1 Department of Anaesthetics and Intensive Care, Faculty of Medicine, and 2 Biophysics Section, Department of Biological Sciences, Imperial College London, UK. 3 Magill Department of Anaesthesia, Intensive Care and Pain Management, Chelsea and Westminster Hospital, Chelsea and Westminster Healthcare NHS Trust, London, UK
Corresponding author. E-mail: m.maze@ic.ac.uk Declaration of interest. Professor Maze and Professor Franks are Board members of an Imperial College spin-out company (Protexeon Ltd) that is interested in developing clinical applications for medical gases, including xenon. Both Professor Franks and Professor Maze are paid consultants in this activity. In addition, Air Products have funded, and continue to fund, work in the authors laboratories that bears on the actions of xenon as an anaesthetic and neuroprotectant, and Air Products has a financial stake in Protexeon Ltd.
Abstract
Br J Anaesth 2003; 91: 70917
Keyword: anaesthesia, neuroprotection; anaesthetics gases, xenon; heart, cardiovascular stability; receptors, V-methyl-D-aspartate
Xenon derives its name from the Greek for stranger because of its rarity, representing no more than 8.75 x 106% of the atmosphere or 0.0875 ppm. Discovered in 1898, it is manufactured by fractional distillation of air and is used commercially for lasers, high intensity lamps, flash bulbs, jet propellant in the aerospace industry, X-ray tubes, and in medicine. The total amount of xenon in the atmosphere would occupy around 1014 litres at atmospheric pressure, which is more than 10 million times the amount currently produced each year. Xenon has been used experimentally in clinical anaesthetic practice for more than 50 yrs.8 Over this period of time, reports of clinical studies reveal that several hundred surgical patients have successfully received this noble gas as part of their anaesthetic regimen. Xenons safety and efficacy profile in this setting appears to be unequalled and only its relatively high cost has precluded its more widespread clinical use. Concerns over cost are now being mitigated by technological developments in the delivery and recycling of xenon that will permit much less total gas to be expended for each anaesthetic administration.
Over the last decade there has been renewed interest in the use of xenon as an anaesthetic, as investigators have sought to find a safe and effective substitute for nitrous oxide, which has caused environmental concerns because of its ozone-depleting properties.33 Since then, studies have demonstrated several advantages of using xenon when compared with not only nitrous oxide, but most other potent inhalation agents. These include:
1. A pharmacokinetic benefit as a result of its extremely low blood/gas partition coefficient,24 which results in a rapid onset and offset of its action.23 46
2. Less cardiovascular depression.4 10 33 35
This review will deal with some of the benefits of xenon anaesthesia, with a view to identifying those areas where it may be used to clinical advantage.
Mechanisms of action
Xenon potently inhibits N-methyl-D-aspartate (NMDA) receptors non-competitively, with little effect on GABAA receptors or non-NMDA glutamatergic receptors.9 12 Franks and colleagues9 12 (Fig. 1), demonstrated that 80% xenon reduced NMDA-activated currents by approximately 60%. These results further showed that the pre-synaptic effects of xenon must be minimal, consistent with the observation that several voltage-gated ion channels in cardiac tissue are unaffected by clinically relevant concentrations of xenon.58 Nitrous oxide has also been shown to be effective at inhibiting the NMDA receptor.30
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It is not possible to state categorically which of these effects on ligand-gated and receptor-gated ion channels are causally linked to the anaesthetic action of xenon. As with nitrous oxide and cyclopropane, xenon distinguishes itself from all other volatile and gaseous anaesthetic agents by exerting no action at the GABAA receptor. On balance, it is likely that antagonism of the NMDA receptor is responsible, at least in part, for its anaesthetic action.
