CYCLOPROPANE: THE ESSENTIAL FEATURES

Brit. J. Anaesth. (1965), 37, 671

CYCLOPROPANE: THE ESSENTIAL FEATURES BY

I. R. VERNER

The Middlesex Hospital, London

HISTORY

Cyclopropane was discovered by Freund (1882), but the anaesthetic properties of hydrocarbons with the general formula CnH2n were appreciated earlier. John Snow (1858), for example, administered amylene (C5H10) to 238 patients. In 1923, ethylene (C2H4) was introduced into clinical anaesthesia, but its low potency and inflammability restricted its use. At the University of Toronto, research by G. H. W. Lucas and V. E. Henderson on propylene (CH3.CH:CH2) revealed certain samples to show marked cardiac toxicity. Lucas suggested that the toxicity might arise from one of the impurities present in the samples, the cyclic isomer of propylene, cyclopropane. Pure samples of cyclopropane were prepared and this, when tested by Lucas and Henderson, proved to be a

more potent and suitable anaesthetic agent than propylene. The results of their animal experiments were published in 1929 (Lucas and Henderson, 1929). An unfavourable surgical climate resulting from three recent catastrophes prevented the clinical trial of cyclopropane in Toronto. However, the potentialities of the agent were apparent to Dr. R. M. Waters, who immediately introduced cyclopropane into regular use at the hospitals associated with the University of Wisconsin and published the first reports of its administration to 447 patients four years later (Waters and Schmidt, 1934; Stiles et al., 1934). This initial comprehensive and intelligent evaluation of cyclopropane led to the swift acceptance of the agent. No previous inhalational agent had been subjected to so thorough a clinical trial before being released to the profession, and it was fortunate that Waters had previously pioneered closed-circuit techniques since the high cost of the gas (25 dollars for 50 gallons) demanded this type of administration. In Canada, isolated cases were given cyclopropane by Griffiths in 1933, and in December of that year Dr. R. M. Muir of Cape Town brought a cylinder of the gas to London and demonstrated its use on several patients at the Cancer Hospital. The first British report described the administration of cyclopropane to thirteen patients in Leeds (Sykes, 1934), and it is of interest to note that the author, though well aware of the inflammable nature of the gas, states it to be "of no practical importance, owing to the closed-circuit method of administration". A series of 250 patients anaesthetized by cyclopropane was reported in the following year (Rowbotham, 1935a, b). As in America, the initial careful evaluation of the agent coupled with its undoubted qualities ensured its rapid acceptance in Britain (Lancet, 1935a, b, 1936a, b). A further impetus was provided by the lecture tour of this country by Waters in 1936 (Waters, 1936). In Britain, supplies of cyclopropane were at first limited by the need to import cylinders of the agent privately from America.

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015

Cyclopropane has now been in clinical use throughout the world for over a quarter of a century. At the time of its introduction into clinical anaesthesia it offered clear advantages over the other agents then employed, and some of those advantages still apply today. In North America, cyclopropane remains the agent of choice in many centres and the volume of research into its properties is little abated. In Great Britain, however, due to an early acceptance of the muscle relaxants and the newer inhalational agents and a very wide use of the diathermy in surgical practice, the popularity of cyclopropane has declined markedly over the past ten years. Even so, the agent is still frequently employed, very often on moribund patients, and this alone means that a familiarity with cyclopropane should form part of the background of the practising anaesthetist. The scope of this article prevents a comprehensive review of the agent being given, and it will remain limited to certain important features of cyclopropane. The excellent and comprehensive monograph by Robbins (1958) still serves as the definitive work on cyclopropane, and is recommended to the reader for further study.

BRITISH JOURNAL OF ANAESTHESIA

672

As supplied, the gas is 99-5 per cent or more pure, but possible impurities include propylene, allene, cyclohexane, nitrogen, carbon dioxide, and bromor chloropropane. Propylene is the most important contaminant, up to 1 per cent being acceptable, but concentrations over 3 per cent are toxic. Preparation. Stroll quantities of cyclopropane have been prepared from natural deposits of the gas in the United States, but current practice involves the reaction of trimethylene glycol with hydrobromic acid to form l:3-dibromopropane. The latter compound, in the presence of zinc dust, converts to the cyclic compound, cyclopropane. The chemical reaction is shown in figure 1.

2 HBr

r-

PHYSICAL AND CHEMICAL CHARACTERISTICS

Cyclopropane (C3H6) is the simplest possible cyclical hydrocarbon, and has the structural formula: CH 2 / \ Though saturated, its cyclical structure endows it with some of the properties associated with unsaturated compounds. It is relatively stable chemically, does not isomerize or polymerize during prolonged storage under normal conditions, and does not react with soda lime in the presence of heat. The gas is colourless, sweet smelling and, in concentrations in excess of 50 per cent, is slightly irritant to respiratory mucosa. The molecular weight of the gas is 42 08 and the vapour density (air=10) is 1-75 at 20°C (Macintosh, Mushin and Epstein, 1963). The boiling point of liquid cyclopropane is — 33°C at a pressure of 760 Torr, and the critical temperature is 125CC. The critical pressure is 54 atmospheres, but at room temperature the gas liquefies when exposed to pressures of 5 lb./sq.in. In Great Britain it is supplied in bright orange cast steel cylinders at a pressure of 75 lb./sq.in., each ounce of the liquid being equivalent to 3-5 Imperial gallons of gas. Cylinders containing 8, 20 and 40 gallons are available, at a current price of 2s. 9d. per gallon.

