Emergence and early cognitive function in the elderly after xenon or desflurane anaesthesia: a double-blinded randomized controlled trial

British Journal of Anaesthesia 98 (6): 756 62 (2007) doi:10.1093/bja/aem103 Advance Access publication May 7, 2007 Emergence and early cognitive function in the elderly after xenon or desflurane anaesthesia: a double-blinded randomized controlled trial M. Coburn 1 * #, J.-H. Baumert 1 #, D. Roertgen 1, V. Thiel 1, M. Fries 1, M. Hein 1, O. Kunitz 1, B. Fimm 2 and R. Rossaint 1 1 Department of Anaesthesiology and 2 Department of Neuropsychology, University Hospital Aachen of the RWTH Aachen, Pauwelsstreet 30, D-52074 Aachen, Germany *Corresponding author. E-mail: mcoburn@ukaachen.de Background. Postoperative cognitive impairment after general anaesthesia, especially in the elderly, is a well-recognized problem. Xenon, known to be an N-methyl-D-aspartate antagonist, may be advantageous. In this study, the early cognitive function in the elderly after general anaesthesia with xenon was compared with that after desflurane. Methods. After approval by the local ethical committee and after obtaining written informed consent, patients were enrolled in this randomized, double-blinded, controlled study. Thirty-eight patients (65 75 yr old, ASA status I III) undergoing an elective surgery with a planned duration of 60 180 min were allocated to either the xenon (n¼18) or the desflurane (n¼20) anaesthesia group. The primary outcome was the cognitive Test for Attentional Performance (TAP) with its subtests Alertness, Divided Attention, and Working Memory. After baseline assessment 12 24 h before operation, patients were followed-up 6 12 and 66 72 h after operation. Secondary outcomes were emergence times from anaesthesia and the modified Aldrete score. Results. No difference was found between the groups in the TAP at 6 12 and 66 72 h after operation. In the xenon group, emergence time was significantly faster for the following parameters: time to open eyes (P¼0.001), to react on demand (P¼0.001), to extubation (P¼0.001), and for time and spatial orientation (P¼0.007). The modified Aldrete score was significantly higher after 30, 45 and 60 min in the xenon group. Conclusions. There was no difference in the postoperative cognitive testing at 6 12 and 66 72 h. Xenon was associated in the elderly with a faster emergence from general anaesthesia than desflurane. Br J Anaesth 2007; 98: 756 62 Keywords: anaesthetics gases, xenon; anaesthetics volatile, desflurane; anaesthesia, geriatric; recovery, cognitive; recovery, postoperative Accepted for publication: March 7, 2007 Cognitive impairment can be a problem in elderly patients during the early postoperative period and rapid recovery from anaesthesia may offer advantages in these patients. 1 Age can be a risk factor for early and late postoperative cognitive dysfunction. 2 Xenon is an N-methyl-D-aspartate (NMDA) receptor antagonist 3 and exhibits considerable protective effects in in vitro and in vivo models of neuronal injury. 4 6 In recent multicentre trials, xenon has proven to be a safe anaesthetic agent 7 8 with good haemodynamic stability. 9 13 A licence for xenon to be used as an anaesthetic was issued by the German Medical Products and Drugs authorities in October 2005. Xenon and desflurane have similar pharmacokinetic properties, with low bloodgas partition coefficients [xenon (0.115) and desflurane 14 15 (0.42)], that favour rapid emergence from anaesthesia. The aim of this study was to determine whether xenon, Declaration of interest. This work was supported by Air Liquide Deutschland GmbH (donor of xenon) and Baxter Germany GmbH (financial support). None of the authors received any corporate support, honoraria, etc. from any of the above-mentioned sponsors of this study. # The first two authors contributed equally. # The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Cognitive function after xenon or desflurane anaesthesia in comparison with desflurane [age-adapted minimum alveolar concentration (MAC)], can positively influence early cognitive function in the elderly after general surgery with a planned anaesthesia time of 60 180 min. The primary outcome measure was the Test for Attentional Performance (TAP) along with the subtests of Alertness, Divided Attention, and Working Memory. Methods This study was designed as an inpatient, randomized, double-blinded, controlled trial. The study