract |
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Background: The effects of xenon on regional cerebral blood flow (rCBF) are controversial. Moreover, the precise sites of action at which xenon exerts its effects in the human brain remain to be established.
Methods: rCBF was sequentially assessed by H215O positron emission tomography in six volunteers. rCBF was determined at baseline and during general anaesthesia induced with propofol and maintained with one minimum alveolar concentration xenon. rCBF measurements were started after the calculated plasma concentration of propofol had decreased to subanaesthetic levels (<1.0 µg ml–1). Changes in rCBF were calculated for 13 cerebral volumes of interest by measurement of a semi-quantitative perfusion index (PI). In addition, voxel-wise changes in rCBF were analysed using statistical parametric mapping.
Results: Xenon had only minor effects on PI in grey matter volumes of interest. In contrast, PI was increased in white matter [from 1.01 (0.11) to 1.24 (0.15) kcnt ml–1 MBq–1, P=0.05, mean (SD)]. Voxel-based analysis showed an increase of rCBF in white matter and a relative decrease of rCBF during xenon anaesthesia in distinct grey matter regions, particularly the orbito- and mesiofrontal cortex, cingulate gyrus, thalamus, hippocampus and bilateral cerebellum (P<0.05 corrected). When correlating PI with cerebral metabolic rate of glucose (previously obtained in another group of six volunteers using 18F-fluorodeoxyglucose as tracer), the flow–metabolism coupling was preserved during xenon anaesthesia.
Conclusions: Xenon exerted distinct regional effects on CBF: relative decreases in several cortical, subcortical, and cerebellar areas were accompanied by an increase in white matter. Flow–metabolism coupling was not impaired during xenon anaesthesia.
Keywords: anaesthetics gases; brain, blood flow; brain, metabolism; neurophysiology; special drugs, xenon
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Introduction |
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The effects of xenon on the central nervous system are only incompletely understood. Xenon was demonstrated not to enhance the activity of inhibitory gamma-aminobutyric acid type-A receptors, but to interfere with excitatory neural mechanisms by inhibiting N-methyl-D-aspartate (NMDA) glutamate receptors.1 Moreover, xenon was shown to activate background potassium channels, thereby inducing neuronal hyperpolarization.2 In a recent positron emission tomography (PET) study, we demonstrated that xenon induces a widespread pattern of metabolic depression in the human brain similar to that of volatile anaesthetics, but contrasting that of ketamine. This pattern suggests that NMDA receptor-antagonism may not be the primary mechanism of anaesthetic action for xenon in the human brain.3
Under physiological conditions, regional cerebral metabolic rate of glucose (rCMRglc) reflects neuronal activity, while regional cerebral blood flow (rCBF) is closely coupled to rCMRglc.4 Hence, a decrease in cerebral metabolism as induced by xenon should be accompanied by a decrease in rCBF. During anaesthesia, however, flow–metabolism coupling may be impaired in humans due to possible vasodilatory effects of anaesthetics.5 6 Therefore, it is fundamental to analyse the effects of xenon on human rCBF in addition to its known effects on rCMRglc. In animal studies, xenon has been demonstrated to induce ambiguous effects on CBF, depending on the different experimental conditions, the species under investigation, and the concentrations of xenon.7–9 Likewise, studies in humans have produced conflicting results.10 11
In order to further explore the neural mechanisms of xenon anaesthesia, we studied the effects of general anaesthesia with one minimum alveolar concentration (MAC) of xenon on rCBF with PET. On the background of our recent findings of a marked metabolic depression induced by xenon in the human brain, we hypothesized that xenon anaesthesia would induce a widespread decrease in rCBF.
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This study was approved by the Institutional Review Board (Ethik-Kommission, Medical Faculty, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany) and the Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, Salzgitter, Germany). Written informed consent was obtained from each participant.
