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DIVINYL ETHER
Brit. J. Anaesth. (1965), 37, 661
DIVINYL ETHER BY BASIL FINER
Department of Anaesthesia, University Hospital, Uppsala, Sweden PREPARATION
Diethyl ether is chlorinated to give j3, P'dichloro-diethyl ether (CH,CH I ) 2 O + 2 a 2 -» (CH 3 Q CH 2 ) 3 O+2Ha. 0, /3'-dichloro-diethyl ether is hydrolyzed with caustic potash using ammonia as a catalyst. (CH 3 aCH 3 ) 2 The solid KOH separates out and is filtered off and the filtrate is distilled in three fractions. The distillates below and above 28 °C are discarded, while that at 28 °C is collected. It is packed in 11-ml bottles with a rubber cap and 25-ml bottles with a screw top (Vinydan). (In England, it is obtainable in 3-ml or 5-ml ampoules or in 25-ml bottles under the name of Vinesthene.) PROPERTIES
DEVELOPMENT
Physical. Divinyl ether is a dear, colourless, highly volatile liquid, with a sweet, ethereal, non-irritating odour. The molecular weight is 70, specific gravity 0.77 at 20°C, specific gravity of vapour in relation to air 2.2; the vapour pressure at 25 °C is 600 mm Hg, boiling point 28.3 °C and heat of vaporization 90 cal/gm. The solubility in water is 5.25 g/1., the oil/water solubility coefficient probably 41.3, the oil/blood coefficient probably > 2 0 at 37-37.5 "C, and the partition coefficient, solubility in blood
By imaginative use of intellectual reasoning, Leake secured and tested compounds combining the chemical characteristics of diethyl ether and ethylene for anaesthetic potency on mice (Leake and Chen, 1930). Only 12 ml of each of six impure unsaturated ethers were available, but this was sufficient to show that divinyl ether had a higher oil/water solubility coefficient than diethyl ether. Equimolecular concentrations of each substance in air were given in open jars and compared with diethyl ether. The induction and recovery times were shorter for divinyl ether, and solubility in the gaseous phase mucous membrane irritation less. Following their preparation of the pure subThe rate of elimination (Ruigh, 1939) restance, Ruigh and Major (1931) subsequently sembles that of cyclopropane in being much more tested it on humans (Gelfan and Bell, 1933) and rapid than that of diethyl ether at first, but less animals (Leake, Knoefel, and Guedel, 1933). The rapid later, presumably due to difference in oil/ results of both groups confirmed the previous water solubility (see Papper, 1964). It is excreted comparisons with diethyl ether, emphasizing the unchanged by the body, mainly through the similar explosiveness and susceptibility to im- lungs, but there are also traces in the urine, sweat purities, and justified further clinical trials. and other body secretions.
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Anaesthetic fashions change and agents, once popular, are superseded by others possessing more advantages and fewer disadvantages. At the same time, newer agents often require more complicated apparatus for their administration and where such facilities are not available, e.g. during war or in underdeveloped countries, simpler techniques still have a place. The popularity of divinyl ether can be gauged by the annual quantity of Vinydan supplied to Austria, France, Germany, Holland, Hungary, Scandinavia and Switzerland, which amounts to about 6,000 kg or nearly 8,000,000 ml of anaesthetic fluid (courtesy of W. Hougs, Lundbeck, Copenhagen). Despite the relative paucity of experimental work on divinyl ether in recent years, the agent still has a significant place in anaesthetic practice.
BRITISH JOURNAL OF ANAESTHESIA
662 It is highly explosive with air 1.7-27.0 per cent, oxygen 1.9-86.0 per cent and nitrous oxide 1.424.8 per cent, ranges similar to those for diethyl ether. The peak pressure during combustion of a 5 per cent divinyl ether/air mixture in a closed vessel exceeds 7 atm (Macintosh, Mushin and Epstein, 1958). The very high vapour pressure at room temperature can lead to leakage and it must therefore be stored away from a source of ignition. Chemical.
CLINICAL PHARMACOLOGY
Central nervous system. Midbrain reticular formation: Sensory evoked potentials from the contralateral superficial radial nerve were recorded in cats from the thalamus and midbrain (Davis et al., 1958). Both thalamic and midbrain potentials were reversibly depressed by divinyl ether 4—12 per cent in oxygen, but without change in conduction latency or background activity. No cardiovascular disturbances were produced by this stimulation. With the agents used, the potency was 10 per cent diethyl ether>2 per cent chloroform>4 per cent divinyl ether>2 per cent trichloroethylene.
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CH, = CH—O—CH = CH 2 . Divinyl ether. The name divinyl oxide has been suggested, the more easily to distinguish divinyl ether from diethyl ether, but it is not in common use. Divinyl ether is unsaturated and unstable, decomposed by light, heat and air, forming peroxides, aldehydes and acids, some of which polymerize, when allowed to stand for several months, into a gelatinous resin. To avoid this, the ether is stabilized by amines, e.g. 0.01 per cent phenyl-a-naphthylamine, the bottles are usually brown in colour and are tightly stoppered. The stabilizer is alkaline and gives a faint violet fluorescence. In addition, 3.5 per cent absolute alcohol is added to raise the boiling point and prevent ice formation on the mask from the expired air with the risk of burns. Protected from light and air, divinyl ether is stable for two years or more, but if the fluid is yellow it should be discarded. Once opened, it should be used in 1—4 days. It should be kept cool. It is stable in the presence of soda lime and compatible with odier gases, such as nitrous oxide, and other anaesthetics, such as ether.
