When it was released in 1956, halothane appeared to be an ideal anaesthetic agent. It provided an easy and rapid induction, excellent recovery with minimal side effects and moderately good muscle relaxation. This combination, together with the fact that it was nonflammable, ensured its rapid acceptance. The fluorine chemical technology which had led to the development of halothane had produced many other prospective anaesthetic compounds but enthusiasm for further research waned with the success of halothane. With time it was realised that halothane had limitations. It was a respiratory depressant, sensitised the myocardium to arrhythmias in the presence of adrenaline, caused uterine relaxation and was associated with rare cases of hepatitis. As these deficiencies became apparent interest in research for a replacement was rekindled.
Having created such a successful drug with halothane the industry was keen to define criteria for an ideal anaesthetic agent and judge all prospective agents against this list. Obviously the ideal anaesthetic agent had to be chemically stable and nonflammable. Ideally it would produce minimal respiratory and cardiovascular depression, provide a rapid, pleasant induction and recovery, be sufficiently potent to allow high concentrations of oxygen, offer good muscle relaxation and not sensitise the myocardium to catecholamines. Clearly cost was also a factor.
Leonard Fabian and his colleagues (1) tested 15 synthetic fluorocarbons in the laboratory. Thirteen of these were unsatisfactory and caused convulsions in mice but two related fluoropropanes were more promising. One of these, halopropane, reached clinical trials but triggered cardiac arrhythmias on induction.
There was some success with methoxyflurane but problems with prolonged recovery and renal toxicity limited its usefulness as a general anaesthetic. Another compound, teflurane, initially showed some promise (2). It was a halogenated compound with a low boiling point (8[degrees]C) and was stored under pressure in liquid form in cylinders. It was often refered to as "nonexplosive cyclopropane". Teflurane produced rapid induction and recovery and was undergoing clinical trials in 1962 when laboratory experiments showed renal degeneration in dogs. This was not confirmed in further experiments and clinical trials recommenced in 1967. Teflurane was shown to sensitise the myocardium to catecholamines and caused clinical hypotension. Essentially it proved to be similar to halothane with a greater propensity for arrhythmias and considerable hypotension so there was little enthusiasm for further research into the drug.
R. C. Terrell at Ohio Medical Laboratories in New Providence developed a series of methyl ethyl ethers and the 347th one, Compound 347, appeared to have desirable anaesthetic properties and was stable without the addition of preservatives (3). Preliminary animal studies confirmed that it produced rapid, smooth induction without salivation or irritation of the bronchial tree. This compound was 2-chloro-1,1,2-trifluorethyl difluoromethyl ether and was named enflurane (Ethrane). Early clinical trials began in the U.S. in 1966 (4) and it was introduced clinically in 1968. The only initial area of concern was that tonic-clonic movements were observed in a few patients in association with respiratory alkalosis and deep anaesthesia.
Enflurane gained rapid acceptance in the U.S. and was in general use by 1971. It was similar to halothane in that it produced rapid induction, an easily adjustable depth of anaesthesia and good muscle relaxation. There was minimal nausea and vomiting and rapid recovery. At anaesthetic concentrations it did not cause serious cardiovascular depression and there were fewer arrhythmias than with halothane. Investigation of the spontaneous muscle activity revealed that it was associated with electroencephalographic (EEG) changes and was only seen with deep anaesthesia and hyperventilation. Adjustment to ventilation and enflurane delivery returned the EEG to normal (5). Other studies revealed that there were some EEG changes which persisted for up to 16 days after anaesthesia (6).
The other area of concern was that metabolism produced inorganic fluoride ions, similar to methoxyflurane. The levels were well below the nephrotoxic level in normal individuals but its use was not recommended in patients with renal failure. There was also the possibility of hepatitis as with halothane but the initial feeling was that, as it was less fat soluble than halothane, it rapidly cleared from the body with little time for liver metabolism (7).
It is interesting that enflurane gained such rapid acceptance in the U.S. There had been a marked reduction in the use of halothane because of the fear of litigation in the event of halothane induced liver damage. It seems remarkable that anaesthetists switched to enflurane, a largely unknown drug which caused EEG changes, produced inorganic fluoride ions and had an uncertain effect on the liver. Yet by 1980 it was the most widely used anaesthetic agent in the U.S.
Other countries were more circumspect in the adoption of enflurane. Europe and Australia introduced it several years after the U.S., by which time several million anaesthetics had been given with no reports of liver damage, renal damage or any apparent untoward sequelae from the EEG changes. Britain was even more cautious. Clinical trials only began in 1977, the same year that A. R. Hunter predicted "It seems unlikely that enflurane will in fact achieve general use as an inhalational anaesthetic in spite of its obvious advantages ... Epileptogenic activity is too serious to be disregarded" (8).
C. Prys-Roberts failed to disguise his lack of enthusiasm for enflurane in a 1977 editorial in the British Journal of Anaesthesia (9). "Perhaps the hesitancy of the pharmaceutical industry to introduce enflurane in Britain, and the natural conservatism of the British anaesthetist, may yet allow us the advantage of waiting for isoflurane ... In the meantime, we still have the glorious opportunity to explore the alternative: supplementation of nitrous oxide with iv anaesthetics."
Enflurane did find a place in anaesthesia in Britain, as it did everywhere else. Eventually isoflurane, an isomer of enflurane with some superior properties, became readily available. By the mid-1990s isoflurane was more realistically priced and enflurane was gradually replaced.
(1.) Fabian LW, Dewitt H, Carnes MA. Laboratory and clinical investigation of some newly synthesized fluorocarbon anesthetics. Anesth Analg 1960; 39: 456-462.
(2.) Black GW, Clarke RSJ. Recently introduced anesthetic drugs. Int Anesthesiol Clin 1971; 9:171-196.
(3.) Vitcha JF. A History of Forane. Anesthesiology 1971; 35:4-7.
(4.) Virtue RW, Lund LO, Phelps McK jr, Vogel JHK, Beckwitt H, Heron M. Difluoromethyll,1,2-trifluoro-2-chloro-ethyl ether as an anaesthetic agent. Results with dogs and a preliminary note on observations in man. Can Anaesth Soc J 1966; 13:233.
(5.) Black GW, Johnston HML, Scott MG. Clinical impressions of enflurane. Br J Anaesth 1977; 49:875.
(6.) Burchiel KJ, Stockard JJ, Rowe MJ, Calverley RK Smith NT, Eger II EI. EEG abnormalities following enflurane anaesthesia. Abstracts of scientific papers, American Society of Anesthesiologists Annual Meeting. 1975; 335.
(7.) Corall IM, Knights KM, Strunin L. Enflurane (Ethrane) anaesthesia in man. Br J Anaesth 1977; 49:881.
(8.) Hunter AR. New Drugs. In: Langton Hewer C, Atkinson RS eds. Recent Advances in Anaesthesia and Analgesia, Vol 16, No 1. p. 1-15.
(9.) Prys-Roberts C. Editorial: New wine in old bottles. Br J Anaesth 1977; 49: 845-846.
C. BALL, R. N. WESTHORPE
Geoffrey Kaye Museum of Anaesthetic History
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|Title Annotation:||COVER NOTE|
|Author:||Ball, C.; Westhorpe, R.N.|
|Publication:||Anaesthesia and Intensive Care|
|Article Type:||Drug overview|
|Date:||Jun 1, 2007|
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