Br.J. Anaesth. (1978), 50, 979
POTENCY OF MIXTURES OF GENERAL ANAESTHETIC AGENTS R. F. CLARKE, S. DANIELS, C. B. HARRISON, M. J. JORDAN, W. D. M. PATON, E. B. SMITH
AND R. A. SMITH SUMMARY
The potency of mixtures of anaesthetic substances is of theoretical interest. If the mechanism by which general anaesthetic agents act involves specific structural changes, then it is possible for anaesthetic potencies in mixtures to be non-additive. Thus Pauling (1961), in discussing the implications of his gas hydrate theory of anaesthesia, noted that different classes of hydrates could be formed according to the properties of the anaesthetic agent. From a consideration of the stability of mixed hydrates, he suggested that certain anaesthetics might behave synergistically. Using similar reasoning based on an aqueous phase theory of anaesthetic action, Miller (1961) also suggested that synergism may occur in anaesthetic mixtures. On the other hand, those theories of the mode of action of anaesthetics based on the MeyerOverton lipid solubility hypothesis predict the simple additivity of potency in all mixtures of anaesthetic substances (Miller and Smith, 1973). Indeed, one exception to this prediction would cast doubt on the validity of the physical assumptions which underlie this class of theories. On the whole, previous studies have found strictly additive behaviour. Thus careful measurements of the potency of ethylene-halothane and xenon-halothane mixtures (chosen specifically to test Pauling's predictions of synergism) showed only additivity (Miller et al., 1969). Occasional reports of non-additive behaviour have appeared, but in these instances R. F. CLARKE, B.A.; S. DANIELS, B.A.; C. B. HARRISON, B.A.; M. J. JORDAN, B.A.; W. D. M. PATON, M.A., B.M., B.CH., D.M., F.R.C.P., F.R.S., C.B.E.; E . B . SMITH, B.SC, M.A., PH.D.;
R. A. SMITH, B.A., D.PHIL.; Department of Pharmacology
and Physical Chemistry Laboratory, South Parks Road, Oxford. 0007-0912/78/0050-0979 $01.00
there is reason to doubt the accuracy of the experimental methods employed. Thus DiFazio and colleagues (1972) reported antagonism in ethylenecyclopropane and nitrous oxide-cyclopropane mixtures. The experimental measurements were restricted to high concentrations of cyclopropane and the potencies of nitrous oxide and ethylene estimated by extensive extrapolation. Studies covering a larger range of concentration are desirable to confirm this apparently irregular behaviour. We have studied the potencies of the three binary mixtures which can be made from nitrous oxide, argon and sulphur hexafluoride. These gases were selected to cover a wide range of physical properties. Sulphur hexafluoride has anomalous solubility properties and, although its fat solubility is reasonably great, it is less soluble in water than is helium. This behaviour has been of value in providing a critical test of the various models of anaesthetic action and in elucidating what molecular properties are relevant in causing decompression sickness (Smith, 1966; Miller et al., 1972). As certain anomalies were observed in mixtures containing SF 6 , another fluoro-chemical, carbon tetrafiuoride (CF4) was studied also in mixtures containing argon and SF 6 .
METHODS
The index of potency used in this work was the partial pressure of anaesthetic required to abolish the righting response in 50% of the experimental animals in a slowly rotating chamber. Two animal species were employed in the experiments: mice (C. D. Tuck No. 1) in the weight range 25-30 g and newts (Triturus cristatus carnifex). The experiments were © Macmillan Journals Ltd 1978
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on July 6, 2015
The anaesthetic potencies of binary mixtures of the gases argon (Ar), nitrous oxide (N2O) and sulphur hexafluoride (SF6) have been measured using mice. The mixtures SF 6 -N 2 O and N 2 O-Ar showed additive behaviour, whereas the constituents of the mixture SF 6 -Ar were non-additive, having a smaller total potency than expected. Further experiments on this mixture with Italian Great Newts and on the carbon tetrafiuoride mixtures CFj-Ar and CF 4 -SF 6 with mice suggested that the anomalous potencies may arise from specific pulmonary effects associated with the breathing of SF 6 accompanied by a high pressure of some other gas.