Six adult right-handed male volunteers were recruited through flyers and the internet and underwent a careful medical examination before admittance to the study. All subjects were ASA-I, non-smokers, and in excellent medical condition. None of them had a history of neuropsychiatric, other systemic diseases or drug abuse which was confirmed with a toxicological urine test. All volunteers received financial compensation for their inconvenience.
The subjects underwent three PET scans twice in a fixed order: the first three scans were acquired when the subjects were awake, the subsequent three PET scans were taken during general anaesthesia with one MAC xenon. rCBF was measured using 15O-labelled water (H215O) as PET tracer. Owing to the relatively high noise level of H215O PET, scans were performed in triplicate. The scans were performed with an inter-scan interval of at least 10 min, sufficient for virtually complete decay of the remaining radioactivity of the preceding scan given the short half-life of 15O (122 s). The subjects fasted for at least 8 h and were refrained from consuming caffeine and alcohol for 24 h before undergoing the first PET scan. All PET studies were performed at low ambient noise and dimmed light. During the awake-scans, the volunteers were instructed to lie down motionless, relax and close their eyes while breathing room air. In two subjects, only two PET scans were acquired during xenon anaesthesia because of technical problems.
During each scan, monitoring consisted of ECG, oscillometric arterial pressure measurement, pulse oximetry (all Datex Ohmeda GmbH, Duisburg, Germany), measurements of inspired and expired oxygen, nitrogen, carbon dioxide and xenon (Physioflex, Dräger Medical Deutschland GmbH, Lübeck, Germany), electroencephalography using the bispectral index (BISTM A-2000TM monitor, Aspect Medical Systems, Leiden, The Netherlands), and measurements of tympanic membrane temperature. Two i.v. catheters were placed into antecubital veins, one on each side, one was dedicated to administering H215O, the other for basic fluid substitution (2–3 ml kg–1h–1 Ringer's solution) and the induction dose of propofol.
After 5 min of pre-oxygenation with 100% oxygen, anaesthesia was induced with a target-controlled infusion (TCI) of propofol (‘Pilot Anaesthesia’ syringe pump with a ‘Master TCI’ unit, Becton Dickinson, Heidelberg, Germany). The pump was controlled by the ‘Diprifusor’ TCI software algorithm (AstraZeneca, Macclesfield, UK). Anaesthesia was induced with a target plasma concentration of 10.4 (1.2) µg ml–1 propofol to allow the insertion of a laryngeal mask (LMA). The propofol infusion was stopped once the airway was secured. Anaesthesia was then maintained with xenon [60 (1)% in oxygen] using a closed-circuit anaesthesia machine (Physioflex; Dräger Medical Deutschland GmbH, Lübeck, Germany). Subjects were ventilated with pressure control maintaining normocapnia.
H215O was administered when the following criteria were met:
- the calculated propofol plasma concentrations were below 1.0 µg ml–1, that is, in a subanaesthetic range;12
- a deep level (suggested by a bispectral index <35) and steady-state of general anaesthesia with one MAC xenon was achieved.
Both criteria were achieved within 54 (9) min of xenon anaesthesia. After this time, equilibration of xenon with the grey and the white matter of the brain is achieved.13 Following the last PET scan, administration of xenon was stopped and the LMA removed after spontaneous breathing had resumed. After emergence from anaesthesia, subjects were monitored for stable vital signs for at least 1 h and were discharged according to the standards of our department for outpatient anaesthesia.
