Anaesth Intens Care (1992), 20, 66-70
Review Anaesthesia and the 'Inert' Gases with Special Reference to Xenon R. R. KENNEDY,* J. W. STOKESt AND P. DOWNINGt Department of Anaesthesia and Intensive Care, University of Otago Medical School and Dunedin Hospital, Dunedin, New Zealand SUMMARY
Xenon has many of the properties of the ideal anaesthetic agent and has been proposed as a suitable replacementfor nitrous oxide in routine clinical anaesthesia. Xenon, krypton and argon are chemically inert under most circumstances, yet all have anaesthetic properties. Xenon is ofparticular interest because it is the only 'inert' gas which is an anaesthetic under normobaric conditions. Because ofthis property, xenon has an important place in the history of the development of theories of anaesthetic action and of concepts such as MAC. Cost is likely to be a major impediment to the regulqr use of xenon.
Key Words:
ANAESTHETICS, GASES:
inert gases, xenon, argon, krypton
There has been renewed interest in xenon as an anaesthetic agent because it is both potent and effective. 1,2 Xenon has a blood-gas partition coefficient of 0.14 (N 20 0.47) and a MAC of 71 % (N 20 110%).3 Xenon is non-explosive, non-toxic, non-teratogenic, I probably does not undergo biotransformation 4 and offers rapid induction of and recovery from anaesthesia. I,2,5 These properties make xenon an almost ideal anaesthetic agent which could replace nitrous oxide were it not for the cost.I,2 The main purpose of this paper is to review the history of inert gas anaesthesia since the first reports in the 1940s. The study of the anaesthetic effects of the 'inert' or 'noble' gases helium, argon, xenon and krypton and also nitrogen (which is effectively inert when breathed) has played a significant role in the development and evaluation of theories of anaesthetic action. Xenon is the only one of these gases which is anaesthetic under normobaric conditions. The 'inert' or 'noble' gases The gases argon, krypton and xenon from Group o of the periodic table (the noble gases) have been studied for their anaesthetic properties, some of *F.F.A.R.A.C.S., Consultant Anaesthetist. tB.Sc., F.F.A.R.A.C.S., Senior Lecturer. *MedicaI Student. Address for Reprints: Dr. R. R. Kennedy, Department of Anaesthesia and Intensive Care, Dunedin Hospital, Dunedin, New Zealand. Accepted for pu!>lication October \0, 1991
which are detailed in Table 1. Although originally considered to be non-reactive and hence 'inert', a variety of compounds containing both krypton and xenon have been identified since 1962. 6 It appears that argon does not form true chemical compounds. Argon was discovered by Lord Rayleigh and William Ramsay in 1894. Xenon and krypton were discovered by Ramsay and Travers in 1898. William Ramsay (1852-1916) was awarded the Nobel prize for chemistry in 1904. Table 2 illustrates some of the chemical and physical properties of these 'inert' gases. The main use of all three gases is in a variety of lamps. 6 Argon is also used in arc welding and as an 'inert blanket' in the preparation of titanium and for growing silicon and germanium crystals. Xenon is used widely in the atomic energy field where its high molecular weight is of value. It is also potentially useful as a gas for ion engines6 which may provide a means of propulsion for longdistance space travel. 131Xenon is used as a radioisotope for ventilation scans and organ blood flow measurements. Uses for krypton have been limited because of its high cost. However, between 1960 and 1963, the international standard for the metre was defined in terms of the wavelength of the orange-red spectral line of 86krypton. Xenon is prepared by fractional distillation of air, and in Britain the cost of xenon is now reported to be as low as £7.60 per litre. 1In New Zealand and Anaesthesia and Intensive Care, Vol. 20, No. I, February, 1992
67
XENON AND ANAESTHESIA 1
TABLE
Anaesthetic properties
0/ selected 'inert' gases and nitrous oxide (adapted jrom Steward et af.3 and Koblin and Eger14)
OiUgas partition coefficient
Agent Xenon Nitrous oxide Krypton Argon Nitrogen Helium
Blood/gas partition coefficient
Mouse righting reflex (ED95) (atm)
MAC (in man) (atm)
0.14 0.47 0.06
0.95 1.54 4.5 15.2 34.3
0.71 1.01 3
1.9 1.4 0.5 0.15 0.072 0.015
0.015
Australia the cost ofxenon is $60-$65 per litre. * All xenon used in Australia and New Zealand, including radio-isotopes used in medicine, is imported from the U.S.A. and thus transport charges contribute significantly to the cost. Only 500 litres of xenon are used each year in New Zealand and apart from small amounts of radioisotopes for medical use, this is all for the production of lamps.