980
TABLE I. Potencies of pure anaesthetic agents
Species Mouse
Agent N2O AT
SF 6 CF 4 Newt
Ar
ED 6 0 ±SEM (atm) 1.46 ±0.03 16.4 ±0.4 5.3 ±0.2 22.9 ±0.5 16.9±0.9 1.93 + 0.12
additive to within the experimental error. However, the Ar-SF 6 mixture showed significant deviations from additivity (fig. lc). It may be seen that, in the case of this mixture, the end-point was reached only with doses 10-20% greater than those appropriate to additivity. If one pair of gases from the three shows non-additive behaviour while the other pair behaves in a regular manner the implications for the theory of anaesthetic action would be radical. No simple physical theory is likely to predict such behaviour and only a model invoking highly specific structural changes would be appropriate. Because of the The animals were placed in one of the chambers importance of this finding the results were repeated, and the chamber flushed with 100% oxygen for 1 min. and confirmed, over a period of 3 years by three The anaesthetic gas (or two gases if a mixture was research workers working independently. Nevertheunder investigation) was added. After allowing less, in view of the unexpected nature of the results, between 30 and 40 min for uptake and equilibration the possibility of an experimental artefact cannot be the chamber was set rotating. The experiments discounted, although a number of explanations may lasted up to 2 h and no change in ED 50 was detected be suggested. in this time. Each animal was assigned a score of zero The first explanation investigated was that the if it turned through 360 degrees during one complete anomaly arose in some way simply because of the revolution of the chamber and a score of one if this high density of mixtures containing SF 6 ; the molecondition was not satisfied. Three sets of five revolu- cular weights of SF 6 , Ar and N 2 O are 146, 40 and 44 tions, commencing at 4-min intervals were performed respectively. Accordingly, experiments were perand a total score out of 15 was recorded as the level formed with carbon tetrafluoride (CF4). The EDgo of the rolling response. Measurements at different alone was found to be 22.9 atm. At this pressure, the pressures, and over a range of concentrations for gas density of CF 4 is about 2.5 times that of an mixtures, enabled dose-response curves to be con- equipotent pressure of SF 6 and much higher than that structed. The partial pressure of anaesthetic gas that attained with the equipotent Ar-SF 6 mixture, yet no reduced the rolling response to 50% (ED50) was cal- adverse effect was seen on the animals. Even greater culated by probit analysis as a measure of potency. gas densities have been tolerated by mice in neon atmospheres of more than 140 atm (Lever et al., 1971). RESULTS AND DISCUSSION In addition, in limited experiments with Ar-CF 4 The potencies observed for the pure gases (table I) mixtures, there was no evidence of non-additive are in good agreement with the results of previous behaviour (fig. 2). It should be recalled also that studies (a more extensive compilation of the anaes- SF 6 -N 2 O mixtures, with SF 6 partial pressures thetic potencies of those compounds has been varying three-fold, did not show deviations from simple additivity. published previously (Miller et al., 1972)). A second explanation might be that there was some The first set of experiments on mice with mixtures (fig. 1A, B) showed that N 2 O-Ar and N 2 O-SF 6 were peculiarity about the mixture of Ar-SF 6 with regard
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on July 6, 2015
carried out in two pressure vessels. One was constructed from a hollow perspex tube of length 30.5 cm, i.d. 9 cm and thickness 2.5 cm, sealed with two Dural end-plates. The interior was divided into four compartments by perforated screens. An end compartment contained electrical connections and an induction motor driving a fan and a thermocouple junction to monitor the temperature. Each of the remaining compartments was designed to accommodate a mouse. They were separated by double screens and the space between the screens was filled partially by muslin bags containing soda-lime. Provision was made to rotate the chamber on a roller bed at 4 rev min~x. The whole assembly was housed in a constant temperature enclosure. The environmental temperature was maintained at 30 ± 1 CC for experiments with mice (to minimize the effects of hypothermia and heat stress (Speden, 1963)) and 20 ± 1 °C when newts were employed. Mass spectrometric analysis of the gas within the chamber showed that the partial pressure of carbon dioxide did not exceed 0.02 atm after 2 h of operation. Experiments with newts were carried out also in a stainless steel cylindrical chamber (12 x 5 cm) with a 2.5-cm thick perspex window.
BRITISH JOURNAL OF ANAESTHESIA
981
POTENCY OF GENERAL ANAESTHETIC MIXTURES 100
100 o an
S
A
\ 80 -
\ \
60
v \
40
+ i
i
20
40
40
,
20
\
.X
60 80 % N 2 0 ED50
60
100
80 %SF6 ED50
to its anaesthetic action. This prompted a trial of this mixture on the Italian newt (fig. 3). However, this showed no significant deviation from simple additivity for three different proportions of the gases. With the normal behaviour of SF 6 -N 2 O, Ar-N 2 O and Ar-CF 4 in mice, this suggests that any hypothesis involving anomalies in anaesthetic action (depending, for example, on non-linearities in solution properties, or on abnormal sensitivity to pressure reversal (Lever et al., 1971; Miller et al., 1973) at pressure of the order of 20 atm) would create more difficulties than it explained. A third possibility was that the deviation from additivity was linked, in some way, to the presence of
0
20
40
60
80 100 % N 2 0 E050
FIG. 1. ED 60 determined for mixtures of two gases administered to mice: A = SF 6 -N 2 O; B = N 2 O-Ar; c = Ar-SF 6 . The doses are expressed as a percentage of the ED 60 of the pure gases. The lines represent additive behaviour and points lying above the line indicate antagonism. A = Series I (R. A. Smith); Q = Series II (M. J. Jordan); • = Series III (R. A. Clarke). The bars indicate SEM.