Positron emission tomography imaging
H215O was synthesized online using an ODS 111 cyclotron (Siemens/CTI, Knoxville, TN, USA). PET examinations were done on an ECAT 922/47 scanner (Siemens/CTI) in two-dimensional mode. Subjects were positioned under laser guidance in canthomeatal orientation. The laser beams of the scanner and reference skin marks were used to monitor subject positioning and correct for possible head movements. Attenuation correction was performed by 68Ge/68Ga transmission scanning (10 min). To accommodate for head movements during airway instrumentation, two transmission scans were acquired: one immediately before the first awake PET scan (for correction of the awake scans), the other after the final anaesthesia scan (for correction of the anaesthesia scans). Dynamic PET emission scanning lasting 261 s (frame sequence: 7x3, 6x5, 6x10, 3x20, and 3x30 s) started with injection of a target radioactivity dose of 700 MBq H215O. Injection was done as a slow bolus over 10 s using a syringe pump. Reconstruction of 47 transversal slices (thickness 3.38 mm; matrix 128x128) was performed using filtered back projection with a Hanning filter (cut-off frequency 0.45 Ny) and zoom factor of 3.0 resulting in pixel size of 1.72x1.72 mm2.
For further image analyses, an integral PET image of the first 60 s after arrival of the tracer in the subject's head reflecting relative rCBF was calculated.14 Time of tracer arrival was determined for each scan individually using a whole brain region of interest. Dynamic image integration and region or volume of interest (VOI)-based analyses were done using commercial software packages (PMOD V.2.65, PMOD Technologies, Adliswil, Switzerland). Employing the Statistical Parametric Mapping software package (SPM2; Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London, UK)15 implemented on Matlab (The Mathworks, Inc., Natick, MA, USA), all integral PET images of one subject were realigned to each other and subsequently spatially normalized to the SPM PET template by applying the normalization parameters of the spatially normalized mean integral image to all individual images (yielding a voxel size of 2x2x2 mm3 in 128x128x128 matrix).
A standard VOI set was created by defining irregular VOI on the SPM MRI T1 template, which corresponds spatially to the aforementioned PET template. The following 13 VOI were defined: frontal cortex, frontobasal cortex, temporal cortex, mesiotemporal region (including hippocampus, amygdala and the overlaying mesiotemporal cortex), parietal cortex, occipital cortex, cingulate gyrus, insula, striatum, thalamus, cerebellum, pons, and centrum semiovale. Quantification of the relative rCBF changes was performed as previously proposed by Arigoni and colleagues.16 Side-averaged regional integrals of radioactivity concentrations over 60 s were read-out from the integral PET images using the standard VOI set and normalized to the injected dose (referred to as perfusion index, PI). The relative change in rCBF was subsequently calculated as the per cent change of the PI during anaesthesia relative to the PI during wakefulness. This measure has previously been shown to be highly correlated with relative changes of absolutely quantified rCBF as observed during an acetazolamide challenge for assessment of cerebrovascular reserve capacity.16
In addition to the VOI-based analyses, we performed voxel-wise statistical analyses using SPM2 to assess effects of xenon anaesthesia on rCBF on a voxel level. This analysis employed proportional scaling of the PET datasets to remove the effect of inter-individual and -condition (wakefulness/anaesthesia) variations in global CBF. The mean voxel value was determined using the standard ‘within per image fullmean/8’ mask. This analysis highlights CBF changes that fall below or exceed global changes. After a preceding Gaussian smoothing (10 mm full width at half maximum), the spatially normalized individual integral PET images were used to calculate statistical parametric t-maps (multi-subject design: condition effect, no covariates), which were thresholded at a t-value (height-threshold) of 6.54 (corresponding to P<0.05, corrected for multiple comparisons) and 30 voxels (0.24 cm3; extent threshold). The Montreal Neurological Institute (MNI) coordinates (McGill University, Montreal, Quebec, Canada) of significant clusters provided by SPM2 were converted to Talairach coordinates.17 The Talairach Daemon software (University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; available at: http://ric.uthscsa.edu/projects/talairachdaemon.html, accessed October 5, 2007) was employed for guidance in anatomical localization.