Respiratory centre: In cats, anaesthetized with chloralose-urethane, nerve impulses were recorded from the central end of the cut right phrenic nerve (Hougs, 1962). Some increase in the number of impulse waves was found, with shortening of each single wave, but this was less marked than with diethyl ether. Spinal cord: The monosynaptic patellar reflex was mechanically released in cats under chloralose-urethane anaesthesia (Hougs, 1962). No changes were found in the reflex with divinyl ether concentrations of 5-20 per cent, as opposed to diethyl edier and 20 per cent oxygen in nitrous oxide, where a pronounced reduction occurred. Abnormal running movements: In dogs, "running movements" were seen in 108 divinyl ether anaesthesias in 46 animals (Martin and Rovenstine, 1941). They were first noted by Goldschmidt et al. (1934). They disappeared when anaesthesia was deepened to complete intercostal paralysis, and when the neuraxis was sectioned down to the level of the cord; and were nearly always prevented by morphine-scopolamine premedication. In 1,418 infants and children receiving divinyl ether by an open technique with simultaneous administration of oxygen, two kinds of movement were noted (Di Giovanni and Dripps, 1956). There were jerky, violent "twitchings" in 1.6 per cent, leading on to generalized convulsions in 1.0 per cent additional cases; and gross, slow, less violent, more automatic and rhythmical movements in 0.7 p:r cent. The convulsions have been further subdivided into those occurring during deep anaesthesia with soda lime absorption in over 1,500 adults, about 1 in 40, and during the recovery period following light anaesthesia in over 10,000 children, about 1 in 400 (Dawkins, 1958, 1959). Abnormal motor movements: Treatment is limited to giving 100 per cent oxygen under pressure, when the movements disappear spontaneously, usually within 1 minute (Di Giovanni and Dripps, 1956) but may last up to 30 minutes (Dawkins, 1958, 1959). There has never been a fatality. (For further discussions of convulsions during anaesthesia in which divinyl ether is mentioned, see Kucher, Richter and Steinbereithner, 1959; Aigner, 1960; Pirringer et al., 1961.) Intracranial pressure: This is only slightly and insignificantly changed, but headache can follow anaesthesia.
DIVINYL ETHER
Respiratory tract. Salivation: This may be copious during induction, especially if prolonged, but is controllable by atropine. In outpatient work this can usually be disregarded. It seldom leads to vomiting. Pharyngeal and laryngeal reflexes: These are depressed in stage HI. CLINICAL PHARMACOLOGY
Respiratory tract. Pharyngeal and laryngeal reflexes disappear in plane 2—3. Coughing and laryngeal spasm can occur but are seldom severe. Bronchi: These are dilated and bronchospasm is uncommon. Alveoli: The epithelial lining is not irritated. Respiration: In stage HI, respiration is more rapid than in the waking state, but as stage IV is approached, the amplitude decreases. Inspired concentration: Analgesia (stage I) is achieved with approximately 0.2 per cent, unconsciousness (stage H) with 2-4 per cent, anaesthesia (stage HI) with 4 per cent and respiratory * Adverse effects refer to the respiratory, circulatory, gastrointestinal and renal systems.
arrest with 10-12 per cent. When respiratory arrest occurs, the circulation is still adequate, so that ventilation with oxygen or air until the concentration of divinyl ether falls, allows spontaneous respiration to return. No studies of alveolar ventilation using modern analytical methods have appeared. Blood. Oxygen capacity: This is unchanged. Carbon dioxide combining power: This is slightly elevated. Blood concentrations: Stage HI; plane 1, 11 mg/100 ml, plane 2, 16 mg/100 ml, plane 3, 28 mg/100 ml; Stage IV, 68 mg/100 ml. Adrenal. The content of adrenaline is unchanged. However, divinyl ether has some sympathomimetic activity, though weaker than that of diethyl ether. The blood sugar is raised and a sinus tachycardia often develops. Oxygen consumption. Peoples (1938) found in rats that oxygen consumption increased at the beginning of anaesthesia, but decreased as anaesthesia deepened. Ngai and Papper (1962) refute this work. Heart. The most characteristic effect of divinyl ether on the heart not previously sensitized by adrenaline is a sinus tachycardia. There is no significant stimulating effect on the autonomic tissues, as judged by arrhythmias following injections of adrenaline, neosynephrin and cofebrin (Orth et al., 1940). In man, divinyl ether was administered with oxygen in a closed circuit, following induction with thiopentone 0.5 g (Johnstone, 1951). Fourteen patients had normal cardiovascular systems and the fifteenth early hypertensive heart disease. There was a sinus tachycardia in thirteen and a sinus bradycardia in two; AV nodal rhythm in nine; auricular flutter in one; ventricular arrhythmias in two; and the hypertensive patient developed marked changes in the QRS and T complexes. The arrhythmia was not peculiar to any stage or plane of anaesthesia, was transient in some cases and persistent in others. Blood pressure falls as the depth of anaesthesia increases.
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Blocking of sensory pathways: In a plea for anaesthetic techniques adequate to produce sensory, mental, motor and "adverse effect" blocks, Woodbridge (1963) classifies divinyl ether as producing sensory, mental, some motor and adverse effect block.* This means that divinyl ether, in common with other inhalational agents, can help to protect a patient against autonomic disturbances arising from too strong surgical stimulation during a standard barbiturate-relaxant-nitrous oxide-oxygen-controlled respiration anaesthesia. Signs of anaesthesia: These are comparable to those of diethyl ether, i.e. analgesia, stage I; unconsciousness, stage II; surgical anaesthesia, stage HI; and respiratory arrest, stage IV. However, the eye signs are not reliable indices of anaesthetic depth. The eyelash reflex disappears at the onset of stage HI, but the light reflex remains active and there is a horizontal nystagmus almost until stage IV is reached. Abdominal relaxation is not as deep as with divinyl ether and there is no exaggerated movement of the diaphragm. The masseter muscle relaxes early.