SF 6 in a mixture in which the total pressure was increased also to a high value. It will have been noted that when normal results were obtained the total pressures were not greater than 5.3 atm for SF 6 N 2 O, but were as great as 16.4 atm for SF6-Ar when deviation occurred. Further, it was possible that the deviation was linked in some way to a respiratory effect. It has been found during experiments with SF 6 on decompression sickness that respiratory difficulty was observed frequently and severe pulmonary oedema occurred commonly after decompression in this gas (Smith, 1966; Lever, Paton and Smith, 1969; Daniels, Paton and Smith, 1978). Although these effects were revealed only on return to
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on July 6, 2015
20 -
20
80
60
40 -
0
o
Q
BRITISH JOURNAL OF ANAESTHESIA
982 100
100 o *n
O LU
80
^,80 ©"*
60 60
40 50
20
20
40
60 %CF,
80
100
ED SO
FIG. 2. ED 60 determined for mixtures of argon and carbon tetrafluoride administered to mice. Other features as described in the caption to figure 1. 100
80
60
40
20
20
40
60
80 °/oSF6 ED 50
100
FIG. 3. ED 60 determined for mixtures of Ar and SF 6 administered to newts. Other features as described in the caption to figure 1.
atmospheric pressure, they indicated idiosyncratic properties of SF 6 . Such a respiratory effect would account for the normal response to Ar-SF 6 by the amphibious Italian newt. Accordingly, a further test was made in which a single SF 6 -CF 4 mixture was studied: with this, the effect of SF 6 was combined
20
40
60
80 ED 50
100
FIG. 4. ED50 determined using mice for mixtures of SF 0 and CF 4 administered to mice. Other features as described in the caption to figure 1.
with a total pressure of approximately 20 atm (fig. 4). It will be seen that there was an unequivocal and substantial deviation from simple additivity of about 20% from ED50, as had occurred with SF 6 -Ar. Because of the normal behaviour of SF 6 -N 2 O, Ar-N 2 O and Ar-CF 4 mixtures with mice, and of ArSF 6 with the newt, we conclude that such anomalies as exist do not suffice to throw doubts on the simple fat-solubility theories of anaestheisia. However, we are not able to give adequate reasons why a combination of SF 6 with Ar or CF 4 to give a total pressure of 10-20 atm should result in a modest increase in the dose required for anaesthesia greater than that expected by simple additivity. One possibility is that it depends on the conjunction of two factors: a pulmonary effect of SF 6 (possibly affecting gaseous diffusion), and the high density of the gas mixture producing decreased gas exchange, with some hypoxia and carbon dioxide retention. Chemoreceptor stimulation may antagonize slightly the anaesthetic effect of the gases, as shown by a behavioural response, although for nociceptive responses in the dog with halothane under steady-state conditions, hypoxia or hypercarbia separately have been found to have the opposite effect (Eisele, Eger and Muallem, 1967; Cullen and Eger, 1971). The antagonism required need only be slight, since the deviations we have recorded, although consistent, are of the order of only 10-20% of the EDg,,.
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on July 6, 2015
20
POTENCY OF GENERAL ANAESTHETIC MIXTURES ACKNOWLEDGEMENTS
This research was sponsored in part by the Physiology Branch, Office of Naval Research, Washington, D.C., under contracts F61052-676-0077 and N00014-76-G0065.
