Inert gases as the future inhalational anaesthetics?

Best Practice & Research Clinical Anaesthesiology Vol. 19, No. 3, pp. 365–379, 2005 doi:10.1016/j.bpa.2005.01.002 available online at http://www.sciencedirect.com

4 Inert gases as the future inhalational anaesthetics? Benedikt Preckel*

MD, DEAA

Privatdozent of Anaesthesiology

Wolfgang Schlack MD, DEAA Professor of Anaesthesiology Department of Anaesthesiology, Du¨sseldorf University Hospital, P.O. Box 10 10 07, D-40001 Du¨sseldorf, Germany

Of all the inert gases, only xenon has considerable anaesthetic properties under normobaric conditions. Its very low blood/gas partition coefficient makes induction of and emergence from anaesthesia more rapid compared with other inhalational anaesthetics. In experimental and clinical studies the safety and efficiency of xenon as an anaesthetic has been demonstrated. Xenon causes several physiological changes, which mediate protection of the brain or myocardium. The use of xenon might therefore be beneficial in certain clinical situations, as in patients at high risk for neurological or cardiac damage. Key words: anaesthesia; xenon; nitrous oxide; inhalational anaesthetics; volatile anaesthetics; cardioprotection; neuroprotection; preconditioning.

The noble gases, which constitute group VIII of the periodic table of elements, include the gases helium, neon, argon, krypton, xenon, and the radioactive element radon. All these elements have outer shells completely filled with electrons, making them mostly non-reactive and hence ‘inert’ to forming covalent bonds with other elements. The interest in inert gases in anaesthesia results from observations from the early 1930s of air pressure on mentation in relation to deep diving.1 Central nervous system (CNS) effects of air at 4 atm were abolished by breathing pure oxygen and were attributed to nitrogen. Several years later, Benke et al demonstrated that argon at normobaric and hyperbaric conditions had more potent narcotic effects than nitrogen.2 Lawrence et al then postulated a narcotic effect of krypton and xenon.3 In their experiments, mice were exposed to up to 80% xenon, and rapid-onset CNS effects (ataxia, convulsive movements, limb weakness) were observed within 2 minutes; these effects were * Corresponding author. Tel.: C49 211 81 18669; Fax: C49 211 81 16253. E-mail address: [email protected] (B. Preckel).

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reversible 15 minutes after the removal of xenon. The narcotic effects were attributed to xenon’s high fat solubility and high oil/water coefficient (20.0, the highest of any of the noble gases) according to the Meyer–Overton principle. In contrast, 50% krypton administered for 1 hour had no narcotic effect.3 Helium and neon failed to produce any anaesthetic effect even under hyperbaric conditions.4 Taking all these early reports together, xenon is the only noble gas with considerable anaesthetic properties under normobaric conditions.

THE NOBLE GAS XENON Xenon was discovered by Sir William Ramsay (Nobel prize for chemistry recipient, 1904) and Morris W. Travers in 1898. It represents only 0.0875 ppm of the atmosphere (Table 1). Xenon exists as a monoatomic gas and is prepared by fractional distillation of air. It is mainly used in a variety of lamps, in the atomic energy industry and in space travel.131Xenon is used as a radio-isotope for ventilation scans and organ blood flow measurements in medicine. The first inhalations of xenon in human volunteers were performed by Cullen and Gross in 1951.5 They demonstrated an increase in pain threshold and an incipient loss of consciousness after inhalation of 50% xenon and a pronounced narcotic effect after 80% xenon. They then performed the first successful xenon anaesthesia in an 81-yearold man undergoing orchiectomy. Anaesthesia for ligature of the tube of a 38-year-old woman could also be handled with 80% Xe/20% O2. The authors concluded that “a chemically inert gas is capable of producing complete anaesthesia and it may materially assist in solving one of the important theoretical problems of anaesthesia”.5 The same group then reported about five successfully performed xenon anaesthesias in herniotomias.6 Following these first uses of xenon, there were only a few publications about xenon as an anaesthetic during the 1950–1970s7–11, and it was nearly forgotten, probably because of its high costs.12 Since the early 1990s there has been increasing experimental and clinical interest in xenon anaesthesia resulting predominantly from haemodynamic stability during these procedures. Xenon has often been called an ideal anaesthetic, although several features of this gas do not fit with this description (Table 2). Evidence exists from experimental data that, although chemically inert, xenon Table 1. Components of the air. Substance Nitrogen Oxygen Argon Neon Helium Krypton Xenon Carbon dioxide Methane Nitrous oxide Carbon monoxide Hydrogen