Measuring the xenon anaesthetic state
Several surrogate measures have been advocated as indicating the depth of the anaesthetic state and the effect of xenon on these is now considered. EEG changes are similar during anaesthesia with either xenon or nitrous oxide, exhibiting attenuation of waves at lower concentrations, with the appearance of
and
wave activity at higher concentrations.31 The bispectral index (BIS), an electroencephalographic-derived univariate scale, is thought to reflect the level of hypnosis in anaesthetized patients.56 As the BIS algorithm was empirically developed from EEG recordings from GABAergic anaesthetics (e.g. propofol), it has not fared as well in relation to general anaesthetics with NMDA antagonistic properties such as ketamine.43 59 Goto and colleagues22 investigated the suitability of BIS to monitor the emergence from xenon anaesthesia compared with isoflurane anaesthesia. A BIS value lower than 50 (a value normally associated with deep hypnosis57) did not guarantee adequate hypnosis during xenon anaesthesia, a property shared by other non-GABAergic anaesthetics (e.g. ketamine, nitrous oxide,2 and
2 adrenergic agonists68). Mid-latency auditory evoked potentials (MLAEPs) may predict wakefulness during anaesthesia, defined as the presence of a response to verbal command.17 49 61 Goto and colleagues,21 randomly assigned 60 patients to receive xenon, isoflurane, sevoflurane, or nitrous oxide supplemented with epidural anaesthesia. They found that the MLAEP is closely associated with responsiveness to verbal command during emergence from anaesthesia with xenon, isoflurane, and sevoflurane but not with nitrous oxide. The close correlation of MLAEPs to the hypnotic state during xenon anaesthesia, suggests that this may be a more appropriate form of monitoring than BIS monitoring and highlights a further difference between xenon and nitrous oxide (for which neither system appears effective).
Minimum alveolar concentration
In the first assessment of the MAC for xenon, Cullen and colleagues estimated a value of 71% of an atmosphere;7 subsequently it has been estimated to be somewhat lower at 63%.45 It is important to note that both these MAC values were determined in studies in which another inhalation anaesthetic (halothane or sevoflurane) was co-administered and thus the MAC value for xenon was extrapolated by the lowering of the MAC of the inhalation agent in the presence of xenon.45 While it is preferable that MAC studies be done in the absence of other anaesthetic compounds, the risk of hypoxia in a closed-circuit system with xenon at concentrations greater than 70% makes such a study unfeasible.
The MAC-awake value for xenon was determined in 90 female patients to be 33% or 0.46 times its MAC.20 In terms of the MAC-fraction, this is smaller than that for nitrous oxide (0.61 MAC), but greater than those for isoflurane and sevoflurane (both 0.35 MAC). The same study found that unlike nitrous oxide, xenon interacts additively with isoflurane and sevoflurane on MAC-awake.
Animal studies have established MAC values for dogs (1.19 atm11), rats (1.61 atm32), rabbits (0.85 atm16), and rhesus monkeys (0.98 atm63).
Clinical features
Induction and emergence
Xenon has a blood:gas partition coefficient of only 0.115,24 which is significantly lower than those for other inhalation anaesthetics (nitrous oxide 0.47, sevoflurane 0.65, and desflurane 0.42). Consequently, several studies have revealed extremely short induction and emergence times for xenon anaesthesia. Induction of anaesthesia with xenon is faster than with sevoflurane (71 (21) vs 147 (59) s).46 Emergence from xenon anaesthesia is two or three times faster than that from equi-MAC concentrations of nitrous oxide/isoflurane or nitrous oxide/sevoflurane anaesthesia.23 Furthermore, prolonged xenon anaesthesia does not lengthen the emergence time. Dingley and colleagues,10 reported a significantly quicker recovery time when compared with an equivalent depth of propofol anaesthesia (3 min 11 s compared with 25 min 23 s). The extremely rapid emergence times after xenon anaesthesia may be used to advantage not only in outpatient settings but also in cardiac surgery, where both fast tracking and cardiovascular stability are desirable features (see below).6
Cardiovascular system
Xenon anaesthesia is associated with remarkable cardiovascular stability, with only a clinically insignificant decrease in heart rate being reported.4 10 33 35 Lachmann33 suggested that the haemodynamic stability was a result of less stress-induced sympathetic stimulation, a theory supported by the observation of stable epinephrine levels during xenon anaesthesia.4 Compared with nitrous oxide anaesthesia, much less fentanyl was required to main tain cardiovascular stability during xenon anaesthesia.4 33 Perioperatively, plasma cortisol and epinephrine increased in the nitrous oxide group but did not change in the xenon group, despite the fact that more fentanyl was used during nitrous oxide anaesthesia.4 When Dingley and colleagues directly compared the cardiovascular effects of post-cardiac surgical patients sedated with either propofol or xenon,10 they noted that xenon caused no change in heart rate or MAP, and higher filling pressures and systemic vascular resistance were seen than were evident in propofolsedated patients. Xenon anaesthesia compared favourably with total i.v. anaesthesia (pentobarbital and buprenorphine), with respect to haemodynamic variables in the pig.41
The autonomic nervous system effects of xenon anaesthesia were compared with those caused by either isoflurane or nitrous oxide/isoflurane in 39 patients (ASA III); xenon was found to depress both sympathetic and parasympathetic transmission more than isoflurane at 0.8 MAC.29 The mechanism behind the autonomic actions of xenon has yet to be elaborated.