Early use of inert gases in anaesthesia Early interest in the anaesthetic properties of inert gases grew out of studies on the effect of pressure on mentation, particularly in relation to deep diving. Benke in 1935 7 observed the effects of air at 4 atm and noted that these were abolished by breathing 100% 02 and inferred the effects were due to the nitrogen which was found to be more soluble in fat than water. In 1938 the same group8 studied the effects of argon to see if the effects of atmospheric argon at pressure contributed to the 'narcotic' effects of air. Argon 69% was breathed under normobaric and hyperbaric conditions. Trained divers. who could TABLE
23
normally accurately estimate their depth by the subjective effects of air, consistently overestimated their depth by a factor of two. It was concluded that argon had more potent narcotic effects than nitrogen and it was also noted that the relationship of the oiUgas partition coefficients of helium, argon and nitrogen was similar to the relationship of the narcotic effects. In 1946, based on the work of Benke, 8 Lawrence et a/. 9 postulated that 80% krypton at atmospheric pressure should be as potent as air at 6 atm and xenon should be equivalent in anaesthetic potency to air at 25 atm. They tested this hypothesis on mice at atmospheric pressure. Five mice were exposed to 60-80% xenon and rapid onset of eNS effects such as ataxia, convulsive movements, and limb weakness was observed. These effects were seen within two minutes, and reversed within 15 minutes of removal of the xenon. In contrast one mouse exposed to 50% krypton for one hour showed no narcotic effects, demonstrating that this concentration of krypton was significantly less potent as an anaesthetic agent than 80% xenon. They considered this result to be consistent with 2
Physical properties o/some inert gases (adaptedjrom data in CRC Handbook o/Chemistry and Physics6) Argon
Krypton
Xenon
Atomic number Molecular weight Freezing point
18 39.9 -189.2
36 83.8 -156.6
54 131.3 -111.9
Boiling point Atmospheric concentration: Earth Mars
-185.7
-152.3
-107.1
0.94% 1.6%
1 ppm 0.3 ppm
0.05 ppm 0.08 ppm
rC) rC)
*New Zealand Industrial Gases prices range from $NZ275 for 1 litre to $NZ6000 for 100 litres, while the Anaesthesia and Intensive Care, Vol. 20, No. 1, FebTUlJry, 1992
lowest price quoted by Commonwealth Industrial Gases is $A3237 for 50 litres.
68
R. R.
KENNEDY ET AL.
the Myer-Overton hypothesis that anaesthetic potency correlates best with lipid solubility.9,10 Lawrence et a[.9 then went on to review and investigate the olive oil/gas solubilities of a range of inert gases and found values at 37°C for argon (0.14), krypton (0.43) and xenon (0.17) which are very close to those accepted today.lO The first use of xenon in man In 1951 Cullen and Gross 5 reported the first use of xenon for surgical anaesthesia in humans. In reviewing possible theories of anaesthetic action they noted that ' ... if inert gases can be considered true anaesthetics [this] furnishes the most conclusive demonstration that anaesthetics need not depend on the effect of any structural grouping'. That is, the action of anaesthetics would be shown to not be dependent on a specific chemical bond, thus supporting the Myer-Overton hypothesis. Rats, rabbits and mice were then exposed to 80% N 20, 80% Xe and 80% of a 19: 1 Kr:Xe mixture. Little anaesthetic effect was seen with the krypton/ xenon mixture but 80% xenon produced equivalent effects on lid reflex and response to pain as 80% N 20. The SUbjective experiences of humans to 80% krypton were described as 'change in voice ... [and] . . . unequivocal dizziness'. They concluded that krypton did not possess significant narcotic effects under these conditions. As predicted, the experience with xenon was more positive; the volunteers reported an incipient loss of consciousness and a 15% increase in pain threshold was observed with 50% xenon. With 80% xenon the 'effects were more pronounced'. Xenon obviously showed promise as an anaesthetic agent because it was then administered to two patients. The first patient to receive xenon anaesthesia was an 81-year-old man undergoing orchidectomy. After premedication with atropine and 10 minutes' preoxygenation (or denitrogenation), 80% xenon was administered. 'Within three minutes of the beginning of inhalation ... the patient lost consciousness, and within ten minutes the operation began'. There was no reaction to surgical stimuli and the patient appeared to be in first-plane third-stage anaesthesia. They also reported that ' ... pulse and blood pressure remained within normal limits for the patient and there were no abnormal respiratory patterns. Color was good, as would be expected from the satisfactory concentration of oxygen in the mixture'. At the conclusion of the procedure the patient ' ... recovered within two minutes to the extent that he could identify himself and within five minutes ... he could orientate himself.