Formula N2 O2 Ar Ne He Kr Xe CO2 CH4 N2O CO H2

% Volume 78.08 20.95 0.934 0.0018 0.0005 0.00011 0.0000087 0.035 0.00017 0.00003 0.00002 0.00005

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Table 2. The ideal anaesthetic. Properties of an ideal anaesthetic

Applicable to xenon

Non-explosive Volatile or gaseous Chemical stability No reaction with absorbents Environmentally friendly Not expensive Easy to produce Odourless Tasteless Low blood/gas partition coefficient High potency Analgesic Minimal side-effects Minimal to no biodegradation No toxicity

Yes Yes Yes Yes Yes No No Yes Yes Yes No Yes Yes (mostly) Yes Yes

may cause several physiological changes. These biological ‘side-effects’ could mediate organ protection, and the use of xenon might therefore be beneficial in certain clinical situations.

PHARMACOKINETIC PROPERTIES Xenon is a non-flammable, non-explosive, odourless and tasteless gas. Its melting point is K111.9 8C and the boiling point is K107.1 8C. Its density and viscosity is 3.2 times and 1.7 times greater than that of air, respectively. The most exciting property relevant to anaesthesia is its very low blood/gas partition coefficient of 0.1413, which is even lower than that of sevoflurane (0.69), nitrous oxide (0.47) or desflurane (0.42). A more recent investigation has demonstrated that this coefficient might even be lower at 0.115, as measured by gas chromatography/mass spectrometry.14 The low blood/gas solubility, together with lack of airway irritability, provides smooth and rapid onset of anaesthesia and rapid emergence. Xenon caused a faster, more uneventful inhalational induction associated with a smaller decrease in tidal volume and respiratory rate compared with sevoflurane.15 Emergence times from xenon anaesthesia were one half to one third of those of nitrous oxide/sevoflurane or nitrous oxide/isoflurane anaesthesia.16 In contrast to the use of nitrous oxide/isoflurane, the duration of anaesthesia had no impact on emergence after xenon anaesthesia of 1.0–6.5 hours.17 There was no difference in recovery from xenon/remifentanil or propofol/remifentanil anaesthesia in 160 patients.18

MINIMAL ALVEOLAR CONCENTRATION (MAC) The MAC of xenon was first established to be 71% in humans by observing the response to skin incision after 15 minutes in patients breathing a predetermined xenon

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concentration.10,19 Xenon was additive when used in combination with halothane, and no synergism was found.10 A more recent investigation determined the MAC to be 63% in humans20, and it may be even lower in elderly women (51%).21 As for volatile anaesthetics, the MAC of xenon is higher in different animal species compared with humans.4,19,22,23 MAC-awake describes the alveolar concentration during recovery that permits subjects to respond to command. For modern volatile anaesthetics this value is approximately one third of MAC.24 The MAC-awake of xenon is 33% or 0.46 times its MAC (which is greater than that for isoflurane or sevoflurane).24,25 In contrast to nitrous oxide, xenon interacts additively with isoflurane and sevoflurane on MACawake.25 Xenon was compared with propofol sedation in postoperative cardiac surgery patients, and a significantly faster recovery from xenon than from propofol sedation was observed.26

TOXICITY AND ENVIRONMENTAL CONSIDERATIONS Studies on different species have not revealed any toxic, allergic, mutagenic or carcinogenic properties of xenon.27 Lane et al investigated the foetotoxicity of nitrous oxide and xenon in pregnant rats.11 They observed an increased rate of hydrocephalus, gastroschisis and skeletal abnormalities in those foetuses subjected to nitrous oxide, while xenon had no effect. Xenon is not a greenhouse gas and does not lead to global warming. It simply goes back to the atmosphere (where it comes from) after leaving the anaesthesia machine. Unlike nitrous oxide and volatile anaesthetics, xenon does not affect the ozone layer. However, one has to consider that the production of xenon (e.g. liquefaction and purification by fractional distillation) requires a considerable amount of energy, much higher than e.g. that used to produce nitrous oxide.28