983
PUISSANCE DES MELANGES D'AGENTS ANESTHESIQUES GENERAUX RESUME
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on July 6, 2015
La puissance anesth6siante des melanges binaires de gaz: argon (Ar), protoxyde d'azote (N2O) et hexafluorure de soufre (SF6) a ete mesuree en se servant de souris. Les REFERENCES melanges SF -N 2 O et N 2 O-Ar ont accusi un comporteCullen, D. J., and Eger, E. I. (1971). The effects of hypoxia ment additif, 6alors que les composants du melange SF 6 -Ar and isovolemic anemia on the halothane requirement ont et£ non additifs, ayant une puissance totale inferieure a (M.A.C.) of dogs. Anesthesiology, 32,28. celle a laquelle on s'attendait. D'autres experiences effecDaniels, S., Paton, W. D. M., and Smith, E. B. (1978). The tuees sur ce melange a l'aide de tritons cr£t£s italiens et sur use of exotic gases for the study of decompression les melanges (tetrafluorure de carbone) CF -Ar et CF -SF sickness; in Proceedings of the VI Symposium on Under- a l'aide de souris, laissent penser que les 4puissances 4anor-6 water Physiology (ed. C. J. Lambertsen). Bethesda, males peuvent provenir de certains effets pulmonaires Maryland: F.A.S.E.B. specifiques associes a la respiration de SF 6 , accompagnes DiFazio, C. A., Brown, R. E., Ball, C. G., Heckel, C. G., d'une forte pression de certains autres gaz. and Kennedy, S. S. (1972). Additive effects of anesthetics and theories of anesthesia. Anesthesiology, 36, 57. Eisele, J. H., Eger, E. I., and Muallem, M. (1967). Narcotic STARKEN VON GEMISCHEN DER properties of carbon dioxide in the dog. Anesthesiology, 28, ANASTHETISCHEN AGENS 856. Lever, M. J., Miller, K. W., Paton, W. D. M., and Smith, ZUSAMMENFASSUNG E. B. (1971). Pressure reversal of anaesthesia. Nature Die anasthetischen Starken der dinaren Gasgemische von (JUmd.), 231, 368. Paton, W. D. M., and Smith, E. B. (1969). Decom- Argon (Ar), Lachgas (N2O) und Schwefel-Hexafluorid pression characteristics of the inert gases; in Proc. Fourth (SF6) an Mausen als Versuchstieren gemessen. Die GeUnderwater Physiology Conference, Philadelphia (ed. mische SF 6 -N 2 O und N 2 O-Ar verhielten sich additive, wahrend die Bestandteile des Gemischs SF6-Ar, mit C. J. Lambertsen), p. 123. New York: Academic Press. Miller, K. W., Paton, W. D. M., Smith, E. B., and Smith, geringerer totalen Starke als erwartet, sich nicht additive R. A. (1972). Physiochemical approaches to the mode of verhielten. Weitere Experimente mit diesem Gemisch an italienischen Grossmolchen und mit den Gemischen CF 4 action of general anesthetics. Anesthesiology, 36,339. Smith, R. A., and Smith, E. B. (1973). The Ar und CF 4 -SF 6 an Mausen schienen zu zeigen, dass die pressure reversal of anaesthesia on the critical volume abweichenden Starken von speziellen pulmonareffekten herruhren, die mit der Einatmung von SF 6 und einem hypothesis. Molec. Pharmacol., 9, 131. Smith, E. B. (1973). Intermolecular forces and the anderen Gas unter hohem Druck zusammenhangen. pharmacology of simple molecules; in A Guide to Molecular Pharmacology-Toxicology (ed. R. M. Featherstone), Chapter 11. New York: Dekker. POTENCIA DE LAS MEZCLAS DE AGENTES Miller, R. D., Wahrenbrock, E. A., Schroeder, C. F., ANESTESICOS GENERALES Knipstein, T. W., Eger, E. I., and Buechel, D. R. (1969). SUMARIO Ethylene-halothane anesthesia: addition or synergism? Anesthesiology, 31,301. Se han medido las potencias anest&icas de mezclas binarias Miller, S. L. (1961). Theory of gaseous anesthetics. Proc. de los gases arg6n (Ar), oxido nitroso (N2O) y hexafluoruro de azufre (SF6), empleando ratones. Las mezclas SFe-Nj.O Natl. Acad. Sci. U.S.A., 47, 1515. Pauling, L. (1961). A molecular theory of general anesthesia. y N2O-Ar acusaron un comportamiento de aditivo, mientras que los componentes de la mezcla SF8-Ar no incluyeron Science, 134, 15. Smith, E. B. (1966). Decompression experiments with aditivos, contando con una potencia total inferior a la various inert gases; in Proc. Third Underwater Physiology anticipada. Otros experimentos que se llevaron a cabo Symposium, Washington (ed. C. J. Lambertsen), p. 425. empleando Grandes Lagartijas Acuaticas Italianas y ratones con las mezclas CF4-AR y CF 4 -SF 8 sugirieron que las Baltimore: Williams and Wilkins. Speden, R. N. (1963). Kinetics and mechanism of action potencias an6malas podian ser producidas por efectos of some volatile anaesthetics. D.Phil. Thesis, Oxford pulmonares especificos asociados con la inspiraci6n de SF 6 , acompanado por la elevada presion de algiin otro gas. University.