The second patient to receive xenon anaesthesia was a 38-year-old woman having a tuballigation 48 hours post partum. Skin incision was again ten minutes after induction when '. . . she did not respond by movement but . . . had some vocalisation and mild laryngeal spasm'. After administration of '0.050 g meperidine intravenously ... she appeared to be in first-plane anaesthesia' . They thus concluded ' . . . it appears 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 anesthesia'. In 1953 the same group" used xenon as the primary anaesthetic agent in five patients aged between 28 and 45 years undergoing inguinal herniorraphy. After premedication with atropine or scopolamine and a period of denitrogenation, the patients inhaled 80% xenon delivered to the circuit using a nitrous oxide rotameter. In three patients pethidine was administered intravenously. All patients received at least one hour of xenon anaesthesia. There were no reported problems with the anaesthetics. In addition they reported no changes in the ECG, blood pressure, pulse or any predisposition to arrythmia. If anything, there was a tendency to bradycardia. The aim of this study was to determine the clinicopathological effects of xenon. They were unable to detect any changes in blood or urine biochemistry that were attributable to xenon. In 1956 Braken et al. 12 made the first British contribution to the subject. He demonstrated rapid reversible anaesthesia in rabbits, with no changes noted on post mortem after up to 48 hours' exposure to 50-80% xenon. As part of their work to establish the validity of the concept of MAC, Eger et alP determined the MAC in dogs of a number of agents including xenon. The MAC for xenon was found to be 119%. This value was less than the 188% determined by Domino 14 but this earlier study had looked at EEG effects and the concentration needed for 'light anaesthesia', which is in fact greater than MAC,13 Eger et al. 13 noted the close correlation between MAC and oil/gas partition coefficient for all the agents investigated. In 1969 in a study reported by Cullen et al.,15 xenon was again used to help solve the mystery of the site and mode of action of anaesthetics. In this study the combined effects of xenon and N 20 were investigated. The hydrate theory of anaesthesia of Pauling and Miller 10, 16 suggested that the combined effects of xenon and N 20 would be synergistic rather than simply additive because xenon would Anaesthesia and Intensive Care, Vol. 20. No. 1, February, 1992
69
XENON AND ANAESTHESIA form a type I hydrate,* while N 20 would form a type 11 hydrate. Ifboth agents acted at the same site, a combined effect greater than the sum would be expected. In contrast it was felt that the correlation between lipid solubility and anaesthetic potency would suggest a simple additive effect. In this study, Cullen et al. 15 first established the MAC of xenon to be 71 % in humans observing the response to skin incision after 15 minutes breathing a predetermined xenon concentration in a number of patients. Forty subjects were then exposed to either 113 MAC xenon and 2f3 MAC N20 or 112 MAC xenon and 112 MAC N 20. The N 20 concentration was varied slightly to determine the MAC of the mixture. The equivalent MAC for the mixture was 1.01-1.04 of the MAC predicted by summing the fractional MACs of the components of the mixture, demonstrating a simple additive effect. They therefore concluded that if hydrates were formed by these agents they must act at different sites. Recent use of xenon Two recent publications have reported on xenon as an anaesthetic agent. I ,2 Both papers have been from the same institution and examined xenon's safety and efficacy and compared its haemodynamic and neurohumoral effects with nitrous oxide. In the study of Lackmann et aU, 40 patients were randomised to receive either 70% nitrous oxide or 70% xenon in oxygen. No volatile agent was used and fentanyl was used to supplement anaesthesia after induction with thiopentone. All patients were paralysed. The operations were of medium duration (about one hour). The xenon group had a lower opiate requirements, less tendency to desaturation following induction and reported 'nice feelings and pleasant dreams'. Surprisingly in none of the patients was the use of an inhalational agent deemed necessary. It should be noted that the doses of nitrous oxide and xenon used were not equipotent (1 MAC xenon and 0.7 MAC nitrous oxide), however the authors felt that this was insufficient to explain the observed differences between the two agents. In a similar study, Boomsma ei aI., I using an almost identical anaesthetic protocol, found less alteration of stress hormones during xenon anaesthesia than during nitrous oxide anaesthesia. Specifically serum