ANAESTHETIC AND ANALGESIC EFFECTS The neuronal system Possible mechanisms by which inhalational anaesthetics produce general anaesthesia include stimulation of inhibitory pathways and/or inhibition of excitatory pathways. Stimulation of the N-methyl-D-aspartate (NMDA) receptor, for example, is an excitatory pathway, while stimulation of the g-aminobutyric acidA (GABAA) receptor is an example of an inhibitory pathway. Franks and colleagues demonstrated that xenon, like nitrous oxide or ketamine, is a potent non-competitive NMDA receptor antagonist.29 The GABAA receptors (which are the target of e.g. barbiturates, benzodiazepines, propofol and inhalational anaesthetics) as well as non-NMDAdependent glutamate receptors (AMPA receptor) play only a minor role in xenon anaesthesia.29–32 Yamakura and Harris showed a blockade of the nicotinic acetylcholine receptor31, while Shichino et al demonstrated an activation of cholinergic cell activity in the CNS.33 A recently published study revealed that xenon has non-competitive and voltage-independent inhibitory actions at the nicotinic acetylcholine receptor.34 The 5HT3A receptor, which plays a role in peripheral and central nociception and may be involved in postoperative nausea and vomiting, is competitively blocked by xenon.35

Inert gases as inhalational anaesthetics? 369

Another important target for the anaesthetic action of xenon might be the so-called two-pore-domain potassium channels.36 Through inhibition of the excitatory NMDA pathway, neuroprotective effects can be achieved. Despite neuroprotective properties, NMDA receptor antagonists have psychotomimetic and neurotoxic properties in humans.37 Neuroprotective effects of xenon by blockade of the NMDA receptor have been investigated in vitro and in vivo.38 Xenon reduced the neuronal cell damage after NMDA or glutamate application or oxygen deprivation in neuronal and glial cells from the cerebral cortex of neonatal mice.38 The neurological and neurocognitive deficit after cardiopulmonary bypass was significantly lower after use of 60% xenon, and was more pronounced than the protection by other NMDA receptor antagonists.39 After focal cerebral ischaemia by transient middle cerebral artery occlusion in mice, xenon reduced the cerebral infarct volume and improved functional outcome in vivo.40 These data are supported by another investigation using 50% xenon in rats.41 However, David et al also showed a possible neurotoxic effect at higher concentrations of xenon (75%).41 Xenon in combination with isoflurane produced a synergistic protective effect against neuronal injury after oxygen–glucose deprivation.42 Many NMDA receptor antagonists may reduce the neuronal damage after cerebral ischaemia, but concomitantly produce psychotomimetic side-effects.43,44 These effects were observed after ketamine and nitrous oxide administration, but not after xenon.45 A reliable marker of neuronal sideeffects is the c-Fos expression in distinct cerebral regions. Nitrous oxide alone produced a small amount of c-Fos expression and significantly enhanced ketamineinduced neurotoxicity, while xenon alone had no effect and dose-dependently reduced the ketamine-induced c-Fos expression.46 In addition to the effects mediated via the NMDA receptor, xenon protects cortical neurons against hypoxia-related cell damage via Ca2C-dependent mechanisms.47 Like other inhalational anaesthetics, xenon inhibited in a dose-dependent manner the plasma membrane Ca2C-ATPase activity in rat brain synaptic plasma membranes.48 There is as yet little information on the effects of xenon on cerebral metabolism. A reduction in cerebral glucose utilization49 and changes in cerebral arteriovenous oxygen difference have been reported.50 However, additional investigations in patients are required on this topic. The hypothalamus is a crucial homeostatic centre in the brain, and its norepinephrinergic neuronal activity is closely related to physiological variables, including the regulation of consciousness and haemodynamics. In rats, xenon stimulates norepinephrinergic neurons more potently than does nitrous oxide, and this may be one mechanism contributing to the hypnotic effects of xenon.51 In anaesthetized cats, a stimulatory action on the CNS background activity and a suppressive action on CNS reactive capability by xenon was suggested.52 In the electroencephalogram (EEG) xenon produces slow, synchronized waveforms during clinical anaesthesia, and burst suppression could not be observed even during hyperbaric conditions.8 Depth of anaesthesia has been estimated using different indices. The bispectral analysis (BIS) of the EEG is thought to reflect the level of hypnosis in anaesthetized patients, but does not predict responsiveness to verbal commands in patients during recovery from xenon anaesthesia.53 In contrast, the midlatency auditory-evoked potential might be a suitable measurement of arousal, because it is closely related to responsiveness to verbal commands during emergence from xenon anaesthesia.54 The potent analgesic actions of xenon were compared with those of other agents.55–57 For example, in comparison to a nitrous oxide-based anaesthesia, xenontreated patients required less fentanyl to maintain haemodynamic stability.58