FIG. 1 The conversion of trimethylene glycol to cyclopropane.

l:3-dichloropropane may also be used for the preparation of cyclopropane, but will lead to a smaller yield. l:2-dibromo- or dichloropropane cannot be used in the process since they lead to the formation of propylene, not cyclopropane. Fortunately trimethylene glycol, which is a byproduct in the fermentation of molasses, reacts with hydrobromic acid to form the l:3-dibromosubstitution compound. Mono-, di-, and tri-methyl substituted compounds of cyclopropane have been prepared, but have proved to be too toxic for use as anaesthetic agents. Estimation of cyclopropane.

Cyclopropane reacts with filming sulphuric acid to form propyl acid sulphate, with complete absorption of the gas. This reaction enables gas samples to be analyzed for cyclopropane by the addition of sulphuric acid to standard gas analysis

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015

However, as the use of cyclopropane grew, the gas was imported in bulk and decanted in this country, and production in Britain was begun as early as 1935 (B.O.C. Ltd., personal communication; Lancet, 1935b). By 1939 supplies of the gas could be easily obtained (Lancet, 1939) and the agent enjoyed great popularity, especially in the field of thoracic anaesthesia (Nosworthy, 1941). Its use continued to grow during and immediately after the Second World War, but with the introduction of the muscle relaxants and newer volatile agents its popularity began to decline. Recent consumption is difficult to judge accurately, but one American manufacturer has quoted a 50 per cent increase in the distribution of cyclopropane in the period 1953-57 (Robbins, 1958), whereas a 50 per cent reduction of usage in Great Britain is stated by the manufacturers (I.C.I. Ltd., personal communication) to have occurred since 1952.

CYCLOPROPANE: THE ESSENTIAL FEATURES

Solubility constants. Cyclopropane is sparingly soluble in water, but strongly lipophilic. This is shown by a water/gas partition coefficient of 0-204 (Orcutt and Seevers, 1937) and an oil/gas coefficient of 11-2 (Blumberg et al., 1952). The strong lipoid and protein afiBnities of the gas lead not only to the carriage of 2-5 times more cyclopropane by red cells than plasma, but also to a blood/gas partition coefficient which varies with both the haemoglobin concentration and the plasma fat content of blood (Robbins, 1958). The Ostwald solubility coefficient for cyclopropane and whole blood at 37CC, and with 15 g Hb per 100 ml, is 0-415 (Posati and Faulconer, 1958). The similarity of the blood/gas partition coefficients for nitrous oxide (0-48; Kety et al., 1948) and cyclopropane accounts for the rapid and parallel uptake and elimination of these agents, but the greater fat solubility of cyclopropane (N2O oil/gas partition coefficient=1-4; Meyer and Gottleib-Billroth, 1920) leads to delayed recovery after prolonged cyclopropane anaesthesia (Papper, 1964). Cyclopropane is soluble in rubber, but not to an extent which noticeably alters its concentration in anaesthetic circuits. ACTIONS

Inspired concentrations of cyclopropane of 4-6 per cent are analgesic and subanaesthetic, of 8-10

per cent produce light anaesthesia, and of 20-30 per cent, deep anaesthesia. Full surgical anaesthesia is induced in approximately 5 minutes by the inhalation of a 50 per cent mixture of the gas in oxygen. Transient mild excitement (usually limited to breath-holding) may be seen during induction, especially in unpremedicated patients. When a normal ventilation/perfusion ratio exists in the lungs, 80 per cent saturation of wellperfused tissues (as measured by the ratio of the end-expiratory to inspiratory concentrations of cyclopropane) takes place in approximately 10 minutes (Sechzer, 1963). Stage HI, plane 3 anaesthesia is maintained in man by blood concentrations of cyclopropane ranging between 10 and 15 mg per 100 ml (Cohen and Beecher, 1951), respiratory arrest requiring concentrations in the region of 25-30 mg per 100 ml (Robbins, 1958). A high index of correlation has been found to exist between the blood concentrations of cyclopropane and. the accompanying electro-encephalographic activity (Posati et al., 1953). Cyclopropane is commonly described as a "potent" anaesthetic. Though the latter term is capable of multiple interpretation it should be noted that, in terms of inspired tensions and blood levels, relatively large concentrations of cyclopropane are required to produce surgical anaesthesia. Elimination of cyclopropane at the termination of anaesthesia is rapid and is almost entirely effected by the lungs, though minute quantities are excreted by the skin. Approximately 50 per cent of the cyclopropane in the body is eliminated within 10 minutes of discontinuing administration, but small concentrations may be detected in venous blood several hours later (Robbins, 1936b). The physical properties of cyclopropane enable it to fit the standard theories of anaesthetic action. Lately, Pauling (1961) has classified cyclopropane as a non-hydrogen-bonding anaesthetic and calculated that its molecular size and properties would enable it to enter into clathrate formation in cerebral tissues. Cardiovascular effects Even when ventilation is artificially maintained, the continued administration of 60-80 per cent cyclopropane to animals eventually leads to cardiac arrest (Meek, Hathaway and Orth, 1937). Cardiac arrest is usually preceded by arrhythmia, and in their original contributions both Lucas and

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015

systems. Descriptions of suitable apparatus and techniques are given by Robbins (1936a) and Meek, Hathaway and Orth (1937). A rapid and accurate method for the estimation of gaseous cyclopropane has been more recently described by Iinde and Price (1958). Solutions of cyclopropane, as well as the gas, may be analyzed by passing samples over heated iodine pentoxide (Robbins, 1958), the method having an accuracy of ± 1 per cent. Blood levels may also be determined with a modified Van Slyke-Neill apparatus (Orcutt and Seevers, 1937). Additional methods for gas analysis include infrared absorption, gas chromatography, and mass spectrometry. The collision-broadening effect of nitrous oxide during infra-red analysis, and the partial absorption of carbon dioxide by certain reagents are sources of errors which may arise during the analysis of respired anaesthetic gases for cyclopropane.