*A Structure I hydrate is a clathrate composed of a gas encaged in a distorted ice matrix where there are six to ten water molecules for each anaesthetic molecule. A Structure 11 hydrate contains a larger cavity for the anaesthetic molecule and the ratio of water to anaesthetic molecules is 17 to 1. Structure I hydrates can be formed only with smaller anaesthetic molecules while larger anaesthetic molecules form only the larger Structure 11 hydrate.1 5. Anaesthesia and Intensive Care, VoL. ZO, No. 1, February, 1992
adrenaline and cortisol levels did not rise in the xenon group during surgery. The authors concluded xenon was slightly superior to nitrous oxide as an anaesthetic. Xenon in clinical anaesthesia Xenon is of interest as an anaesthetic agent because it could provide a totally inert, and slightly more potent, replacement for nitrous oxide. Because it is the only inert gas which is anaesthetic under normobaric conditions it has played an important role in the development of theories of anaesthesia. Cost will be a major impediment to the widespread acceptance of xenon as a replacement for nitrous oxide. It is still very expensive, especially in those countries such as Australia and New Zealand where xenon is imported. The hospital bulk supply price of nitrous oxide in New Zealand is 2.77 cll, less than 112000 the cost of xenon. Because the uptake of xenon is less than that of nitrous oxide, the actual increase in the cost of an anaesthetic may be less than this factor. There would be a further slight saving in the use of supplements such as volatile anaesthetics and opioids l ,2 because xenon is more potent than nitrous oxide. Using the figures quoted by Boomsma et al.l approximately 8 litres of xenon are required for the first hour of a totally closed circuit anaesthetic. This amount ofxenon would cost $480 in Australia and New Zealand. The use ofxenon in place of nitrous oxide would not remove the ability to inadvertently deliver a hypoxic gas mixture. The introduction of xenon would require modification of anaesthetic machines, with appropriate rotameters etc., and also of anaesthetic technique, since cost would dictate the use of closed circuit anaesthesia. Therefore, despite possessing many features close to that of the ideal anaesthetic agent, including a possible beneficial neurohumoral effect, it seems unlikely that xenon will find a place in routine clinical anaesthesia in the near future. REFERENCES
Boomsma F, Rupneht J, Man in 't Veld AJ et al. Haemodynamic and neurohumoral effects of xenon anaesthesia. Anaesthesia 1990; 45:273-278. 2. Lachmann B, Armbruster S, Schairer W et al. Safety and efficacy of xenon in routine use as an inhalational anaesthetic. Lancet 1990; 335:1413-1415. 3. Steward A, Allott PR, Cowle AL, Mapelson WW. Solubility coefficients for inhaled anaesthetics for water, oil and biological media. Br J Anaesth 1973; 45:282-293. 4. Lane GA, Nahrwold ML, Tait AR et at. Nitrous oxide is teratogenic: xenon is not! (abstract). Anesthesiology 1978; 51 :S260. 1.
70
R. R. KENNEDY ET AL.
5. Cullen SC, Gross EG. The anesthetic properties of xenon in animals and human beings, with additional observations on krypton. Science 1951; 113:580-582. 6. CRC Handbook of Chemistry and Physics. Lide OR, ed. Chapter 4: 'The Elements'. 71st Ed. CRC Press, Boston 1990. 7. Benke AR, Thomson RM, Motley EP. The physiologic effects from breathing air at 4 atmospheres pressure. Am J Physiol 1935; 112:554-558. 8. Benke AR, Yarbough OD. Respiratory resistance, oil-water solubility, and mental effects of argon, compared with helium and nitrogen. Am J Physiol 1939; 126:409-415. 9. Lawrence JH, Loomis WF, Tobias CA, Turpin FH. Preliminary observations on the narcotic effect of xenon with a review ofvalues for solubilities of gases in water and oils. J Physiol 1946; 105: 197-204. 10. Koblin DD, Eger El. 'How do inhaled anaesthetics work?' In: Anesthesia. RD Miller, ed. 2nd Ed. Churchill Livingstone 1986; Ch 18.
11. Pittinger CB, Moyers J, Cullen SC, Featherstone RM, Gross EG. Clinicopathologic studies associated with xenon anesthesia. Anesthesiology 1953; 14:10-17. 12. BrakenA, Burns THS, Newland DS. A trial of xenon as a non-explosive anaesthetic. Anaesthesia 1956; 11:40-49. 13. Eger El, Brandstater B, Saidman U, Regan MJ, Severinghaus JW, Munson ES. Equipotent alveolar concentrations of methoxyflurane, halothane, diethyl ether fluroxene, cyclopropane, xenon and nitrous oxide in the dog. Anesthesiology 1965; 26:771-777. 14. Domino EF, Gottlieb SF, Brauer RW, Cullen SC, Featherstone RM. Effects of xenon at elevated pressures in the dog. Anesthesiology 1964; 25:43. 15. Cullen SC, Eger El, Cullen BF, Gregory P. Observations on the anesthetic effect of the combination of xenon and halothane. Anesthesiology 1969; 31 :305-309. 16. Pauling L. A Molecular Theory of General Anesthesia. Science 1961; 134(3471):15-21.
