Volatile Anaesthetics: Recent Developments
I. A . E w a r t a n d R. M. J o n e s
Before considering recent developments in the field of volatile anaesthetic agents, it will be of value to review the properties of a theoretically ideal volatile agent, and then discuss how closely the new a g e n t s - desflurane and sevoflurane - - approach these properties.
The ideal volatile agent 1'2 1. The ideal agent should have minimal cardiovascular and respiratory side-effects. 2. It should possess inherent molecular stability i.e., it should not be broken down by exposure to extremes of temperature, light, or by exposure to soda-lime, thus allowing it to be used in low-flow systems. It should not require the presence of preservatives to prolong its shelf life. 3. The molecule should not be subject to biotransformation and should be devoid of any organ-specific toxic effects even in the event of chronic low-dose exposure such as may be encountered by personnel in operating theatres. 4. There should be no adverse or unpredictable interactions with other drugs. 5. It should be reasonably potent, so allowing its use with normal, or increased oxygen concentrations. 6. It should have a low blood-gas solubility coefficient, permitting rapid induction of, and emergence from, anaesthesia and permitting
Volatile agents and awareness The incidence of awareness during certain types of anaesthesia has been shown to be decreased by the presence of relatively low levels (0.6 MAC) of a volatile agent. In a recent letter 3 Lunn and Rosen put forward guidelines for reducing the incidence of awareness during anaesthesia and suggested that a minimum concentration of volatile agent was an essential part of most anaesthetic techniques.
New inhalational anaesthetic agents
I. A. Ewart BSc, FCAnaes, Consultant Anaesthetist, Southendon-Sea Hospital, Southend-on-Sea, UK, R. M. Jones MD, FCAnaes, Professor of Anaesthetics, Academic Department of Anaesthetics, St Mary's Hospital, Paddington, London W2 1NY, UK
History and early development. Sevoflurane started its development in 1969 during the investigation of a series of fluorinated isopropyl ethers at Travenol
Current Anaesthesia and Critical Care (1991) 2, 243-250
1991 Longman Group UK Ltd
the rapid alteration in depth of anaesthesia to meet the changing degree of surgical stimulus. It should be non-irritant to the upper airway, allowing smooth inhalational induction, should this be required. Effects on the central nervous system should be rapidly reversible, and the relationship between cerebral metabolic rate and cerebral blood flow should not be altered. It should not be inflammable or explosive at any concentration in air, oxygen, or nitrous oxide. It should not sensitise the heart to the effects of circulating catecholamines. In an increasingly cost-conscious environment it is an advantage if a new agent is not disproportionately more expensive than existing agents.
CURRENT ANAESTHESIA AND CRITICAL CARE 1
MAC in oxygen Partition coeffs. Olive oil:gas Blood:gas Boiling point (deg C) Vapour pressure at 20°C (kPa) Molecular Wt. (Daltons) Stability in moist soda-lime Preservative
Laboratories, Morton Grove, Illinois. Bernard Regan, one of three research pharmacologists working on this project, first synthesized sevoflurane and noted its anaesthetic properties, in conjunction with his co-workers, Wallin and Napoli. 4'5 The first trials in man were undertaken by Holladay and Smith at the University of Miami and reported in 1981; it is freely available for clinical use in Japan but not in Europe or America (at the time of writing, 1991). Physical characteristics. The physical properties of sevoflurane and desflurane, compared with isofiurane, enflurane and halothane, are detailed in Table 1. In general, the potency of volatile agents increases with increasing molecular weight, 6 as can be observed with desflurane compared with isoflurane and enflurane. This general rule does not necessarily apply when considering structurally dissimilar compounds, and thus sevoflurane, which is an isopropyl ether (rather than a methyl ethyl ether) has a higher molecular weight than isoflurane and enflurane but is somewhat less potent than either. Boiling point. Sevoflurane boils at 58.5°C and has a vapour pressure of 21.33kPa at 20°C, increasing to 26.66kPa at 25°C. In this respect its characteristics are similar to other volatile agents and conventional vaporizer techniques may be used to deliver it to the patient. Partition coefficients. The blood:gas partition coefficient of sevoflurane is 0.60, 7 somewhat lower than that of the other agents, and approaching that of desflurane and nitrous oxide at 0.42 and 0.46 respectively. 