Xenon: elemental anaesthesia in clinical practice

Abstract

The ‘noble’ gases have been known to have anaesthetic properties for 50 years yet only recently has their application become a clinical reality. In this review we describe the preclinical and clinical studies that have led to a resurgence of interest in the use of the element xenon as an anaesthetic. Furthermore, we highlight specific areas where xenon demonstrates advantages over other anaesthetics, including safety, beneficial pharmacokinetics, cardiovascular stability, analgesia and neuroprotection.

Introduction

The ‘noble’ gas xenon possesses numerous salubrious qualities which are currently underutilized in the world of clinical medicine; most notably in the field of anaesthesia. Xenon exists naturally as nine isotopes, of which ¹³²Xe, with a mean atomic weight of 131.293, is the most abundant. However, the gas is extremely rare, representing no more than 8.75×10⁻⁶% of atmospheric gases, and hence derives its name from the Greek for ‘stranger’. Discovered in 1898 by Travers and Ramsay, xenon is now manufactured by fractional distillation of air and is used commercially for lasers, high-intensity lamps, flash bulbs, fuel for ion thrusters in the aerospace industry, X-ray tubes and in medicine. Xenon has been used in clinical radiological¹ and anaesthetic practice² for 50 years, and in this article we discuss its potential application in clinical anaesthetic practice, highlighting areas in which its unique properties can be exploited.

Anaesthetic mechanism of action

Currently anaesthetics are thought to produce anaesthesia via interaction with receptor targets, most commonly GABA_A receptors and possibly other receptors such as the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptor³ which potentiate inhibitory neurotransmission and inhibit excitatory neurotransmission, respectively. Xenon is thought to exert anaesthetic action by potent non-competitive inhibition of NMDA receptors,^4,5 with little effect on GABA_A receptors or non-NMDA glutamatergic receptors.^4–6 Franks and colleagues^4,5 demonstrated that 80% xenon reduced NMDA-activated currents by approximately 60% (Fig. 1), grouping xenon with nitrous oxide,⁷ cyclopropane⁸ and ketamine⁹ in a class of anaesthetics with effects on NMDA receptors but not on GABA_A receptors.

Fig. 1

Xenon inhibits NMDA receptors in cultured rat hippocampal neurons. NMDA activates an inward current (in neurons clamped at −60 mV) with an EC₅₀ concentration of 24 ± 2 µM NMDA and a Hill coefficient of 1.2 ± 0.1. Xenon (80%) inhibited the current by approximately 60%, but did not significantly change either the EC₅₀ or the Hill coefficient. Each data point represents the mean peak current from at least six cells. The inset shows typical current traces (at 100 µM NMDA) in the presence and absence of xenon. Reproduced with permission from Franks et al., Nature, 396, 324, 1998.

Recent studies have implicated neuronal background potassium channels (two-pore-domain potassium channels such as TREK and TASK), which modulate neuronal excitability, as potential targets of anaesthetic action,^10–12 and xenon, nitrous oxide and cyclopropane have been shown to activate TREK-1 but not TASK-3 channels.¹³ Xenon (80%) activated TREK-1 channels by 35 ± 2% (Fig. 2) but had little effect on TASK-3 channels, unlike the known GABAergic anaesthetic halothane which activates both.¹³ Activation of TREK channels leads to neuronal hyperpolarization which reduces cellular excitability; in addition, this effect is likely enhance NMDA receptor blockade due to the voltage-gated kinetics of this channel. As TREK channel activation is a consistent effect of the anaesthetics tested so far^10–13 it may become a common mechanism of action for all anaesthetics.

Fig. 2

Xenon concentration–response curve for the activation of TREK-1 channels expressed in HEK 293 cells. Data are mean ± SEM (n = 7–14 cells). Reproduced with permission from Gruss et al., Mol. Pharmacol., 65, 443–52, 2004.

It is still not known how anaesthetics produce anaesthesia, but significant progress has been made in this field over the last two decades. Study of how an ‘inert’ element such as xenon can produce anaesthesia will be an important probe in furthering inquiry into anaesthetic mechanisms. Currently, antagonism of the NMDA receptor is thought to be xenon’s prime site for anaesthetic action and recent work has also highlighted the role of TREK-1 channels; although their relative contributions are hard to estimate, both sites of action are likely to be involved. It is possible that further targets contributing to the anaesthetic state produced by xenon will be isolated in the future.