Ventricular function, as assessed by transoesophageal echocardiography, is unchanged during xenon anaesthesia.35 44 The lack of effect of xenon on cardiac contractility was confirmed in preparations of isolated guinea pig ventricular muscle bundles; in comparison, in the same study, isoflurane was found to decrease myocardial force development by 30%.58 Xenon induced no obvious electrical, mechanical, or metabolic cardiac effects, or nitric oxide-dependent flow response in isolated guinea pig hearts. These inert cardiac properties of this noble gas probably have their basis in the fact that xenon has little effect on major cation currents including those for sodium [INa], calcium [ICa, L], or potassium [IKir]) in guinea pig myocytes.58
Even in the presence of compromised myocardium, xenon anaesthesia is remarkably stable. In a study of 20 patients undergoing elective coronary artery bypass grafting, xenon decreased indices of cardiac function significantly less than nitrous oxide. Heart rate did not change significantly although it tended to decrease, and the cardiac output and sympathetic tone were maintained in these patients with limited cardiovascular reserve.28
In animal models of cardiac disease, the beneficial properties of xenon are further revealed. Rabbits with chronically compromised left ventricular function (through coronary artery ligation), exhibit no cardiac deterioration,55 and the echocardiographic changes were insignificant with 70% xenon. Furthermore, inhaled xenon (70%) during early reperfusion after coronary artery occlusion reduced infarct size after regional ischaemia in the rabbit heart in vivo.54 In dogs with pacing-induced cardiomyopathy, the addition of xenon produced minimal cardiovascular effects.27
Neuroprotection
As stated above, xenon is an inhibitor of glutamatergic NMDA receptors. As activation of the NMDA receptor appears to be crucial to the initiation of neuronal injury and death from a variety of insults,34 xenons putative neuroprotective effects have been examined in a series of in vitro and in vivo studies.
In a primary culture of neuronal and glial cells from the cerebral cortex of neonatal mice, predictable injury (reflected by the amount of LDH released into the culture medium) can be produced with either NMDA, glutamate, or oxygen deprivation. In order to assess the possible neuroprotective effects of xenon, LDH assays were performed 6 h after brief exposures to either NMDA or glutamate, in the presence of increasing concentrations of xenon. LDH release was significantly reduced at all concentrations tested (Fig. 2) with xenon IC50 concentrations for neuroprotection being 19 (6) and 28 (8)% atm for NMDA and glutamate-induced injury, respectively. Xenon was also effective in protecting against the injury caused by depriving the cell cultures of oxygen for 90 mins with an IC50 concentration of 10 (4)% atm.64 As the MAC of xenon has most recently been estimated as 63%, the concentrations required for neuroprotection are significantly sub-anaesthetic. Thus, in contrast to other anaesthetics that require anaesthetic or supra-anaesthetic doses to act as a neuroprotectant,64 66 xenon may be effective at more clinically acceptable concentrations.
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Investigation into the effects of xenon (33%) inhalation for 20 min in 13 patients, 3 days after severe head injury, showed clinically significant increases in ICP and cerebral perfusion pressure.53 Despite these changes, there was no deterioration in arteriovenous oxygen difference values which would be indicative of cerebral oligaemia or ischaemia.