POTENCY OF MIXTURES OF GENERAL ANAESTHETIC AGENTS R. F. CLARKE, S. DANIELS, C. B. HARRISON, M. J. JORDAN, W. D. M. PATON, E. B. SMITH
AND R. A. SMITH SUMMARY
The potency of mixtures of anaesthetic substances is of theoretical interest. If the mechanism by which general anaesthetic agents act involves specific structural changes, then it is possible for anaesthetic potencies in mixtures to be non-additive. Thus Pauling (1961), in discussing the implications of his gas hydrate theory of anaesthesia, noted that different classes of hydrates could be formed according to the properties of the anaesthetic agent. From a consideration of the stability of mixed hydrates, he suggested that certain anaesthetics might behave synergistically. Using similar reasoning based on an aqueous phase theory of anaesthetic action, Miller (1961) also suggested that synergism may occur in anaesthetic mixtures. On the other hand, those theories of the mode of action of anaesthetics based on the MeyerOverton lipid solubility hypothesis predict the simple additivity of potency in all mixtures of anaesthetic substances (Miller and Smith, 1973). Indeed, one exception to this prediction would cast doubt on the validity of the physical assumptions which underlie this class of theories. On the whole, previous studies have found strictly additive behaviour. Thus careful measurements of the potency of ethylene-halothane and xenon-halothane mixtures (chosen specifically to test Pauling's predictions of synergism) showed only additivity (Miller et al., 1969). Occasional reports of non-additive behaviour have appeared, but in these instances R. F. CLARKE, B.A.; S. DANIELS, B.A.; C. B. HARRISON, B.A.; M. J. JORDAN, B.A.; W. D. M. PATON, M.A., B.M., B.CH., D.M., F.R.C.P., F.R.S., C.B.E.; E . B . SMITH, B.SC, M.A., PH.D.;
R. A. SMITH, B.A., D.PHIL.; Department of Pharmacology
and Physical Chemistry Laboratory, South Parks Road, Oxford. 0007-0912/78/0050-0979 $01.00
there is reason to doubt the accuracy of the experimental methods employed. Thus DiFazio and colleagues (1972) reported antagonism in ethylenecyclopropane and nitrous oxide-cyclopropane mixtures. The experimental measurements were restricted to high concentrations of cyclopropane and the potencies of nitrous oxide and ethylene estimated by extensive extrapolation. Studies covering a larger range of concentration are desirable to confirm this apparently irregular behaviour. We have studied the potencies of the three binary mixtures which can be made from nitrous oxide, argon and sulphur hexafluoride. These gases were selected to cover a wide range of physical properties. Sulphur hexafluoride has anomalous solubility properties and, although its fat solubility is reasonably great, it is less soluble in water than is helium. This behaviour has been of value in providing a critical test of the various models of anaesthetic action and in elucidating what molecular properties are relevant in causing decompression sickness (Smith, 1966; Miller et al., 1972). As certain anomalies were observed in mixtures containing SF 6 , another fluoro-chemical, carbon tetrafiuoride (CF4) was studied also in mixtures containing argon and SF 6 .
METHODS
The index of potency used in this work was the partial pressure of anaesthetic required to abolish the righting response in 50% of the experimental animals in a slowly rotating chamber. Two animal species were employed in the experiments: mice (C. D. Tuck No. 1) in the weight range 25-30 g and newts (Triturus cristatus carnifex). The experiments were © Macmillan Journals Ltd 1978
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on July 6, 2015
The anaesthetic potencies of binary mixtures of the gases argon (Ar), nitrous oxide (N2O) and sulphur hexafluoride (SF6) have been measured using mice. The mixtures SF 6 -N 2 O and N 2 O-Ar showed additive behaviour, whereas the constituents of the mixture SF 6 -Ar were non-additive, having a smaller total potency than expected. Further experiments on this mixture with Italian Great Newts and on the carbon tetrafiuoride mixtures CFj-Ar and CF 4 -SF 6 with mice suggested that the anomalous potencies may arise from specific pulmonary effects associated with the breathing of SF 6 accompanied by a high pressure of some other gas.