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The plasma concentration of fentanyl necessary to suppress somatic and haemodynamic responses to surgical incision was lower during xenon than nitrous oxide anaesthesia, indicating that xenon has a more potent analgesic effect.59 When used in a sub-anaesthetic concentration, the analgesic effects of xenon and nitrous oxide against heat-stimulated pain were similar.60 For both analgesia and immobility in anaesthesia, the spinal cord plays a crucial role as a site of action for anaesthetics.61 In spinal-cordtransected cats, xenon had greater inhibitory effects on spinal dorsal horn neurons than nitrous oxide, suggesting a more potent analgesic effect of xenon at the level of the spinal cord.62 These observations in a spinal cord transection model suggest that xenon exerts its analgesic effect directly at the spinal cord, without requiring higher supraspinal centres. Descending inhibitory systems may play no role in the spinal analgesic effects.63 One analgesic mechanism is that xenon suppresses the synaptic transmission of the slow ventral root potential at the spinal cord, which reflects the main nociceptive transmission.64 In contrast to other NMDA receptor antagonists, the analgesic effects of xenon have been shown to be age-independent in rats.65 Cardiac system Haemodynamic stability during xenon anaesthesia has often been cited. However, there is a discrepancy between the increasing amount of experimental data and the lack of larger clinical studies. Most studies on the effects of xenon have been performed in small patient groups.26,66,67 Only two studies included larger numbers of patients.18,68 In addition, in the clinical studies, as well as in most of the experimental investigations, data were obtained from subjects with a healthy myocardium. So far, few data are available from patients with compromised myocardium or haemodynamic instability.69 During in vitro experiments, xenon had no significant effects on the myocardium; in isolated, buffer-perfused rat hearts, a mixture of xenon 50%–O2 45%–CO2 5% had no effect on coronary perfusion pressure, heart rate, or left ventricular developed pressure (calculated as left ventricular peak systolic minus end-diastolic pressure) compared with N2 50%–O2 45%–CO2 5%.70 However, in these experiments, oxygen delivery to the heart was 50% lower than in the control state, itself resulting in a reduced contractility in control hearts. In isolated guinea-pig hearts, xenon 40–80% did not significantly alter heart rate, atrioventricular conduction time, left ventricular pressure, coronary flow, oxygen extraction or consumption, cardiac efficiency, or flow responses to bradykinin.71 In isolated cardiomyocytes, the amplitudes of the NaC, the 2C L-type Ca and the inward-rectifier KC channels were not altered by xenon 80%, suggesting that the noble gas does not affect the cardiac action potential.71 These results indicate that xenon has no physiologically important effects on the guinea-pig heart. Xenon did not depress L-type Ca2C currents in human atrial myocytes72, and it neither depressed myocardial contractility nor influenced the positive inotropic stimulation of isoproterenol or the force-frequency relation in cardiac muscle bundles.73 While in vitro experiments can be performed in the absence of other anaesthetics, in vivo studies with xenon normally use supplementary baseline anaesthesia because the MAC of xenon in animals is higher than 80 vol.%. In pentobarbital-anaesthetized pigs, cardiac index, central venous pressure, aortic pressure, and systemic vascular resistance were not significantly altered by xenon 30–70%.74 In isoflurane-anaesthetized dogs, the coupling between oxygen consumption and cardiac output was maintained during xenon inhalation.75 The cardiovascular stability was accompanied by

