Isoflurane was almost abandoned in the research laboratory (1). R. C. Terrell of Ohio Medical Laboratories in New Providence developed a series of methyl ethyl ethers in the 1960s. Compound 347, enflurane was isolated in 1963 and its isomer, compound 469 or isoflurane, in 1965. Isoflurane was much harder to synthesise than enflurane and very difficult to purify. Eventually Louise Speers, working in the same laboratory, developed a compound which enabled the separation of the contaminants and animal testing of isoflurane was demonstrated.
The physical characteristics of isoflurane are close to the ideal for an anaesthetic agent. It is highly stable, has low blood solubility, is non-flammable and undergoes very little biodegradation. Initial testing on dogs and monkeys revealed that it was a very satisfactory anaesthetic with a smooth induction and rapid recovery. Hypoxia and hypercarbia induced during isoflurane anaesthesia in dogs produced fat vacuolisation in some kidney specimens. This did not occur under normal conditions and no other evidence of any organ toxicity was revealed.
Clinical trials commenced in 1971 and the initial results confirmed that it was an excellent anaesthetic agent. Induction and recovery were rapid, muscle relaxation was excellent and blood pressure and cardiac output were maintained. Respiratory depression was noted along with an increase in cerebral blood flow and uterine muscle relaxation. Despite this, it appeared that isoflurane was superior to other agents on the market, namely halothane and enflurane. One group that participated in the early clinical trials, Pauca and Dripps, concluded:
From the observations available to date it seems that isoflurane will enrich the armamentarium of the anesthesiologist, but much remains to be learned about it. Will it cause renal, hepatic or central nervous system damagg and if so, under what circumstances? Is it teratogenic? Are there drug incompatibilities yet undetected? What is the meaning of the el ectroencephalogaphic observations? These and other questions will be answered by further trials in man. (2)
Unfortunately, it was not man that created the problem but mice (3). Just as plans were being made in 1975 to introduce isoflurane into clinical practice, a preliminary study by Thomas Corbett in Michigan suggested that isoflurane was a hepatic carcinogen in mice.
In the early 1970s there was concern expressed about the dangers of occupational exposure to trace anaesthetic agents. Reports were conflicting, but in 1974 the American Society of Anesthesiologists' Ad Hoc Committee on the Effects of Trace Anesthetics on the Health of Operating Room Personnel found a significantly increased incidence of cancer in female operating personnel (4). Further epidemiological studies were not conclusive and death rates from cancer among specialists were too low to provide meaningful data. Corbett's original study looked at all the alpha chloroether compounds, some of which are very reactive and known to cause cancer in man and animals. Although isoflurane is an alpha chloroether it is very stable and undergoes minimal metabolism, which makes the production of DNA altering active radicals unlikely. These initial results were surprising but also alarming. The other commonly used anaesthetic agents, namely methoxyflurane, enflurane and halothane, undergo far greater metabolism than isoflurane and this study raised the possibility that they too might be carcinogenic.
As a result of this report the Food and Drug Administration withheld approval for isoflurane pending further testing. Edmond Eger and his colleagues designed an animal study in cooperation with Corbett to reproduce the original study and compare the carcinogenic potential of other modern anaesthetic agents. The results of this large trial suggested that the risk of malignancy due to anaesthetic exposure was very small or even nonexistent but the first results still needed to be explained.
In Michigan in 1973, between 500 and 1000 pounds of a fire retardant containing polybrominated biphenyls (PBBs), a known carcinogen, was accidentally shipped as a magnesium supplement for dairy feeds. The Firemaster disaster, as it was known, had widespread implications for the whole food chain in Michigan and a devastating effect on farmers; thousands of cattle and poultry had to be destroyed, along with the produce such as eggs and milk. Clearly it had implications for scientific experiments too. Subsequently the feed given to the mice in the first trial was found to be contaminated with PBBs and this, along with some design errors, was enough to explain the results.
Isoflurane was introduced for general use in North America in 1981. Its release was unusual as the delay had allowed a wealth of data from clinical and animal experiments to be accumulated prior to its general introduction. Generally the release of a new anaesthetic agent merits an editorial but this drug was greeted with review articles of many pages. Its acceptance was rapid and once it was priced more competitively it superseded all the other agents on the market.
In 1983 James Forrest concluded:
It is possible that isoflurane will be the last inhalational anaesthetic to be develop! There are two reasons for holding this view. Firstly the enormous present cost to develop new drugs can only be justified if they are better than existing drugs Secondly, if isoflurane is indexed close to the ideal inhalation anaesthetic, there is little point in developing another which will give only marginal improvement. (3)
Today isoflurane is a popular anaesthetic and in many institutions is still the most widely used agent. Clearly others such as sevoflurane and desflurane have been developed since, but it remains to be seen whether these will relegate isoflurane to the history books.
(1.) Vitcha J. A history of isoflurane. Anesthesiology 1971; 35:4-7.
2. Pauca AL, Dripps RD. Clinical experience with isoflurane (Forane). Br J Anaesth 1973; 45:697-703.
3. Forrest JB. Isoflurane: past, present and future. Clin Anesth 1983:1:251-274.
4. Eger EL White AE, Brown CL, Biava CG, Corbett TH, Stevens WC. A test of the carcinogenicity of enflurane, isoflurane, halothane, methoxyflurane and nitrous oxide in mice. Anesth Analg 1978; 57:678-694.
C. BALL, R. N. WESTHORPE
Geoffrey Kaye Museum of Anaestheic 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:||Aug 1, 2007|
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