8,9 The low partition coefficient suggests that the rates of uptake and elimination will be rapid. The blood:gas partition coefficient of neonates compared with adults has been found to be similar. 10 The oil:gas partition coefficient of sevoflurane is 53.4 in olive oil. 7 It must be noted that oil:gas partition coefficients vary according to the oil being used, and therefore care must be taken when comparing coefficients to ensure that the same oils were used. A study of partition coefficients for components of anaesthetic circuits consistently ranked desflurane and sevoflurane below halothane and isoflurane, suggesting
that absorption of either by circuit components should not hinder induction or recovery from anaesthesia in any significant way. 11 A relationship exists between oil:gas partition coefficients and M A C which, until the advent of the new volatile agents, was such that the product of the two was very similar for all agents. 6'12 The products for sevoflurane, isoflurane and desflurane (106, 109 and 114 respectively) are notably similar, and less than half that of the other agents (halothane 249; enflurane 258; nitrous oxide 263). 12 These data are open to several interpretations, and readers are directed to the accounts by Eger, 12 Halsey, 13 Lynch 14 and T a r g e t al. 6 A critical assessment of the available literature suggests the conclusion that the molecular basis for the action of anaesthetics varies according to the specific agent in question. Stability in soda-lime. When considering the use of expensive agents such as sevoflurane or desflurane, it is important to consider such factors as their suitability for use with low-flow anaesthetic delivery systems. In doing so it is necessary to know the extent to which they are absorbed or degraded by exposure to soda-lime. It is likely that all agents are subject to some degree of both, but that the relative proportions of each factor as well as the total amount that is removed by contact with soda-lime will vary according to the agent. The extent to which sevofiurane is absorbed rather than degraded is not clear at present 7'15 but it is clear that some degree of degradation does occur. Whilst the absorption of an agent by soda-lime is principally of economic interest, degradation is of major importance since unstable agents may degrade to toxic products both in vivo 16 and in vitro. 17 In general, stability decreases as temperature increases, 17'18 and dry soda-lime has a greater absorptive capacity than moist sodaqime.19'20 The order of stability would appear to be desflurane > isoflurane > halothane > sevoflurane.15,18,21 Recent work suggests that the hydroxy group of soda-lime is the moiety responsible for increasing the level of breakdown of sevofiurane. 2° The same investigators also reported the results of work with sodalime-A (a new form of soda-lime containing only
VOLATILE ANAESTHETICS: RECENT DEVELOPMENTS 245 Ca(OH)2 and N a O H ) which showed that whilst reaction products P2 and P5 were reduced, P1 was increased. (Breakdown products were measured using gas chromatography, with the analysis peaks designated P1-P5). 22 Baralyme has been shown to degrade sevoflurane to an even greater degree than soda-lime. 23 It is clear from these reports that sevoflurane is degraded to some extent by soda-lime and that this is enhanced at increased temperatures, and in the presence of K O H . Potency. The M A C of sevoflurane has been examined in two studies, giving values of 1.71 (SE 0.007)% 24 and 2.05 (SE 0.08)%. 