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Dr John Dingley - Consultant Anaethetist, Morriston Hospital

A brief introduction to xenon

Xenon is a noble gas which constitutes 0.0000087% of the atmosphere. It was discovered in 1898 by Ramsay and Travers and is produced by fractional distillation of air [1]. The gas has been used for many years for radiological investigations of regional cerebral blood flow during which sedative and respiratory depressant properties were noted [2]. Further research made apparent that Xenon possesses many characteristics of an ideal anaesthetic agent. The minimal alveolar concentration (MAC) of Xenon is 71% and a low blood - gas partition coefficient of 0.115 (Nitrous oxide 0.47) results in rapid induction and emergence from anaesthesia [3-6]. Xenon is unlikely to undergo biotransformation and is of low toxicity. Current research into mechanisms of anaesthesia points at N-methyl-D-aspartate (NMDA) receptor inhibition as the main cellular site of action, a potential explanation of the analgesic properties of the gas [7].

Xenon appears to have remarkably few cardiovascular effects, a characteristic that suggests that this agent may be useful in patients with poor cardiovascular reserve [8-12].

The high cost of Xenon (approximately US$10 per litre) makes the use of fully closed low flow anaesthetic breathing circuits an economic necessity. With the development of these circuits the use of Xenon may become a potential alternative to current methods of providing anaesthesia and sedation [13-17]. The specific design of such circuits will be covered in another lecture and detailed reviews of the properties of xenon are available elsewhere [15-16].

For the purpose of this abstract I shall concentrate on the very recent discoveries with respect to protection against hypoxic brain damage.

The significance of this is that xenon may in the future change status from being an esoteric anaesthetic agent to a therapeutic drug with mainstream medical applications.

Neuroprotection.

Glutamate is an important excitatory neurotransmitter in the brain. However, excessive activation of glutamate receptors, especially the NMDA subtype, can lead to cell death by a process called "neurointoxication" [18] or "excitotoxicity" [19]. This cell death can precipitate a chain reaction of glutamate release and further cell death and it is possible that such processes occur after acute events such as stroke, cardiopulmonary bypass and brain trauma [19]. These processes may also involve many calcium ion related events at cellular level [18].

It would seem wise to find or develop drugs which block the NMDA receptor for use after such acute events, to block any such chain reactions of cell death. Existing NMDA antagonists include ketamine, phencyclidine and dizolcipine maleate (MK801). These however produce profound behavioural changes and have also been observed to alter brain histology. Nevertheless the search continues for a therapeutic drug with such properties and a large number of promising molecules have been patented but have proved to have unacceptable side-effects.

Xenon is also an NMDA antagonist [7]. As we already know from anaesthesia studies, it is effectively inert, has few side effects, and crosses the blood/brain barrier giving a rapid onset/offset of action. This makes it a good candidate for use as a neuroprotective therapeutic drug. Few gases have ever been developed and licensed as therapeutic drugs and the best and maybe the only example is nitric oxide (NO).

Is there a need for neuroprotective drugs? As a cardiac anaesthetist I shall use cognitive dysfunction after cardiopulmonary bypass (CPB) as an example: The incidence of stroke after CPB is around 2%. However, the incidence of more subtle cognitive dysfunction is as much as 80-90% immediately post-operatively, falling gradually to about 40% at 2-3 months and 25% at one year [20]. The economic impact of adverse cerebral outcome after cardiac surgery could be as much as $400 million per year worldwide [20].

Exciting evidence is emerging that xenon does have a profound neuroprotective effect.

The main findings in cell culture experiments:

1. Xenon is an NMDA receptor antagonist and blocks the effect of glutamate [19].
2. Xenon inhibits cell division in vitro at metaphase and this can be reversed by calcium ions. It may therefore also affect calcium regulated processes within cells [18]. The Ca++ calmodulin-activated kinase II (CaMKII) complex is known to be crucial for cell division and is a likely candidate as a site of action.
3. Cortical neurons in culture will release glutamate under conditions of hypoxia when placed in 100% nitrogen. Eventually they will die. However when placed in a 100% xenon atmosphere, there is no increase in release compared to controls in air, even after 2 hours of complete hypoxia. This is a very unusual finding [18].
4. The protective effect in iii) is dose related [18].
5. Nitrous oxide produces the same effect as 100% nitrogen (no protection).
6. A series of experiments have shown that the protective effects of xenon against hypoxia in cell cultures are greater than those of specific NMDA blocking drugs. This suggests other additional modes of action for xenon [18].
7. If a drug is administered which binds calcium ions, there is then no protective effect of xenon in cell culture hypoxia experiments [18].

It has therefore been suggested that:

1. Xenon blocks the NMDA receptor (neuroprotection by protecting cell against excess glutamate).
2. Xenon inhibits the CaMKII system. This system is involved in many cellular processes and is also, importantly, involved in glutamate release (neuroprotection by reducing glutamate release).
3. There is evidence that there may be yet more mechanisms of neuroprotection for xenon.