980
TABLE I. Potencies of pure anaesthetic agents
Species Mouse
Agent N2O AT
SF 6 CF 4 Newt
Ar
ED 6 0 ±SEM (atm) 1.46 ±0.03 16.4 ±0.4 5.3 ±0.2 22.9 ±0.5 16.9±0.9 1.93 + 0.12
additive to within the experimental error. However, the Ar-SF 6 mixture showed significant deviations from additivity (fig. lc). It may be seen that, in the case of this mixture, the end-point was reached only with doses 10-20% greater than those appropriate to additivity. If one pair of gases from the three shows non-additive behaviour while the other pair behaves in a regular manner the implications for the theory of anaesthetic action would be radical. No simple physical theory is likely to predict such behaviour and only a model invoking highly specific structural changes would be appropriate. Because of the The animals were placed in one of the chambers importance of this finding the results were repeated, and the chamber flushed with 100% oxygen for 1 min. and confirmed, over a period of 3 years by three The anaesthetic gas (or two gases if a mixture was research workers working independently. Nevertheunder investigation) was added. After allowing less, in view of the unexpected nature of the results, between 30 and 40 min for uptake and equilibration the possibility of an experimental artefact cannot be the chamber was set rotating. The experiments discounted, although a number of explanations may lasted up to 2 h and no change in ED 50 was detected be suggested. in this time. Each animal was assigned a score of zero The first explanation investigated was that the if it turned through 360 degrees during one complete anomaly arose in some way simply because of the revolution of the chamber and a score of one if this high density of mixtures containing SF 6 ; the molecondition was not satisfied. Three sets of five revolu- cular weights of SF 6 , Ar and N 2 O are 146, 40 and 44 tions, commencing at 4-min intervals were performed respectively. Accordingly, experiments were perand a total score out of 15 was recorded as the level formed with carbon tetrafluoride (CF4). The EDgo of the rolling response. Measurements at different alone was found to be 22.9 atm. At this pressure, the pressures, and over a range of concentrations for gas density of CF 4 is about 2.5 times that of an mixtures, enabled dose-response curves to be con- equipotent pressure of SF 6 and much higher than that structed. The partial pressure of anaesthetic gas that attained with the equipotent Ar-SF 6 mixture, yet no reduced the rolling response to 50% (ED50) was cal- adverse effect was seen on the animals. Even greater culated by probit analysis as a measure of potency. gas densities have been tolerated by mice in neon atmospheres of more than 140 atm (Lever et al., 1971). RESULTS AND DISCUSSION In addition, in limited experiments with Ar-CF 4 The potencies observed for the pure gases (table I) mixtures, there was no evidence of non-additive are in good agreement with the results of previous behaviour (fig. 2). It should be recalled also that studies (a more extensive compilation of the anaes- SF 6 -N 2 O mixtures, with SF 6 partial pressures thetic potencies of those compounds has been varying three-fold, did not show deviations from simple additivity. published previously (Miller et al., 1972)). A second explanation might be that there was some The first set of experiments on mice with mixtures (fig. 1A, B) showed that N 2 O-Ar and N 2 O-SF 6 were peculiarity about the mixture of Ar-SF 6 with regard
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on July 6, 2015
carried out in two pressure vessels. One was constructed from a hollow perspex tube of length 30.5 cm, i.d. 9 cm and thickness 2.5 cm, sealed with two Dural end-plates. The interior was divided into four compartments by perforated screens. An end compartment contained electrical connections and an induction motor driving a fan and a thermocouple junction to monitor the temperature. Each of the remaining compartments was designed to accommodate a mouse. They were separated by double screens and the space between the screens was filled partially by muslin bags containing soda-lime. Provision was made to rotate the chamber on a roller bed at 4 rev min~x. The whole assembly was housed in a constant temperature enclosure. The environmental temperature was maintained at 30 ± 1 CC for experiments with mice (to minimize the effects of hypothermia and heat stress (Speden, 1963)) and 20 ± 1 °C when newts were employed. Mass spectrometric analysis of the gas within the chamber showed that the partial pressure of carbon dioxide did not exceed 0.02 atm after 2 h of operation. Experiments with newts were carried out also in a stainless steel cylindrical chamber (12 x 5 cm) with a 2.5-cm thick perspex window.
BRITISH JOURNAL OF ANAESTHESIA
981
POTENCY OF GENERAL ANAESTHETIC MIXTURES 100
100 o an
S
A
\ 80 -
\ \
60
v \
40
+ i
i
20
40
40
,
20
\
.X
60 80 % N 2 0 ED50
60
100
80 %SF6 ED50
to its anaesthetic action. This prompted a trial of this mixture on the Italian newt (fig. 3). However, this showed no significant deviation from simple additivity for three different proportions of the gases. With the normal behaviour of SF 6 -N 2 O, Ar-N 2 O and Ar-CF 4 in mice, this suggests that any hypothesis involving anomalies in anaesthetic action (depending, for example, on non-linearities in solution properties, or on abnormal sensitivity to pressure reversal (Lever et al., 1971; Miller et al., 1973) at pressure of the order of 20 atm) would create more difficulties than it explained. A third possibility was that the deviation from additivity was linked, in some way, to the presence of
0
20
40
60
80 100 % N 2 0 E050
FIG. 1. ED 60 determined for mixtures of two gases administered to mice: A = SF 6 -N 2 O; B = N 2 O-Ar; c = Ar-SF 6 . The doses are expressed as a percentage of the ED 60 of the pure gases. The lines represent additive behaviour and points lying above the line indicate antagonism. A = Series I (R. A. Smith); Q = Series II (M. J. Jordan); • = Series III (R. A. Clarke). The bars indicate SEM.