protocol was approved by the local ethical committee and took place in the University Hospital, Aachen. The study subjects were randomly allocated to a xenon or desflurane anaesthesia group using an allocation sequence generated with the software RandList Version 1.0 copyright DatInf. Patients and investigators assessing the data in the post-anaesthetic care unit and the TAP were blinded with regard to group allocation. Blinding the anaesthetist was not possible owing to the different administration methods of the inhaled anaesthetics. All patients gave informed, written consent before participation in the clinical trial. The primary outcome measure was the TAP with the tests for Alertness, Divided Attention, and Working Memory. Secondary outcome measures were the emergence times from anaesthesia and the modified Aldrete scores in the post-anaesthetic care unit. After a patient was assessed for eligibility, the baseline TAP (discussed later) was accomplished 12 24 h before operation, in a quiet room. The study subjects were visited by the investigator and were instructed, in a standard way, on the use of the test. The postoperative testing at 6 12 h and 66 72 h was assessed in the same way for each patient. Thirty-eight patients aged 65 75 yr with ASA status I III undergoing elective general surgery of a planned duration of 60 180 min were enrolled in this study. The study subjects were scheduled for surgery in trauma, ear, nose, and throat, gynaecology and urology. Exclusion criteria included: chronic alcohol or drug abuse, disturbed liver and renal function, diabetes mellitus, disabling neuropsychiatric disorders, history of stroke, CPR and brain trauma in the last 12 months, hypersensitivity to anaesthetics, emergency operation, increased intracranial pressure, history of myocardial infarction, adrenal insufficiency, congestive heart failure, and lack of cooperation or legal incapacity. Monitoring of the patients included ECG, pulse oximetry, non-invasive blood pressure, temperature (AS/3 monitor, GE Datex-Ohmeda, Helsinki, Finland), bispectral index monitoring (BIS Model A-2000 w, software version 2.21, Aspect Medical Systems), end-tidal carbon dioxide, oxygen, and anaesthetic gas concentration. The study subjects were preoxygenated with 100% oxygen for 3 min. In both groups, anaesthesia was induced i.v. with a single dose of propofol 2.0 mg kg 21 and remifentanil at 0.5 mgkg 21 by infusion over 60 s. Tracheal intubation was facilitated by rocuronium 0.6 mg kg 21. Xenon administration was started (xenon group) with 60% xenon in 30% oxygen reflecting a MAC value of xenon of approximately 0.95. Desflurane was started with age-adapted equipotent MAC values of 1 with 5.2 5.5 vol% in 30% oxygen (Cato w, Draeger, Lübeck, Germany). 16 Xenon of medical quality was provided by Air Liquide Deutschland GmbH (Business Unit, Krefeld, Germany) in steel cylinders and administered using a closed circuit anaesthesia machine (Physioflex w, Draeger, Lübeck, Germany) with modified software to reduce xenon consumption under minimal flow conditions. Inspiratory xenon concentration was determined using a thermo-conductivity measuring device incorporated in the anaesthesia machine (accuracy: +3 vol%), which was calibrated automatically when starting. Maintenance of anaesthesia was achieved by either xenon or desflurane. Remifentanil was administered by infusion at a base rate of 0.15 mg kg 21 min 21 and then titrated to clinical needs based on the patient s haemodynamic (systolic arterial blood pressure or heart rate more than 20% from baseline), autonomic (sweating, salivation, flushing), and somatic signs (movement, swallowing). The remifentanil infusion was increased by increments of 0.05 mg kg 21 min 21 until symptoms were resolved. Standard treatment of blood loss and fluid replacement strategy were used if necessary. Depth of anaesthesia was monitored using bispectral index monitoring aiming to produce a BIS value between 40 and 60 in both groups (noting that BIS monitoring has not been validated for xenon anaesthesia). Twenty minutes before the estimated end of surgery piritramide 0.05 mg kg 21 for postanaesthetic pain management was administered i.v. and a short infusion of metamizole 15 mg kg 21 was given. Ten minutes before the estimated end of surgery the inhaled anaesthetics were reduced to 0.5 MAC. Anaesthesia was discontinued when all surgical interventions, including the bandaging