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Urogenital system. Kidney: During light anaesthesia for short periods, divinyl ether does not affect renal function, but in deep or repeated anaesthesia, the urea clearance diminishes to complete anuria (Orth et al., 1940). The urinary sphincters are also relaxed in deep anaesthesia. Uterus: Using internal tocometry for recording uterine contractions, Lindgren (1959) found no change in motility following the administration of 10-20 g divinyl ether. It does not produce a hard, tonically contracted uterus, so suturing is easy in classical Caesarean section. Placenta: In common with other inhalational
agents, divinyl ether crosses the placental barrier to the foetus. CLINICAL USE
Administration. The agent can be given by the open-drop method, the dosed inhaler, the semi-open and the dosed system with carbon dioxide absorption. Open-drop method. The open mask technique is expensive. There are a number of variations depending on the number of drops per minute, the number of layers of gauze, and whether or not oxygen is led in under the mask. Especially in children, the psychological management of the anaesthesia is of importance, since many children and some adults are terrified of any form of medical or dental treatment as a result of a previous, ineptly administered, open-drop anaesthetic. The child can be premedicated at home by the mother with a promethazine suppository, 10-25 mg, according to size, about an hour before coming to hospital, in the fasting state and with the bladder emptied. A quiet, confident, friendly atmosphere should meet the child in the anaesthetic room or operating theatre and induction should be unhurried. The mask size should be such as to fit comfortably over the mouth and nose and four to eight layers of gauze is suitable. About 2-4 ml divinyl ether is poured rapidly on to the inside of the mask, the lower end of the mask is then placed on the chin, with the upper end some inches away from the face. The child is encouraged to concentrate on blowing away the smell, which is not particularly unpleasant, and this is facilitated if the anaesthetist blows lightly on the child's forehead in time with its own respiration. Concentration on blowing distracts the child from the inevitable inspiration through an open mouth which follows. The anaesthetic agent is rapidly breathed in and if gentle encouragement is maintained, the child experiences no fear. At the same time divinyl ether is dropped rapidly on the outside of the mask, which is gently but rapidly lowered on to the face. This verbal premedication, rapid rapport, with concentration on something pleasant and detachment from something unpleasant, is a very light form of hypnosis (Finer, 1964). The child is usually asleep in less than 1 minute and with less than 10 ml. This is adequate for adsnoidectomy (Finer
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Alimentary tract. Gastrointestinal activity: Gastric tonus is increased, but contractions are inhibited. However, gastric emptying time is delayed by only 7 per cent. Intestinal tonus is decreased and contractions are inhibited. Liver: In the rat, no liver damage is produced, but in dogs, oxygen lack or low carbohydrate diet predisposes to central zonal necrosis (Goldschmidt, Ravdin and Lucke, 1937). Later work in dogs (Orth et al., 1940) showed that liver damage occurred even with adequate oxygen, but the effect of diet was not investigated. In man, five cases of acute atrophy of the liver had been reported by 1941 (Dawkins, 1958). hi each case, more than 300 ml had been given and the operations had lasted longer than 1^ hours. Dawkins has never had a case of acute yellow atrophy of the liver, even with anaesthesias lasting more than 3 hours, but he has never used more than 200 ml. He feels that the standard textbook warning of an upper time limit of 30—45 minutes is unnecessary, as long as this maximum dose is not exceeded. No dear statement of mode of administration is given. Gallbladder: The secretion of bile is decreased during anaesthesia, but returns to normal or is increased during recovery. In the rabbit, the effect is very slight (Molitor and Kuna, 1941). In the literature, there are repeated pleas for studies of liver function tests during divinyl ether anaesthesia, to detect non-lethal liver damage, but no such study has been found. Sphincters are relaxed in deep anaesthesia.
BRITISH JOURNAL OF ANAESTHESIA
DIVINYL ETHER
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and Stahle, 1961). Similar techniques are used in tration arc limited, it can be given as an adjuvant otorhinolaryngology in general (Appaix, Pech and for long periods of time without fear of toxicity. Closed. The agent can be used widi basal Cahier-Lacombe, 1964); dental extractions (Fiirst, 1958; Adriani, 1959); paediatric surgery (Hiigin, oxygen on the closed circuit without any danger 1958; Bovay, 1958); outpatient anaesthesia of toxic interaction with soda lime (Adriani and (Benke, 1957); obstetric anaesthesia and analgesia Rovenstine, 1941). The volume required is com(Dawkins, 1959) and anaesthesia for Caesarean paratively small. section and evacuation of the uterus (Miihlbauer Indications. and Prettenhofer, 1956). The bottle should always Divinyl ether is specially indicated for analgesia be warmed with the hand before use, otherwise in minor operations of short duration, e.g. denthe agent may drop too slowly. tistry and obstetrics, and for anaesthesia for brief Induction of anaesthesia with divinyl ether can surgical procedures, e.g. adenoidectomy, guillobe continued for maintenance of a long anaes- tine tonsillectomy, dental extractions, obstetric thesia with diethyl ether. In 1937, Bourne intro- interventions especially for the occasional anaesduced the "Vinethene Anesthetic Mixture" thetist (Dawkins, 1959). It can be used as a (V.A.M.), containing 25 per cent divinyl ether preliminary to open-drop diethyl ether to shorten and 75 per cent diethyl ether. This combined the the second stage, as a complement to nitrous advantages of both agents, giving a smoother oxide oxygen anaesthesia, or in combination with induction and recovery, while being relatively diethyl ether. non-toxic for long procedures. Closed inhalers. Two inhalers are in use, the Contraindications. Goldman (1935) and the Oxford (Boston and It is specially contraindicated in liver disease, Salt, 1940). These consist of small containers "convulsive states", in the presence of diathermy, containing sponges on to which anaesdietic agent sparks or flames, during long operations requiring can be poured, connected at one end to an anaes- more than 200 ml agent, and anoxia. thetic mask, and at the other end to an anaesthetic bag. In addition, the latter has a one-way Advantages. Induction is rapid and pleasant, without spasm inlet valve for air which comes into action only or coughing, with excitement only rarely. The if and when the bag is empty, when it allows the respiratory tract is not irritated. Respiration is patient to draw in supplementary air and also a minimally depressed, the circulation not at all, bypass allowing the concentration of anaesthetic and if respiratory failure occurs, the circulation vapour to be increased gradually. For a child, is adequate, providing artificial respiration is 3 ml are used, but over the age of 5 years 5 ml. maintained. All planes of anaesthesia can be obThe mask is lightly applied to the face, two tained, without notably affecting important phyexpirations are collected in the bag or the bag siological functions, and it can be combined with filled with oxygen, and then the mask is applied nitrous oxide or with ether. It is useful for acute more firmly. To-and-fro breathing takes place over the agent into the bag and anaesthesia minor surgery. Recovery is rapid and usually pleasant, without rapidly develops in about six breaths. The advannausea or vomiting. There is no "drunkenness" tages of this method are the comparatively small with impaired judgement several hours after, volume required for anaesthesia and the rapidity which might impair driving a car home from the of induction. However, patients requiring rehospital after recovery. peated anaesthesia by this method sometimes No heavy and complicated equipment is necescomplain of the unpleasant feeling of having the sary for administration. mask placed on the face from the beginning and prefer the open-drop method. Disadvantages. Semi-open. Divinyl ether is combined with The odour may be objectionable at first and as nitrous oxide and oxygen in a standard anaesthetic it is highly volatile, it may be wasteful and hard apparatus. It can be volatilized from a bottle or to hold. At the same time, it is much more exdrip feed system. If the total volume and concen- pensive than diethyl ether. It is less stable than
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BRITISH JOURNAL OF ANAESTHESIA
cjther volatile agents and it is explosive. Salivation may be excessive and troublesome and headache after anaesthesia sometimes occurs. Abdominal relaxation is inadequate and the eye signs of anaesthesia are unreliable. There is a possibility of convulsions, especially in unpremedicated subjects and of hepatic or renal damage if the maximum dose is exceeded.