25 Whilst there are some differences in the methods employed in the two studies, it is also likely that inter-racial genetic differences may have some bearing on the results, the studies having been performed in Japan and North America respectively. Uptake and elimination. The low blood gas solubility of sevoflurane indicates that the rate of rise of alveolar concentration towards that of inspired concentration will be rapid. Therefore induction of, and recovery from, anaesthesia should also be rapid. A study in mongrel dogs has demonstrated the rapid rise in alveolar concentration of sevoflurane, but did not report on elimination of the agent, z6 The importance of tissue solubility becomes greater with increasing time after induction particularly in the vessel-rich group of organs. In terms of tissue solubility, sevoflurane more closely approaches the values of the other agents (desflurane is appreciably less soluble). Thus, its wash-in and wash-out times, as determined in a study using pigs, are longer than desflurane, but are nevertheless shorter than those of isoflurane and halothane. 27 Studies in rats have provided similar results, when viewed in terms of recovery times from anaesthesia of similar depth and duration. 28 Cardiorespiratory effects. The respiratory effects of all of the volatile anaesthetics are similar in that a dose-dependent depression of ventilation occurs as evidenced by an increase in PaCO2 .2'29'3°'31 The response to both hypoxia 29'32 and hypercarbia 29'33 is blunted. The respiratory rate usually increases and the tidal volume decreases, and thus the ventilatory minute volume may be relatively unchanged. The effects of sevoflurane seem very similar to those of the other agents in this respect, with 1MAC levels inducing a 20% increase in end tidal CO2 or PaCO2, with an increase in the ventilatory rate, but little change in minute volume. 34 The cardiovascular effects of sevoflurane are similar to those of isoflurane and it does not appear not to sensitise the heart to circulating catecholamines. 35 Volunteer studies have shown a decrease in systemic arterial pressure with diastolic decreasing to a greater degree than systolic, and rate being little changed. 34 Studies carried out using animals have revealed more about the behaviour of the cardiovascular
system exposed to this agent. In chronically instrumented dogs 36'37 and acutely instrumented newborn piglets, 38 sevoflurane produced a dose-dependent decrease in systemic arterial pressure and myocardial contractility. The study in dogs 36 showed that the major difference between the myocardial effects of isoflurane and sevoflurane was that of a greater increase in heart rate with isoflurane than with sevoflurane at levels above 1.2MAC. Another study compared the effects of several volatile agents on cardiac conductive tissue properties. It was found that sevoflurane ranked below halothane and enflurane for prolongation of sinus cycle length and conduction times. 39 Hepatorenal effects and biotransformation. The major difference between sevoflurane and desflurane is that sevoflurane cannot be said to be a very stable molecule (see stability in soda-lime above). This has implications for the potential for biostransformation. Exposure to sevoflurane for 1 MAC-hour produced a mean inorganic fluoride level of 22.1 ~mol/litre34; the values are thus similar to those seen after comparable MAC-hour exposure to enflurane anaesthesia. Animal studies have provided similar results 7,4° and levels in excess of 10 p~mol/litre have been found in rats 41 and in guinea pigs; 4° potentially nephrotoxic levels have been suggested as being above 50 ~mol/ litre. 2 This study 4° also showed some evidence of sevoflurane induced hepatotoxicity. It was suggested that this may be due to decreased hepatic blood flow, although the role of liver blood flow in the production of hepatotoxicity seems unclear, with no gross changes in liver function being reported by Holaday and Smith in their volunteer trials with sevoflurane.34 Some evidence exists to show that sevoflurane decreases renal blood flow but despite evidence indicated in the studies above there has been no evidence of gross renal damage in man 34 or animals. 41'42 Similarly, the first volunteer trials showed no gross changes in liver function in man exposed to sevoflurane,34 although studies using an in vitro rat model 43 have shown that sevoflurane decreased the synthesis of fibrinogen, transferrin and albumin at levels within the therapeutic range. This reduction was greater (with the exception of enflurane and its effects on albumin synthesis) than with any other agent.