of the surgical fields, were completed and complete recovery of neuromuscular block was reached. From this time point, end-expiratory carbon dioxide was allowed to increase to 6.6 kpa. The patients tracheas extubated when the upper airway reflexes were fully recovered and their respiratory function was adequate (regular breathing at.8 breaths min 21 and Sa O2.95% at FI O2 100%) and they were haemodynamically stable. The emergence times from anaesthesia were recorded, including the time of tracheal extubation. At 20 s intervals, starting from discontinuation of the anaesthetic, a blinded investigator asked each patient to open his or her eyes, squeeze the investigator s hand, state time and spatial orientation until correct answers were given. All patients were discharged from the operating room to the post-anaesthetic care unit for immediate recovery. In the post-anaesthetic care unit, piritramide 0.05 mg kg 21 was 757

Coburn et al. given if VAS for pain was.3. The modified Aldrete scores with a 10-point scale were recorded in the post-anaesthetic care unit at 5, 15, 30, 45, 60 min and at discharge. 17 The primary outcome measure was cognitive function assessed with the computerized TAP (Version 1.7; Psytest, 2002). The TAP is designed to control for a number of factors that would interfere with testing, such as sensory and motor failures, disturbances of memory, and speech disturbances. Therefore, the test consists of low complexity tasks, to allow the evaluation of very specific deficiencies, using simple and easily distinguishable stimuli that the patients react to by a simple motor response. In addition, the subtests Alertness, Divided Attention, and Working Memory were used. The Alertness test includes a simple and a cued reaction time task with a visual test stimulus and an acoustic cue. The simple reaction time has been shown to be a valid measure of general slowness, whereas the difference between simple and cued reaction time is a measure of phasic alertness. The Divided Attention performance is investigated by dual tasks. The visual task consists of crosses that appear in a random configuration in a 44 matrix. The subject has to detect whether the crosses form the corners of a square. The acoustical task includes a regular sequence of high and low beeps. The subject is instructed to detect an irregularity in the sequence. The Working Memory test requires a continuous control of the information flow through short-term memory. For this, numbers are presented on the screen that must be compared with numbers subjects were previously exposed to. The repetition of a number within a short interval has to be answered by pressing a key. The test was administrated with the highest level of difficulty. Test efficiency was measured by assessing quality and speed. This was done by rating the reaction times of all valid reactions. As a measure of efficiency quality, the number of valid reactions is counted. These include all reactions, excluding false reactions, lapses, or reactions outside a certain time gap. The TAP assessment was completed by the study subjects in about 30 min. The sample size was calculated for the primary outcome measure with a power of b¼0.8 and significance level of a¼0.05, considering a difference of 20% as relevant. Median and standard deviation were taken from the TAP databases (patients aged.65 yr, with the subtests Alertness, Divided Attention, and Working Memory). The power was calculated for each subtest of the TAP (Alertness, Divided Attention, and Working Memory) with n¼8 17 per group. The trial size to be analysed was determined in total with n¼38. The power analysis was calculated with the SAS software version 8.0 w (SAS Institute Inc.). The significance criterion for all used tests was a¼0.05. Age, height, and weight were tested with one-way ANOVA and shown as mean and standard deviation. Gender, education, ASA classification, PONV, and nicotine abuse are calculated with the two-tailed Fisher s exact test and shown in total numbers. Average anaesthetic gas concentrations are displayed as mean and standard deviation. The type of surgery is shown as frequencies and percentage of total, and is tested with the two-tailed Fisher s exact test. Anaesthesia and surgery time, remifentanil consumption, intra- and postoperative piritramide consumption, and assessment times are tested with the one-way ANOVA. Emergence times from anaesthesia are presented