REFERENCES
Adriani, J. (1959). Fundamentals of General Anesthesia for Students and Practitioners of Dentistry. Oxford: Blackwell. Rovenstine, E. A. (1941). Experimental studies in carbon dioxide absorbers for anesthesia. Anesthesiology, 2, 1. Aigner, E. (1960). Ober Narkoskrampfe. Munch, med. Wschr., 19, 943. Appaix, A., Pech, A., and Cahicr-Lacombe, S. (1964). L'anesthisie en oto-rhino-laryngologie. Paris: Librairie Arnette. Benke, A. (1957). Probleme der ambulantcn Anasthesie. Prakt. Arzt. Wien, 11, 243. Boston, F. K., and Salt, R. (1940). An improved Vinesdiene inhaler. Lancet, 2, 623. Bourne, W., McDowell, J. F., and Whyte, J. C. (1937). Further studies in vinyl ether (Vinesthene) obstetrical anesthesia mixtures with ethyl ether: effect on coagulation time of blood. Curr. Res. Anesth., 16, 46. Raginsky, B. B. (1935). Vinyl ether (Vinesthene) anaesthesia in dogs: effects upon normal and impaired liver. Brit. J. Anaesth., 12, 62. Bovey, Ch. (1958). Acquisitions nouvelles en anesth&iologie. Med. Hyg. Geneve, 16, 111. Davis, H. S., Dillon, W. H., Collins, W. F., and Randt, C. T. (1958). The effect of anesthetic agents on evoked central nervous system responses. Anesthesiology, 19, 441. Dawkins, M. (1958). The safety of vinyl ether. Brit, med. J., I, 1116. (1959). Obstetric anaesthesia with vinyl ether. Acta anaesth. scand., Suppl. 2, 5. Di Giovanni, A. J., and Dripps, R. D. (1956). Abnormal motor movements during divinyl ether anesthesia. Anesthesiology, 17, 353. Farman, J. V. (1962). The problem of anaesdiesia in the underdeveloped countries. Brit. J. Anaesth., 34, 897. Finer, B. (1964). Hypnosis in Anaesthesiology: an International Symposium. Berlin: Springer-Veriag.
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In general, however, divinyl ether is a useful inhalational anaesthetic agent, widely used because of its pleasant properties, especially in children, dentistry, otorhinolaryngology, acute minor surgery, obstetrics for the occasional anaesthetist, and combined with diethyl ether for longer procedures. It is expensive, explosive, and can cause convulsions or liver damage. It deserves continued interest and research.
Finer, B., and Stahl, J. (1961). Anesthesia for adenoidectomy in Sweden. Arch. Otolaryng. (Chicago), 74, 272. Fiirst, R. (1958). Zentrale Analgesic und Kurznarkose. Osterr. Zschr. Stomat., 55, 382. Gelfan, G., and Bell, I. R. (1933). The anesthetic action of divinyl oxide on humans. J. Pharmacol, exper. Ther., 47, 1. Goldman, V. (1936). Vinyl edier: a new method of administration. Brit. med. J., 2, 122. Goldschmidt, S., Ravdin, I. S., and Lucke, B. (1937). I. The protective action of oxygen against the necrotising effect of certain anesthetics on the liver. J. Pharmacol, exper. Therap., 59, 1. Muller, G. P., Johnstone, C G., and Ruigh, W. L. (1934). Divinyl ether experimental and clinical studies. J. Amer. med. Ass., 102, 21. Hougs, W. (1962). The influence of anaesthetics and analgesics on potentials recorded from die phrenic nerve. Proc. 1st Europ. Congr. Anaesthesiology, 236. Hiigin, W. (1958). Die Kindersterblichkeit in der chirurgie und ihre senkung durch Verfanerung der Anaesthesie. Chintrgische Praxis, 1, 5. Kucher, R., Richter, W., and Steinbereithner, K. (1959). Beitrag zum Problem der Narkoskrampfe. Anaesthesist, 8, 345. Leake, C D., and Chen, M. Y. (1930). The anesthetic properties of certain unsaturated ethers. Proc. Soc. exp. Biol, 28, 151. Knocfel, P. K.., and Guedel, A. E. (1933). The anesthetic action of divinyl oxide in animals. J. Pharmacol, exp. Ther., 47, 5. Lindgren, L. (1959). The influence of anaesthetics and analgesics on different types of labour. Acta anaesth. scand., Suppl. 2, 49. Macintosh, Sir R., Mushin, W. W., and Epstein, H. G. (1958). Physics for the Anaesthetist. Oxford: Blackwell. Martin, S. J., and Rovenstine, E. A. (1941). Vinesthene: recent laboratory and clinical evaluation. Anesthesiology, 2, 285. Muhlbauer, W., and Prettenhofer, H. (1956). Selektiye Anasthesie in der operativen gynakologie. Geburtsh. u. Frauenhk., 16, 662. Ngai, S. H., and Papper, E. M. (1962). Metabolic Effects of Anesthesia. Springfield: Thomas. Orth, O. S., Slocum, H. C, Stutzman, J. W., and Meek, W. J. (1940). Studies of vinethene as an anesdietic agent. Anesthesiology, 1, 246. Papper, E. M. (1964). The pharmacokinetics of inhalation anaesthetics: clinical applications. Brit. J. Anaesth., 36, 124. Peoples, S. A. (1938). The effects of ethyl ether and vinethene on the oxygen consumption of rats. Curr. Res. Anesth., 17, 130. Pittinger, C , Mitchell, C , Alen, F., and Page, W. (1961). Convulsive phenomena in hyperthermic dogs during anesthesia. Anesthesiology, 22, 893. Ruigh, W. L. (1939). Rate of elimination of divinyl ether. Proc. Soc. exp. Biol., 49, 608. Major, R. T. (1931). Preparation and properties of pure divinyl ether. J. Amer. chem. Soc., 53, 2662. Woodbridge, P. D. (1963). The components of general anesthesia. J. Amer. med. Ass., 186, 641.