Xenons effect on cerebral metabolic rate needs clarification. Frietsch and colleagues13 found no significant changes in metabolism although cerebral glucose utilization decreased in 18 of 40 brain structures investigated with xenon at 70% atm. Plougmann and colleagues53 suggested that xenon was not metabolically neutral as they found fluctuations in the arteriovenous oxygen difference. It is also apparent from this study that there is a great deal of individual variation in the effects of xenon in head-injured patients. More research is required in humans to define the impact of xenon anaesthesia on cerebral metabolic and haemodynamic variables.
Analgesia
Xenon exhibits more potent analgesic action than nitrous oxide, the only other anaesthetic gas with true analgesic efficacy. Supplementation with fentanyl was lower in a xenon-based anaesthetic compared with that of nitrous oxide (fentanyl 0.05 vs 0.24 mg), and fewer patients required supplementation (35 vs 95%).33 As changes in haemodynamic variables were used as surrogate markers of the need for further fentanyl, the study may be biased because of the independent effects of each drug on these variables (none with xenon vs sympathetic stimulation with nitrous oxide). Analgesic efficacy was investigated using a different approach in which the fentanyl concentrations required to suppress both somatic (Cp50) and haemodynamic (Cp50-BAR) responses were measured in patients at the time of incision.48 In the presence of 0.7 MAC nitrous oxide, significantly higher concentrations of fentanyl were required (Cp50 of 3.26 ng ml1; Cp50-BAR 4.17 ng ml118) compared with patients receiving 0.7 MAC xenon (Cp50 0.72 ng ml1 and Cp50-BAR 0.94 ng ml148). As both sevoflurane and xenon are relatively haemodynamically stable, cardiovascular variables in response to painful stimuli can be used as surrogates to directly compare the analgesic efficacy of these two drugs. Using this approach, xenon is three times more efficacious at blocking cardiovascular responses to incision than sevoflurane at equi-MAC concentrations.
The difference in analgesic potency between nitrous oxide and xenon is more difficult to define when tested in volunteers with experimental pain. When heat stimulation was used to provoke pain, nitrous oxide and xenon were equivalent analgesics.65 When electrical stimulation is used to provoke pain, xenon is 1.5 times more potent than nitrous oxide.52
In pre-clinical studies designed to determine the mechanism of analgesic action, it appears that xenon differs from nitrous oxide although both these gases are NMDA receptor antagonists.9 12 30 Nitrous oxide provokes release of endogenous ligands for opiate receptors in the periaqueductal grey region, which indirectly activates descending inhibitory neurons in the spinal cord. Here, the released norepinephrine activates adrenergic receptors to mediate the antinociceptive effect.15 Yet, neither an opiate antagonist nor an 2 adrenergic antagonist attenuated the antinociceptive properties of xenon.50 Comparison between the effects of nitrous oxide and xenon on spinal cord dorsal horn neurons in spinal cord-transected cats anaesthetized with alpha-chloralose and urethane demonstrated that while xenon suppressed the effects of both pinch and touch on the firing of wide dynamic range neurons, nitrous oxide was ineffective.42 Thus, Adachi and colleagues42 postulated that the antinociceptive action of xenon was greater at the level of the spinal cord than nitrous oxide, with no role for descending inhibitory systems in its analgesic effect, a finding supported by their earlier work.62
Toxicity
In vivo and in vitro experiments suggest that xenon does not trigger malignant hyperthermia (MH) in MH-susceptible swine.3 14 Burov and colleagues reported no evidence of toxicity in several in vitro and in vivo paradigms involving two species given xenon either acutely or sub-chronically.5 Studies of microorganisms and mice showed xenon has no mutagenic or carcinogenic properties.5 No embryotoxic or teratogenic changes were found in pregnant Wistar rats, nor was xenon found to be allergenic.5 Xenon was shown to moderately stimulate the immune response and increase the cellularity of lymphoid organs.5
Pharmacoeconomics
Xenon is an expensive gas; the current cost of 1 litre of xenon with a purity of 99.99% is approximately $10, but may change depending on market forces. Therefore, closed-circuit delivery appears to be an economic necessity for the application of xenon anaesthesia.36 An analysis of the cost of a 40-yr-old ASA I, adult male weighing 70 kg undergoing simulated elective surgery, found that 240 min of closed-circuit xenon anaesthesia would cost $356.47 The bulk of this cost is attributed to the priming and flushing of the delivery circuit; if the delivery technology could be refined to remove nitrogen without the need for priming and flushing,25 then xenon anaesthesia would cost a more affordable $108, assuming the availability of the closed-circuit delivery device.
