7. ETHERS ANCIENT AND MODERN
Ethers. R-O-R1. A group of organic compounds formed by the condensation of two alcohol molecules.
Diethyl ether (see chapter 2)
O – C2H5
CH2= CH –
O – CH = CH2
Methyl propyl ether
O – CH2.CH2.CH3
Ethyl vinyl ether
O – CH = CH2
O – CH3
O – CH = CH2
O – CHF2
O – CHF2
O – CHF2
O – CH.(CF3)2
‘Well, John, I think you've got the hang of this now,’ said Dr Pitts encouragingly.
He was referring to the task of first putting the children for tonsillectomy off to sleep with ethyl chloride, then changing to open ether and finally gas-oxygen-ether. Since I had been at it now for nearly three months, and there were never less than eight children on each list and there were usually four lists a week I was inclined to agree.
‘We'll use something different for this last case. We'll try some Vinesthene for induction, instead of ethyl chloride. It's quite good stuff, you know, but rather wasteful if you use it in an open drop technique because it is expensive and very volatile.’
I had never heard of it before.
‘Vinesthene? What's that?’
‘Oh, it's the trade name for divinyl ether. It's been around for thirty years or so but it is not really so convenient as ethyl chloride, nor as cheap, but it works very well, especially if you are using it for just a short anaesthetic on its own. The patient wakes up more clear-headed than with ethyl chloride. It also softens up the jaw muscles better during light anaesthesia. Yes, we'll try some.’
He went off to look for some Vinesthene. He came back holding a small brown bottle and a box which contained several even smaller glass ampoules.
‘These have got Vinesthene in them,’ he said pointing to the ampoules, ‘and this is a bottle of 'VAM', or Vinesthene Anaesthetic Mixture, which is 25% Vinesthene and 75% ordinary ether. It's a good mixture because the two liquids vaporise at roughly the same rate and you get the ease of induction of the one with the good muscle relaxation of the other.’
‘Which are we going to use?’
‘Both. We'll start with some Vinesthene and then go over to VAM before we go into theatre. Someone has designed a special inhaler for Vinesthene but we haven't got one here, so what we'll do is this: we'll wrap one ampoule in some gauze, like this, and pop it into a rebreathing bag which we'll now fill with oxygen and attach to an anaesthetic mask. See, like this. I'll put my finger over the end. When the time comes I'll crush the ampoule inside the bag and put the mask onto the child's face. That's it. We are ready now. Let's have the next child in.’
It worked really well. The child was very sleepy after his premed and though he struggled a bit when the mask was put onto his face he was unconscious after taking six or seven breaths.
‘If he was just going to have a tooth out we could go ahead now and in a few minutes he would be awake again, but we'll go over to VAM now on a Schimmelbusch mask. We could have started off with this just as well but I wanted you to see the Vinesthene on its own.’
He swapped the apparatus for a Schimmelbusch mask and started dripping the VAM onto it. The child continued to breath the mixture smoothly and soon it was time to move into the theatre and get the gas-oxygen-ether flowing down the side tube of the tongue plate on the Doughty gag.
I tried out VAM several times in the next few weeks but it was not really much better than ethyl chloride and anyway our stock in the store cupboard was getting very low.
One day I was talking to Dr Gavin about it.
‘Have you tried Neothyl?’ he asked.
‘No. What is Neothyl?’
‘Oh, it's another ether that we have been trying out, but it is very volatile and not very powerful so you get through a bottle very quickly, which is rather inconvenient. Still it works well enough. I'll see if there is any left.’
He went to the cupboard in the corner of the room and rummaged through the shelves.
‘Here it is ,’ he said, as he produced a glass bottle containing a pale green liquid from the depths of the cupboard rather like a conjuror pulling a rabbit out of a hat. I took it and looked at the label: NEOTHYL (Methyl n-propyl ether).
‘It looks rather like weak lime juice,’ I said.
‘Oh, I don't think that's its real colour. They’ll have put some sort of dye in it.’
I took the top off and smelled it. It was certainly still ‘ethereal’ but it was different all the same from the other ethers I had been smelling.
We put some in the ether bottle which already was on the anaesthetic machine; this was really designed for ordinary diethyl ether, but Dr Gavin said it would be perfectly all right for any old ether. We persuaded the surgeon to manage without the diathermy and we used it for the next patient, who was having a hernia repaired. It worked splendidly but the level in the bottle fell very quickly and we thought we might run out before the end of the operation, but we had just enough.
I told Dr Pitts about it next time I saw him.
‘I don't think it will catch on,’ he said, ‘It's advantages are very slight for the extra cost and the inconvenience of having to keep topping up the bottle all the time. Still it was interesting to try. It's a bit like EVE, really.’