DIVINYL ETHER BY BASIL FINER
Department of Anaesthesia, University Hospital, Uppsala, Sweden PREPARATION
Diethyl ether is chlorinated to give j3, P'dichloro-diethyl ether (CH,CH I ) 2 O + 2 a 2 -» (CH 3 Q CH 2 ) 3 O+2Ha. 0, /3'-dichloro-diethyl ether is hydrolyzed with caustic potash using ammonia as a catalyst. (CH 3 aCH 3 ) 2 The solid KOH separates out and is filtered off and the filtrate is distilled in three fractions. The distillates below and above 28 °C are discarded, while that at 28 °C is collected. It is packed in 11-ml bottles with a rubber cap and 25-ml bottles with a screw top (Vinydan). (In England, it is obtainable in 3-ml or 5-ml ampoules or in 25-ml bottles under the name of Vinesthene.) PROPERTIES
DEVELOPMENT
Physical. Divinyl ether is a dear, colourless, highly volatile liquid, with a sweet, ethereal, non-irritating odour. The molecular weight is 70, specific gravity 0.77 at 20°C, specific gravity of vapour in relation to air 2.2; the vapour pressure at 25 °C is 600 mm Hg, boiling point 28.3 °C and heat of vaporization 90 cal/gm. The solubility in water is 5.25 g/1., the oil/water solubility coefficient probably 41.3, the oil/blood coefficient probably > 2 0 at 37-37.5 "C, and the partition coefficient, solubility in blood
By imaginative use of intellectual reasoning, Leake secured and tested compounds combining the chemical characteristics of diethyl ether and ethylene for anaesthetic potency on mice (Leake and Chen, 1930). Only 12 ml of each of six impure unsaturated ethers were available, but this was sufficient to show that divinyl ether had a higher oil/water solubility coefficient than diethyl ether. Equimolecular concentrations of each substance in air were given in open jars and compared with diethyl ether. The induction and recovery times were shorter for divinyl ether, and solubility in the gaseous phase mucous membrane irritation less. Following their preparation of the pure subThe rate of elimination (Ruigh, 1939) restance, Ruigh and Major (1931) subsequently sembles that of cyclopropane in being much more tested it on humans (Gelfan and Bell, 1933) and rapid than that of diethyl ether at first, but less animals (Leake, Knoefel, and Guedel, 1933). The rapid later, presumably due to difference in oil/ results of both groups confirmed the previous water solubility (see Papper, 1964). It is excreted comparisons with diethyl ether, emphasizing the unchanged by the body, mainly through the similar explosiveness and susceptibility to im- lungs, but there are also traces in the urine, sweat purities, and justified further clinical trials. and other body secretions.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on June 11, 2015
Anaesthetic fashions change and agents, once popular, are superseded by others possessing more advantages and fewer disadvantages. At the same time, newer agents often require more complicated apparatus for their administration and where such facilities are not available, e.g. during war or in underdeveloped countries, simpler techniques still have a place. The popularity of divinyl ether can be gauged by the annual quantity of Vinydan supplied to Austria, France, Germany, Holland, Hungary, Scandinavia and Switzerland, which amounts to about 6,000 kg or nearly 8,000,000 ml of anaesthetic fluid (courtesy of W. Hougs, Lundbeck, Copenhagen). Despite the relative paucity of experimental work on divinyl ether in recent years, the agent still has a significant place in anaesthetic practice.
BRITISH JOURNAL OF ANAESTHESIA
662 It is highly explosive with air 1.7-27.0 per cent, oxygen 1.9-86.0 per cent and nitrous oxide 1.424.8 per cent, ranges similar to those for diethyl ether. The peak pressure during combustion of a 5 per cent divinyl ether/air mixture in a closed vessel exceeds 7 atm (Macintosh, Mushin and Epstein, 1958). The very high vapour pressure at room temperature can lead to leakage and it must therefore be stored away from a source of ignition. Chemical.
CLINICAL PHARMACOLOGY
Central nervous system. Midbrain reticular formation: Sensory evoked potentials from the contralateral superficial radial nerve were recorded in cats from the thalamus and midbrain (Davis et al., 1958). Both thalamic and midbrain potentials were reversibly depressed by divinyl ether 4—12 per cent in oxygen, but without change in conduction latency or background activity. No cardiovascular disturbances were produced by this stimulation. With the agents used, the potency was 10 per cent diethyl ether>2 per cent chloroform>4 per cent divinyl ether>2 per cent trichloroethylene.
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CH, = CH—O—CH = CH 2 . Divinyl ether. The name divinyl oxide has been suggested, the more easily to distinguish divinyl ether from diethyl ether, but it is not in common use. Divinyl ether is unsaturated and unstable, decomposed by light, heat and air, forming peroxides, aldehydes and acids, some of which polymerize, when allowed to stand for several months, into a gelatinous resin. To avoid this, the ether is stabilized by amines, e.g. 0.01 per cent phenyl-a-naphthylamine, the bottles are usually brown in colour and are tightly stoppered. The stabilizer is alkaline and gives a faint violet fluorescence. In addition, 3.5 per cent absolute alcohol is added to raise the boiling point and prevent ice formation on the mask from the expired air with the risk of burns. Protected from light and air, divinyl ether is stable for two years or more, but if the fluid is yellow it should be discarded. Once opened, it should be used in 1—4 days. It should be kept cool. It is stable in the presence of soda lime and compatible with odier gases, such as nitrous oxide, and other anaesthetics, such as ether.