The effects of xenon on physiologic variables were compared using Student's t-test for paired samples. Per cent changes in PI induced by xenon were compared with xenon-induced effects on CMRglc previously studied in six different subjects by our group using 18F-fluorodeoxyglucose as tracer. In these subjects, we employed the identical anaesthetic protocol as in the present study (induction of anaesthesia with a TCI of propofol, maintenance of anaesthesia with one MAC of xenon, assessment of CMRglc during steady-state of xenon anaesthesia).3 For this comparison, parametric CMRglc PET image datasets were re-analysed using the procedure described above (spatial normalization, identical VOI analyses), and the Mann–Whitney U-test was used for statistical comparison. In order to investigate whether xenon anaesthesia affects the regression slope (rCMRglcxcondition interaction) between rCMRglc and regional PI, we performed an analysis of covariance (ANCOVA) with regional PI as dependent variable, and rCMRglc (continuous variable) and the condition (wakefulness/xenon; categorical) being independent variables. Furthermore, the PI calculation included normalization for injected dose per body weight to remove the effect of differences in body weight between subjects. In each case, a two-sided P<0.05 was considered statistically significant. Data are presented as mean (SD).
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The volunteers were of age 38(8) years, weight 90(7) kg, and height 188(6) cm. Inhalation of one MAC xenon [60 (1) vol%] was associated with a deep state of anaesthesia, as judged by clinical signs and bispectral index. No participant reported an episode of awareness after emerging from anaesthesia. Xenon anaesthesia was well tolerated by all participants. Cardiopulmonary variables did not differ from those in the awake condition, except from a moderate decrease in the heart rate (Table 1).
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Xenon decreased the PI in all grey matter VOIs, particularly in the thalamus, cingulate gyrus, and cerebellum. Although these changes are visually appreciable when comparing the group mean spatially normalized PI images of both conditions (see Fig. 1), these effects failed to reach statistical significance (Fig. 2A) because of the high inter-individual variability. In contrast, white matter rCBF was increased in every participant (group mean PI increased from 1.01 (0.11) to 1.24 (0.15) kcnt ml–1MBq–1, P=0.05) (Figs 1 and 2A). When compared with glucose metabolism, general anaesthesia with one MAC xenon decreased CMRglc in excess of the effects on rCBF in all brain regions studied (Fig. 2B). This finding was most pronounced in white matter (centrum semiovale), where, in fact, xenon induced a decrease in rCMRglc but an increase in rCBF. Using an ANCOVA, flow–metabolism coupling was, however, found not to be impaired by xenon anaesthesia (Fig. 3). Only CMRglc exhibited a significant effect on regional PI [CMRglc regression parameter=0.348 (0.120), P=0.008; intercept=157.4 (4.1), P<0.0001; ANCOVA F(2,25)=5.23, r2=0.31, P=0.013], while this correlation was affected neither by the condition (wakefulness/xenon; P>0.76) nor by the interaction CMRglcxcondition (P>0.74; i.e. testing the difference in regression slopes for the association of PI and CMRglc between both conditions).
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CMRglc vs
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SPM analyses revealed highly significant effects of one MAC xenon on rCBF. After proportional scaling (i.e. removal of global CBF effects), rCBF was increased in white matter (Fig. 4). In contrast, xenon anaesthesia induced rCBF decreases in distinct grey matter regions (Table 2, Fig. 5). In particular, rCBF was bilaterally reduced in the orbito- and mesiofrontal cortex, anterior and posterior cingulate gyrus, thalamus, hippocampus, and cerebellum. No relative rCBF increases could be detected in any grey matter region.
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We demonstrated that general anaesthesia with one MAC xenon caused distinct effects on rCBF. Relative rCBF decreases in several cortical, subcortical, and cerebellar areas were paralleled by an rCBF increase in white matter. In addition, we found the coupling of cerebral glucose metabolism and blood flow preserved during xenon anaesthesia.