Anaesthesia and Intensive Care. Vo/. 20, No. 1, February, 1992
Review Anaesthesia and the 'Inert' Gases with Special Reference to Xenon R. R. KENNEDY,* J. W. STOKESt AND P. DOWNINGt Department of Anaesthesia and Intensive Care, University of Otago Medical School and Dunedin Hospital, Dunedin, New Zealand SUMMARY
Xenon has many of the properties of the ideal anaesthetic agent and has been proposed as a suitable replacementfor nitrous oxide in routine clinical anaesthesia. Xenon, krypton and argon are chemically inert under most circumstances, yet all have anaesthetic properties. Xenon is ofparticular interest because it is the only 'inert' gas which is an anaesthetic under normobaric conditions. Because ofthis property, xenon has an important place in the history of the development of theories of anaesthetic action and of concepts such as MAC. Cost is likely to be a major impediment to the regulqr use of xenon.
Key Words:
ANAESTHETICS, GASES:
inert gases, xenon, argon, krypton
There has been renewed interest in xenon as an anaesthetic agent because it is both potent and effective. 1,2 Xenon has a blood-gas partition coefficient of 0.14 (N 20 0.47) and a MAC of 71 % (N 20 110%).3 Xenon is non-explosive, non-toxic, non-teratogenic, I probably does not undergo biotransformation 4 and offers rapid induction of and recovery from anaesthesia. I,2,5 These properties make xenon an almost ideal anaesthetic agent which could replace nitrous oxide were it not for the cost.I,2 The main purpose of this paper is to review the history of inert gas anaesthesia since the first reports in the 1940s. The study of the anaesthetic effects of the 'inert' or 'noble' gases helium, argon, xenon and krypton and also nitrogen (which is effectively inert when breathed) has played a significant role in the development and evaluation of theories of anaesthetic action. Xenon is the only one of these gases which is anaesthetic under normobaric conditions. The 'inert' or 'noble' gases The gases argon, krypton and xenon from Group o of the periodic table (the noble gases) have been studied for their anaesthetic properties, some of *F.F.A.R.A.C.S., Consultant Anaesthetist. tB.Sc., F.F.A.R.A.C.S., Senior Lecturer. *MedicaI Student. Address for Reprints: Dr. R. R. Kennedy, Department of Anaesthesia and Intensive Care, Dunedin Hospital, Dunedin, New Zealand. Accepted for pu!>lication October \0, 1991
which are detailed in Table 1. Although originally considered to be non-reactive and hence 'inert', a variety of compounds containing both krypton and xenon have been identified since 1962. 6 It appears that argon does not form true chemical compounds. Argon was discovered by Lord Rayleigh and William Ramsay in 1894. Xenon and krypton were discovered by Ramsay and Travers in 1898. William Ramsay (1852-1916) was awarded the Nobel prize for chemistry in 1904. Table 2 illustrates some of the chemical and physical properties of these 'inert' gases. The main use of all three gases is in a variety of lamps. 6 Argon is also used in arc welding and as an 'inert blanket' in the preparation of titanium and for growing silicon and germanium crystals. Xenon is used widely in the atomic energy field where its high molecular weight is of value. It is also potentially useful as a gas for ion engines6 which may provide a means of propulsion for longdistance space travel. 131Xenon is used as a radioisotope for ventilation scans and organ blood flow measurements. Uses for krypton have been limited because of its high cost. However, between 1960 and 1963, the international standard for the metre was defined in terms of the wavelength of the orange-red spectral line of 86krypton. Xenon is prepared by fractional distillation of air, and in Britain the cost of xenon is now reported to be as low as £7.60 per litre. 1In New Zealand and Anaesthesia and Intensive Care, Vol. 20, No. I, February, 1992
67
XENON AND ANAESTHESIA 1
TABLE
Anaesthetic properties
0/ selected 'inert' gases and nitrous oxide (adapted jrom Steward et af.3 and Koblin and Eger14)
OiUgas partition coefficient
Agent Xenon Nitrous oxide Krypton Argon Nitrogen Helium
Blood/gas partition coefficient
Mouse righting reflex (ED95) (atm)
MAC (in man) (atm)
0.14 0.47 0.06
0.95 1.54 4.5 15.2 34.3
0.71 1.01 3
1.9 1.4 0.5 0.15 0.072 0.015
0.015
Australia the cost ofxenon is $60-$65 per litre. * All xenon used in Australia and New Zealand, including radio-isotopes used in medicine, is imported from the U.S.A. and thus transport charges contribute significantly to the cost. Only 500 litres of xenon are used each year in New Zealand and apart from small amounts of radioisotopes for medical use, this is all for the production of lamps.