Among the recent technological advances to improve the cost-efficiency of xenon anaesthesia are xenon recycling systems, including one pioneered by Burov and colleagues in Russia, in which xenon can be purified to more than 99%.5 For the efficient use of the recycling system, anaesthesia would have to be maintained with another agent while xenon was recovered.
Environmental effect
The ecological impact of an anaesthetists work is increasingly coming under scrutiny. Our major volatile anaesthetics are CFC based and are known to deplete the ozone layer. Nitrous oxide is 230 times more potent as a greenhouse gas than carbon dioxide, takes 120 yr to breakdown, and the amount released as an anaesthetic contributes 0.1% of the greenhouse effect.19 In comparison, xenon appears to be environmentally safe.
Conclusions
Xenon is a potent inhalation anaesthetic with many salubrious qualities; expense has so far mitigated the development of its use for anaesthesia, but recent research has suggested a niche for xenon, based on its pharmacokinetic, cardiac, neuroprotective, and analgesic properties. For example, xenon may be the anaesthetic of choice for fast-track cardiac surgery where its rapid emergence, cardiostability, and neuroprotective qualities can come to the fore. Furthermore, settings in which the risk of intraoperative neurological injury is high (e.g. major intracranial vascular surgery) may be another opportunity for the clinical application of xenon. We await the results of clinical trials to investigate whether neurocognitive deficits can be reduced by the administration of xenon in cardiac surgical patients.
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1 Allen HL, Iversen LL. Phencyclidine, dizocilpine, and cerebrocortical neurons. Science 1990; 247: 221[ISI][Medline]
2 Barr G, Jakobsson JG, Owall A, Anderson RE. Nitrous oxide does not alter bispectral index: study with nitrous oxide as sole agent and as an adjunct to i.v. anaesthesia. Br J Anaesth 1999; 82: 82730
3 Baur CP, Klingler W, Jurkat-Rott K, et al. Xenon does not induce contracture in human malignant hyperthermia muscle. Br J Anaesth 2000; 85: 7126
4 Boomsma F, Rupreht J, Man in t Veld AJ, de Jong FH, Dzoljic M, Lachmann B. Haemodynamic and neurohumoral effects of xenon anaesthesia. A comparison with nitrous oxide. Anaesthesia 1990; 45: 2738[ISI][Medline]
5 Burov NE, Kornienko LI, Makeev GN, Potapov VN. Clinical and experimental study of xenon anesthesia. Anesteziol Reanimatol 1999; 5660
6 Cheng DC, Karski J, Peniston C, et al. Early tracheal extubation after coronary artery bypass graft surgery reduces costs and improves resource use. A prospective, randomized, controlled trial. Anesthesiology 1996; 85: 130010[ISI][Medline]
7 Cullen SC, Eger EI, Cullen BF, Gregory P. Observations on the anesthetic effect of the combination of xenon and halothane. Anesthesiology 1969; 31: 3059[ISI][Medline]
8 Cullen SC, Gross EG. The anaesthetic properties of xenon in animals and human beings, with additional observations on krypton. Science 1951; 113: 5802[ISI]
9 De Sousa SL, Dickinson R, Lieb WR, Franks NP. Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon. Anesthesiology 2000; 92: 105566[ISI][Medline]
10 Dingley J, King R, Hughes L, et al. Exploration of xenon as a potential cardiostable sedative: a comparison with propofol after cardiac surgery. Anaesthesia 2001; 56: 82935[CrossRef][ISI][Medline]