Desflurane History and early development. Desflurane (Suprane) is one of the products of a research programme undertaken by Terrel and associates at Ohio Medical Products (now Anaquest) between 1959 and 1966. This project involved the synthesis of more than 700 compounds in a search for a superior volatile anaesthetic agent. 44 Two products of this programme are already enjoying widespread use as the volatile agents enflurane and isoflurane. Both are halogenated methyl ethyl ethers, and have surpassed halo-
CURRENT ANAESTHESIA AND CRITICAL CARE
thane as first-choice agents in most developed countries. The few undesirable features of these agents led to a re-examination of several of Terrel's compounds. One compound which had previously been discarded (the 653rd in the series) due to difficulties in synthesis, had been noted to have anaesthetic properties and was halogenated entirely with fluorine, a feature which was predicted to confer on it a low blood solubility coefficient and excellent stability. However, it had a vapour pressure of 88.53kPa at room temperature and thus it could not be delivered using a standard vaporizer. However, the increasing role of day case surgery, with the requirement for rapid recovery, renewed interest in this agent and it underwent its first exposure in volunteers in 1988 under the direction of Jones and his colleagues in the University of London. It is currently (1991) undergoing clinical trials in North America and Europe. Physical characteristics. The physical characteristics of desflurane compared with sevoflurane and the other volatile agents are given in the corresponding section for sevoflurane. Desflurane is a fluorinated methyl ethyl ether, and when compared with isoflurane, it can be seen that the potency of the agent is decreased by a factor of four due to the substitution of fluorine for chlorine on the ethyl carbon. 6
Boiling point. The boiling point of desflurane (23.5°C) is close to room temperature, giving it a vapour pressure of 88.53 kPa at 20°C. Thus, the agent cannot be used with conventional vaporizer systems and special techniques have been developed to deliver desflurane safely and accurately. Direct metering vaporisation, in which a thermostatically controlled vaporizer is maintained at 23-25°C, has been used in the early clinical trials. The vapor is metered into the fresh gas flow delivered to the patient via a flowmeter calibrated in ml/min of desflurane (this in some respects resembles the Copper Kettle). 45
Partition coefficient. The blood:gas partition coefficient of desflurane is 0.42, 8 this figure being lower than that of nitrous oxide (0.46). 9 As with sevoflurane, this extremely low coefficient implies very rapid uptake and elimination times. This impression was borne out by a study in pigs, 26 which confirmed desflurane as having the most rapid wash-in/wash-out times of any of the volatile agents. The oil:gas partition coefficient of desflurane is 18.78 and thus the agent is less potent than all existing halogenated inhalation agents. However, it has sufficient potency for it to be used with high (90%) concentrations of oxygen. Table 2 shows the comparative tissue blood partition coefficients for desflurane, sevoflurane, isoflurane and halothane in man. Stability in soda-lime. It appears that desflurane is the most stable of the currently available agents, is This has important implications for the use of high cost agents with low-flow breathing systems and soda-
Table 2 Tissue: blood partition coefficientsin man. (Data from , with permission) Desflurane Brain Fat Heart Kidney Liver Muscle
1.29 27.2 1.29 0.94 1.31 2.02
Sevoflurane Isoflurane Halothane 1.70 47.5 1.78 1.15 1.85 3.13
1.57 44.9 1.61 1.05 1.75 2.92
1.94 51.1 1.84 1.16 2.07 3.38