as mean and upper and lower 95% confidence intervals. Modified Aldrete scores are presented as mean and standard deviation. Emergence time and modified Aldrete scores are analysed with one-way ANOVA. The values of the TAP are transformed into normalized values using the 12 24 h preoperative assessment as baseline. The normalized values are presented as means, standard deviation, and 95% confidence intervals, and are tested with one-way ANOVA. The lesser or greater than 20% deviation of normalized values of the TAP are shown as frequencies and percentage of the total, and are tested with the two-tailed Fisher s exact test. Statistical analysis was performed using the SPSS software version 12.0 w (SPSS Inc.). Results A total of 38 patients, 18 in the xenon and 20 in the desflurane group, were included in this study. The 6 12 h postoperative assessment was completed by 17 patients in the xenon and 19 patients in the desflurane group and the 66 72 h assessment by 14 and 15 patients, respectively. The reasons for dropout are given in Figure 1. The two study groups were comparable with respect to age, height, weight, gender, education level, and ASA status (Table 1). There was no difference between the type of surgery or surgery and anaesthesia times (Table 2). Intraoperative remifentanil and piritramide requirements did not differ. The intraoperative blood loss was,200 ml per patient in both groups, except for one patient in the xenon group who had a total blood loss of about 500 ml. None of the patients received a blood transfusion. Maintenance of anaesthesia was with an end-tidal concentration of 53 (2)% xenon or 4.0 (0.2)% desflurane. The assessment of the TAP was carried out at similar time points. The 6 12 and 66 72 h postoperative tests results were normalized to the 12 24 preoperative baselines. There was no difference between the groups for 6 12 and 66 72 h postoperative values of the mean reaction times and valid reactions for the Alertness (P¼0.62 and P¼0.46; P¼0.63 and P¼0.46), Divided Attention (P¼0.29 and P¼0.49; P¼0.21 and P¼0.56), and Working Memory (P¼0.07 and P¼0.46; P¼0.52 and P¼0.9) (Table 3). The numbers above or below the +20% deviation from the 12 24 h preoperative baseline did not differ between the xenon and desflurane groups at the 6 12 and 66 72 h postoperative assessment for all the tests (Table 4). 758

Cognitive function after xenon or desflurane anaesthesia Fig 1 Flow chart. Emergence times for the xenon group were significantly faster for the following parameters: time to open eyes (P,0.01), to react on demand (P,0.01), to extubation (P,0.01), and for time and spatial orientation (P,0.01) (Table 5). In the post-anaesthetic care unit, the modified Aldrete scores were significantly higher after 30, 45, and 60 min, but were not different by the time of discharge (Table 6). Table 1 Patient data. Age is given as mean (range). Height and weight of the study subjects are given as mean (SD). Gender, total school education,12 or 12 yr, and ASA classification are given in numbers. No significant differences between the groups were noted Desflurane (n520) Xenon (n518) P-value Age (yr) 70 (65 75) 69 (65 75) 0.21 Height (cm) 167 (7) 172 (6) 0.06 Weight (kg) 77 (14) 79 (12) 0.64 Gender male/female 11/9 13/5 0.11 Education,12/12 yr 18/2 14/4 0.28 ASA I/II/III 2/14/4 0/12/6 0.29 Discussion Early cognitive function in the elderly was compared after xenon or desflurane anaesthesia. The primary outcome measure, the TAP, showed no difference between the groups at the 6 12 and 66 72 h postoperative assessments. The emergence times from xenon anaesthesia were faster than those for desflurane. The modified Aldrete scores were similar or at some time points higher in the xenon group. To ensure comparability, we chose desflurane because of the rapid emergence from anaesthesia. Xenon was used with an average concentration of 53.1% which equals 84.3% of a MAC. For desflurane, a mean of 4.0% was used which is around 75% of an age-adapted MAC. 16 Though no age-adapted MAC values for xenon are known, we assumed that the concentrations of the anaesthetics used were comparable. Previous studies have looked at different outcome measures of early cognitive function in the elderly after general anaesthesia with desflurane or sevoflurane. Chen and colleagues 18 used the Mini-Mental State test and 759