11 Eger EI, Brandstater B, Saidman LJ, Regan MJ, Severinghaus JW, Munson ES. Equipotent alveolar concentrations of methoxy flurane, halothane, diethyl ether, fluroxene, cyclopropane, xenon and nitrous oxide in the dog. Anesthesiology 1965; 26: 7717[ISI][Medline]
12 Franks NP, Dickinson R, de Sousa SL, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature 1998; 396: 324[CrossRef][ISI][Medline]
13 Frietsch T, Bogdanski R, Blobner M, Werner C, Kuschinsky W, Waschke KF. Effects of xenon on cerebral blood flow and cerebral glucose utilization in rats. Anesthesiology 2001; 94: 2907[ISI][Medline]
14 Froeba G, Marx T, Pazhur J, et al. Xenon does not trigger malignant hyperthermia in susceptible swine. Anesthesiology 1999; 91: 104752[ISI][Medline]
15 Fujinaga M, Maze M. Neurobiology of nitrous oxide-induced antinociceptive effects. Mol Neurobiol 2002; 25: 16789[ISI][Medline]
16 Fukuda T, Nakayama H, Yanagi K, et al. The effects of 30% and 60% xenon inhalation on pial vessel diameter and intracranial pressure in rabbits. Anesth Analg 2001; 92: 124550
17 Gajraj RJ, Doi M, Mantzaridis H, Kenny GN. Analysis of the EEG bispectrum, auditory evoked potentials and the EEG power spectrum during repeated transitions from consciousness to unconsciousness. Br J Anaesth 1998; 80: 4652[CrossRef][ISI][Medline]
18 Glass PS, Doherty M, Jacobs JR, Goodman D, Smith LR. Plasma concentration of fentanyl, with 70% nitrous oxide, to prevent movement at skin incision. Anesthesiology 1993; 78: 8427[ISI][Medline]
19 Goto T. Is there a future for xenon anesthesia? Le xenon a-t-il un avenir en anesthesie? Can J Anaesth 2002; 49: 3358
20 Goto T, Nakata Y, Ishiguro Y, Niimi Y, Suwa K, Morita S. Minimum alveolar concentration-awake of Xenon alone and in combination with isoflurane or sevoflurane. Anesthesiology 2000; 93: 118893[ISI][Medline]
21 Goto T, Nakata Y, Saito H, Ishiguro Y, Niimi Y, Morita S. The midlatency auditory evoked potentials predict responsiveness to verbal commands in patients emerging from anesthesia with xenon, isoflurane, and sevoflurane but not with nitrous oxide. Anesthesiology 2001; 94: 7829[ISI][Medline]
22 Goto T, Nakata Y, Saito H, et al. Bispectral analysis of the electroencephalogram does not predict responsiveness to verbal command in patients emerging from xenon anaesthesia. Br J Anaesth 2000; 85: 35963
23 Goto T, Saito H, Shinkai M, Nakata Y, Ichinose F, Morita S. Xenon provides faster emergence from anesthesia than does nitrous oxide-sevoflurane or nitrous oxide-isoflurane. Anesthesiology 1997; 86: 12738[ISI][Medline]
24 Goto T, Suwa K, Uezono S, Ichinose F, Uchiyama M, Morita S. The blood-gas partition coefficient of xenon may be lower than generally accepted. Br J Anaesth 1998; 80: 2556[CrossRef][ISI][Medline]
25 Hanne P, Marx T, Musati S, Santo M, Suwa K, Morita S. Xenon: uptake and costs. Int Anesthesiol Clin 2001; 39: 4361
26 Hartmann A, Wassman H, Czernicki Z, Dettmers C, Schumacher HW, Tsuda Y. Effect of stable xenon in room air on regional cerebral blood flow and electroencephalogram in normal baboons. Stroke 1987; 18: 6438[Abstract]
27 Hettrick DA, Pagel PS, Kersten JR, et al. Cardiovascular effects of xenon in isoflurane-anesthetized dogs with dilated cardiomyopathy. Anesthesiology 1998; 89: 116673[ISI][Medline]
28 Ishiguro Y. Cardiovascular effects of xenon. Int Anesthesiol Clin 2001; 39: 7784[Medline]