lime, in that sevoflurane appears to be unsuited to use in this context, whereas desflurane may be ideal. Potency. Desflurane has a M A C of about 6.0% ; this value was determined in surgical patients in N. America. 47 It is therefore somewhat less potent than the other agents. Uptake and elimination. As with sevoflurane, the low solubility of desflurane in blood and tissue suggests a rapid rate of increase of alveolar and tissue concentrations, and an equally rapid decrease on cessation of administration. Volunteer studies confirmed the rapid rise in alveolar concentrations, with the ratio of alveolar to inspired concentrations being 0.82 at 10min exposure. The rate of elimination was also rapid, with the ratio of alveolar concentration to last delivered concentration being only 0.11 at 10min. 48 Animal studies have shown that the tissue:blood partition coefficient of desflurane is significantly lower than that of any of the other agents and that the wash-in/wash-out times for desflurane are the shortest of all the agents. 46 Cardiorespiratory effects. The cardiorespiratory effects of desflurane are similar to those of the other volatile agents, and in particular, those of isoflurane. There is a dose-dependent decrease in systemic arterial pressure and no apparent sensitization of the myocardium to circulating catecholamines. In a recent study, the possible interactions of desflurane and isoflurane with a number of commonly used anaesthetic drugs (atracurium, atropine, fentanyl, thiopentone and nitrous oxide) was examined and the conclusion reached that the standard therapeutic doses of these drugs have no significant cardiovascular interactions with either of the volatile agents studies. 49 A study in human volunteers 5° confirmed the similarity of desflurane to the other volatile halogenated ethers in man. The cerebral vascular and metabolic effects of desflurane have only been reported in dogs to date. 51 This study showed that desflurane produced a doserelated decrease in cerebral vascular resistance with a small increase in cerebral blood flow (CBF) at concentrations up to 1.5MAC. At 2.0MAC, CBF decreased, but this was associated with a decrease in mean arterial pressure. It was found that desflurane produced a small increase in intracranial pressure at 0.5 MAC, but this did not rise with increasing levels of desflurane. E E G activity followed a similar pattern to
VOLATILE ANAESTHETICS: RECENT DEVELOPMENTS 247 that of isoflurane, with burst suppression and attenuation. Hepatorenal effects and biotransformation. In contrast to sevoflurane, desflurane appears to be a remarkably stable molecule. After about 1MAC-h exposure to desflurane, mean plasma inorganic fluoride concentrations did not exceed control levels at any time up to 1 week after exposure. This study was carried out on healthy volunteers. 52 Animal studies have also produced similar results; Koblin et a153used the phenobarbitone pretreated rat model to compare the effects of halothane, methoxyflurane, isoflurane and desflurane. They found a massive increase in fluoride concentrations in animals exposed to either halothane or methoxyflurane, with a small but measureable rise being noted following exposure to isoflurane. Desflurane produced results virtually indistinguishable from control values. Studies using swine have shown that fluoride ion concentration rises by a factor of 300% after 5.5 MAC-h exposure to isoflurane. After similar levels of desflurane, a rise of only 17% could be found at 4h post-exposure 54 and further work showed no evidence of hepato-cellular injury or increases in aminotransferase activity following up to 9.7MAC-h exposure to isoflurane or desflurane. 55 Volunteer studies also showed no change in liver or renal function 52 and repeated exposure of animals to desflurane, or exposure in enzyme-induced, hypoxic rats showed no difference from control groups. 56'57 Thus it appears that desflurane has little or no potential for major organ toxicity, and the evidence so far suggests that desflurane is less subject to biotransformation than any other agent.
Current market shares and costs. The relative positions of the volatile agents, in terms of market share, is in a state of flux. Commercial data show that the market share of halothane is declining. In the U K at the time of writing (1991) approximately 65% of procedures involve the use of enflurane and isoflurane with each enjoying an equal market share. In Japan, the near simultaneous introduction of isoflurane and sevoflurane has resulted in a rapid decline in halothane usage, with sevoflurane and isoflurane having comparable market shares. The costs of the new agents relative to halothane remains high, and although the cost of desflurane cannot be predicted the difficulties in synthesis and relatively low potency suggest that it may cost relatively more per procedure than other agents. Cost benefit~effectiveness. Against the factors above must be weighed the benefits of the new agents; desflurane offers the best currently available combination of stability and clinical effects and certainly looks more attractive when used in a low-flow system. Sevoflurane seems to have a few problems regarding