673

674

are elevated, and it is postulated that this is the mechanism whereby irregularities arise during cyclopropane anaesthesia with underventilation. Arrhythmias may also arise after the injection of adrenaline or noradrenaline during cyclopropane narcosis. In these circumstances the blood levels of catecholamines required to initiate arrhythmias are found to be higher than similarly effective levels induced by carbon dioxide retention; in the latter instance, carbon dioxide retention is possibly more effective because catecholamines are locally released in the neighbourhood of cardiac receptors. Drug-induced protection against arrhythmias has received considerable attention. Amongst the agents employed have been diethyl ether (Stutzman, Allen and Meek, 1942), atropine (Johnstone, 1951), barbiturates (Orth, Wangeman and Meek, 1941), procaine (Allen, Stutzman and Meek, 1940), procaine amide (Morris and Haid, 1951), dibenamine (Nickerson and Brown, 1951), and reserpine (Roberts, 1964). None gives absolute protection. Pronethalol, however, will invariably abolish ventricular extrasystoles during cyclopropane anaesthesia (Payne and Senfield, 1964). Attention has recently been focused on the site of origin of the arrhythmias arising during cyclopropane anaesthesia. Dresel (1964) has evidence of a source located in the A-V node or the bundle of His, whilst Roberts (1964) finds the foci to lie in ventricular muscle outside of vagal influence. Both these workers have discussed the question of "sensitdzation" of the myocardium to catecholamines by cyclopropane. They agree that arrhythmias induced by carbon dioxide retention or adrenaline infusion in "sensitized" (i.e. subjected to cyclopropane) and non-sensitized animals have quite separate characteristics, the arrhythmias in the sensitized animals being more serious in nature. Nearly all pressor amines arc capable of causing arrhythmias during cyclopropane anaesthesia. Stutzman and Pettinga (1949), after investigating twenty-six such compounds, found only methoxamine and phenylephrine to be free of this property. Morphine premedication has also been implicated in arrhythmia production (Robbins, 1958). Whatever the nature of "sensitization", it is doubtful whether that produced by cyclopropane will ultimately be found to differ materially from that induced by other inhalational agents such as chloroform or halothane.

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015

Henderson (1929) and Waters and Schmidt (1934) noted cardiac irregularities in dogs and man exposed to cyclopropane. Seevers et al. (1934) studied the relationships between arrhythmias, respiratory exchange, and cyclopropane concentrations in dogs, while Waters (1936) noted that ventricular fibrillation was a frequent precursor of death during cyclopropane anaesthesia in man. Since then, no other aspect of cyclopropane has received so much attention as its tendency to cause cardiac dysfunction. Virtually every type of arrhythmia may arise during cyclopropane anaesthesia, the most frequent being bradycardia, tachycardia, nodal extrasystole and bigeminal rhythm. All may eventually lead to ventricular escape or fibrillation. It was recognized early that arrhythmias arose with high concentrations of the agent and in the presence of anoxia; further, it was known that established arrhythmias might be corrected by reducing cyclopropane concentrations or by instituting artificial ventilation. Guedel (1940), in a masterly paper, related cyclopropane concentrations and arrhythmias in man, and theorized a zone of cardiac irritability that could be left either by decreasing or increasing the inspired concentration of cyclopropane. It is important to note that the arrhythmias he described occurred with cyclopropane concentrations that were causing respiratory insufficiency, and that artificial ventilation was invariably instituted at the same time as he raised or lowered the inspired concentrations. The views of Guedel were later challenged by Lee et al. (1943). The realization that the catecholamine levels and carbon-dioxide tensions of the blood, rather than the actual tensions of cyclopropane, might be more directly concerned in the production of arrhythmias (Allen, Stutzman and Meek, 1940; Stutzman and Pettinga, 1949) led to more detailed investigations of these parameters. Clinical studies by Johnstone (1950), Lurie et al. (1958) and Price et al. (1958) were in agreement that arrhythmias were most prone to arise in the presence of hypercarbia or anoxia. With a blood level of cyclopropane of 18 mg/100 ml, Price et al. (1958) found the carbon dioxide threshold for the production of arrhythmias to lie within the range of 44-100 mm Hg, and to be inversely related to the cyclopropane concentration. Catecholamine levels in the body are known to rise when carbon dioxide tensions