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an increased oxygen consumption which was independent of the autonomic nervous system. In midazolam/piritramide-anaesthetized dogs, inhalation of xenon up to 70% had no effect on myocardial function.76 In contrast, regional administration of xenon 70% directly into the coronary artery reduced the indices of regional myocardial contractility measured by sonomicrometry by about 8%, indicating a small negative inotropic effect in vivo. Compared with the negative inotropic action of isoflurane, this effect was negligible.76 Most clinical studies investigating the cardiovascular effects of xenon have compared its effects to another routinely used anaesthetic agent. No significant effect on arterial blood pressure could be observed in patients anaesthetized with xenon 70% in comparison to nitrous oxide. Fractional area change obtained by echocardiography was not altered by xenon 65% in healthy patients.66 The only change observed was a tendency to a decreased heart rate accompanied by an increased variability of the cardiac rhythm.66,67 In addition, xenon produces analgesia, thereby suppressing haemodynamic and catecholamine response to surgical stimulation. The interpretation of all these clinical studies is limited by the small numbers of patients included. In the first randomized controlled multicentre trial, xenon provided safe and effective anaesthesia, and resulted in faster recovery compared with isoflurane-nitrous oxide anaesthesia.68 In the xenon group, a higher mean arterial pressure and a more pronounced decrease in heart rate from baseline was observed. The need for inotropic substances was lower in the xenon group, whereas the need for antihypertensives was higher. In another study from the same authors, xenon/remifentanil anaesthesia significantly reduced heart rate, but had less effect on systolic and diastolic blood pressure compared with propofol/remifentanil.18 Recovery was similar between the two groups. However, patients at high risk of undesirable cardiac events were excluded from both studies. The effects of xenon in compromised hearts has been addressed in experimental studies. In isoflurane-anaesthetized dogs with dilated cardiomyopathy, xenon decreased heart rate and increased the time constant of left ventricular relaxation, but had no effect on arterial or left ventricular pressures or the indices of left ventricular preload and afterload.77 In rabbits with chronically compromised left ventricular function 9 weeks after permanent coronary artery ligation, the inhalation of xenon 70% had no effect on left ventricular function measured by echocardiography in closed-chest animals.78 With invasive measurements, a decrease in left ventricular pressure and left ventricular dP/dt of 10% was observed, indicating only a small negative inotropic effect. In the presence of regional myocardial ischaemia and reperfusion, xenon caused a small reduction in cardiac output and an increase in mean aortic pressure, resulting in an increase in systemic vascular resistance.79 Xenon also has cardioprotective effects: given during reperfusion, it reduced infarct size after regional myocardial ischaemia in rabbits in vivo.79 In addition, xenon can protect the heart against the consequences of ischaemia by pharmacological preconditioning.80 This effect is mediated by activation of the isoform 3 of protein kinase C (PKC), by a translocation of PKC from the cytosol to the cell membrane, and by the p38 mitogen-activated protein kinase (MAPK).80 Xenon preconditioning also induces phosphorylation of small heat shock protein 27 downstream of PKC and p38 MAPK.81 Xenon improved the recovery from myocardial stunning after regional ischaemia as measured by sonomicrometry in dogs.82 Only two studies have investigated the effects of xenon in patients with pre-existing cardiac disease. Postoperative sedation with xenon/remifentanil in patients after coronary artery bypass grafting did not affect heart rate and mean aortic pressure compared with propofol sedation.26 In contrast to propofol sedation, xenon had no