Clinical features

Recently, a large multicentre randomized control trial was conducted across Europe to assess the efficacy and safety profile of xenon anaesthesia.¹⁴ This study of 224 patients (ASA I–III; 218 patients completed the protocol) demonstrated that xenon (60 ± 5%) was not only safe but also had a faster post-anaesthesia recovery time than isoflurane (end-tidal concentration 0.5%) combined with nitrous oxide (60%). As we will discuss below, xenon was found to be cardiovascularly stable (‘cardiostability’), with a tendency to an increased analgesic effect. Furthermore, xenon’s cardiovascular, analgesic and safety profile has been evaluated with success in the field of critical care medicine.¹⁵ Clinical application in the field of cardioprotection and neuroprotection will also be discussed.

Anaesthetic potency and depth

Cullen et al.¹⁶ originally estimated a minimum alveolar concentration (MAC) value for xenon of 71% of an atmosphere (71% atm); more recently, Nakata et al.¹⁷ have estimated it to be somewhat lower, at 63% atm (in a middle-aged population). The same group also noted a gender-dependent difference in MAC values in the elderly (≥65 years), with females having a significantly lower MAC than men (51% atm vs. 69% atm)¹⁸ (Fig. 3). This is especially interesting as volatile anaesthetic agents only show gender-dependent differences in MAC during pregnancy,¹⁹ and the observations of Goto et al.¹⁸ may represent a class effect for all NMDA antagonists.

Fig. 3

The probability of no patient movement in response to skin incision is plotted against the concentration of xenon for patients aged ≥65 years. The continuous and broken curves represent the logistic regression curves for men and women, respectively. By definition, the concentration associated with a 50% probability of no movement (the intersection between the horizontal bar and the regression curve) is the MAC for xenon for each sex. The horizontal bars represent the 95% confidence intervals of the MACs. Reproduced with permission from Goto et al., Anesthesiology, 97, 1129–32, 2002.

The MAC-awake value for xenon was determined in 90 female patients to be 33% atm or 0.46 times its MAC.²⁰ Therefore xenon is ranked between nitrous oxide (MAC-awake of 0.61 MAC), and isoflurane and sevoflurane (MAC-awake of 0.35 MAC for both). Furthermore, xenon interacts additively with isoflurane and sevoflurane on MAC-awake, unlike nitrous oxide which is infra-additive with either agent.

While there is no effective method for measuring anaesthetic depth, two methods currently being evaluated are mid-latency auditory evoked potentials (MLAEPs), which predict responsiveness to verbal command,^21,22 and bispectral index (BIS) monitoring, which is an electroencephalographic-derived univariate scale thought to reflect the level of hypnosis in anaesthetized patients.²³ Goto et al.²⁴ found that, unlike isoflurane, BIS monitoring did not correlate with hypnotic depth on emergence from xenon anaesthesia. Later, they found that MLAEPs correlated more closely with depth of hypnosis and concluded that this was a more appropriate form of monitoring xenon anaesthesia.²⁵ Recently, work from Russia has suggested that BIS is particularly inaccurate on induction and emergence from anaesthesia with xenon but may provide adequate assurance of established anaesthetic depth.²⁶ Two conclusions can be drawn from these investigations: MLAEPs correlate more closely with the xenon hypnotic state than BIS monitoring, and there is insufficient information available to assure us that either method is completely effective for assessing depth of anaesthesia.

Induction and emergence

Xenon possesses a favourable pharmacokinetic profile with fast induction and emergence^14,27–29 which is independent of the duration of anaesthesia.^15,28 This effect is attributable to its low blood–gas partition coefficient of 0.115,³⁰ which is significantly lower than those for other inhalational anaesthetics (nitrous oxide, 0.47; sevoflurane, 0.65; desflurane, 0.42). Xenon has been shown to induce anaesthesia faster than sevoflurane (71 ± 21 s vs. 147 ± 59 s),²⁷ though xenon induction may be associated with agitation, particularly in men.¹⁸ The Xenon Study Group¹⁴ demonstrated the rapid emergence from xenon anaesthesia, showing that xenon exhibited significantly faster recovery than equi-MAC nitrous oxide–isoflurane. Emergence from xenon anaesthesia proved to be two or three times faster than emergence from equi-MAC concentrations of nitrous oxide–isoflurane or nitrous oxide–sevoflurane anaesthesia.²⁸ Xenon also demonstrated significantly quicker recovery time than an equivalent depth of propofol anaesthesia after coronary artery bypass grafting in 10 male patients in a randomized cross-over study (mean values 3 min 11 s vs. 25 min 23 s).²⁹

Rapid emergence times following anaesthesia may be advantageous in a broad spectrum of applications including ‘day-surgery’ out-patient settings, critical care medicine (to afford clinical examination¹⁵) and cardiac surgery, where both ‘fast tracking’³⁰ and cardiovascular stability are desirable features.