SF 6 in a mixture in which the total pressure was increased also to a high value. It will have been noted that when normal results were obtained the total pressures were not greater than 5.3 atm for SF 6 N 2 O, but were as great as 16.4 atm for SF6-Ar when deviation occurred. Further, it was possible that the deviation was linked in some way to a respiratory effect. It has been found during experiments with SF 6 on decompression sickness that respiratory difficulty was observed frequently and severe pulmonary oedema occurred commonly after decompression in this gas (Smith, 1966; Lever, Paton and Smith, 1969; Daniels, Paton and Smith, 1978). Although these effects were revealed only on return to
Downloaded from http://bja.oxfordjournals.org/ at Carleton University on July 6, 2015
20 -
20
80
60
40 -
0
o
Q
BRITISH JOURNAL OF ANAESTHESIA
982 100
100 o *n
O LU
80
^,80 ©"*
60 60
40 50
20
20
40
60 %CF,
80
100
ED SO
FIG. 2. ED 60 determined for mixtures of argon and carbon tetrafluoride administered to mice. Other features as described in the caption to figure 1. 100
80
60
40
20
20
40
60
80 °/oSF6 ED 50
100
FIG. 3. ED 60 determined for mixtures of Ar and SF 6 administered to newts. Other features as described in the caption to figure 1.
atmospheric pressure, they indicated idiosyncratic properties of SF 6 . Such a respiratory effect would account for the normal response to Ar-SF 6 by the amphibious Italian newt. Accordingly, a further test was made in which a single SF 6 -CF 4 mixture was studied: with this, the effect of SF 6 was combined
20
40
60
80 ED 50
100
FIG. 4. ED50 determined using mice for mixtures of SF 0 and CF 4 administered to mice. Other features as described in the caption to figure 1.
with a total pressure of approximately 20 atm (fig. 4). It will be seen that there was an unequivocal and substantial deviation from simple additivity of about 20% from ED50, as had occurred with SF 6 -Ar. Because of the normal behaviour of SF 6 -N 2 O, Ar-N 2 O and Ar-CF 4 mixtures with mice, and of ArSF 6 with the newt, we conclude that such anomalies as exist do not suffice to throw doubts on the simple fat-solubility theories of anaestheisia. However, we are not able to give adequate reasons why a combination of SF 6 with Ar or CF 4 to give a total pressure of 10-20 atm should result in a modest increase in the dose required for anaesthesia greater than that expected by simple additivity. One possibility is that it depends on the conjunction of two factors: a pulmonary effect of SF 6 (possibly affecting gaseous diffusion), and the high density of the gas mixture producing decreased gas exchange, with some hypoxia and carbon dioxide retention. Chemoreceptor stimulation may antagonize slightly the anaesthetic effect of the gases, as shown by a behavioural response, although for nociceptive responses in the dog with halothane under steady-state conditions, hypoxia or hypercarbia separately have been found to have the opposite effect (Eisele, Eger and Muallem, 1967; Cullen and Eger, 1971). The antagonism required need only be slight, since the deviations we have recorded, although consistent, are of the order of only 10-20% of the EDg,,.
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POTENCY OF GENERAL ANAESTHETIC MIXTURES ACKNOWLEDGEMENTS
This research was sponsored in part by the Physiology Branch, Office of Naval Research, Washington, D.C., under contracts F61052-676-0077 and N00014-76-G0065.
