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The Manhattan legacy.

SUMMARY

The Manhattan Project was the highly secret American atomic research study which led to the making of the atom bomb. What is not so well known is that before the Project, fluorine was a difficult and dangerous element, while afterwards it became a key ingredient in all the new inhalational anaesthetics. Prior to this, the only practical inhalational agents available apart from nitrous oxide, ethylene and cyclopropane, (and a few others of short-lived popularity like acetylene) were non-halogenated ethers and some chlorinated compounds such as chloroform and ethyl chloride.

When chemists learnt how to handle fluorine, a whole new world opened up, first with the 'Freons' as used in refrigeration and then the halogenated anaesthetics. Along the way, many halogenated compounds other than ethers were tried but abandoned, and now we are left effectively with two halogenated ethers. Is this the end of the line for inhalational anaesthesia?

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The "Manhattan Project" was the highly secret American atomic research study which led to the making of the atom bomb. Its formal name was "The Manhattan Engineering District", and refers to the period 1942-1946, under the command of General Leslie R Groves and the physicist Robert Oppenheimer (Figure 1). What is perhaps not so well known is that before the Project, fluorine was a difficult and dangerous element, while afterwards it became a key ingredient in all the new inhalational anaesthetics.

Prior to the development of fluorinated agents, the only practical inhalational anaesthetics, apart from nitrous oxide, ethylene and cyclopropane, (and a few others of short-lived popularity like acetylene), were non-halogenated ethers and chlorinated hydrocarbons such as chloroform, trichloroethylene and ethyl chloride. It may be noted in passing that even from the time of John Snow, many other substances such as amylene were tried and abandoned.

Prior to the ether demonstration at the Massachusetts General Hospital by WTG Morton in October 1846, even though some others had administered ether (e.g. Clarke in New York and Crawford Long in Georgia) and others had used nitrous oxide (Horace Wells), most surgical procedures were done without anaesthesia, while after Morton most were done with it. If we number the years from 1846 as "pm"--i.e. post-Morton, then around the year zero we had ether, nitrous oxide and chloroform. Ninety-three years later (i.e. 93 pm or 1939), which just happens to coincide with Germany's invasion of Poland (a relevant event as will be shown), we still had the above three and not much else. It's true that some were using ethylene and acetylene, ethyl chloride and cyclopropane, di-vinyl ether and trichloroethylene, but none of these was ideal. However, at 160 pm (i.e. today) we have even fewer--for practical purposes sevoflurane and desflurane.

[FIGURE 1 OMITTED]

Volatile anaesthetics are simple substances, unlike most other chemicals of medical significance. They contain only the atoms C, H and O and one or more of the halogens (F, Cl, Br and I) (Table 1). There are very few exceptions (e.g. xenon and nitrous oxide). One can only speculate as to why no complicated organic volatile substance has been found which has anaesthetic properties.

Two stimuli led to increased research into the fluorine atom and to very much increased manufacture. The first was the call for the development of better (and safer) refrigerants, and the second was tied up with the fact that fluorine forms interesting compounds known as hexafluorides. It does this with only certain other atoms, mostly rather rare ones of no significance to us, but we know sulphur hexafluoride from its use in ophthalmology and, most importantly, uranium hexafluoride, a gas which can be centrifuged to allow separation of the isotopes and so 'enrich' uranium.

The history of fluorine goes back to 1670 when Schwandhard found that the mineral fluorspar (also known as fluorite), when treated with acid, would produce a substance which etched glass. The substance was hydrofluoric acid. It was studied further by many scientists, including Scheele, Davy, Gay-Lussac and Lavoisier. However, the preparation of elemental fluorine proved dangerous and difficult, and it was not isolated until 1886, by Moissan (Figure 2), after many years of research. The effort to prepare the substance cost many researchers their health and even their lives (the so-called "fluorine martyrs") and earned Moissan the Nobel prize.