Cardiovascular system

Xenon is regarded as a cardiostable anaesthetic; inotropic preservation and only a clinically insignificant decrease in heart rate are consistently reported.^{14,29,31–34} This effect may be due to less stress-induced sympathetic stimulation,³² a theory supported by the observation of stable epinephrine levels during xenon anaesthesia.³³ Perioperative plasma cortisol and epinephrine did not rise in the xenon group unlike the rise observed in the nitrous oxide group, despite the fact that more fentanyl was used during nitrous oxide anaesthesia.³³ However, Bedi et al.¹⁵ recently showed that there was no difference in plasma catecholamine levels compared with propofol to account for xenon’s cardiostability. Xenon is also considered to suppress both sympathetic and parasympathetic transmission,³⁵ and therefore xenon’s cardiostability is likely be a consequence of a combination of autonomic direct myocardial and indirect catecholaminergic actions.

Assessment of xenon’s effects on compromised myocardium may be more relevant when determining whether xenon will be efficacious in the clinical arena. Dingley et al.²⁹ have directly compared the cardiovascular effects of post-cardiac surgical patients sedated with either propofol or xenon, noting that xenon caused no change in heart rate or mean arterial pressure, and that higher filling pressures and systemic vascular resistance were seen than were evident in propofol-sedated patients. Indeed, ventricular function, as assessed by trans-oesophageal echocardiography, is unchanged during xenon anaesthesia.³⁴ In a study of 20 patients scheduled for elective coronary artery bypass grafting, xenon decreased indices of cardiac function significantly less than nitrous oxide.³⁶ In a critical care setting, xenon maintained blood pressure better than propofol throughout an 8 h period, and the authors concluded that xenon’s cardiostable properties may have a niche application in states of sepsis or shock where other sedative agents may induce myocardial depression.¹⁵ Animal models of cardiac dysfunction (left ventricular compromise³⁷ and cardiomyopathy³⁸) have also been used to demonstrate xenon’s cardiostablity. Furthermore, inhaled xenon (70%) was shown to be cardioprotective during early reperfusion following coronary artery occlusion, reducing infarct size after regional ischaemia in rabbit heart in vivo.³⁹ This would not only be of great advantage to patients who experience ischaemic events under anaesthesia, but is also of great potential for the application of xenon following myocardial infarction.

Xenon’s cardiostable effect has been investigated in vitro where it was found to exert little effect on major cation currents, including those for sodium (I_Na), calcium (I_Ca,L) and potassium (I_K,ir), in guinea pig myocytes.⁴⁰ Xenon exerts no effects on l-type calcium channels in human atrial myocytes, even in the presence of the β-adrenergic agonist isoproterenol, unlike the known myocardial depressant halothane.⁴¹ In contrast with volatile anaesthetics,⁴² xenon showed no deleterious effects on cardiac function in preparations of isolated guinea pig ventricular muscle bundles.⁴⁰ Thus xenon appears to be relatively ‘inert’ in in vitro models of cardiac function.

Clinical application of xenon is likely to succeed in arenas where cardiovascular compromise can be predicted, such as high-risk, cardiac and emergency surgery, and potentially also in situations of shock and sepsis. In addition, patients with cardiac disease may benefit from the cardioprotective nature of xenon anaesthesia.