BRITISH JOURNAL OF ANAESTHESIA

CYCLOPROPANE: THE ESSENTIAL FEATURES

myocardial function, and require to be evaluated in conjunction with studies of the peripheral resistance. Bleeding from cutaneous tissues of patients under cyclopropane anaesthesia has been studied by McLoughlin (1954). In planes 1 and 2 of stage III anaesthesia, he noted that bleeding was inversely proportional to the depth of anaesthesia. In deeper planes of this stage of anaesthesia bleeding was invariably increased in amount, but could be reduced by artificial ventilation. Once again attention is directed towards carbon dioxide as a possible causative factor. In summary, the cardiovascular actions of cyclopropane would seem to vary with the conditions imposed by various studies, but a general pattern of catecholamine release, a sensitization of the heart to the actions of these amines (especially in the presence of a raised PCO2), and maintenance of tonus in the circulation, has emerged. So, too, has the realization that hypoxia or hypercarbia during exposure to cyclopropane almost invariably leads to a deterioration in cardiovascular homeostasis. In particular, both conditions favour the appearance of disordered cardiac rhythm. Respiratory actions. A progressive depression of ventilation is a dominant feature in cyclopropane anaesthesia, and was stressed in the original clinical reports. The central depressant actions of cylopropane are so powerful that the raised carbon dioxide concentrations consequent upon diminished ventilation do not lead to the normal reflex correction of respiration. In addition, cyclopropane is commonly administered in oxygen-rich mixtures that preclude respiratory stimulation by hypoxia. Shackell and Blumenthal (1934) demonstrated that when inspired oxygen concentrations were held in the region of 70 per cent, respiratory arrest in monkeys was produced by 28 per cent cyclopropane; if the oxygen tension was lowered to 20 per cent, cyclopropane concentrations had to be increased to 34 per cent to achieve the same effect. Such considerations make it imperative to maintain artificial ventilation at all stages of cyclopropane anaesthesia, in order to prevent the development of a respiratory acidosis. The role of adequate ventilation in the prevention of both cardiac arrhythmias and "cyclopropane shock" has been previously mentioned. The blood concentrations

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015

Circulatory dynamics. Cyclopropane has been shown to have a variable effect on the systemic blood pressure, some investigators finding it to cause no change (Waters, 1936; Li and Etsten, 1957; McArdle and Black, 1963), some slight depression (Rovenstine, 1935), and others an elevation (Rowbotham, 1935a; Taylor, 1941; Jones et al., 1960). In general, the blood pressure is found to be well maintained or slightly elevated during light cyclopropane anaesthesia. Catecholamine release due to carbon dioxide retention will cause an increase in the systemic blood pressure. This phenomenon was regularly observed by Dripps (1947) during his elegant study on the aetiology of the hypotension frequently seen after' prolonged cyclopropane anaesthesia. His work clearly demonstrated the importance of avoiding carbon dioxide accumulation during anaesthesia, in order to avoid postoperative "cyclopropane shock". Hershey and Zweifach (1950) showed that peripheral vascular homeostasis was well maintained with cyclopropane anaesthesia, and indicated that this property might well be put to good use in shocked patients. Baez (1964) has recently shown the metarterioles and capillaries of the microcirculation to be consistently narrowed during exposure to cyclopropane, and to become severely constricted when stressed with adrenaline. A marked decrease in the splanchnic circulation of man during cyclopropane anaesthesia, indicative of an increase in activity of the sympathetic fibres to the liver and intestine, has just been described by Price et al. (1965). These last two reports make it clear that, despite a satisfactory systemic pressure, tissue perfusion may be adversely affected by cyclopropane. Central venous pressures have been found to rise during cyclopropane anaesthesia, a phenomenon attributed to myocardial depression (Price, Connor and Dripps, 1953), or increased pulmonary and systemic resistance from catecholamine release (Li and Etsten, 1957). Studies on cardiac output during cyclopropane anaesthesia have shown inconsistent results, Li and Etsten (1957) finding it to be reduced due to bradycardia coupled with an increase in the peripheral resistance, whilst Jones and his co-workers (1960) demonstrated a consistent increase in output with low inspired concentrations of the agent. Cardiac output determinations, per se, are not necessarily indicative of

675

BRITISH JOURNAL OF ANAESTHESIA

676

anaesthesia to the presence of only markedly diffusable gases in the alveoli in the immediate postoperative period. Rapid diffusion of cydopropane through alveolar walls was shown by Lemmer and Rovenstine (1935). With reduced alveolar ventilation, either during or after cydopropane anaesthesia, the absence of any "supporting" gas may lead to peripheral alveolar collapse and a decrease in arterial oxygen saturation. To prevent this event, the introduction of air into the anaesthetic circuit towards the end of anaesthesia has been advised. Secondly, it has recently been shown that the physiological deadspace steadily increases during anaesthesia with cyclopropane (Askrog et al., 1964), and this, too, has been attributed to pulmonary atalectasis. Both these observations further emphasize the need to maintain ventilation at, or above, predicted normal values during the clinical use of cydopropane. INFLAMMABILITY

The cyclical structure of cydopropane confers on it a degree of chemical instability. This is shown by the violence with which it combines with oxygen, or oxygen-containing compounds, under certain conditions of activation. The characteristics of cydopropane with regard to inflammability are given in table I. Certain features should be noted. Firsdy both detonations and deflagrations occur with mixtures of cydopropane and oxygen; mixtures with air and nitrous oxide are capable of deflagration only (Macintosh, Mushin and Epstein, 1963). Since cydopropane is commonly administered in oxygen-

TABLE I

FlammabUity characteristics of mixtures of cyclopropane in oxygen, air, and nitrous oxide. (Data from Macintosh et al., 1963.) Concentrations of cyclopropane in

Flammable concentrations (voL per cent of cyclopropane) Upper limit Lower limit Stochiometric mixtures* (vol. per cent of cyclopropane) Most ignitable mixtures (vol. per cent of cyclopropane) Minimum ignition energy (milli-Joules)

Oxygen

Air

Nitrous oxide

60.0

10.3

30.0

2.5

2.4

1.6

18.2

4.5

10.0

16.0 0.001

7.0

0.180

—

* A stochiometric mixture is one in which the proportions of fuel and oxygen are such that, after combustion, there remains no uncombined residue of either constituent.