Coburn et al. Table 2 Anaesthesia data and time points of testing. Average anaesthetic gas concentration is given as mean (SD). Type of surgery is presented in number and percentage of the total in parentheses. Anaesthesia and surgery times are displayed as means with the upper and lower 95% confidence interval. Remifentanil values and intra- and postoperative piritramide consumption are presented as mean (SD). All time points are shown in hours and minutes with the upper and lower 95% confidence interval Desflurane Xenon P-value Average anaesthetic gas concentration (%) 4.0 (0.2) 53 (2) Type of surgery 0.74 Trauma 8 (40) 7 (38.9) Head, neck, and ear 3 (15) 2 (11.1) Gynaecology 5 (25) 3 (16.7) Urology 4 (20) 6 (33.3) Anaesthesia time (min) 126 (102 150) 118 (98 138) 0.58 Surgery time (min) 101 (79 123) 90 (72 108) 0.42 Remifentanil consumption (mg kg 21 min 21 ) 0.112 (0.035) 0.139 (0.040) 0.08 Intraoperative piritramide consumption (mg) 6.4 (2.4) 5.6 (1.2) 0.22 Postoperative piritramide consumption (mg) 8.3 (4.4) 5.8 (4.2) 0.32 Preoperative assessment (h:min) 18:26 (18:02 18:51) 17:57 (17:32 18:22) 0.09 6 12 h postoperative assessment (h:min) 18:41 (18.17 19:01) 18:33 (18:09 18:57) 0.66 66 72 h postoperative assessment (h:min) 17:39 (17:00 18:19) 17:54 (17:25 18:22) 0.51 Table 3 TAP after xenon or desflurane anaesthesia in the elderly. Mean reaction times and valid reactions of Alertness, Divided Attention, and Working Memory are presented in values normalized to the 12 24 h preoperative assessment. The values display the change in per cent from the 12 24 h preoperative baseline as mean (SD) [lower and upper 95% confidence interval] 6 12 h postoperative 66 72 h postoperative Xenon (n517) Desflurane (n519) P-value Xenon (n514) Desflurane (n515) P-value Alertness, mean values 109 (12) [103 116] 112 (20) [99 125] 0.62 105 (14) [96 113] 101 (24) [85 117] 0.63 Divided Attention, mean values 103 (13) [96 110] 98 (9) [93 104] 0.29 99 (19) [88 111] 91 (9) [85 98] 0.21 Working Memory, mean values 92 (23) [80 104] 108 (21) [94 121] 0.07 97 (23) [83 102] 92 (15) [82 102] 0.52 Alertness, valid reaction 102 (16) [94 111] 99 (9) [93 104] 0.46 101 (3) [100 103] 107 (24) [90 123] 0.46 Divided Attention, valid reaction 104 (22) [92 115] 98 (22) [84 112] 0.49 108 (30) [90 127] 102 (26) [84 119] 0.56 Working Memory, valid reaction 142 (155) [62 221] 107 (35) [80 104] 0.46 146 (137) [64 229] 141 (93) [78 203] 0.91 Table 4 Twenty per cent deviation of normalized TAP. RT, mean reaction time; VR, valid reaction; values are numbers and per cent of total (in parentheses) greater than 20% of the normalized (normalized to the 12 24 h preoperative baseline) values 6 12 h postoperative >20% 66 72 h postoperative >20% Xenon (n517) Desflurane (n519) P-value Xenon (n514) Desflurane (n515) P-value Alertness, RT 4 (23.5) 4 (21.1) 1.0 2 (14.3) 2 (13.3) 1.0 Alertness,VR 1 (5.9) 0 (0) 0.47 0 (0) 2 (13.3) 0.48 Divided Attention, RT 3 (17.6) 0 (0) 0.10 2 (14.3) 0 (0) 0.22 Divided Attention, VR 2 (11.8) 2 (10.5) 1.0 2 (14.3) 2 (13.3) 1.0 Working Memory, RT 3 (17.6) 2 (10.5) 0.65 2 (14.3) 1 (6.7) 0.60 Working Memory, VR 5 (29.4) 3 (15.8) 0.43 5 (35.7) 5 (33.3) 1.0 found, only at 1 h after anaesthesia, an impairment in the test compared with the baseline in both the groups. Heavner and colleagues 19 did not find any difference between desflurane and sevoflurane in the elderly after general anaesthesia when they were assessed with the Digit Symbol Substitution Test. We decided to use the more clinically relevant computerized TAP, in particular, the Alertness, Divided Attention, and Working Memory subtests. The assessment was completed by the study subjects in about 30 min. The TAP is the standard device for measuring attention in German-speaking countries. It was introduced in 1992 and has been used widely (details can be found at www.psytest-fimm.com). It is available in several languages. Though there is no precedent for the use of the TAP in a study of this nature, we are reasonably sure that the TAP did not negatively bias the result. There are some possible reasons for the negative findings in the primary Table 5 Emergence from anaesthesia. All time points are presented in minutes as mean and lower and upper 95% confidence intervals in parentheses Time Desflurane Xenon P-value To open eyes 8.1 (6.3 9.9) 4.8 (3.9 5.7) 0.001 To react on demand 8.6 (6.7 10.6) 4.9 (3.7 6.0) 0.001 To extubation 8.9 (6.6 11.2) 4.9 (3.9 5.8) 0.001 To time and spatial orientation 10.8 (8.7 13.0) 7.4 (6.1 8.8) 0.007 760