stability, but has the advantage of greater potency and good induction characteristics (probably better than desflurane, although to date there have been no direct comparison studies). The recent upsurge in day-case surgery may prove to be a good use for sevoflurane and desflurane, with their rapid wash-in/ wash-out times. Circle/low-flow systems. There appears to be a resurgence of interest in circle systems, and this may prove to be most timely for agents such as desflurane, with its potential for relatively high cost and low potency. The use of low flow systems with agents such as this could widen the market for these drugs by maximising efficiency of use, and minimising wastage and pollution. Whilst this may aid the spread of desflurane within the anaesthetic community, this may not be so for sevoflurane, until a clearer picture emerges concerning the use of sevoflurane in low flow systems. With currently used systems and methods of carbon dioxide absorption sevoflurane would not appear to be a suitable agent for this type of delivery system. The future. It is likely that desflurane will become available for general clinical use in the next 2-3 years and there is at least the possibility that sevoflurane will also become available at some time in the future (it is undergoing clinical trials at a variety of centres in America). There is still much debate over the target sites of anaesthetic agents 58,59,60 and future agents will surely benefit from the elucidation of the molecular basis of action of anaesthetics. Where, though, does this site lie? Recent work by Franks and Lieb at Imperial College, London centering on light emitting enzyme luciferase has shown that a wide range of anaesthetic agents not only bind to, but also inhibit, the action of an enzyme system at concentrations produced under normal anaesthesia. 6°'61 Another interesting observation is that the correlation plotted between ED50 concentrations for anaesthesia in various animal models and the EDso for inhibition of luciferase activity is a straight line; this indicates that the Meyer and Overton hypothesis can be interpreted in terms of protein binding of anaesthetics as easily as it can in terms of lipid solubility. 61 This line of research opens up the possibility of a new concept of anaesthetic drugs. Once the ultimate site(s) of action of anaesthetic drugs is known, molecules tailored to fit the site(s) can be synthesized, putting an end to the synthesis of vast numbers of molecules in the hope that a few may have useful anaesthetic properties. The prospect of truly specific anaesthetic agents devoid of effects on other organ systems thus exists for the future. The present. Whilst we have the prospects of drugs acting at known specific sites for the future, what do we have at present? The current position sees the market share of halothane decreasing, with enflurane and isoflurane well ahead. Desflurane appears to have several advantages over the currently available alternatives; in particular, its rapid uptake and elimination with excellent stability. The disadvantages in
CURRENT ANAESTHESIA AND CRITICAL CARE
terms of synthesis and delivery methods can be accommodated but may result in an agent of higher cost, for which administration via a circle system with absorber would seem to be mandatory. Sevotturane also has rapid uptake and elimination and is significantly more potent than desflurane; it can also be used with conventional vaporiser technology. However its stability leaves something to be desired. It may, however, have a role in gaseous induction of anaesthesia and early evidence suggests that it may be at least as well tolerated as halothane in this respect. References 1. Heijke S, Smith G. Quest for the ideal anaesthetic agent. Br J Anaesth 1990; 64:3-6 2. Jones RM. Clinical comparison of inhalational anaesthetic agents. Br J Anaesth 1984; 56: 57-69S 3. Lunn JN, Rosen M. Anaesthetic awareness. Br Med J 1990; 300:938 4. Wallin RF, Napoli MD. Sevoflurane (fluoromethyl-1, 1, 1, 3, 3, 3,-hexafluoro-2-propyl ether): a new inhalation