Respiratory centre: In cats, anaesthetized with chloralose-urethane, nerve impulses were recorded from the central end of the cut right phrenic nerve (Hougs, 1962). Some increase in the number of impulse waves was found, with shortening of each single wave, but this was less marked than with diethyl ether. Spinal cord: The monosynaptic patellar reflex was mechanically released in cats under chloralose-urethane anaesthesia (Hougs, 1962). No changes were found in the reflex with divinyl ether concentrations of 5-20 per cent, as opposed to diethyl edier and 20 per cent oxygen in nitrous oxide, where a pronounced reduction occurred. Abnormal running movements: In dogs, "running movements" were seen in 108 divinyl ether anaesthesias in 46 animals (Martin and Rovenstine, 1941). They were first noted by Goldschmidt et al. (1934). They disappeared when anaesthesia was deepened to complete intercostal paralysis, and when the neuraxis was sectioned down to the level of the cord; and were nearly always prevented by morphine-scopolamine premedication. In 1,418 infants and children receiving divinyl ether by an open technique with simultaneous administration of oxygen, two kinds of movement were noted (Di Giovanni and Dripps, 1956). There were jerky, violent "twitchings" in 1.6 per cent, leading on to generalized convulsions in 1.0 per cent additional cases; and gross, slow, less violent, more automatic and rhythmical movements in 0.7 p:r cent. The convulsions have been further subdivided into those occurring during deep anaesthesia with soda lime absorption in over 1,500 adults, about 1 in 40, and during the recovery period following light anaesthesia in over 10,000 children, about 1 in 400 (Dawkins, 1958, 1959). Abnormal motor movements: Treatment is limited to giving 100 per cent oxygen under pressure, when the movements disappear spontaneously, usually within 1 minute (Di Giovanni and Dripps, 1956) but may last up to 30 minutes (Dawkins, 1958, 1959). There has never been a fatality. (For further discussions of convulsions during anaesthesia in which divinyl ether is mentioned, see Kucher, Richter and Steinbereithner, 1959; Aigner, 1960; Pirringer et al., 1961.) Intracranial pressure: This is only slightly and insignificantly changed, but headache can follow anaesthesia.
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Respiratory tract. Salivation: This may be copious during induction, especially if prolonged, but is controllable by atropine. In outpatient work this can usually be disregarded. It seldom leads to vomiting. Pharyngeal and laryngeal reflexes: These are depressed in stage HI. CLINICAL PHARMACOLOGY
Respiratory tract. Pharyngeal and laryngeal reflexes disappear in plane 2—3. Coughing and laryngeal spasm can occur but are seldom severe. Bronchi: These are dilated and bronchospasm is uncommon. Alveoli: The epithelial lining is not irritated. Respiration: In stage HI, respiration is more rapid than in the waking state, but as stage IV is approached, the amplitude decreases. Inspired concentration: Analgesia (stage I) is achieved with approximately 0.2 per cent, unconsciousness (stage H) with 2-4 per cent, anaesthesia (stage HI) with 4 per cent and respiratory * Adverse effects refer to the respiratory, circulatory, gastrointestinal and renal systems.
arrest with 10-12 per cent. When respiratory arrest occurs, the circulation is still adequate, so that ventilation with oxygen or air until the concentration of divinyl ether falls, allows spontaneous respiration to return. No studies of alveolar ventilation using modern analytical methods have appeared. Blood. Oxygen capacity: This is unchanged. Carbon dioxide combining power: This is slightly elevated. Blood concentrations: Stage HI; plane 1, 11 mg/100 ml, plane 2, 16 mg/100 ml, plane 3, 28 mg/100 ml; Stage IV, 68 mg/100 ml. Adrenal. The content of adrenaline is unchanged. However, divinyl ether has some sympathomimetic activity, though weaker than that of diethyl ether. The blood sugar is raised and a sinus tachycardia often develops. Oxygen consumption. Peoples (1938) found in rats that oxygen consumption increased at the beginning of anaesthesia, but decreased as anaesthesia deepened. Ngai and Papper (1962) refute this work. Heart. The most characteristic effect of divinyl ether on the heart not previously sensitized by adrenaline is a sinus tachycardia. There is no significant stimulating effect on the autonomic tissues, as judged by arrhythmias following injections of adrenaline, neosynephrin and cofebrin (Orth et al., 1940). In man, divinyl ether was administered with oxygen in a closed circuit, following induction with thiopentone 0.5 g (Johnstone, 1951). Fourteen patients had normal cardiovascular systems and the fifteenth early hypertensive heart disease. There was a sinus tachycardia in thirteen and a sinus bradycardia in two; AV nodal rhythm in nine; auricular flutter in one; ventricular arrhythmias in two; and the hypertensive patient developed marked changes in the QRS and T complexes. The arrhythmia was not peculiar to any stage or plane of anaesthesia, was transient in some cases and persistent in others. Blood pressure falls as the depth of anaesthesia increases.
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Blocking of sensory pathways: In a plea for anaesthetic techniques adequate to produce sensory, mental, motor and "adverse effect" blocks, Woodbridge (1963) classifies divinyl ether as producing sensory, mental, some motor and adverse effect block.* This means that divinyl ether, in common with other inhalational agents, can help to protect a patient against autonomic disturbances arising from too strong surgical stimulation during a standard barbiturate-relaxant-nitrous oxide-oxygen-controlled respiration anaesthesia. Signs of anaesthesia: These are comparable to those of diethyl ether, i.e. analgesia, stage I; unconsciousness, stage II; surgical anaesthesia, stage HI; and respiratory arrest, stage IV. However, the eye signs are not reliable indices of anaesthetic depth. The eyelash reflex disappears at the onset of stage HI, but the light reflex remains active and there is a horizontal nystagmus almost until stage IV is reached. Abdominal relaxation is not as deep as with divinyl ether and there is no exaggerated movement of the diaphragm. The masseter muscle relaxes early.