Cognitive function after xenon or desflurane anaesthesia Table 6 Modified Aldrete scores. Values shown as mean (SD). Modified Aldrete scores were recorded after operation at arrival in the post-anaesthetic care unit after 5, 15, 30, 45, and 60 min, and before discharge from the post-anaesthetic care unit Aldrete arrival Aldrete 5 Aldrete 15 Aldrete 30 Aldrete 45 Aldrete 60 Aldrete end Desflurane 9.3 (0.9) 9.4 (0.9) 9.4 (0.7) 9.3 (0.7) 9.5 (0.5) 9.1 (0.6) 9.7 (0.6) Xenon 9.6 (0.6) 9.7 (0.5) 9.7 (0.6) 9.8 (0.6) 9.9 (0.3) 9.9 (0.4) 9.7 (0.7) P-value 0.24 0.18 0.15 0.04 0.02,0.01 1.0 outcome. The 12 24 h preoperative baseline for the testing is critical, as it may not reflect a cognitive baseline under normal circumstances. However, this study used a 12 24 h preoperative assessment due to feasibility. The studies Chen and colleagues 18 and Heavner and colleagues 19 used a baseline taken before premedication was given. Earlier measurement of the preoperative baseline would be of benefit. Making an earlier postoperative assessment is of questionable value, as many patients would be incapable of getting through a 30 min test only 1 h after undergoing an operation. The results could have been influenced by a learning effect. Retest reliability has been shown previously for the TAP, but not for such a short interval as used in this study. 20 Though the patients were comparable in this study, further environmental factors cannot be excluded and may have influenced these findings. In this study, the high dropout rate during the late follow-up might have modified the results and may lead to a type II error (Fig. 1) and this finding should be treated with caution. A previous study showed no differences in cognitive function between the third and fifth day and at 3 months after xenon or propofol anaesthesia, but as different cognitive tests were used and xenon or propofol were used for supplementary general anaesthesia, a direct comparison with this study is limited. 21 We tested cognitive function in elderly patients undergoing surgery with lower risk of cognitive dysfunction. If we had used high-risk operations such as cardiac surgery, where the incidence of early neurocognitive deficit is as high as 80%, the results might have been different. 22 Our study assessed postoperative cognitive function and not postoperative delirium, which is an acute confusional state characterized by fluctuating symptoms including inattention, disturbances of consciousness, or disorganized thinking. In this study, the emergence times from xenon were significantly faster than those of the desflurane group. This reflects the low blood-gas partition coefficient of xenon 14 15 The with 0.115 vs 0.42 of desflurane. emergence times from xenon anaesthesia were in agreement with emergence times for middle-aged patients from xenon. 7 These authors showed that recovery from anaesthesia was significantly faster in the xenon group compared with an isoflurane nitrous oxide anaesthesia. The modified Aldrete scores in the xenon group were all at high levels in the post-anaesthetic care unit. In both groups, the Aldrete scores were quite high on arrival in the post-anaesthetic care unit, and those of the xenon group were statistically significantly higher at the 30 60 min time points compared with the desflurane group, but the scores were similar at the time of discharge. It is difficult to argue that the significant differences in scores at 30, 45, and 60 min are clinically relevant. This was also confirmed in an earlier study of 160 middle-aged patients receiving either xenon or total i.v. anaesthesia with propofol. We also reported high levels of the modified Aldrete scores in the xenon group, but no difference between the groups was found. 8 In conclusion, xenon was associated in the elderly with a faster emergence from general anaesthesia than desflurane. There was no difference in Alertness, Divided Attention, and Working Memory 6 12 and 66 72 h after operation between xenon and desflurane anaesthesia, though these findings are limited due to a high dropout rate in the later assessment. References 1 Parikh SS, Chung F. Postoperative delirium in the elderly. Anesth Analg 1995; 80: 1223 32 2 Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 1998; 351: 857 61 3 Franks NP, Dickinson R, de Sousa SL, Hall AC, Lieb WR. How does xenon produce anaesthesia? 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