Early use of inert gases in anaesthesia Early interest in the anaesthetic properties of inert gases grew out of studies on the effect of pressure on mentation, particularly in relation to deep diving. Benke in 1935 7 observed the effects of air at 4 atm and noted that these were abolished by breathing 100% 02 and inferred the effects were due to the nitrogen which was found to be more soluble in fat than water. In 1938 the same group8 studied the effects of argon to see if the effects of atmospheric argon at pressure contributed to the 'narcotic' effects of air. Argon 69% was breathed under normobaric and hyperbaric conditions. Trained divers. who could TABLE
23
normally accurately estimate their depth by the subjective effects of air, consistently overestimated their depth by a factor of two. It was concluded that argon had more potent narcotic effects than nitrogen and it was also noted that the relationship of the oiUgas partition coefficients of helium, argon and nitrogen was similar to the relationship of the narcotic effects. In 1946, based on the work of Benke, 8 Lawrence et a/. 9 postulated that 80% krypton at atmospheric pressure should be as potent as air at 6 atm and xenon should be equivalent in anaesthetic potency to air at 25 atm. They tested this hypothesis on mice at atmospheric pressure. Five mice were exposed to 60-80% xenon and rapid onset of eNS effects such as ataxia, convulsive movements, and limb weakness was observed. These effects were seen within two minutes, and reversed within 15 minutes of removal of the xenon. In contrast one mouse exposed to 50% krypton for one hour showed no narcotic effects, demonstrating that this concentration of krypton was significantly less potent as an anaesthetic agent than 80% xenon. They considered this result to be consistent with 2
Physical properties o/some inert gases (adaptedjrom data in CRC Handbook o/Chemistry and Physics6) Argon
Krypton
Xenon
Atomic number Molecular weight Freezing point
18 39.9 -189.2
36 83.8 -156.6
54 131.3 -111.9
Boiling point Atmospheric concentration: Earth Mars
-185.7
-152.3
-107.1
0.94% 1.6%
1 ppm 0.3 ppm
0.05 ppm 0.08 ppm
rC) rC)
*New Zealand Industrial Gases prices range from $NZ275 for 1 litre to $NZ6000 for 100 litres, while the Anaesthesia and Intensive Care, Vol. 20, No. 1, FebTUlJry, 1992
lowest price quoted by Commonwealth Industrial Gases is $A3237 for 50 litres.
68
R. R.
KENNEDY ET AL.
the Myer-Overton hypothesis that anaesthetic potency correlates best with lipid solubility.9,10 Lawrence et a[.9 then went on to review and investigate the olive oil/gas solubilities of a range of inert gases and found values at 37°C for argon (0.14), krypton (0.43) and xenon (0.17) which are very close to those accepted today.lO The first use of xenon in man In 1951 Cullen and Gross 5 reported the first use of xenon for surgical anaesthesia in humans. In reviewing possible theories of anaesthetic action they noted that ' ... if inert gases can be considered true anaesthetics [this] furnishes the most conclusive demonstration that anaesthetics need not depend on the effect of any structural grouping'. That is, the action of anaesthetics would be shown to not be dependent on a specific chemical bond, thus supporting the Myer-Overton hypothesis. Rats, rabbits and mice were then exposed to 80% N 20, 80% Xe and 80% of a 19: 1 Kr:Xe mixture. Little anaesthetic effect was seen with the krypton/ xenon mixture but 80% xenon produced equivalent effects on lid reflex and response to pain as 80% N 20. The SUbjective experiences of humans to 80% krypton were described as 'change in voice ... [and] . . . unequivocal dizziness'. They concluded that krypton did not possess significant narcotic effects under these conditions. As predicted, the experience with xenon was more positive; the volunteers reported an incipient loss of consciousness and a 15% increase in pain threshold was observed with 50% xenon. With 80% xenon the 'effects were more pronounced'. Xenon obviously showed promise as an anaesthetic agent because it was then administered to two patients. The first patient to receive xenon anaesthesia was an 81-year-old man undergoing orchidectomy. After premedication with atropine and 10 minutes' preoxygenation (or denitrogenation), 80% xenon was administered. 'Within three minutes of the beginning of inhalation ... the patient lost consciousness, and within ten minutes the operation began'. There was no reaction to surgical stimuli and the patient appeared to be in first-plane third-stage anaesthesia. They also reported that ' ... pulse and blood pressure remained within normal limits for the patient and there were no abnormal respiratory patterns. Color was good, as would be expected from the satisfactory concentration of oxygen in the mixture'. At the conclusion of the procedure the patient ' ... recovered within two minutes to the extent that he could identify himself and within five minutes ... he could orientate himself.