Neuroprotection

Xenon’s capability to act as a neuroprotective agent has also been investigated. As NMDA receptors appear to be crucial to the initiation of neuronal injury and progression to cell death as a result of a variety of insults,^43–45 xenon has been evaluated in various paradigms of neuronal injury. In vitro xenon reduced mouse cortical co-culture neuronal injury, quantified by the amount of lactate dehydrogenase (LDH) released into the culture medium, induced by NMDA, glutamate or oxygen–glucose deprivation (OGD). LDH release was significantly reduced at all concentrations of xenon tested (Fig. 4) with xenon IC₅₀ concentrations for neuroprotection being 19 ± 6% atm 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 and glucose for 90 min with an IC₅₀ concentration of 10 ± 4% atm.⁴⁶ Further in vitro work on rat cortical cultures showed that xenon (50%) could attenuate hypoxia-induced LDH release,⁴⁷ accompanied by a 60% reduction in glutamate release; this effect could be partially antagonized by intracellular calcium chelation. Recent observations have suggested that some calcium signalling in the neuropathological situation is protective,^45,48 dissociating calcium load and neuronal death;⁴⁴ in the case of xenon, preliminary evidence suggests that preservation of some calcium signalling is necessary for neuroprotection. In clinical practice xenon is likely to be administered in combination with other anaesthetic agents, and therefore we investigated whether co-administration of isoflurane, a GABA_A agonist,⁵ which is also neuroprotective,⁴⁹ would enhance xenon neuroprotection. The combination proved to be synergistic⁵⁰ (Fig. 5), with the IC₅₀ (mean ± SEM) for xenon neuroprotection significantly decreasing from the predicted value of 28 ± 2.0% atm (assuming additivity) to 18.9 ± 2.5% atm in the presence of 0.6% isoflurane.

Fig. 4

Dose-dependent effect of xenon vs. injury produced by (A) NMDA or (B) glutamate in vitro. Co-cultures of mouse neuronal–glial cells were treated with (A) NMDA 250 mM or (B) glutamate 100 mM for 10 min during exposure to oxygen–carbon dioxide–xenon–nitrogen. The xenon and nitrogen concentrations were changed reciprocally such that their aggregate was 75% atm. After 6 h the culture medium was harvested and assayed for LDH. Data are expressed as the percentage mean ± SEM (n = 3) of LDH released into the medium over the 6 h period normalized to LDH release when no xenon is present. Reproduced with permission from Wilhelm et al., Anesthesiology, 96, 1485–91, 2002.

Fig. 5

Xenon and isoflurane alone and in combination inhibited LDH release, expressed as a fraction of maximum LDH release in the absence of agents (mean ± SEM, n = 3 or 4) induced by oxygen–glucose deprivation for 75 min. (A) Closed circles, xenon alone, IC₅₀ = 35.9 ± 2.2% atm; open circles, xenon in the presence of 0.6% isoflurane, IC₅₀ = 18.9 ± 2.5% atm. (B) Closed circles, isoflurane alone, IC₅₀ = 2.72 ± 0.35%; open circles, isoflurane in the presence of 14% xenon, IC₅₀ 0.92 ± 0.13% atm. Reproduced with permission from Ma et al., Anesthesiology, 99, 748–51, 2003.

In vivo xenon attenuated neuronal injury induced by administration of N-methyl-l-aspartate (NMA) to rats (Fig. 6).⁴⁶ Furthermore, we demonstrated the neuroprotective effect of xenon in a focal ischaemia model by administering 70% xenon during transient middle cerebral artery occlusion in mice and found a significant reduction in total, cortical and subcortical infarct size compared with nitrous oxide.⁵¹ This difference in efficacy may be attributable to a differing potency of antagonism of the NMDA receptor (and its subtypes).

Fig. 6

Dose-dependent neuroprotective effect of xenon in vivo on NMA-induced neuronal injury. Rats were injected with NMA 100 mg/kg subcutaneously and humanely killed 4 h later after exposure to air (n = 7) or xenon (n = 5–8). The arcuate nucleus was sectioned and stained with cresyl violet and the number of degenerated neurons (pyknotic nuclei surrounded by vacuolated cytoplasm) were counted (mean ± SD). *P < 0.05, **P < 0.01 compared with control. Reproduced with permission from Wilhelm et al., Anesthesiology, 96, 1485–91, 2002.