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015

of cyclopropane needed to produce respiratory arrest in dogs spontaneously breathing cydopropane-oxygen mixtures were shown by Robbins (1936b) to have an average value of 28 mg/100 ml. If artificial ventilation was maintained, blood concentrations some 10-20 mg/100 ml greater were required to initiate cardiac irregularity or arrest. Jones et al. (1960) demonstrated a constant decrease in alveolar ventilation during cydopropane anaesthesia in man, which they attributed to intercostal paralysis. Cydopropane concentrations of more than 50 per cent are slightly irritant to the respiratory mucosa, and are said to produce laryngeal spasm (Dundee, 1959). Harrison and Vanik (1963) found laryngeal spasm to be initiated equally in cats with or without exposure to cydopropane, and further noted that atropine did not appear to protect against laryngospasm. The presence of vagal efferent fibres to striated musde in the larynx made it unlikdy, in their opinion, that atropine could exert a depressant effect. When subjected to cydopropane, bronchioles of excised lung tissue have been shown to constrict (Adriani and Rovenstine, 1943), an effect that was counteracted by atropine. Reports of severe bronchoconstriction occurring during cyclopropane anaesthesia are rare, but the irritant and bronchoconstrictor actions of the agent should be borne in mind with susceptible subjects. Two further aspects of cydopropane's action on the respiratory system deserve mention. Firstly, Jones and Burford (1938) attributed massive pulmonary collapse occurring after cydopropane

CYCLOPROPANE: THE ESSENTIAL FEATURES

Protection against explosions.

The most obvious protective measure is the exclusion of all obvious sources of ignition from the areas where cyclopropane is present. However, discharges of static electricity are known to account for at least 50 per cent of explosions and, unfortunately, there is at present no known means of positively preventing these discharges. Some measure of protection is afforded by the use of conductive materials throughout the anaesthetic circuit, on the soles of footwear, and wherever else necessary; but diminishing conductivity with age, and effective insulation by surface layers of dust on such materials, prevents reliance being placed on their effectiveness. Humidity of over 65 per cent in the atmosphere greatly reduces the possibility of static discharge, but such humidity is uncomfortable for theatre personnel. Anaesthetic mixtures of cyclopropane and oxygen may be made non-explosive by the addition

of certain concentrations of nitrogen or helium. These "quenching" gases, by virtue of their high thermal conductivity and specific heat, dissipate the thermal activity which occurs when cyclopropane and oxygen unite and thus prevent the development of a detonation. A mixture containing 50 per cent cyclopropane, helium, and less than 38 per cent of oxygen is non-flammable; if the cyclopropane concentration is reduced to 4 per cent, the oxygen content must be lowered to 12 per cent or less for the mixture to remain non-explosive. Comparable figures apply when nitrogen is used, and attention is drawn to the fact that when cyclopropane concentrations are low, oxygen levels must necessarily be below physiological levels. Techniques and machines for the delivery of non-flammable cydopropane/oxygen/diluent gas mixtures have been described (Jones and Thomas, 1941; Bourne and Morton, 1955; Hingson, 1958), but none has gained popularity. Their unpopularity is justified when it is remembered that once the anaesthetic circuit is flushed with oxygen, as may be necessary in an emergency, the mixtures and techniques immediately become inflammable. Some mixtures of cyclopropane and air are not inflammable. Haas and his colleagues (1940) used cyclopropane and air to produce surgical anaesthesia, but the unsuitability of their technique is evident from their reported inspired oxygen tensions of between 15 and 6 per cent. Vickers (1965) has lately measured the duration of the explosion risk in patients who are induced with cyclopropane and then transferred to nonflammable anaesthetic mixtures for maintenance purposes. In general, the respired gases became non-explosive in a to-and-fro rebreathing circuit 6 minutes after cyclopropane was discontinued. This period was reduced to 1 minute if the circuit employed after stopping cyclopropane was nonrebreathing, and the ventilation artificially maintained at 10 l./minute. THE PRESENT POSITION OF CYCLOPROPANE

Now that intravenous barbiturates, muscle relaxants and halothane may be combined to form flexible anaesthetic techniques that are unaccompanied by any risk of explosion and with a low incidence of cardiac arrhythmia, it may be questioned whether cyclopropane merits a place in modern anaesthesia. In attempting to answer

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015

rich mixtures, detonations may occur within the anaesthetic circuit. On the other hand, they do not happen as the result of a cyclopropane cylinder leaking into room air, as deflagration only is possible in this situation. Secondly, it should be remembered that the stochiometric and the most ignitable mixtures of cyclopropane and oxygen are similar to those used for the maintenance of anaesthesia. Thirdly, all mixtures of cyclopropane and oxygen used for anaesthesia are capable of detonation. Lastly, the addition of anaesthetically effective concentrations of cyclopropane to nitrous oxide/oxygen mixtures will result in inflammable or explosive mixtures. The minimum energy required to ignite mixtures of cyclopropane and oxygen is very small, and of an order easily obtained from static discharges. The minimum ignition energy for cyclopropane/air mixtures is nearly two hundred times greater, but is still very small. The temperature needed to ignite mixtures of cyclopropane and air is 498°C, considerably less than the temperature of visibly glowing objects (Walter, 1964). Lawrence and Bastress (1959) have measured the rate of increase in pressure and the absolute pressure developed in cyclopropane/oxygen mixtures just before detonation, and found that both were considerably greater than those occurring in detonable mixtures containing diethyl ether, fluromar, or vinamar.