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Urogenital system. Kidney: During light anaesthesia for short periods, divinyl ether does not affect renal function, but in deep or repeated anaesthesia, the urea clearance diminishes to complete anuria (Orth et al., 1940). The urinary sphincters are also relaxed in deep anaesthesia. Uterus: Using internal tocometry for recording uterine contractions, Lindgren (1959) found no change in motility following the administration of 10-20 g divinyl ether. It does not produce a hard, tonically contracted uterus, so suturing is easy in classical Caesarean section. Placenta: In common with other inhalational
agents, divinyl ether crosses the placental barrier to the foetus. CLINICAL USE
Administration. The agent can be given by the open-drop method, the dosed inhaler, the semi-open and the dosed system with carbon dioxide absorption. Open-drop method. The open mask technique is expensive. There are a number of variations depending on the number of drops per minute, the number of layers of gauze, and whether or not oxygen is led in under the mask. Especially in children, the psychological management of the anaesthesia is of importance, since many children and some adults are terrified of any form of medical or dental treatment as a result of a previous, ineptly administered, open-drop anaesthetic. The child can be premedicated at home by the mother with a promethazine suppository, 10-25 mg, according to size, about an hour before coming to hospital, in the fasting state and with the bladder emptied. A quiet, confident, friendly atmosphere should meet the child in the anaesthetic room or operating theatre and induction should be unhurried. The mask size should be such as to fit comfortably over the mouth and nose and four to eight layers of gauze is suitable. About 2-4 ml divinyl ether is poured rapidly on to the inside of the mask, the lower end of the mask is then placed on the chin, with the upper end some inches away from the face. The child is encouraged to concentrate on blowing away the smell, which is not particularly unpleasant, and this is facilitated if the anaesthetist blows lightly on the child's forehead in time with its own respiration. Concentration on blowing distracts the child from the inevitable inspiration through an open mouth which follows. The anaesthetic agent is rapidly breathed in and if gentle encouragement is maintained, the child experiences no fear. At the same time divinyl ether is dropped rapidly on the outside of the mask, which is gently but rapidly lowered on to the face. This verbal premedication, rapid rapport, with concentration on something pleasant and detachment from something unpleasant, is a very light form of hypnosis (Finer, 1964). The child is usually asleep in less than 1 minute and with less than 10 ml. This is adequate for adsnoidectomy (Finer
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Alimentary tract. Gastrointestinal activity: Gastric tonus is increased, but contractions are inhibited. However, gastric emptying time is delayed by only 7 per cent. Intestinal tonus is decreased and contractions are inhibited. Liver: In the rat, no liver damage is produced, but in dogs, oxygen lack or low carbohydrate diet predisposes to central zonal necrosis (Goldschmidt, Ravdin and Lucke, 1937). Later work in dogs (Orth et al., 1940) showed that liver damage occurred even with adequate oxygen, but the effect of diet was not investigated. In man, five cases of acute atrophy of the liver had been reported by 1941 (Dawkins, 1958). hi each case, more than 300 ml had been given and the operations had lasted longer than 1^ hours. Dawkins has never had a case of acute yellow atrophy of the liver, even with anaesthesias lasting more than 3 hours, but he has never used more than 200 ml. He feels that the standard textbook warning of an upper time limit of 30—45 minutes is unnecessary, as long as this maximum dose is not exceeded. No dear statement of mode of administration is given. Gallbladder: The secretion of bile is decreased during anaesthesia, but returns to normal or is increased during recovery. In the rabbit, the effect is very slight (Molitor and Kuna, 1941). In the literature, there are repeated pleas for studies of liver function tests during divinyl ether anaesthesia, to detect non-lethal liver damage, but no such study has been found. Sphincters are relaxed in deep anaesthesia.
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and Stahle, 1961). Similar techniques are used in tration arc limited, it can be given as an adjuvant otorhinolaryngology in general (Appaix, Pech and for long periods of time without fear of toxicity. Closed. The agent can be used widi basal Cahier-Lacombe, 1964); dental extractions (Fiirst, 1958; Adriani, 1959); paediatric surgery (Hiigin, oxygen on the closed circuit without any danger 1958; Bovay, 1958); outpatient anaesthesia of toxic interaction with soda lime (Adriani and (Benke, 1957); obstetric anaesthesia and analgesia Rovenstine, 1941). The volume required is com(Dawkins, 1959) and anaesthesia for Caesarean paratively small. section and evacuation of the uterus (Miihlbauer Indications. and Prettenhofer, 1956). The bottle should always Divinyl ether is specially indicated for analgesia be warmed with the hand before use, otherwise in minor operations of short duration, e.g. denthe agent may drop too slowly. tistry and obstetrics, and for anaesthesia for brief Induction of anaesthesia with divinyl ether can surgical procedures, e.g. adenoidectomy, guillobe continued for maintenance of a long anaes- tine tonsillectomy, dental extractions, obstetric thesia with diethyl ether. In 1937, Bourne intro- interventions especially for the occasional anaesduced the "Vinethene Anesthetic Mixture" thetist (Dawkins, 1959). It can be used as a (V.A.M.), containing 25 per cent divinyl ether preliminary to open-drop diethyl ether to shorten and 75 per cent diethyl ether. This combined the the second stage, as a complement to nitrous advantages of both agents, giving a smoother oxide oxygen anaesthesia, or in combination with induction and recovery, while being relatively diethyl ether. non-toxic for long procedures. Closed inhalers. Two inhalers are in use, the Contraindications. Goldman (1935) and the Oxford (Boston and It is specially contraindicated in liver disease, Salt, 1940). These consist of small containers "convulsive states", in the presence of diathermy, containing sponges on to which anaesdietic agent sparks or flames, during long operations requiring can be poured, connected at one end to an anaes- more than 200 ml agent, and anoxia. thetic mask, and at the other end to an anaesthetic bag. In addition, the latter has a one-way Advantages. Induction is rapid and pleasant, without spasm inlet valve for air which comes into action only or coughing, with excitement only rarely. The if and when the bag is empty, when it allows the respiratory tract is not irritated. Respiration is patient to draw in supplementary air and also a minimally depressed, the circulation not at all, bypass allowing the concentration of anaesthetic and if respiratory failure occurs, the circulation vapour to be increased gradually. For a child, is adequate, providing artificial respiration is 3 ml are used, but over the age of 5 years 5 ml. maintained. All planes of anaesthesia can be obThe mask is lightly applied to the face, two tained, without notably affecting important phyexpirations are collected in the bag or the bag siological functions, and it can be combined with filled with oxygen, and then the mask is applied nitrous oxide or with ether. It is useful for acute more firmly. To-and-fro breathing takes place over the agent into the bag and anaesthesia minor surgery. Recovery is rapid and usually pleasant, without rapidly develops in about six breaths. The advannausea or vomiting. There is no "drunkenness" tages of this method are the comparatively small with impaired judgement several hours after, volume required for anaesthesia and the rapidity which might impair driving a car home from the of induction. However, patients requiring rehospital after recovery. peated anaesthesia by this method sometimes No heavy and complicated equipment is necescomplain of the unpleasant feeling of having the sary for administration. mask placed on the face from the beginning and prefer the open-drop method. Disadvantages. Semi-open. Divinyl ether is combined with The odour may be objectionable at first and as nitrous oxide and oxygen in a standard anaesthetic it is highly volatile, it may be wasteful and hard apparatus. It can be volatilized from a bottle or to hold. At the same time, it is much more exdrip feed system. If the total volume and concen- pensive than diethyl ether. It is less stable than
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cjther volatile agents and it is explosive. Salivation may be excessive and troublesome and headache after anaesthesia sometimes occurs. Abdominal relaxation is inadequate and the eye signs of anaesthesia are unreliable. There is a possibility of convulsions, especially in unpremedicated subjects and of hepatic or renal damage if the maximum dose is exceeded.