In order to provide functional correlates (i.e. a cognitive parallel) of this histological effect⁴⁶ we studied the effect of xenon in a model of neurological injury induced by cardiopulmonary bypass (CPB).⁵² In this model, neuromotor skills, visuospatial memory and spatial memory were assessed for up to 12 days after rats were subjected to CPB in the presence of either xenon or nitrogen (65% atm). Xenon attenuated the neurocognitive dysfunction caused by CPB; this effect was superior to that seen with MK801 (dizolcipine), another NMDA antagonist (Fig. 7).⁵² Furthermore, in our focal ischaemia model in mice, xenon provided superior neurocognitive protection to that provided by nitrous oxide, as evidenced in two out of three cognitive tests conducted 24 h after ischaemia.⁵¹

Fig. 7

Spatial memory following CPB. After CPB animals were subjected to 10 consecutive days of Morris water maze testing where they had to locate a submerged platform in one of four quadrants of a pool of water. Twelve days after CPB, animals were subjected to a probe trial, in which there was no platform present, for 60 s. The percentage of time spent in the quadrant of the former platform position was obtained as a measure of spatial bias. Animals in the Sham and CPB+Xe groups spent a longer period in the quadrant of the former platform, which indicates that they have a better spatial memory function than the other groups. The results are mean ± SD (n = 10). *P < 0.05, **P < 0.01 compared with the CPB group. †P < 0.05 compared with the CPB + Xe group. Reproduced with permission from Ma et al., Anesthesiology, 98, 690–8, 2003.

Spontaneous neuronal injury, such as occurs with stroke and perinatal brain injury, cannot necessarily be approached in a prospective manner, i.e. application of the agent before the injury. Therefore investigation of whether an agent is effective with post-injury administration is important for clinical application in these scenarios. In a model of transient global ischaemia (temporary middle cerebral artery occlusion in adult rats for 90 min), application of 50% xenon for 3 h, starting 15 min after the insult, significantly reduced neuronal damage in the cortex and striatum; interestingly, 70% xenon was ineffective.⁵³ As a large degree of neuronal damage post-insult occurs in the penumbral region of infarct, xenon appears to preserve this region. Theoretically, retrospective treatment with xenon could be applied to neurological conditions such as stroke; however, it will be prudent to establish a ‘window’ of effective retrospective treatment in animals before extrapolating this treatment to human trials.

The MAC of xenon is estimated to be 63–71% atm;^16,17 therefore the concentrations required for neuroprotection are significantly sub-anaesthetic. Thus, in contrast with other anaesthetics that require anaesthetic or supra-anaesthetic doses to act as a neuroprotectant,^49,54,55 xenon maybe effective at more clinically acceptable concentrations or where anaesthesia is not required or may even be detrimental (e.g. in patients with cardiovascular compromise). It should be noted that other NMDA receptor antagonists have faired poorly in clinical trials so far despite showing promise in preclinical experiments. In some instances, this is because of unfavourable pharmacological properties which prevent rapid transfer of the NMDA antagonist across the blood–brain barrier. Almost all NMDA antagonists tested so far exhibit psychomimetic behavioural changes;^56,57 pyramidal neuronal damage in the posterior cingulate and retrosplenial (PC/RS) cortices^7,58,59 are considered to be morphological correlates of the behavioural changes. We showed that ketamine and nitrous oxide increased c-Fos expression in PC/RS cortices dose dependently, a neurotoxic feature not caused by xenon (Fig. 8).⁶⁰ In addition, xenon,⁶¹ like haloperidol⁶⁰ and eliprodil,⁶² can ameliorate the neurotoxic effects of other NMDA antagonists.

Fig. 8

Concentration or dose–response effects of xenon, nitrous oxide and ketamine on the number of c-Fos positive neurons in the posterior cingulate and retrosplenial cortices. Rats were exposed to increasing doses or concentrations of three anaesthetics which antagonize the NMDA receptor. The rats were killed and the brains harvested and prepared for c-Fos immunostaining. MK 801 is included as a known positive control for the production of a c-Fos immunohistochemical lesion in the posterior cingulate and retrosplenial cortices. Results are shown as mean ± SEM. *P < 0.05, **P < 0.01 vs. control. Reproduced with permission from Ma et al., Br. J. Anaesth., 89, 739–46, 2002.

Recent in vitro research has suggested that xenon acts not only on NMDA channels but also on TREK-1 channels (discussed above). TREK-1 channels are also activated by the neuroprotective agents riluzole,⁶³ a therapeutic agent used to treat amyotrophic lateral sclerosis, and polyunsaturated fatty acids.⁶⁴ Consequently, it has been postulated that these channels contribute to neuroprotection. As TREK-1 channels are activated by intracellular acidosis and reduce neuronal excitability, this is certainly feasible.

