2006 Annual Scientific Meeting - CLICK FOR PROGRAMME

Intravenous Xenon?      

Dr J Dingley, FRCA, MD   University of Wales Swansea

In 1999 an anaesthetist was the winner of the international Braunschweig award in Germany for his research which had shown that it was possible to produce anaesthesia by intravenous injection of xenon dissolved in lipid emulsions. Xenon anaesthesia offers rapid induction/emergence, analgesia, excellent haemodynamic stability and a lack of side effects. This new form of intravenous anaesthesia offered anaesthesia in the manner of a switch being turned on and off, ideal for day case surgery.

As with many medical discoveries, once the initial euphoria had passed, the difficult task of translating this research into clinical reality produced some problems. Some authors disputed the original findings.^1,2 The problem mainly concerned the difficulty of dissolving enough xenon in a carrier to allow anaesthesia without the need to infuse very large volumes of, for example, IntraLipid^®. Another complicating factor is that xenon is relatively insoluble in blood (explaining the fast emergence) and much of any injected xenon will exit via the lungs without ever reaching the brain.³ This phenomenon has even been claimed as advantageous, offering the prospect of true target-controlled xenon infusion using the end-tidal xenon concentration as a surrogate for the blood concentration (the target).⁴

A closed circuit breathing system could be adopted such that this xenon loss eventually self-limits, creating an equilibrium state. Arguably however, having gone to all this trouble one might as well then add the xenon to the breathing circuit. In view of this, one manoeuvre proposed to reduce the induction dose is to induce intravenous xenon anaesthesia during apnoea.⁴

There are conflicting reports regarding the maximum volume of xenon that can be dissolved in IntraLipid^® emulsions.^1,5 Factors include the temperature and pressure at which this is being performed. It has for example been proposed that xenon be dissolved in lipid under high pressure and kept in this state in a pressurised ampoule. A problem with this is that it might theoretically cause the liberation of bubbles once injected into the circulation causing a state similar to the “bends” in diving medicine. Despite these controversies, there appears to be reasonable agreement that 1ml of 20% IntraLipid^® will carry approximately 0.3ml xenon when saturated at atmospheric pressure.^1,5 It has also been shown that the volume of dissolved xenon is proportional to the soya bean oil content of the IntraLipid.²

Research has focused on optimising the injectable carrier liquid to dissolve as much xenon per ml of liquid as possible.^5,6

Pigs of mean weight approximately 40kg received 1ml kg^-1 hr^-1 of 10% lipid-Xe emulsion (approx. 0.3mlXe ml^-1 lipid) and it was found that compared to a control group there was a reduction in blood adrenaline level, heart rate and also a reduction in supplementary anaesthetic requirement (pentobarbitone) by approximately 70%.

When repeated with a 40% perfluorocarbon emulsion in pigs of approximate mean weight 35kg, 2.1mlXe ml^-1 of emulsion was achieved. With this more efficient emulsion, anaesthesia was induced with 20ml over 20sec and then maintained with 10ml Xe kg^-1 hr^-1 (which represents 4.8ml emulsion kg^-1 hour^-1).

Although anaesthesia was achieved it can be seen that for a 70kg human this would represent 336ml hr^-1 of intravenous perfluorocarbon which is a considerable volume.

While some difficulties remain for intravenous xenon anaesthesia, perhaps there may be other medical applications for which a sub-anaesthetic infusion rate would be sufficient.

Xenon has been found to be neuroprotective, limiting damage from; hypoxia in cell cultures⁷, experimental insults^8,9 and hypoxia-ischaemia combinations in vivo^{10, 11, 12} if applied soon after the insult. Mechanisms include NMDA receptor blockade and reduction of transmitter release,^13,7 so limiting the receptor overstimulation leading to cell “suicide” (apoptosis) seen as a chain reaction after many brain insults. Suggested neuroprotective applications of xenon include: Stroke,¹⁴ Parkinson’s disease, Alzheimer’s, withdrawal from drug/alcohol addiction, before (via the placenta) or after birth-asphyxia in neonates, neurosurgery, and to limit cardiopulmonary bypass induced cognitive deficit after cardiac surgery among others.¹⁵

Many of these applications are already in clinical use in Russia, where in addition, xenon is currently being offered as a neuroregenerative (as opposed to neuroprotective) therapy, delivering multiple treatment episodes over a long period in situations where there has been an interval of anything up to 6 months or more between brain/nerve damage and onset of the treatment course. This is not illogical as in addition to other factors, xenon has been shown to increase levels of brain-derived neurotrophic factor.¹¹

It is possible that these therapeutic applications may not require full anaesthetic doses of xenon and so may be more appropriate uses for intravenous xenon delivery than anaesthesia. A number of patents have been filed for such applications suggesting the use of xenon alone or in combination with other existing or novel therapies.¹⁶

1. Xenon-i.v. fails to produce anesthesia in rodents. Applied Cardiopulmonary Pathophysiology 2000;9:79-82.

2. The partition coefficients of xenon in lipid emulsion and its components. ASA October 24^th 2005. A746.

3. The blood-gas partition coefficient of xenon may be lower than generally accepted. Br J Anaesth. 1998;80:255-6.

4. Patent No: US 6,197,323 Medicinal preparation containing a lipophilic inert gas.

5. Patent Application No: JP19980076605 Apparatus for controlled anesthesia, pain killing and sedation.

6. Solubility of xenon in 45 organic solutes. J Chem Phys 1989;90(11):6569-79.

7. Prevention of neurotoxicity in hypoxic cortical neurons by the noble gas xenon. Life Sciences. 2003;72:1909-18.

8. Wilhelm S et al. Effects of xenon on in vitro and in vivo models of neuronal injury. Anesthesiology. 2002;96:1485-91.

9. Xenon preconditions against oxygen-glucose deprivation induced neuronal death. ASA October 2005. A218.

10. Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol. 2005;58:182-93.

11. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. J Cer Blood Flow Metab.2006;26(2):199-208

12. Xenon provides short-term neuroprotection in neonatal rats when after hypoxia-ischemia. Stroke 2006;37:501-6.

13. How does xenon produce anaesthesia? Nature 1998;396:324.

14. Xenon as neuroprotectant in acute stroke? Med Hypotheses. 2001;56:227-8.

15. Patent US 2003180375. Use of xenon for treating neurointoxications.

16. Patent application No GB2352633. Anaesthetic formulation comprising NMDA antagonist and alpha-2 adrenergic agonist.