anesthetic agent. Fed Proc 1971; 30:442 5. Wallin RF, Napoli MD, Regan BM. Laboratory investigations of a new series of inhalational anesthetic agents: the halomethyl polyfluorisopropyl ethers. In: Fink BR, ed. Cellular Biology and Toxicity of Anesthetics. Baltimore: Williams and Wilkins, 1972; 285-295 6. Targ AG, Yasuda N, Eger E1 ii, Huang G, Vernice G, Terrell RC, Koblin DD. Halogenation and potency. Anesth Analg 1989; 68:59%602 7. Wallin RF, Regan BM, Napoli MD, Stern IJ. Sevoflurane: a new inhalational anesthetic agent. Anesth Analg 1975; 54: 758-766 8. Eger E1 ii. Partition coefficients for 1-653 in human blood, saline and olive oil. Anesth Analg 1987; 66:971-973 9. Seibeck R. Uber die Aufnahme von Stickoxydul in Blut. Skand Arch Physiol 1909; 21:368-382 10. Malviya S, Lerman J. The blood/gas solubilities of sevoflurane, isoflurane, halothane and serum concentrations in neonates and adults. Anesthesiology 1990; 72:793-796 11. Targ AG, Yasuda N, Eger EI ii. Solubility of 1-653, sevoflurane, and halothane in plastics and rubber composing a conventional anesthetic circuit. Anesth Analg 1989; 69: 218--225 12. Eger EI ii. Anesthetic potency and lipid solubility; a reply. Anesth Analg 1990; 70:118-119 13. Halsey MJ. Mechanisms of general anaesthesia. In: Eger El ii, ed. Anesthetic Uptake and Action. Baltimore: Williams and Wilkins, 1974; 54-76 14. Lynch C. Anesthetic potency and lipid solubility. Anesth Analg 1990; 70:117-118 15. Strum DP, Johnson BH, Eger EI ii. Stability of sevoflurane in soda-lime. Anesthesiology 1987; 67:799-781 16. Cohen EN, Van Dyke RA. Metabolism of Volatile Anesthetics. Implications for Toxicity. Reading: AddisonWesley, 1977 17. Sharp JH, Trudell JR, Cohen EN. Volatile metabolites and decomposition products of halothane in man. Anesthesiology 1979; 50:2-8 18. Eger E1 ii, Strum DP. The absorption and degradation of isoflurane and 1-653 by dry soda-lime at various temperatures. Anesth Analg 1987; 66:1312-1315 19. Grodin WK, Epstein MAF, Epstein RA. Soda-lime adsorption of isoflurane and enfiurane. Anesthesiology 1985; 62:60-64 20. Kudo M, Kudo T, Oyama T, Matsuki A. Reaction products of sevoflurane with components of soda-lime under various conditions. Masui 1990; 39:39-44 21. Grodin WK, Epstein RA. Halothane abosorption complicating the use of soda-lime to humidify anaesthetic gases. Anaesthesia 1982, 54:555-559 22. Kudo M, Kudo T, Matsuki A. Reaction products of sevoflurane with new soda-lime A under various conditions. Masui 1990; 39:626-631
23. Tanifuji Y, Takagi K, Kobayashi K, Yasuda N, Eger EI ii. The interaction between sevoflurane and soda-lime or baralyme. Anesth Analg 1989; 68:$285 24. Katoh T, Ikeda K. The minimum alveolar concentration (MAC) of sevoflurane in humans. Anesthesiology 1987; 66: 301-303 25. Scheller MS, Partridge BL, Saidman LJ. MAC of sevoflurane in humans and the New Zealand white rabbit. Anesthesiology 1987; 67:A373 26. Kazama T, Ikeda K. Comparison of MAC and the rate of rise of alveolar concentration of sevoflurane with halothane and isoflurane in the dog. Anesthesiology 1988; 68:435-437 27. Yasuda N, Targ AG, Eger EI ii, Johnson BH, Weiskopf RB. Pharmacokinetics of desflurane, sevoflurane, isoflurane, and halothane in pigs. Anesth Analg 1990; 71:340-348 28. Eger EI ii, Johnson BH. Rates of awakening from anesthesia with 1-653, halothane, isoflurane and sevoflurane: a test of the effect of anesthetic concentration and duration in rats. Anesth Analg 1987; 66:977-982 29. Eger EI ii. Isoflurane: a review. Anesthesiology 1981; 55: 55%576 30. Fourcade HE, Stevens WC, Larson CP, Cromwell TH, Bahlman SH, Hickey RF, Halsey MJ, Eger EI ii. The ventilatory effects of Forane, a new inhaled anesthetic. Anesthesiology 1971; 35:26-31 31. Knill RL, Mannimen PH, Clement JL. Ventilation and chemoreflexes during enflurane sedation and anaesthesia in man. Can Anaesth Soc J 1979; 26; 353-360 32. Knill RL, Clement JL. Variable effects of anaesthetics on the ventilatory response to hypoxaemia in man. J Anaesth Soc 1982; 29:93-99 33. Wade JG, Stevens WC. Isoflurane: an anesthetic for the eighties? Anesth Analg 1981; 60:666--682 34. Holaday DA, Smith FR. Clinical characteristics and biotransformation of sevoflurane in health human volunteers. Anesthesiology 1981; 54:100-106 35. Doi M, Ikeda K. Sevoflurane anesthesia with adenosine triphosphate for resection