29 Ishiguro Y, Goto T, Nakata Y, Terui K, Niimi Y, Morita S. Effect of xenon on autonomic cardiovascular controlcomparison with isoflurane and nitrous oxide. J Clin Anesth 2000; 12: 196201[CrossRef][ISI][Medline]
30 Jevtovic-Todorovic V, Todorovic SM, Mennerick S, et al. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nature Med 1998; 4: 4603[ISI][Medline]
31 Kawaguchi T, Mashimo T, Yagi M, Takeyama E, Yoshiya I. Xenon is another laughing gas. Can J Anaesth 1996; 43: 6412[ISI][Medline]
32 Koblin DD, Fang Z, Eger EI, et al. Minimum alveolar concentrations of noble gases, nitrogen, and sulfur hexafluoride in rats: helium and neon as nonimmobilizers (nonanesthetics). Anesth Analg 1998; 87: 41924[Abstract]
33 Lachmann B, Armbruster S, Schairer W, et al. Safety and efficacy of xenon in routine use as an inhalational anaesthetic. Lancet 1990; 335: 14135[CrossRef][ISI][Medline]
34 Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994; 330: 61322
35 Luttropp HH, Romner B, Perhag L, Eskilsson J, Fredriksen S, Werner O. Left ventricular performance and cerebral haemodynamics during xenon anaesthesia. A transoesophageal echocardiography and transcranial Doppler sonography study. Anaesthesia 1993; 48: 10459[ISI][Medline]
36 Lynch C III, Baum J, Tenbrinck R. Xenon anesthesia. Anesthesiology 2000; 92: 8658[ISI][Medline]
37 Ma D, Wilhelm S, Maze M, Franks NP. Neuroprotective and neurotoxic properties of the inert gas, xenon. Br J Anaesth 2002; 89: 73946
38 Ma D, Yang H, Lynch J, Franks NP, Maze M, Grocott HP. Xenon attenuates cardiopulmonary bypass-induced neurologic and neurocognitive dysfunction in the rat. Anesthesiology 2003; 98: 6908[ISI][Medline]
39 Malhotra AK, Pinals DA, Weingartner H, et al. NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology 1996; 14: 3017[CrossRef][ISI][Medline]
40 Marubio LM, Mar Arroyo-Jimenez M, Cordero-Erausquin M, et al. Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature 1999; 398: 80510[CrossRef][ISI][Medline]
41 Marx T, Froeba G, Wagner D, Baeder S, Goertz A, Georgieff M. Effects on haemodynamics and catecholamine release of xenon anaesthesia compared with total i.v. anaesthesia in the pig. Br J Anaesth 1997; 78: 3267
42 Miyazaki Y, Adachi T, Utsumi J, Shichino T, Segawa H. Xenon has greater inhibitory effects on spinal dorsal horn neurons than nitrous oxide in spinal cord transected cats. Anesth Analg 1999; 88: 8937
43 Morioka N, Ozaki M, Matsukawa T, Sessler D, Atarashi K, Suzuki H. Ketamine causes a paradoxical increase in the Bispectral Index. Anesthesiology 1997; 87: A502[ISI]
44 Morita S, Goto T, Niimi Y, Ichinose F, Saito H. Xenon produces minimal cardiac depression in patients under fentanyl-midazolam anesthesia. Anesthesiology 1996; 85: A362[ISI]
45 Nakata Y, Goto T, Ishiguro Y, et al. Minimum alveolar concentration (MAC) of xenon with sevoflurane in humans. Anesthesiology 2001; 94: 6114[ISI][Medline]
46 Nakata Y, Goto T, Morita S. Comparison of inhalation inductions with xenon and sevoflurane. Acta Anaesthesiol Scand 1997; 41: 115761[ISI][Medline]
47 Nakata Y, Goto T, Niimi Y, Morita S. Cost analysis of xenon anesthesia: a comparison with nitrous oxide-isoflurane and nitrous oxide-sevoflurane anesthesia. J Clin Anesth 1999; 11: 47781[CrossRef][ISI][Medline]
48 Nakata Y, Goto T, Saito H, et al. Plasma concentration of fentanyl with xenon to block somatic and hemodynamic responses to surgical incision. Anesthesiology 2000; 92: 10438[ISI][Medline]