Xenon is not ‘inert’ with respect to cerebral haemodynamics; increased cerebral blood flow (CBF)^65–67 with preserved cerebral autoregulation^66–68 is thought to occur acutely with xenon administration. This is an area of crucial importance to the clinical application of xenon, as any neuroprotective or anaesthetic agent that may be used in a situation where raised intracranial pressure (ICP) is likely (e.g. neurosurgery) must have a predictable and safe effect on CBF. Indeed, a theoretical concern that increasing CBF may worsen ICP is an important consideration with an agent of this class. There have been no reports of an increase in ICP with xenon administration in animal models, despite reported vasodilatation.⁶⁹ In humans, xenon has been used without compromise in radiology; in one study of head trauma sufferers, xenon appeared to increase intracranial and cerebral perfusion pressure but without any evidence of cerebral oligaemia or ischaemia.⁷⁰ Further information is required to define whether xenon may be used safely in situations of raised ICP.

Analgesia

Consistent with its ability to inhibit the NMDA receptor, xenon provides analgesic effects. In clinical studies xenon consistently provides a significantly greater analgesic effect than nitrous oxide.^{32–34,71,72} However, Rossaint et al.¹⁴ found only a tendency to increased analgesic effect compared with 1 MAC isoflurane–nitrous oxide, although this effect may have been underestimated as xenon was only administered at 0.9 MAC. Indeed, recent work in critical care, where a long duration of sedation is required, has suggested that xenon possesses very potent analgesic action, with only one of 21 patients requiring any more than minimal alfentanil during an 8 h period.¹⁵ Many comparisons have been made between xenon and nitrous oxide; however, not only do they have different potencies, but they also exhibit different analgesic profiles. Nitrous oxide’s mechanism of antinociception has been clarified recently,⁷³ showing a dependence on opiate and adrenergic signalling that xenon does not share.⁷⁴ In addition, xenon is active at the level of spinal cord, whereas nitrous oxide is not,⁷⁵ which may indicate differing potencies in the inhibition of the NMDA receptors in the dorsal horn of the spinal cord. Opposing effects have been further demonstrated, as nitrous oxide does not exert any antinociceptive effect in the formalin test in the neonatal rat⁷⁶ whereas xenon does.⁷⁷ Extrapolation of these results to humans suggests not only that xenon may provide analgesia in the paediatric population but also that the use of nitrous oxide for analgesia may be imprudent. We await clinical studies to address these issues. Xenon may be of particular utility in neonatal anaesthesia as the neonatal myocardium is very sensitive to the depressant effects of volatile anaesthetics;⁷⁸ whether xenon exerts a salubrious cardiostable effect in the neonate is currently not known.

Organ effects

Xenon appears to exert no deleterious effects on other organ systems. Prolonged xenon exposure in the critical care setting was not associated with any further deterioration in haematological and biochemical variables.¹⁵ These data are consistent with previous reports suggesting that xenon exerts no effects on coagulation⁷⁹ or platelet function in vitro⁸⁰ or on the immune system.⁸¹ Xenon does not impair hepatic or renal function^15,82 and has been used safely in hepatic surgery.⁸³ Indeed, as xenon is excreted in the lungs with no modification by the renal or hepatic systems, it may prove to be the anaesthetic of choice in surgery or critical care when these systems are impaired.

Concerns over increased airway pressure during xenon ventilation led to hypotheses centred upon an increased airway resistance induced by this gas.^84,85 However, recent work has suggested that the increase is attributable to the physical properties of the gas and that bronchoconstriction is not a contributing factor.⁸⁶ Calzia et al.⁸⁷ have evaluated the effect of xenon on diffusion hypoxia and concluded that this phenomenon is unlikely to occur with the administration of xenon.

Xenon does not does not trigger malignant hyperthermia in susceptible swine.^88,89 Burov et al.⁹⁰ found no evidence of toxicity in several in vitro and in vivo paradigms involving two species given xenon either acutely (Balb/c mice and Wistar rats) or subchronically (Wistar rats and mongrel dogs).⁹⁰ Studies of microorganisms and mice showed that xenon has no mutagenic or carcinogenic properties.⁹¹ No embryotoxic or teratogenic changes were found in pregnant Wistar rats, nor was xenon found to be allergenic.⁹⁰