Animal studies on the effects of xenon on CBF have produced conflicting results, varying with the different experimental conditions and animal species (i.e. rats,9 pigs,8 and monkeys7). These results are, however, confounded by lack of equipotency due to the species dependency of MAC-values for xenon. In humans, brief periods (5 min) of 35% xenon inhalation were found to increase CBF as assessed by 133xenon-clearance.10 In that study, however, the chosen xenon concentration induced a rather excitatory than anaesthetic state. In contrast, we studied the effects of more than 60% xenon (i.e. one MAC in humans).18 This concentration was associated with a deep state of anaesthesia as suggested by clinical signs. Although not validated for xenon, the bispectral index accordingly showed a profound decrease, probably indicative for a pattern of high voltage—low frequency EEG activity characteristic of anaesthesia.19 Most importantly, our study confirms the observations of Laitio and colleagues.11 Using a comparable study design with steady-state inhalation of 63% xenon, they found that xenon decreased absolute rCBF in a magnitude of 20–30% in 5 of 12 studied grey matter regions, whereas no effects were observed in the remaining regions. In contrast, rCBF was increased by 
22% in white matter, an extent nearly identical to our observations.
Under normal conditions, regional neuronal activity, energy metabolism, and rCBF are tightly coupled within the brain.4 On the other hand, anaesthetics like sevoflurane, desflurane, isoflurane, nitrous oxide, and ketamine are known to affect the delicate balance between flow and metabolism.6 20–22 To our knowledge, the effects of xenon on flow–metabolism coupling have not been studied in humans yet. We therefore compared the effects of xenon on CBF with the effects of xenon on CMRglc. For reasons of radiation protection, the latter have been previously assessed in six different subjects, using 18F-fluorodeoxyglucose as tracer but employing an identical anaesthetic design.3 Interestingly, we found xenon to decrease CMRglc in excess of the effects on CBF. This finding is compatible with the well-known effect of volatile anaesthetics to induce cerebral vasodilation5 and consequently increase rCBF independently from regional metabolic needs. Interestingly, also xenon was found to have direct vasodilatory capacities within the brain.23 However, we did not find convincing evidence that xenon impairs flow–metabolism coupling. In fact, the slopes of the regression lines for the association between PI and CMRglc did not differ during wakefulness and xenon anaesthesia (non-significant ANCOVA interaction term CMRglcxcondition). This finding is in agreement with a previous report in rats where the coupling of CBF and CMRglc was found preserved (but reset to a higher level by xenon).9 On the other hand, xenon decreased CMRglc while even increasing CBF in white matter regions. This may be explained by a relative lack of neuronal activity-dependent glucose metabolism in white matter. Anaesthetics primarily reduce cerebral glucose metabolism (and ultimately blood flow) by suppressing functional neuronal activity, whereas energy metabolism subserving structural intactness is not affected.24 Therefore, anaesthetics preferentially decrease cerebral metabolism and blood flow within grey matter. Since functional neuronal activity is low in white matter already during wakefulness, a further reduction of functional metabolism by anaesthetics appears to be much less pronounced than in grey matter. This may unveil direct effects of xenon on cerebral vasculature within white matter (i.e. effects not related to cerebral metabolism and neuronal activity). Therefore, subtle decreases in rCBF mediated by metabolic depression as a result of a decrease in functional activity may have been offset by predominating direct vasodilatory effects of xenon in white matter.