677

678

considerable experience with the agent, and it is emphasized that cyclopropane anaesthesia is not for the novice. Artificial ventilation should always be employed when cyclopropane is administered, even if only low concentrations are being given as a supplement to other anaesthetic gases. Efficient ventilation coupled with satisfactory carbon dioxide absorption will prevent most of the ills attendant on hypercarbia, which have often erroneously been attributed to cyclopropane. With controlled ventilation, however, it must be remembered that overdosage with cyclopropane may easily occur. With only these provisions cyclopropane might be wholeheartedly recommended, but there remains the additional hazard of explosion. No amount of experience or alteration of technique can lead to absolute freedom from this danger. Though the incidence of explosions is small, some 40 accidents in 13,000,000 anaesthetics according to a recent report (Walter, 1964), each one of these is totally preventable. Certainly every measure of theatre practice and design must be taken to minimize the explosion risk, but the most important precaution of all can be taken by the anaesthetist, namely, the decision not to employ inflammable agents. If this is done, the risk of explosion is reduced to the minimum compatible with the use of compressed oxygen, a fact that is frequently, and perhaps conveniently, forgotten or minimized in discussing the explosion risk. It is increasingly difficult to visualize a situation where non-flammable agents cannot be combined to produce an anaesthetic equal to that given by explosive gases or vapours. It is the author's opinion that the use of cyclopropane is nowadays only justified after considerable deliberation has shown it to possess clear advantages in any particular case. It should never be used for the convenience of the anaesthetist. To advise the total abolition of the agent would be to restrict the freedom of choice of the anaesthetist, but it is suggested that an essential part of the training of the anaesthetist should be to witness a controlled detonation of cyclopropane and oxygen. Such an experience would do much towards ensuring a full appreciation of the dangers that are courted each time the gas is employed, and might lead to the voluntary res-

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015

this question, it is perhaps pertinent to review the present-day usage of cyclopropane. Personal experience reveals that many anaesthetists new to the specialty have never used the agent; those of an older generation who are familiar with cyclopropane appear to employ it in certain situations. Commonly, these are: (1) The induction of anaesthesia in small children; (2) as a supplement to nitrous oxide/oxygen anaesthesia during minor operations; (3) to deepen importunely light anaesthesia; (4) in obstetric patients; (5) for the induction and maintenance of anaesthesia in shocked patients; (6) in patients with respiratory obstruction, or with severe impairment of cardiac or pulmonary function. It would seem that in the first three situations the rapid action of cyclopropane is exploited, whereas in the last three it is the ability to ensure adequate oxygenation and to maintain a vascular status quo which are the goals. Can these properties of cyclopropane be matched by other agents? The rapidity of action is equalled by thiopentone, but this agent demands either an indwelling needle or venepuncture; in the case of small children this may be undesirable. Some feel that the clinical impression that cyclopropane can deepen anaesthesia more rapidly than halothane is borne out by the work of Eger (1963), who showed the estimated half-times for the uptake of 15 per cent cyclopropane and 1 per cent halothane to be respectively 5 and 15 minutes—but 1 per cent halothane in air or oxygen is too small a concentration for induction. Under other conditions, similar figures have been quoted by various workers (Mapleson, 1962; Butler, 1963). The maintenance of arterial blood pressure even during deep anaesthesia is a characteristic of cyclopropane that is not shared by thiopentone, halothane, or all muscle relaxants. However, this characteristic must be equated against the increased peripheral resistance and decreased venous return from the tissues which accompany the apparent vascular stability. The deliberate production of hypotension by, for example, halothane anaesthesia, with the object of maintaining tissue perfusion despite a lowered cardiac output in shocked patients, is a procedure for the expert. For the majority, the maintenance of as near normal arterial tensions as possible is probably still the safer procedure. Even widi cyclopropane such conditions are only achieved regularly after

BRITISH JOURNAL OF ANAESTHESIA

CYCLOPROPANE: THE ESSENTIAL FEATURES traint in the use of cyclopropane unfortunately demanded by its physical properties. REFERENCES