Delivery and recycling systems technology

A major limiting factor in the development of routine xenon anaesthesia is the expense of recovering the gas from the atmosphere; the current cost of 1 litre of xenon with a purity of 99.99% is approximately $10. Therefore closed-circuit delivery appears to be an economic necessity for the application of xenon anaesthesia.⁹¹ The Xenon Study Group recently used a total of 24.6 ± 10.2 litres of xenon for 211 ± 102 min of closed-circuit anaesthesia;¹⁴ we estimate the costs of this to be approximately $70 per hour. A cost analysis for a 40-year-old ASA I adult male weighing 70 kg undergoing simulated elective surgery found that 240 min of closed-circuit xenon anaesthesia would cost $356 (approximately $90 per hour).⁹² Most of this cost can be attributed to priming and flushing the delivery circuit. The reduction in priming costs by denitrogenation of the delivery circuit could be achieved by breathing pure oxygen for 20 min pre-anaesthesia. However, this may not be acceptable for routine theatre activity, and so Rossaint et al.¹⁵ periodically flushed the circuit with a fresh oxygen–xenon mixture. If xenon anaesthesia is to be employed routinely, an economic necessity may be complete denitrogenation pre-anaesthesia.

Dingley and colleagues have been at the forefront of developing xenon closed-circuit anaesthesia, and their experience with a long duration of anaesthesia in critical care suggested that inhalational sedation with xenon was economically viable.¹⁵ They have pointed out that xenon anaesthesia becomes more financially viable with longer duration of administration; after 4 h of administration xenon becomes comparable in cost to other anaesthetics.⁹² Thus xenon may yet prove to be the anaesthetic of choice in settings such as critical care or cardiac surgery, where prolonged administration of anaesthesia is necessary and fast emergence is beneficial.

Measurement of xenon concentration is not accurate with traditional anaesthetic machines, and mass spectrometers and thermal conductivity sensors have been utilized to circumvent this problem. Mass spectrometers are the ‘gold standard’ but are costly, and thermal conductivity, as used by the Xenon Study Group,¹⁴ appears to be a more clinically acceptable method. Thermal conductivity is effective because xenon conducts heat better than other gases found within the anaesthetic circuit. Comparison of the accuracies of mass spectrometry and thermal conductivity suggests that there is no clinically significant difference between the two technologies during xenon anaesthesia.⁹³

Advances in recycling system technology will allow further improvement in the cost efficiency of xenon anaesthesia. Recycling systems which can reclaim xenon to a purity of >99% are available;⁹⁰ however, for the efficient use of the recycling system, anaesthesia would have to be maintained with another agent while xenon was recovered, negating xenon’s beneficial emergence pharmacokinetics. Therefore development of recycling or refining technology may have to occur before the full clinical benefit of xenon anaesthesia can be discovered.

Environmental effects

The major volatile anaesthetics are based on chlorofluorocarbons (CFCs) and are known to deplete the ozone layer; in addition, nitrous oxide is 230 times more potent as a greenhouse gas than carbon dioxide, taking 120 years to break down. The amount of nitrous oxide released as an anaesthetic contributes 0.1% of the greenhouse effect.⁹⁴ In contrast, xenon is a naturally occurring constituent of the environment and has no detrimental ecological effect. However, xenon’s ecological superiority must be balanced against the energy consumed in its recovery by the fractional distillation of liquid air.

Conclusions

The attention that the Xenon Study Group has recently given to xenon anaesthesia is deserved; we have further highlighted its potential clinical applications and exemplary safety record. Xenon has notable pharmacokinetic, cardiostable, neuroprotective and analgesic advantages over other anaesthetics, and further clinical trials are warranted to evaluate its effectiveness in the operating theatre and critical care unit. As delivery technology develops, xenon will become a more viable option in the anaesthetic armamentarium.

Declaration of interest

Professor Maze is a board member of an Imperial College spin-out company (Protexeon Ltd) that is interested in developing clinical applications for medical gases, including xenon. Professor Maze is a paid consultant in this activity. In addition, Air Products has funded, and continues to fund, work in the author’s laboratory that bears on the actions of xenon as an anaesthetic and neuroprotectant, and Air Products has a financial stake in Protexeon Ltd.

Author notes

*Department of Anaesthetics and Intensive Care, Faculty of Medicine, Imperial College London, UK, ^†Biophysics Section, Department of Biological Sciences, Imperial College London, UK and ^‡Magill Department of Anaesthesia, Intensive Care and Pain Management, Chelsea and Westminster Hospital, Chelsea and Westminster Healthcare NHS Trust, London, UK