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PUISSANCE DES MELANGES D'AGENTS ANESTHESIQUES GENERAUX RESUME
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La puissance anesth6siante des melanges binaires de gaz: argon (Ar), protoxyde d'azote (N2O) et hexafluorure de soufre (SF6) a ete mesuree en se servant de souris. Les REFERENCES melanges SF -N 2 O et N 2 O-Ar ont accusi un comporteCullen, D. J., and Eger, E. I. (1971). The effects of hypoxia ment additif, 6alors que les composants du melange SF 6 -Ar and isovolemic anemia on the halothane requirement ont et£ non additifs, ayant une puissance totale inferieure a (M.A.C.) of dogs. Anesthesiology, 32,28. celle a laquelle on s'attendait. D'autres experiences effecDaniels, S., Paton, W. D. M., and Smith, E. B. (1978). The tuees sur ce melange a l'aide de tritons cr£t£s italiens et sur use of exotic gases for the study of decompression les melanges (tetrafluorure de carbone) CF -Ar et CF -SF sickness; in Proceedings of the VI Symposium on Under- a l'aide de souris, laissent penser que les 4puissances 4anor-6 water Physiology (ed. C. J. Lambertsen). Bethesda, males peuvent provenir de certains effets pulmonaires Maryland: F.A.S.E.B. specifiques associes a la respiration de SF 6 , accompagnes DiFazio, C. A., Brown, R. E., Ball, C. G., Heckel, C. G., d'une forte pression de certains autres gaz. and Kennedy, S. S. (1972). Additive effects of anesthetics and theories of anesthesia. Anesthesiology, 36, 57. Eisele, J. H., Eger, E. I., and Muallem, M. (1967). Narcotic STARKEN VON GEMISCHEN DER properties of carbon dioxide in the dog. Anesthesiology, 28, ANASTHETISCHEN AGENS 856. Lever, M. J., Miller, K. W., Paton, W. D. M., and Smith, ZUSAMMENFASSUNG E. B. (1971). Pressure reversal of anaesthesia. Nature Die anasthetischen Starken der dinaren Gasgemische von (JUmd.), 231, 368. Paton, W. D. M., and Smith, E. B. (1969). Decom- Argon (Ar), Lachgas (N2O) und Schwefel-Hexafluorid pression characteristics of the inert gases; in Proc. Fourth (SF6) an Mausen als Versuchstieren gemessen. Die GeUnderwater Physiology Conference, Philadelphia (ed. mische SF 6 -N 2 O und N 2 O-Ar verhielten sich additive, wahrend die Bestandteile des Gemischs SF6-Ar, mit C. J. Lambertsen), p. 123. New York: Academic Press. Miller, K. W., Paton, W. D. M., Smith, E. B., and Smith, geringerer totalen Starke als erwartet, sich nicht additive R. A. (1972). Physiochemical approaches to the mode of verhielten. Weitere Experimente mit diesem Gemisch an italienischen Grossmolchen und mit den Gemischen CF 4 action of general anesthetics. Anesthesiology, 36,339. Smith, R. A., and Smith, E. B. (1973). The Ar und CF 4 -SF 6 an Mausen schienen zu zeigen, dass die pressure reversal of anaesthesia on the critical volume abweichenden Starken von speziellen pulmonareffekten herruhren, die mit der Einatmung von SF 6 und einem hypothesis. Molec. Pharmacol., 9, 131. Smith, E. B. (1973). Intermolecular forces and the anderen Gas unter hohem Druck zusammenhangen. pharmacology of simple molecules; in A Guide to Molecular Pharmacology-Toxicology (ed. R. M. Featherstone), Chapter 11. New York: Dekker. POTENCIA DE LAS MEZCLAS DE AGENTES Miller, R. D., Wahrenbrock, E. A., Schroeder, C. F., ANESTESICOS GENERALES Knipstein, T. W., Eger, E. I., and Buechel, D. R. (1969). SUMARIO Ethylene-halothane anesthesia: addition or synergism? Anesthesiology, 31,301. Se han medido las potencias anest&icas de mezclas binarias Miller, S. L. (1961). Theory of gaseous anesthetics. Proc. de los gases arg6n (Ar), oxido nitroso (N2O) y hexafluoruro de azufre (SF6), empleando ratones. Las mezclas SFe-Nj.O Natl. Acad. Sci. U.S.A., 47, 1515. Pauling, L. (1961). A molecular theory of general anesthesia. y N2O-Ar acusaron un comportamiento de aditivo, mientras que los componentes de la mezcla SF8-Ar no incluyeron Science, 134, 15. Smith, E. B. (1966). Decompression experiments with aditivos, contando con una potencia total inferior a la various inert gases; in Proc. Third Underwater Physiology anticipada. Otros experimentos que se llevaron a cabo Symposium, Washington (ed. C. J. Lambertsen), p. 425. empleando Grandes Lagartijas Acuaticas Italianas y ratones con las mezclas CF4-AR y CF 4 -SF 8 sugirieron que las Baltimore: Williams and Wilkins. Speden, R. N. (1963). Kinetics and mechanism of action potencias an6malas podian ser producidas por efectos of some volatile anaesthetics. D.Phil. Thesis, Oxford pulmonares especificos asociados con la inspiraci6n de SF 6 , acompanado por la elevada presion de algiin otro gas. University.