The second patient to receive xenon anaesthesia was a 38-year-old woman having a tuballigation 48 hours post partum. Skin incision was again ten minutes after induction when '. . . she did not respond by movement but . . . had some vocalisation and mild laryngeal spasm'. After administration of '0.050 g meperidine intravenously ... she appeared to be in first-plane anaesthesia' . They thus concluded ' . . . it appears 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 anesthesia'. In 1953 the same group" used xenon as the primary anaesthetic agent in five patients aged between 28 and 45 years undergoing inguinal herniorraphy. After premedication with atropine or scopolamine and a period of denitrogenation, the patients inhaled 80% xenon delivered to the circuit using a nitrous oxide rotameter. In three patients pethidine was administered intravenously. All patients received at least one hour of xenon anaesthesia. There were no reported problems with the anaesthetics. In addition they reported no changes in the ECG, blood pressure, pulse or any predisposition to arrythmia. If anything, there was a tendency to bradycardia. The aim of this study was to determine the clinicopathological effects of xenon. They were unable to detect any changes in blood or urine biochemistry that were attributable to xenon. In 1956 Braken et al. 12 made the first British contribution to the subject. He demonstrated rapid reversible anaesthesia in rabbits, with no changes noted on post mortem after up to 48 hours' exposure to 50-80% xenon. As part of their work to establish the validity of the concept of MAC, Eger et alP determined the MAC in dogs of a number of agents including xenon. The MAC for xenon was found to be 119%. This value was less than the 188% determined by Domino 14 but this earlier study had looked at EEG effects and the concentration needed for 'light anaesthesia', which is in fact greater than MAC,13 Eger et al. 13 noted the close correlation between MAC and oil/gas partition coefficient for all the agents investigated. In 1969 in a study reported by Cullen et al.,15 xenon was again used to help solve the mystery of the site and mode of action of anaesthetics. In this study the combined effects of xenon and N 20 were investigated. The hydrate theory of anaesthesia of Pauling and Miller 10, 16 suggested that the combined effects of xenon and N 20 would be synergistic rather than simply additive because xenon would Anaesthesia and Intensive Care, Vol. 20. No. 1, February, 1992
69
XENON AND ANAESTHESIA form a type I hydrate,* while N 20 would form a type 11 hydrate. Ifboth agents acted at the same site, a combined effect greater than the sum would be expected. In contrast it was felt that the correlation between lipid solubility and anaesthetic potency would suggest a simple additive effect. In this study, Cullen et al. 15 first established the MAC of xenon to be 71 % in humans observing the response to skin incision after 15 minutes breathing a predetermined xenon concentration in a number of patients. Forty subjects were then exposed to either 113 MAC xenon and 2f3 MAC N20 or 112 MAC xenon and 112 MAC N 20. The N 20 concentration was varied slightly to determine the MAC of the mixture. The equivalent MAC for the mixture was 1.01-1.04 of the MAC predicted by summing the fractional MACs of the components of the mixture, demonstrating a simple additive effect. They therefore concluded that if hydrates were formed by these agents they must act at different sites. Recent use of xenon Two recent publications have reported on xenon as an anaesthetic agent. I ,2 Both papers have been from the same institution and examined xenon's safety and efficacy and compared its haemodynamic and neurohumoral effects with nitrous oxide. In the study of Lackmann et aU, 40 patients were randomised to receive either 70% nitrous oxide or 70% xenon in oxygen. No volatile agent was used and fentanyl was used to supplement anaesthesia after induction with thiopentone. All patients were paralysed. The operations were of medium duration (about one hour). The xenon group had a lower opiate requirements, less tendency to desaturation following induction and reported 'nice feelings and pleasant dreams'. Surprisingly in none of the patients was the use of an inhalational agent deemed necessary. It should be noted that the doses of nitrous oxide and xenon used were not equipotent (1 MAC xenon and 0.7 MAC nitrous oxide), however the authors felt that this was insufficient to explain the observed differences between the two agents. In a similar study, Boomsma ei aI., I using an almost identical anaesthetic protocol, found less alteration of stress hormones during xenon anaesthesia than during nitrous oxide anaesthesia. Specifically serum