Jones, G. W., and Thomas, G. J. (1941). The prevention of cyclopropane-oxygen explosions by dilution with helium. Anesthesiology, 1, 138. Jones, O. R-, and Burford, G. E. (1938). Massive collapse of the lung after cyclopropane inhalation. J. Amer. med. Ass., 110, 1092. Jones, R. E., Guldmann, N., Linde, H. W., Dripps, R. D., and Price, H. L. (1960). Cyclopropane anesthesia. Ill: Effects of cyclopropane on respiration and circulation in normal man. Anesthesiology, 21, 380. Kety, S. S., Harmel, M. H., Broomell, H. T., and Rhode, C. B. (1948). Solubility of nitrous oxide in blood and brain. J. biol. Chem., 173, 487. Lancet (1935a). Annotation, 2, 779. (1935b). Annotation, 2, 1362. (1936a). Present status of cyclopropane, 2, 629. (1936b). Annotation, 2, 860. (1939). Annotation, 1, 1055. Lawrence, J. S., and Bastress, E. K. (1959). Combustion characteristics of anesthetics. Anesthesiology, 20, 192. Lee, W. V., Orth, O. S., Wangeman, C P., and Meek, W. J. (1943). The mechanism of production of spontaneous cardiac irregularities with high concentrations of cyclopropane. Anesthesiology, 4, 487. Lemmer, K. E., and Rovenstine, E. A. (1935). Rate of absorption of alveolar gas in relation to hyperventilation. Arch. Surg. (Chicago), 30, 625. Li, T-H., and Etsten, B. (1957). Effect of cyclopropane anesthesia on cardiac output and related hetnodynamics in man. Anesthesiology, 18, 15. Linde, H. W, and Price, H. L. (1958). Gas analyser for rapid estimation of cyclopropane. Antsthesiology, 19, 757. Lucas, G. H. W., and Henderson, V. E. (1929). A new anaesthetic gas: cyclopropane. Canad. med. Ass. 7., 21, 173. Lurie, A. A., Jones, R. E., Price, A. B., Dripps, R. D., and Price, H. L. (1958). Cyclopropane anesthesia. I: Cardiac rate and rhythm during steady levels of cyclopropane anesthesia at normal and elevated end-expiratory carbon dioxide tensions. Anesthesiology, 19, 457. Macintosh, R., Mushin, W. W., and Epstein, H. G. (1963). Physics for the Anaesthetist, 3rd ed. Oxford: Blackwell. Mapleson, W. W. (1962). The rate of uptake of halothane vapour in man. Brit. J. Anaesth., 34, 11. McArdle, L., and Black, G. W. (1963). The effects of cyclopropane on the peripheral circulation in man. Brit. J. Anaesth., 35, 352. McLoughlin, G. (1954). Bleeding from cut skin and subcutaneous tissue surfaces during cyclopropane anaesthesia. Brit. J. Anaesth., 26, 84. Meek, W. J., Hathaway, H. E., and Orth, O. S. (1937). Effects of ether, chloroform, and cyclopropane on cardiac automaticity. J. Pharmacol, exp. Ther., 51, 240. Meyer, K. H., and Gottlieb-Billroth, H. (1920). Theorie der Narkose durch Inhalationsanaesthetika. HoppeSeyler's Ztschr. Physiol. Chem., 112, 55. Morris, L. E., and Haid, B. (1951). Effects of procaine amide on cardiac irregularities during cyclopropane anesthesia. Anesthesiology, 12, 328.

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015

Adriani, J., and Rovenstine, E. A. (1943). The effect of anesthetic drugs upon bronchi and bronchioles of excised lung tissue. Anesthesiology, 4, 253. Allen, C. R., Stutzman, J. W., and Meek, W. J. (1940). The production of ventricular tachycardia by adrenalin in cyclopropane anesthesia. Anesthesiology, 1, 158. Askrog, V. F., Pender, J. W., Smith, T. C , and Eckenhoff, J. E. (1964). Changes in respiratory deadspace during halothane, cyclopropane, and nitrous oxide anesthesia. Anesthesiology, 25, 342. Baez, S. (1964), in Effects of Anesthetics on the Circulation (eds. Price, H. L., and Cohen, P. J.), ch. 11. Springfield: Charles C. Thomas. Blumberg, A. G., La Du, B. N. jr., Lesser, G. T., and Steele, J. M. (1952). Determination of solubility of cyclopropane in fats and oils with use of Warburg apparatus. J. Pharmacol, exp. Ther., 104, 325. Bourne, J. G., and Morton, H. J. V. (1955). Cyclopropane, dental extractions, and sparks. Lancet, 1, 20. Butler, R. A. (1963). The uptake of halothane. Proc. roy. Soc. Med., 56, 89, 95. Cohen, E. N., and Beecher, H. K. (1951). Narcotics in pre-anesthetic medication: a controlled study. J. Amer. med. Ass., 147, 1664. Dresel, P. (1964), in Effects of Anesthetics on the Circulation (eds. Price, H. L., and Cohen, P. J.), ch. 7. Springfield: Charles C. Thomas. Dripps, R. D. (1947). The immediate decrease in blood pressure seen at the conclusion of cyclopropane anesthesia: "cyclopropane shock". Anesthesiology, 8, 15. Dundee, J. W. (1959), in General Anaesthesia (eds. Evans, F. T., and Gray, C), Vol. 1, p. 325. London : Butterworth. Eger, E. I. (n) (1963), in Uptake and Distribution of Anesthetic Agents (eds. Papper, E. M., and Kitz, R. J.), ch. 8. New York: McGraw-Hill. Freund, A. von (1882). Uber trimethylene. Mh. Chemie, 3, 625. Guedel, A. E. (1940). Cyclopropane anesthesia. Anesthesiology, 1, 13. Haas, H. B., Hibshman, H. J., and Romberger, F. T. (1940). Cyclopropane-air-oxygen anesthesia. Anesthesiology, 1, 31. Harrison, G. A., and Vanik, P. E. (1963). The effect of atropine on laryngeal spasm before and during cyclopropane inhalation in cats anaesthetized with urethane. Brit. J. Anaesth., 35, 760. Hershey, S. G., and Zweifach, B. W. (1950). Peripheral vascular homeostasis in relation to anesthetic agents. Anesthesiology, 11, 145. Hingson, R. A. (1958). The Western Reserve Anesthesia Machine, oxygen inhalator and resuscitator. J. Amer. med. Ass., 167, 1077. Johnstone, M. (1950). Cyclopropane anaesthesia and ventricular arrhythmias. Brit. Heart J., 12, 239. (1951). General anaesthesia and cardiac inhibition. Brit. Heart J., 13, 47.