49 Newton DE, Thornton C, Konieczko KM, et al. Auditory evoked response and awareness: a study in volunteers at sub-MAC concentrations of isoflurane. Br J Anaesth 1992; 69: 1229[Abstract]
50 Ohara A, Mashimo T, Zhang P, Inagaki Y, Shibuta S, Yoshiya I. A comparative study of the antinociceptive action of xenon and nitrous oxide in rats. Anesth Analg 1997; 85: 9316[Abstract]
51 Olney JW, Labruyere J, Price MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989; 244: 13602[ISI][Medline]
52 Petersen-Felix S, Luginbuhl M, Schnider TW, Curatolo M, Arendt-Nielsen L, Zbinden AM. Comparison of the analgesic potency of xenon and nitrous oxide in humans evaluated by experimental pain. Br J Anaesth 1998; 81: 7427
53 Plougmann J, Astrup J, Pedersen J, Gyldensted C. Effect of stable xenon inhalation on intracranial pressure during measurement of cerebral blood flow in head injury. J Neurosurg 1994; 81: 8228[ISI][Medline]
54 Preckel B, Mullenheim J, Moloschavij A, Thamer V, Schlack W. Xenon administration during early reperfusion reduces infarct size after regional ischemia in the rabbit heart in vivo. Anesth Analg 2000; 91: 132732
55 Preckel B, Schlack W, Heibel T, Rutten H. Xenon produces minimal haemodynamic effects in rabbits with chronically compromised left ventricular function. Br J Anaesth 2002; 88: 2649
56 Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998; 89: 9801002[ISI][Medline]
57 Rosow C, Manberg PJ. Bispectral index monitoring. Anesthesiol Clin North Am 2001; 19: 94766[Medline]
58 Stowe DF, Rehmert GC, Kwok WM, Weigt HU, Georgieff M, Bosnjak ZJ. Xenon does not alter cardiac function or major cation currents in isolated guinea pig hearts or myocytes. Anesthesiology 2000; 92: 51622[ISI][Medline]
59 Suzuki M, Edmonds HL, jr, Tsueda K, Malkani AL, Roberts CS. Effect of ketamine on bispectral index and levels of sedation. J Clin Monit Comput 1998; 14: 373[CrossRef][ISI][Medline]
60 Suzuki T, Koyama H, Sugimoto M, Uchida I, Mashimo T. The diverse actions of volatile and gaseous anesthetics on human-cloned 5-hydroxytryptamine3 receptors expressed in Xenopus oocytes. Anesthesiology 2002; 96: 699704[ISI][Medline]
61 Thornton C, Barrowcliffe MP, Konieczko KM, et al. The auditory evoked response as an indicator of awareness. Br J Anaesth 1989; 63: 1135[Abstract]
62 Utsumi J, Adachi T, Miyazaki Y, et al. The effect of xenon on spinal dorsal horn neurons: a comparison with nitrous oxide. Anesth Analg 1997; 84: 13726[Abstract]
63 Whitehurst SL, Nemoto EM, Yao L, Yonas H. MAC of xenon and halothane in rhesus monkeys. J Neurosurg Anesthesiol 1994; 6: 2759[ISI][Medline]
64 Wilhelm S, Ma D, Maze M, Franks NP. Effects of xenon on in vitro and in vivo models of neuronal injury. Anesthesiology 2002; 96: 148591[ISI][Medline]
65 Yagi M, Mashimo T, Kawaguchi T, Yoshiya I. Analgesic and hypnotic effects of subanaesthetic concentrations of xenon in human volunteers: comparison with nitrous oxide. Br J Anaesth 1995; 74: 6703
66 Yamaguchi S, Midorikawa Y, Okuda Y, Kitajima T. Propofol prevents delayed neuronal death following transient forebrain ischemia in gerbils. Can J Anaesth 1999; 46: 5938[Abstract]
67 Yamakura T, Harris RA. Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology 2000; 93: 1095101[ISI][Medline]
68 Young C, Moretti E, Hsu Y, Ping J, Somma J. Sedation and arousal associated with dexmedetomidine infusion. Anesthesiology 2001; 95: A276