*A Structure I hydrate is a clathrate composed of a gas encaged in a distorted ice matrix where there are six to ten water molecules for each anaesthetic molecule. A Structure 11 hydrate contains a larger cavity for the anaesthetic molecule and the ratio of water to anaesthetic molecules is 17 to 1. Structure I hydrates can be formed only with smaller anaesthetic molecules while larger anaesthetic molecules form only the larger Structure 11 hydrate.1 5. Anaesthesia and Intensive Care, VoL. ZO, No. 1, February, 1992
adrenaline and cortisol levels did not rise in the xenon group during surgery. The authors concluded xenon was slightly superior to nitrous oxide as an anaesthetic. Xenon in clinical anaesthesia Xenon is of interest as an anaesthetic agent because it could provide a totally inert, and slightly more potent, replacement for nitrous oxide. Because it is the only inert gas which is anaesthetic under normobaric conditions it has played an important role in the development of theories of anaesthesia. Cost will be a major impediment to the widespread acceptance of xenon as a replacement for nitrous oxide. It is still very expensive, especially in those countries such as Australia and New Zealand where xenon is imported. The hospital bulk supply price of nitrous oxide in New Zealand is 2.77 cll, less than 112000 the cost of xenon. Because the uptake of xenon is less than that of nitrous oxide, the actual increase in the cost of an anaesthetic may be less than this factor. There would be a further slight saving in the use of supplements such as volatile anaesthetics and opioids l ,2 because xenon is more potent than nitrous oxide. Using the figures quoted by Boomsma et al.l approximately 8 litres of xenon are required for the first hour of a totally closed circuit anaesthetic. This amount ofxenon would cost $480 in Australia and New Zealand. The use ofxenon in place of nitrous oxide would not remove the ability to inadvertently deliver a hypoxic gas mixture. The introduction of xenon would require modification of anaesthetic machines, with appropriate rotameters etc., and also of anaesthetic technique, since cost would dictate the use of closed circuit anaesthesia. Therefore, despite possessing many features close to that of the ideal anaesthetic agent, including a possible beneficial neurohumoral effect, it seems unlikely that xenon will find a place in routine clinical anaesthesia in the near future. REFERENCES
Boomsma F, Rupneht J, Man in 't Veld AJ et al. Haemodynamic and neurohumoral effects of xenon anaesthesia. Anaesthesia 1990; 45:273-278. 2. Lachmann B, Armbruster S, Schairer W et al. Safety and efficacy of xenon in routine use as an inhalational anaesthetic. Lancet 1990; 335:1413-1415. 3. Steward A, Allott PR, Cowle AL, Mapelson WW. Solubility coefficients for inhaled anaesthetics for water, oil and biological media. Br J Anaesth 1973; 45:282-293. 4. Lane GA, Nahrwold ML, Tait AR et at. Nitrous oxide is teratogenic: xenon is not! (abstract). Anesthesiology 1978; 51 :S260. 1.
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5. Cullen SC, Gross EG. The anesthetic properties of xenon in animals and human beings, with additional observations on krypton. Science 1951; 113:580-582. 6. CRC Handbook of Chemistry and Physics. Lide OR, ed. Chapter 4: 'The Elements'. 71st Ed. CRC Press, Boston 1990. 7. Benke AR, Thomson RM, Motley EP. The physiologic effects from breathing air at 4 atmospheres pressure. Am J Physiol 1935; 112:554-558. 8. Benke AR, Yarbough OD. Respiratory resistance, oil-water solubility, and mental effects of argon, compared with helium and nitrogen. Am J Physiol 1939; 126:409-415. 9. Lawrence JH, Loomis WF, Tobias CA, Turpin FH. Preliminary observations on the narcotic effect of xenon with a review ofvalues for solubilities of gases in water and oils. J Physiol 1946; 105: 197-204. 10. Koblin DD, Eger El. 'How do inhaled anaesthetics work?' In: Anesthesia. RD Miller, ed. 2nd Ed. Churchill Livingstone 1986; Ch 18.
11. Pittinger CB, Moyers J, Cullen SC, Featherstone RM, Gross EG. Clinicopathologic studies associated with xenon anesthesia. Anesthesiology 1953; 14:10-17. 12. BrakenA, Burns THS, Newland DS. A trial of xenon as a non-explosive anaesthetic. Anaesthesia 1956; 11:40-49. 13. Eger El, Brandstater B, Saidman U, Regan MJ, Severinghaus JW, Munson ES. Equipotent alveolar concentrations of methoxyflurane, halothane, diethyl ether fluroxene, cyclopropane, xenon and nitrous oxide in the dog. Anesthesiology 1965; 26:771-777. 14. Domino EF, Gottlieb SF, Brauer RW, Cullen SC, Featherstone RM. Effects of xenon at elevated pressures in the dog. Anesthesiology 1964; 25:43. 15. Cullen SC, Eger El, Cullen BF, Gregory P. Observations on the anesthetic effect of the combination of xenon and halothane. Anesthesiology 1969; 31 :305-309. 16. Pauling L. A Molecular Theory of General Anesthesia. Science 1961; 134(3471):15-21.
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