of phaeochromocytoma. Anesthesiology 1989; 70:360-363 36. Bernard JM, Wouters PF, Doursout M-F, Florence B, Chelly JE, Merin RG. Effects of sevoflurane and isoflurane on cardiac and coronary dynamics in chronically instrumented dogs. Anesthesiology 1990; 72:659-662 37. Wouters P, Doursout M-F, Florence B, Merin RG, Chelly JE. Hemodynamic effects of sevoflurane in chronically instrumented dogs. Anesthesiology 1989; 71:A508 38. Davis PJ, Thomas EL, Goldstein MC, Canose J, Gorchesky MS, Roeber CM, Motoyama EK. Effect of sevc~flurane on circulation in newborn piglets. Anesthesiology 1989; 71: Ai030 39. Yokota S. Comparative effects of inhalation anesthetics on atrioventricular conduction with and without calcium entry blockers. Hokkaido lgaku Zasshi 1989; 64:43-54 40. Lind RC, Ghantous HN, Gandolfi AJ, Brown BR jr. Sevoflurane biotransformation and hepatotoxicity in the guinea pig. Anesthesiology 1989; 71:A310 41. Cook TL, Beppu WJ, Hitt BA, Kosek JC, Mazze RI. Renal effects and metabolism of sevoflurane in Fisher 344 rats. Anesthesiology 1975; 43:70-77 42. Cook TL, Beppu WJ, Hitt BA, Kosek JC, Mazze RI. A comparison of renal effects and metabolism of sevoflurane and methoxyflurane in enzyme-induced rats. Anesth Analg 1975; 54:829-835 43. Franks J J, Kruskal JB, Holaday DA. Immediate depression of fibrinogen, albumin and transferrin synthesis by halothane, isofiurane sevoflurane and enflurane. Anesthesiology 1989; 71:A238 44. Vitcha JF. A history of Forane. Anesthesiology 1971; 35:4-7 45. Morris LE. A new vaporizer for liquid anesthetic agents. Anesthesiology 1952; 13:587-589 46. Yasuda N, Targ AG, Eger EI ii. Solubility of 1-653, sevoflurane isoflurane and halothane in human tissue. Anesth Analg 1989; 69:370-373 47. Rampil IJ, Zwass M, Lochart S, Eger EI ii, Johnson BH, Yasuda N, Weiskopf RB. MAC of 1-653 in surgical patients. Anesthesiology 1989; 71:A269 48. Jones RM, Cashuan JN, Eger EI ii, Damask M, Johnson BH. Kinetics and potency of desflurane (I-653) in volunteers. Anesth Analg 1990; 70: 3-7.
VOLATILE ANAESTHETICS: RECENT DEVELOPMENTS 49. Weiskopf RB, Eger EI ii, Holmes MA, Yasuda N, Johnson BH, Targ AG, Rampil IJ. Cardiovascular actions of common anesthetic adjuvants during desflurane (I-653) and isoflurane anesthesia in swine. Anesth Analg 1990; 71:144-148 50. Jones RM, Cashman JN, Mant TGK. Clinical impressions and cardiorespiratory effects of a new fluorinated inhalation anaesthetic, desfturane (I-653), in volunteers. Br J Anaesthes 1990; 64:11-15 51. Lutz LJ, Milde JH, Milde LN. The cerebral functional, metabolic and hemodynamic effects of desflurane in dogs. Anesthesiology 1990; 73:125-131 52. Jones RM, Koblin DD, Cashman JN, Eger EI ii, Johnson BH, Damask MC. Biotransformation and hepatorenal function in volunteers after exposure to desflurane (1-653). Br J Anaesthes 1990; 64:482-487 53. Koblin DD, Eger EI ii, Johnson BH, Konopka K, Waskell L. 1-653 resists degradation in rats. Anesth Analg 1988; 67: 534-538 54. Koblin DD, Weiskopf RB, Holmes MA, Konopka K, Rampil IJ, Eger EI ii, Waskell L. Metabolism of 1-653 and isoflurane in swine. Anesth Anatg 1989; 68:147-149 55. Holmes MA, Weiskopf RB, Eger E1 ii, Johnson BH, Rampil IJ. Hepatocellular integrity in swine after prolonged
desflurane (I-653) and isoflurane anesthesia: evaluation of plasma alanine amino-transferase activity. Anesth Analg 1990; 71:249-253 56. Eger EI ii, Johnson BH, Ferrell LD. Comparison of the toxicity of 1-653 and isoflurane in rats: a test of the effect of repeated anesthesia and use of dry soda-lime. Anesth Analg 1987; 66:1230-1233 57. Eger EI ii, Johnson BH, Strum DP, Ferrell LD. Studies of the toxicity of 1-653, halothane and isoflurane in enzymeinduced, hypoxic rats. Anesth Analg 1987; 66:1227-1229 58. Eger E1 ii, Lundgren C, Miller S, Stevens WC. Anesthetic potencies of sulfur hexafluoride, carbon tetrafluoride, chloroform and Ethrane in dogs: correlation with the hydrate and lipid theories of anesthetic action. Anesthesiology 1969; 30:129-135 59. Franks NP, Lieb WR. Molecular mechanisms of general anesthesia. Nature (London) 1982; 300:487-493 60. Franks NP, Lieb WR. Do general anaesthetics act by competitive binding to specific receptors? Nature (London) 1984; 310:599-601 61. Franks NP, Lieb WR. What is the molecular nature of general anaesthetic target sites? Trends Pharmacol Sci 1987; 8:169-174