[FIGURE 2 OMITTED]

When chemists learnt how to handle fluorine, a whole new world opened up, first with the 'Freons' as used in refrigeration. The need for better refrigerants went along with the growth, and indeed the demand, for refrigeration, and the development of the home domestic refrigerator (instead of having ice delivered to the home from a commercial ice-making plant), and also the increasing demand for air-conditioning in homes and cars. In the forefront of the research was one Thomas Midgley (1889-1944) (Figure 3) who was an engineer turned chemist. Though highly-regarded in his lifetime, his discoveries turned out to be rather disastrous. He discovered the anti-knock properties of tetra-ethyl lead, and also the first "CFC" (chlorofluorocarbon), while working for du Pont. The fluorocarbon industry was born around 1930 with the production of the first "Freon[TM]" C[Cl.sub.2][F.sub.2] (dichlorodifluoromethane or "R-12"). It was said of Midgley by one historian, "He had more impact on the atmosphere than any other single organism in earth history". He didn't live to see the later condemnation of both tetra-ethyl lead and the CFCs, because he contracted poliomyelitis. Being an inventive man, he rigged a device of pulleys and ropes to help get in and out of bed, but it malfunctioned one day and he strangled himself!

[FIGURE 3 OMITTED]

But the demand for fluorine escalated rapidly in 1939 with the outbreak of World War II. It is notable that Einstein had signed a letter to Roosevelt just a month before the invasion of Poland, advising research into the possibility of using nuclear fission as a weapon. Millions of pounds of fluorine were then required for the ultra-secret Manhattan Project, racing to produce the first atomic bomb. The du Pont factory in Deepwater, New Jersey, foremost in this effort, was the site of a severe pollution incident in 1944, when a large quantity of fluorine spilled downwind, damaging crops and killing animals. Because of the secretive nature of the work, the whole incident was hushed up.

The war delayed further work on the fluorinated compounds of medical interest, although there were suggestions that some might have anaesthetic properties. It was not until 1946 that Robbins' tested some 46 compounds, after making the observation that there were numerous reports of the "anesthetic activity of the chlorine, bromine and iodine derivatives of the lower members of the methane and ethylene series ...", but none on the fluorine derivatives. The initial studies on mice showed that all the compounds with one exception ([C.sub.4][HCIF.sub.6]) produced anaesthesia, but some produced convulsive movements. The higher boiling-point compounds were more potent. The safety margins seemed better than those of ether and chloroform, especially for the bromine-substituted fluorohydrocarbons. Among the compounds Robbins tested several were recommended for further trial, but none came to be accepted for long-term use, though some, notably trichloroethyliodide and trichloroethylchloride did reach human trials. Unfortunately, one of Robbins' compounds was trifluorodibromoethane, only one atom change from halothane! (trifluorochlorobromoethane). Had Robbins tested the latter, the advent of that most successful anaesthetic could have been many years earlier. Trifluorodibromoethane was among four compounds that Robbins stated "... further investigations of them as possible anesthetic agents are indicated". No further work seems to have been done however. (Because it contains no chlorine, it is not a CFC, but is classed as an "HFBC" (hydroflurobromocarbon), and is considered an "ozone-depleting substance", being listed in Annex C (group II) of the Montreal protocol.) Incidentally, many of the compounds in the trifluoroethane series have anaesthetic properties (Table 2).

Further studies were published by Lu et al in 19532 which led to the clinical use of trifluoroethyl vinyl ether (fluroxene or "Fluoromar"), but its potential flammability was a disadvantage and it enjoyed only limited acceptability. Then followed, in 1956, significant work at ICI by Raventos (3) who discovered halothane ("Fluothane"). Suckling (4) subsequently pointed out how the fluorinated anaesthetics were linked to the refrigerants (known as "Arctons[TM]" by ICI in the U.K.). Interestingly, one of those compounds was tetrafluoroethane, known briefly as "Norflurane", and tested clinically as an anaesthetic by Shulman and Sadoves. This compound, not being a "CFC", is now a most widely used refrigerant ("R-134A') and propellant in spray cans.

Mentioned earlier was trifluoroethyl iodide. This compound was tested on animals and then the principal investigator, Dr William Dornette, volunteered to be anaesthetised with it. This was carried out by pharmacologist Dr JC Krantz, on a table in the department of anaesthesiology library! The subject describes this in his own words: (6)

"The induction was without excitation. The electrocardiogram and the blood pressure remained unchanged. The recovery was rapid and uneventful. There was marked post-operative analgesia. There were no post-operative sequelae".