REFERENCES
Adriani, J. (1959). Fundamentals of General Anesthesia for Students and Practitioners of Dentistry. Oxford: Blackwell. Rovenstine, E. A. (1941). Experimental studies in carbon dioxide absorbers for anesthesia. Anesthesiology, 2, 1. Aigner, E. (1960). Ober Narkoskrampfe. Munch, med. Wschr., 19, 943. Appaix, A., Pech, A., and Cahicr-Lacombe, S. (1964). L'anesthisie en oto-rhino-laryngologie. Paris: Librairie Arnette. Benke, A. (1957). Probleme der ambulantcn Anasthesie. Prakt. Arzt. Wien, 11, 243. Boston, F. K., and Salt, R. (1940). An improved Vinesdiene inhaler. Lancet, 2, 623. Bourne, W., McDowell, J. F., and Whyte, J. C. (1937). Further studies in vinyl ether (Vinesthene) obstetrical anesthesia mixtures with ethyl ether: effect on coagulation time of blood. Curr. Res. Anesth., 16, 46. Raginsky, B. B. (1935). Vinyl ether (Vinesthene) anaesthesia in dogs: effects upon normal and impaired liver. Brit. J. Anaesth., 12, 62. Bovey, Ch. (1958). Acquisitions nouvelles en anesth&iologie. Med. Hyg. Geneve, 16, 111. Davis, H. S., Dillon, W. H., Collins, W. F., and Randt, C. T. (1958). The effect of anesthetic agents on evoked central nervous system responses. Anesthesiology, 19, 441. Dawkins, M. (1958). The safety of vinyl ether. Brit, med. J., I, 1116. (1959). Obstetric anaesthesia with vinyl ether. Acta anaesth. scand., Suppl. 2, 5. Di Giovanni, A. J., and Dripps, R. D. (1956). Abnormal motor movements during divinyl ether anesthesia. Anesthesiology, 17, 353. Farman, J. V. (1962). The problem of anaesdiesia in the underdeveloped countries. Brit. J. Anaesth., 34, 897. Finer, B. (1964). Hypnosis in Anaesthesiology: an International Symposium. Berlin: Springer-Veriag.
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In general, however, divinyl ether is a useful inhalational anaesthetic agent, widely used because of its pleasant properties, especially in children, dentistry, otorhinolaryngology, acute minor surgery, obstetrics for the occasional anaesthetist, and combined with diethyl ether for longer procedures. It is expensive, explosive, and can cause convulsions or liver damage. It deserves continued interest and research.
Finer, B., and Stahl, J. (1961). Anesthesia for adenoidectomy in Sweden. Arch. Otolaryng. (Chicago), 74, 272. Fiirst, R. (1958). Zentrale Analgesic und Kurznarkose. Osterr. Zschr. Stomat., 55, 382. Gelfan, G., and Bell, I. R. (1933). The anesthetic action of divinyl oxide on humans. J. Pharmacol, exper. Ther., 47, 1. Goldman, V. (1936). Vinyl edier: a new method of administration. Brit. med. J., 2, 122. Goldschmidt, S., Ravdin, I. S., and Lucke, B. (1937). I. The protective action of oxygen against the necrotising effect of certain anesthetics on the liver. J. Pharmacol, exper. Therap., 59, 1. Muller, G. P., Johnstone, C G., and Ruigh, W. L. (1934). Divinyl ether experimental and clinical studies. J. Amer. med. Ass., 102, 21. Hougs, W. (1962). The influence of anaesthetics and analgesics on potentials recorded from die phrenic nerve. Proc. 1st Europ. Congr. Anaesthesiology, 236. Hiigin, W. (1958). Die Kindersterblichkeit in der chirurgie und ihre senkung durch Verfanerung der Anaesthesie. Chintrgische Praxis, 1, 5. Kucher, R., Richter, W., and Steinbereithner, K. (1959). Beitrag zum Problem der Narkoskrampfe. Anaesthesist, 8, 345. Leake, C D., and Chen, M. Y. (1930). The anesthetic properties of certain unsaturated ethers. Proc. Soc. exp. Biol, 28, 151. Knocfel, P. K.., and Guedel, A. E. (1933). The anesthetic action of divinyl oxide in animals. J. Pharmacol, exp. Ther., 47, 5. Lindgren, L. (1959). The influence of anaesthetics and analgesics on different types of labour. Acta anaesth. scand., Suppl. 2, 49. Macintosh, Sir R., Mushin, W. W., and Epstein, H. G. (1958). Physics for the Anaesthetist. Oxford: Blackwell. Martin, S. J., and Rovenstine, E. A. (1941). Vinesthene: recent laboratory and clinical evaluation. Anesthesiology, 2, 285. Muhlbauer, W., and Prettenhofer, H. (1956). Selektiye Anasthesie in der operativen gynakologie. Geburtsh. u. Frauenhk., 16, 662. Ngai, S. H., and Papper, E. M. (1962). Metabolic Effects of Anesthesia. Springfield: Thomas. Orth, O. S., Slocum, H. C, Stutzman, J. W., and Meek, W. J. (1940). Studies of vinethene as an anesdietic agent. Anesthesiology, 1, 246. Papper, E. M. (1964). The pharmacokinetics of inhalation anaesthetics: clinical applications. Brit. J. Anaesth., 36, 124. Peoples, S. A. (1938). The effects of ethyl ether and vinethene on the oxygen consumption of rats. Curr. Res. Anesth., 17, 130. Pittinger, C , Mitchell, C , Alen, F., and Page, W. (1961). Convulsive phenomena in hyperthermic dogs during anesthesia. Anesthesiology, 22, 893. Ruigh, W. L. (1939). Rate of elimination of divinyl ether. Proc. Soc. exp. Biol., 49, 608. Major, R. T. (1931). Preparation and properties of pure divinyl ether. J. Amer. chem. Soc., 53, 2662. Woodbridge, P. D. (1963). The components of general anesthesia. J. Amer. med. Ass., 186, 641.