679

680

BRITISH JOURNAL OF ANAESTHESIA

Robbins, B. H. (1958). Cyclopropane Anesthesia, 2nd ed. Baltimore: Williams and Wilkins. Roberts, J. (1964), in Effects of Anesthetics on the Circulation (eds. Price, H. L., and Cohen, P. J.), ch. 7. Springfield: Charles C. Thomas. Rovenstine, E. A. (1935). Cyclopropane in thoracic surgery. Curr. Res. Anesth., 14, 270. cyclopropane. PTOC. roy. Soc. Med., 34, 479. Orcutt, F. S., and Seevers, M H. (1937). The solu- Rowbotham, S. (1935a). Cyclopropane anaesthesia. Lancet, 2, 1110. bility coefficients of cyclopropane for water, oils, (1935b). Cyclopropane. Proc. roy. Soc. Med., 29, and human blood. J. Pharmacol, exp. Ther., 59, 257. 206. Orth, O. S., Wangeman, C P., and Meek, W. J. (1941). Sechzer, P. H. (1963), in Uptake and Distribution of Anesthetic Agents (eds. Papper, E. M., and Kitz, Failure of various barbiturates to prevent cycloR. J.), ch. 21. New York: McGraw-Hill. propane-epinephrine ventricular tachycardia in the dog. Anesthesiology, 2, 628. Seevers, M. H., Meek, W. J., Rovenstine, E. A., and Stiles, J. A. (1934). A study of cyclopropane anesPapper, E. M. (1964). The pharmacokinetics of inhalathesia with special reference to gas concentrations, tion anaesthetics: clinical applications. Brit. J. respiratory and electrocardiographic changes. J. Anaesth., 36, 124. Pharmacol, exp. Ther., 51, 1 (May). Pauling, L. (1961). A molecular theory of general Shackell, L. F., and Blumenthal, R. R. (1934). The anesthesia. Science, 134, 15. effect of cyclopropane on healthy and tubercular Payne, J. P., and Senfield, R. M. (1964). Pronethalol rhesus monkey. Curr. Res. Anesth., 13, 133. in the treatment of ventricular arrhythmias during Snow, J. (1858). On Chloroform and Other Anaesanaesthesia. Brit. med. J., 1, 603. thetics. London: John Churchill. Posati, S., and Faulconer, A. (1958). Effect of concentration of hemoglobin on solubility of cyclopro- Stiles, J. A., Neff, W. B., Rovenstine, E. A., and Waters, R. M. (1934). Cyclopropane as an anespane in human blood. Curr. Res. Anesth., 37, 338. thetic agent: a preliminary clinical report. Curr. Bickford, R. G., and Hunter, R. C. Res. Anesth., 13, Mar.-Apr., 56. (1953). Electroencephalographic patterns during anesthesia with cyclopropane: correlation with Stutzman, J. W., Allen, C. R-, and Meek, W. J. (1942). The prevention of cyclopropane-epinephrine concentration of cyclopropane in arterial blood. tachycardia by di-ethyl ether. Anesthesiology, 3, Curr. Res. Anesth., 32, 130. 259. Price, H. L., Connor, E. H., and Dripps, R. D. (1953). Pettinga, F. L. (1949). Mechanism of cardiac Concerning the increase in central venous and arrhythmias during cyclopropane anesthesia. Anesarterial blood pressure during cyclopropane anesthesiology, 10, 374. thesia in man. Anesthesiology, 14, 2. Fruggiero, E. J. (1949). Cardiac effects of Deutsch, S., Cooperman, L. H., Clement, A. J., methoxamine and desoxyphedrine during cycloand Epstein, R. M. (1965). Splanchnic circulation propane anesthesia. J. Pharmacol, exp. Ther., 97, during cyclopropane anesthesia in normal man. 385. Anesthesiology, 26, 312. Sykes, W. S. (1934). Cyclopropane anaesthesia. Brit. Lurie, A. A., Jones, R. E., Price, A. B., and med. J., 2, 901. Linde, H. W. (1958). Cyclopropane anesthesia. Taylor, I. B. (1941). Cyclopropane anesthesia: with a I I : Epinephrine and nor-epinephrine in initiation report of the results in 41,690 administrations. of ventricular arrhythmias by carbon dioxide inAnesthesiology, 2, 641. halation. Anesthesiology, 19, 619. Vickers, M. D. (1965). The duration of the explosive Robbins, B. H. (1936a). Studies of cyclopropane. I : risk after induction with ether or cyclopropane. The quantitative determination of cyclopropane in Anaesthesia, 20, 86. air, water, and blood, by means of iodine pent- Walter, C. W. (1964). Anesthetic explosions: a conoxide. J. Pharmacol, exp. Ther., 58, 243. tinuing threat. Anesthesiology, 25, 505. (1936b). Studies of cyclopropane. I I : Concentra- Waters, R. M. (1936). Present status of cyclopropane. tions of cyclopropane required in the blood and Brit. med. J., 2, 1013. air for anesthesia, loss of reflexes, and respiratory Schmidt, E. R. (1934). Cyclopropane anesthesia. arrest. J. Pharmacol, exp. Ther., 58, 251. J. Amer. med. Ass., 103, 975. Nickerson, M., and Brown, H. O. (1951). Protection by dibenamine against spontaneous arrhythmias occurring during cyclopropane anesthesia. Anesthesiology, 12, 216. Nosworthy, M. D. (1941). Anaesthesia in chest surgery, with special reference to controlled respiration and

Downloaded from http://bja.oxfordjournals.org/ at The University of British Colombia Library on June 26, 2015