Using proportional scaling in the SPM analyses allows to study variations in regional CBF independent from differences in global CBF among volunteers and between conditions possibly obscuring the relative inter-regional changes caused by xenon itself.25 In fact, general anaesthesia with xenon caused a relative decrease of rCBF in several distinct grey matter areas, beyond possible changes in global CBF. This finding contrasts with observations from anaesthetics interacting with the excitatory NMDA-receptor-system, such as nitrous oxide and ketamine which provoke marked rCBF increases.6 20 In contrast, the decrease of rCBF observed in our study is similar to that reported for volatile anaesthetics and propofol in humans.20 Hence, our results suggest that NMDA receptor-antagonism may not be the primary mode of anaesthetic action for xenon in vivo. In fact, evidence from recent in vitro studies indicates that xenon might exert its effects on the human brain by mechanisms unrelated to glutamatergic signalling.2 Accordingly, we previously demonstrated that xenon anaesthesia in humans is associated with a reduction in global and regional cerebral glucose metabolism resembling that of volatile anaesthetics and opposite to the effects of ketamine and nitrous oxide.3
The pattern of rCBF changes might reveal important sites of action for xenon. For instance, voxel-based analysis with SPM showed a pronounced decrease of rCBF in the thalamus. Hyperpolarization of thalamocortical neurons is postulated to be the essential common neurophysiologic mechanism underlying anaesthetic-induced unconsciousness.26 Other brain areas remarkably affected by xenon were the cingulate gyrus, the orbito- and mesiofrontal cortices, the amygdala and hippocampus. These brain regions are critically involved in the control of consciousness, sleep–wake-rhythm, cognitive functions, memory, autonomic cardiovascular regulation, and pain.27–29 It is therefore tempting to speculate that some of the unique characteristics of xenon anaesthesia may be partly associated with depression of distinct cerebral areas.
We acknowledge that our study suffers from some limitations: for ethical reasons, we avoided arterial cannulation in order to minimize procedure-related risks for the participants. Therefore, absolute quantification of CBF was not possible. Instead, CBF was estimated with PI, for which a high linear correlation with absolute rCBF changes was found previously.16 In addition, our findings based on PI agree with the study of Laitio and colleagues who quantified rCBF absolutely by measurement of arterial blood activity.11 For reasons of radiation protection, we had to assess the effects of xenon anaesthesia on rCBF and rCMRglc in different subject populations. This certainly limits the ability to detect a possible flow–metabolism uncoupling given the high inter-individual variations of CBF and CMRglc.
Securing the airway with a LMA was warranted in order to ensure ventilation and to control end-tidal carbon dioxide concentration, an important determinant of CBF. The use of a LMA represents an important state-related difference associated with pharyngeal stimulation that may have caused a certain degree of arousal counterbalancing the pure effects of xenon anaesthesia on neuronal activity and consequently blood flow.
Anaesthesia was induced with high doses of propofol to allow the insertion of a LMA in the unpremedicated healthy subjects. In order to minimize confounding influences of propofol on xenon-related effects on rCBF, propofol was stopped immediately after insertion of the LMA, and PET-assessments were started only after calculated propofol plasma concentration had fallen below 1.0 µg ml–1. We suggest, however, that the use of propofol did not affect xenon-related effects on CBF to a major extent. In the range of 0.5–1.5 µg ml–1, propofol does not or only slightly affects rCBF.30 Accordingly, we recently demonstrated that subanaesthetic concentrations of propofol as used in the present study are devoid of effects on cerebral metabolism.3 This likely also holds true for CBF since propofol was shown not to disturb flow–metabolism coupling.20
In summary, xenon anaesthesia exerted distinct effects on rCBF. Relative rCBF decreases in several cortical, subcortical, and cerebellar areas were paralleled by a rCBF increase in white matter. In general, effects on rCMRglc exceeded the effects on rCBF. However, flow–metabolism coupling appeared to be preserved during xenon anaesthesia. The rCBF pattern during xenon anaesthesia may explain some of the unique features of xenon anaesthesia. Furthermore, it agrees with recent theories that the inhibition of the glutamatergic system seems to be only of minor significance for the anaesthetic action of xenon in vivo.
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Support was provided from START (AZ 25/02), a research grant of the Rheinisch-Westfälische Technische Hochschule, Aachen, Germany, and from institutional and departmental sources.
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Declaration of Interest. The Department of Anaesthesiology has received funding from Messer-Griesheim GmbH, Business Unit Messer Medical, Krefeld, Germany. 
S. Rex and P. T. Meyers contributed equally to this study.
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