Although a proper clinical trial was advocated, it seems to have never occurred. The analgesia would have been a plus compared with halothane and it would have been the first, and possibly the only, iodine-containing volatile. Similarly, Shulman and Sadove (7) trialled its analogue trifluoroethyl chloride, concluding that it too had a marked analgesic action, and that "further studies were in progress". (These never appeared.) Other agents which went to further trials were Teflurane (8) ([CF.sub.3]CHFBr), a gas, and halopropane (9) ([CF.sub.3][CF.sub.2][CH.sub.2]Br).

But after halothane it was the fluorinated ethers which had the most impact. Trifluoroethyl vinyl ether has already been mentioned. Then in 1959 came the most important of the early fluorinated ethers, namely methoxyflurane. ([CH.sub.3]-O-[CF.sub.2]CH[Cl.sub.2]) which arose from the work of van Poznak and Artusio (10). For a time, this compound enjoyed considerable success in clinical use, and had marked analgesic properties. It is enjoying a resurgence (as "Penthrox") as a self-administered analgesic, particularly for trauma cases. Methoxyflurane was followed by enflurane (1963) and then isoflurane (1967).

And so to the present: we have desflurane dating from 1992 and sevoflurane dating from 1995. It appears that these agents might mean "what you have is what you get", since for more than 10 years there has not been any other inhalational agent on the horizon. Maybe it's a question of "take it or leave it, or use TIVA!" (Does TIVA stand for "take it or vamoose"?)

Accepted for publication on March 26, 2007.

REFERENCES

(1.) Robbins BH. Preliminary studies of the anesthetic activity of fluorinated hydrocarbons. J Pharmacol Exper Therap 1946; 86:179.

(2.) Lu G, Johnson SL, Ling MS, Krantz JC. Anesthesia XLI: The anesthetic properties of certain fluorinated hydrocarbons and ethers. Anesthesiology 1953; 14:466.

(3.) Raventos J. The action of fluothane--a new volatile anaesthetic. Br J Pharmacol 1956; 11:394.

(4.) Suckling CW Some chemical and physical factors in the development of fluothane. Br J Anaesth 1957; 29:466.

(5.) Shulman M, Sadove MS. 1,1,1,2-tetrafluoroethane: an inhalation anesthetic of intermediate potency. Anesth Analg 1967; 46:629.

(6.) Krantz JC, Lu GG, Speers L, Rudo FG, Cascorbi HE Anesthesia LXV. The anesthetic properties of 2,2,2-trifluoroethyl iodide. Anesth Analg 1963; 42:12.

(7.) Shulman M, Sadove MS. Safety evaluation and anesthetic properties of 1,1,1-trifluoroethyl chloride. Toxicol Appl Pharmacol 1965; 7:473.

(8.) Black GW, Clarke RSJ, Howard PJ, McCullough H. The cardiovascular effects of Teflurane in the cat. Br J Anaesth 1969; 41:288.

(9.) Virtue RW, Young RV, Lund LO, Vogel JHK, Grover RE Halopropane anesthesia in man. Anesthesiology 1963; 24:217.

(10.) van Poznak A, Artusio JE Anesthetic properties of a series of fluorinated compounds. Toxicol Appl Pharmacol 1960; 2:374.

C. McK. HOLMES *

Mercy Hospital, Dunedin, New Zealand

This paper was presented at the Australian Society of Anaesthetists National Scientific Congress in Coolum, Queensland, October 2006.

* F.A.N.Z.C.A., Mercy Hospital, Dunedin, New Zealand.
TABLE 1

Volatile anaesthetics are simple aliphatic substances

No atoms apart from C, H, O and halogens

Alkanes: (based on methane, ethane etc.)

Alkenes: (based on ethylene etc.)

Alkynes: (based on acetylene--[C.sub.2][H.sub.2])

Ethers: R-O-R

TABLE 2
Some trifluoroethanes

Halothane [CF.sub.3]CHClBr
Teflurane [CF.sub.3]CHFBr
Norflurane [CF.sub.3][CH.sub.2]F (R-134a)
Forane [CF.sub.3]CHClF
Trifluoroethyl dibromide [CF.sub.3]CH[Br.sub.2]
Trifluoroethyl iodide [CF.sub.3][CH.sub.2]I
Trifluoroethyl chloride [CF.sub.3][CH.sub.2]C1
(Not very potent) [CF.sub.3][CHF.sub.2]
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Title Annotation:Manhattan Project
Author:Holmes, C.McK.
Publication:Anaesthesia and Intensive Care
Geographic Code:1USA
Date:Jun 1, 2007
Words:2116
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