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vasodilatory effects in these patients with cardiovascular impairment, and there were no negative effects on myocardial contractility as determined by left ventricular stroke work index.26 In this investigation, only ten patients were studied, and the mean xenon concentration used for sedation was 27.4G11.8% (meanGSD), much lower than the concentrations necessary for anaesthesia. In 20 patients undergoing coronary artery bypass graft surgery, 60% xenon was administered for 15 minutes after induction of anaesthesia (fentanyl/midazolam) but before the start of surgery.69 Xenon did not affect the systolic function of the left ventricle as determined by trans-oesophageal echocardiography or any other variable such as cardiac index, vascular resistance or pulmonary artery occlusion pressure. Only a minimal decrease in mean arterial pressure was observed. Xenon has been safely used in a patient with Eisenmenger’s syndrome, in whom the main concern was a reduction in systemic vascular resistance.83 Patients with Eisenmenger’s syndrome have lost the ability to adapt to sudden haemodynamic changes because of end-stage pulmonary vascular disease and may benefit from the stable haemodynamics of xenon anaesthesia. Information is still limited about the use of xenon during extracorporeal cardiopulmonary bypass. In rats, cardiopulmonary bypass-induced neurological and neurocognitive dysfunction was attenuated by xenon 60%.39 In these experiments, xenon was added to the perfusion system after the oxygenator. One major problem with the use of xenon during cardiopulmonary bypass is that the noble gas is eliminated during extracorporeal circulation by the oxygenator84, and continuous xenon administration would be necessary to compensate for these losses, increasing substantially the cost of its use. Intravascular air bubbles—which commonly occur during cardiopulmonary bypass—are another concern. Xenon anaesthesia results in gas exchange conditions that favour bubble growth, which may worsen neurological injury from gas embolism.85 Like nitrous oxide, xenon also expands air bubbles, although to a lesser extent, thereby increasing the risk of significant morbidity after cardiopulmonary bypass.86 There are no clinical data available on the use of xenon during heart surgery so far. Respiratory system In cerebral blood flow studies using 33% xenon, a reduction in respiratory rate was observed, along with a compensatory increase in tidal volume, resulting in no change of minute volume.87 Airway resistance depends on airway geometry, and also on flow rate and gas density and viscosity (which are higher for xenon than for air or nitrous oxide—see above). A retrospective study revealed an increase in peak airway pressure in mechanically ventilated patients inhaling 33% xenon.88 Lachman et al observed no changes in expiratory airway resistance in humans.58 In contrast, experimental studies demonstrated an increase in calculated lung resistance in open-chest dogs when compared with nitrogen or nitrous oxide.89 Similar results were reported by Calcia et al, who described an increase in airway pressure and resistance in pigs by 70% xenon.90 This effect was only moderate when compared with baseline conditions but was more pronounced during bronchoconstriction induced by metacholine. The increases in inspiratory airway resistance may be attributed to the higher density and viscosity of the inert gas compared with nitrogen, nitrous oxide and oxygen91, but may be irrelevant during general anaesthesia because the ventilator overcomes the increased resistance

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caused by higher viscosity and density of the inspired gas. Concentrations of 30 or 60% xenon had no effect on diaphragmatic contractility in dogs.92 Diffusion hypoxia is a phenomenon which may occur during washout of nitrous oxide caused by its higher solubility compared with nitrogen. Because the blood/gas partition coefficient of xenon (0.115) is close to that of nitrogen (0.015), diffusion hypoxia is unlikely to occur during recovery from xenon anaesthesia. Alveolar partial pressure of oxygen and carbon dioxide were only minimally altered after xenon anaesthesia compared with nitrous oxide.93 Blood flow and haematological effects In chronically instrumented dogs, cardiovascular stability during xenon anaesthesia was accompanied by an increase in total body oxygen consumption, most likely caused by increased cell metabolism.75 In acutely instrumented dogs, xenon 70% given directly into the coronary artery had no effect on coronary blood flow.76 In pigs, regional perfusion in the brainstem, cerebral cortex, medulla oblongata and cerebellum was increased during xenon 79% inhalation.94 In these animals no effect on liver, kidney, bowel, muscle, skin or cardiac blood flow was observed.94 The relationship between regional cerebral blood flow and cerebral glucose utilization was maintained, although reset at higher levels in rats.49 No influence on regional cerebral blood flow and carbon dioxide autoregulation by up to 70% xenon was observed in propofolanaesthetized pigs95, or in pentobarbital-anaesthetized rabbits.22 A transcranial Doppler study in humans registered regional increases in blood velocities of some cerebral arteries after 65% xenon inhalation.66 In patients with severe head injury, xenon 33% produced an increase in intracranial pressure and decreased cerebral perfusion pressure, although no signs of cerebral ischaemia were observed50, and the observation that xenon 25–35% inhalation increased cerebral blood flow has raised concerns that xenon inhalation may be hazardous in patients with decreased intracranial compliance. Xenon anaesthesia did not lead to pathological alterations of coagulation parameters such as activated partial thromboplastin time (aPTT), fibrinogen concentrations or thromelastographic measurements.96 In human whole blood in vitro, xenon did not affect the unstimulated or agonist-induced platelet glycoprotein (GP) expression, the activation of the GPIIb/IIIa receptor or the platelet-related haemostasis, suggesting no altered platelet function.97 An investigation on neutrophil and monocyte function demonstrated no effect on the respiratory burst activity of these cells, but did show an increased neutrophil phagocytic activity.98 Therefore, xenon preserves neutrophil and monocyte antibacterial capacity in vitro. Xenon increased the removal of selectins from the neutrophil surface, thereby probably inhibiting the adhesion of neutrophils to the endothelium.99 This might have implications in the recruitment of neutrophils to an inflammatory site. In an isolated cardiopulmonary bypass system, xenon had no immunomodulatory effects and did not change interleukin-8 or interleukin-10 levels.100 Renal effects An increase in renal blood flow was suggested in humans58, while no effect on kidney blood flow was observed in anaesthetized pigs.94 No other data on renal physiology during xenon anaesthesia are available.