Does this still hold true in vivo?

1. Xenon reduces cardiopulmonary bypass-induced neurological dysfunction in rats as evidenced by actual neurological testing post-CPB [21].
2. Xenon exerts a neuroprotective effect in a rat model where a neurotoxic dose of N-methyl-DL-aspartic acid (NMA) has previously been injected, as evidenced by histological study [19].

Looking to the future.

I am allowed to speculate at this point.

Xenon is an interesting anaesthetic agent with minimal cardiovascular effects and a rapid onset and offset of action. It is however very expensive. It can be administered at acceptable cost however, if dedicated fully-closed breathing systems are used. Costs can potentially be reduced further by use of recovery and recycling. Suitable technical solutions now exist and have been used clinically. The commercial problem has always been whether such technology is worth developing for an agent that would probably find a niche role for patients with poor cardiovascular reserve [8-12].

Recent developments with respect to neuroprotection may change the whole situation. This is a "holy grail" of medicine. Two commercial patents have been filed on xenon neuroprotection by both interaction with Ca++ based complexes / glutamate release [22] and NMDA antagonism [23]. This may be just the start of research into a whole new avenue of medicine.

There is the real possibility that xenon-based therapeutic interventions could be developed for stroke, neurosurgery, head trauma and cardiac surgery. These represent major areas of hospital medicine and such therapies will necessarily have to be administered by anaesthetists.

You may yet find that you are no longer in a surgical support speciality.

Time of Presentation:

Monday 5 May 2003 - 0945-1030

References:

1. Garrett ME. The production and availability of xenon. Annual Meeting of the Association for Low Flow Anaesthesia (ALFA). Ghent. 1998.
2. Winkler S, Turski P, Holden J, et al. Xenon effects on CNS control of respiratory rate and tidal volume - the danger of apnea. In: Hartmann A, Hoyer S, eds. Cerebral blood flow and metabolism measurement. Berlin: Springer-Verlag, 1985: 356-60.
3. 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. British Journal of Anaesthesia 1998; 80(2): 255-6.
4. Nakata Y, Goto T, Morita S. Comparison of inhalation inductions with xenon and sevoflurane. Acta Anesthesiologica Scandinavica 1997; 41: 1157-61.
5. Goto T, Saito H, Nakata Y, Uezono S, Ichinose F, Morita S. Emergence times from xenon anaesthesia are independent of the duration of anaesthesia. British Journal of Anaesthesia 1997; 79(5): 595-9.
6. 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 1991; 75: 896-902.
7. Franks NP, Dickinson R, deSousa SLM, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature 1998; 396: 324.
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10. Burov NE, Ivanov GG, Ostapchenko DA, Dzhabarov DA, Kornienko L Yu, Shulunov MV. Hemodynamics and myocardial function in xenon anesthesia. Anesteziologiia i Reanimatologiia 1993; 5: 57-9.
11. Dingley J, King R, Hughes L, Terblanche C, Mahon S, Hepp M, Youhana Y, Watkins A. Exploration of xenon as a potential cardiostable sedative: a comparison with propofol after cardiac surgery. Anaesthesia 2001: 56: 829-835.
12. Hettrick DA, Pagel PS, Kersten JR, Tessmer JP, Bosnjak ZJ, Georgieff M, Warltier DC. Cardiovascular effects of xenon in isoflurane-anesthetised dogs with dilated cardiomyopathy. Anesthesiology 1998; 89: 1166-73.
13. Luttropp HH, Rydgren G, Thomasson R, Werner O. A minimal-flow system for xenon anesthesia. Anesthesiology 191; 75(5): 896-902.
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15. Lynch C, Baum J, Tenbrinck R. Xenon anesthesia. Anesthesiology 2000; 92: 865-70.
16. Dingley J, Ivanova-Stoilova TM, Grundler S, Wall T. Xenon: recent developments. Anaesthesia 1999; 54: 335-346.
17. Baeder S, Georgieff M, Marx T. Anaesthetic apparatus with gas-ingredient return system - has compressor delivering to second pressure vessel with cooler to maintain anaesthetic in liquid state. US Patent No: US 5520169 A.
18. Petzelt C, Blom P, Schmehl W, Mullner J, Kox WJ. Prevention of neurotoxicity in hypoxic cortical neurons by the noble gas xenon. Life Sciences 2003; 72: 1909-1918.
19. Ma D, Wilhelm S, Maze M, Franks NP. Neuroprotective and neurotoxic properties of the 'inert' gas, xenon. British Journal of Anaesthesia 2002; 89(5): 739-746.
20. Grocott HP. Cerebral injury during cardiac surgery: understanding the need for a neuroprotective strategy. Journal fur Anasthesie und Intensivbehandlung 2002; 2: S45.
21. 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(3): 690-698.
22. Petzelt C, Kox W. Use of xenon for treating neurointoxications. EP 1158992.
23. Franks NP, Maze M. NMDA antagonist. USP 6274633.