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Hepatic and intestinal effects The effect of 73% xenon on the hepatic perfusion distribution and hepatic oxygenation was investigated in pentobarbital/buprenorphin-anaesthetized pigs.101 Serum alanine aminotransferase (ALT), lactate, lactate dehydrogenase (LDH) and urea production were not altered by xenon. Hepatic venous-blood oxygen content was significantly higher with xenon than with intravenous anaesthesia. In flunitrazepam/ketamineanaesthetized pigs, xenon produced a reduction in mesenteric artery blood flow, but did not impair intestinal oxygenation.102 Like nitrous oxide, xenon may diffuse into air-filled spaces, including the bowel. The amount of gas diffused depends on the transport capacity of the blood as given by the blood/gas partition coefficient. The amount of gas diffused into the bowel was significantly lower during xenon than nitrous oxide anaesthesia in pigs.103 No increases in bowel pressure or tissue perfusion in pigs subjected to a mechanical bowel obstruction were observed during xenon anaesthesia.104 Skeletal system and interaction with muscle relaxants Halogenated anaesthetics interact with the ryanodine receptor, which corresponds to the Ca2C channel of the sarcoplasmic reticulum and plays a central role in excitation– contraction coupling. Volatile anaesthetics increase ryanodine binding and stimulate the release of Ca2C, thereby affecting muscular tone and triggering malignant hyperthermia episodes in susceptible individuals. Xenon slightly inhibited ryanodine binding in skeletal muscle sarcoplasmic reticulum.105 In contrast to halothane, no changes in metabolic and haemodynamic parameters were observed after xenon administration in malignant hyperthermia-susceptible pigs.106 In vitro, the noble gas did not induce contractures in muscle strips from malignant hyperthermia-susceptible patients or normal individuals.107 These data suggest that xenon may not trigger malignant hyperthermia. Potent inhalational anaesthetics influence the neuromuscular blocking effects of nondepolarizing neuromuscular blocking agents. In comparison to sevoflurane, xenon had a smaller effect on recovery from vecuronium-induced neuromuscular block as determined by twitch response using accelerometry in surgical patients.108 After neuromuscular block by rocuronium (0.6 mg/kg), no differences with regard to onset time, duration, recovery index and clinical recovery from neuromuscular blockade were observed when xenon/remifentanil was compared with propofol/remifentanil anaesthesia.109

CONCLUSION Very low fresh gas flows or closed breathing systems, as well as recycling of waste anaesthetics, may become routine and may allow the use of xenon on a more routine basis in the future.110 Until than, xenon should not simply be discarded because of its high costs, but neither should it be considered as the only ideal anaesthetic. Cumulative knowledge of xenon anaesthesia should lead to thorough cost-benefit analyses to justify the use of this special inert gas in certain clinical situations. Current data indicate that xenon has relatively few and minor side effects, and at the same time it may have neuroprotective and cardioprotective properties. Xenon anaesthesia may therefore become a therapeutic option for specific indications, such as patients with neurological

Inert gases as inhalational anaesthetics? 375

disease111, or for patients at high risk of cardiac ischaemia or with severely compromised myocardial function. Future studies in ASA III and ASA IV patients must determine whether these patients will profit from xenon anaesthesia compared with other routinely used anaesthetic agents.

Practice points † xenon has a low blood/gas partition coefficient which allows a rapid onset of and recovery from anaesthesia; because of the high costs, a closed-circuit anaesthesia machine is strongly recommended † xenon anaesthesia has been proven to be safe and efficacious and to produce minimal haemodynamic side-effects under experimental and clinical conditions † xenon offers active neuroprotection and cardioprotection in experimental animal models

Research agenda † closed-circuit anaesthesia machines allowing the application of xenon as well as clinically useful recovery systems are required to minimize the costs of xenon anaesthesia † molecular targets of xenon have to be elucidated to understand the mechanism of action during neuroprotection and cardioprotection † future clinical studies with xenon should focus on patients at high risk for neuronal or cardiac damage, because these indications may justify the higher costs of xenon anaesthesia

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