‘EVE? What's that?’
‘Oh, EVE is ethyl vinyl ether. We've got some of that somewhere.’
So we used that, too, on the next tonsil list, but in the end we went back to ethyl chloride and ordinary (di-ethyl) ether. Not only was this combination the cheapest, we also thought it was the best.
Derek had spent some time and effort telling me about Denver before I had left Bristol. but when I got there I could remember little of what he had said about Fluoromar, except that they used it as though it was non-flammable, though if you sampled the gases in the closed circuit and took the sample outside and put a match to it certainly burned.
‘Tell me about Fluoromar, Dave. I've never met it before to-day.’
‘Why, it's a grand drug, John. We always use it when the surgeon wants both the diathermy and epinephrine during the operation. It suits the neurosurgeons really well. Also it doesn't drop the blood pressure much so it sure is handy when you want to get some relaxation from your anaesthetic without using too much curare. That's why we use it for the transplants. It's not as good as Penthrane when it comes to relaxation but Penthrane lowers the BP much more and the transplant surgeons like a good head of pressure when they take their clamps off.’
‘I've not seen Penthrane used either. What's it like?’
‘Slow, John, very slow You should talk to Doug. He's the expert on Penthrane. Recently he used it for everything for a whole month. Induction, relaxation, intubation and maintenance. Oh, and post-operative analgesia too The patients take hours to wake up and the analgesia lasts and lasts even when they do come round. There is some talk about high output renal failure occurring sometimes so we keep it away from the kidney cases for that reason as well. It's smelly stuff, anyway. Why, it's like marzipan, if you ask me.’
Later on I looked at the label on a bottle of Fluoromar. Fluoromar was the Ohio Chemical Company's trade name for fluoroxene, which in turn was the ‘approved’ name for 1,1,1-trifluoroethyl vinyl ether. I tried to work out what that would look like on a piece of paper. It was obvious if you just stopped and thought for a moment. Ethyl vinyl ether was CH3-CH2-O-CH=CH. 1,1,1 Trifluoroethyl meant that the three hydrogen atoms on the first of the carbons were replaced by fluorine atoms, producing CF3-CH2-O-CH=CH. That would make less flammable and, perhaps, more potent, though you really needed to add chlorine atoms for that. I took the cap off the top of the bottle and sniffed carefully. It changed the smell too It was pleasant enough and not particularly irritant; it did not remind me particularly of the ethyl vinyl ether, or EVE, that we had used all those years ago in Taunton.
I put the bottle down and picked up a smaller bottle covered with a smooth shiny light green plastic coating. It was labelled PENTHRANE, which was the trade name for methoxyflurane, another halogen-substituted ether, but this time the chemists had started with methyl ethyl ether, not ethyl vinyl ether.
I uncapped the bottle. This really was a different smell. Like marzipan, as Ted had said, but it seemed to me that it was rather more like the new style of ‘clean plasticine’ you could buy these days. Anyway it was not very pleasant and though I quickly put the top back on the bottle the smell was extraordinarily persistent and it hung about the room rather like the smell you get with paraldehyde.
Later that day, Bob, the professor, said to me
‘John, I wonder if you would help Doug with a ten month old baby; the neurosurgeons want to do a craniotomy.’
‘Yes, of course.’
I decided to talk to Dave about it first.
‘Tell me, Dave, how do you folk in Denver deal with an infant who is going to have a craniotomy? I thought I should ask; it is all so different here.’
‘Well, John, as I told you this morning we find Fluoromar very useful for neurosurgery and there is a paediatric circle system you can fit on the machine. So that's it basically.’
‘Remind me about the copper kettle and Fluoromar. I think I've got the hang of using it for halothane but what are the figures for Fluoromar?’
‘Fluoromar is slightly more volatile than halothane. The vapour pressure at 20o C is 286 mmHg as opposed to halothane's 243, so that an oxygen flow of 100 ml/min through the kettle produces 60 ml of Fluoromar vapour rather than the 50 ml with halothane. If you dilute this 60 ml to 6000ml you'll get a 1% mixture, but if you dilute it with only 1000 ml you'll get a 6% mixture.’
‘Or if you dilute it with 2000ml you'll get a 3% mixture.’
‘That's right. Now tell me what you would get if you put 150ml of oxygen going through the kettle and dilute the output with 3450ml to make a total of 3600ml’
‘Let me see. If you put 150ml of oxygen through the kettle you would have 90ml of Fluoromar coming out the other end and if you dilute this to 3600ml you would have 4% Fluoromar. Have I got that right?’
‘Why sure, John, that's exactly right.’
But then he added
‘Of course, these figures really apply only at sea-level. The mean pressure in Denver is just 628 mmHg, so we are actually getting stronger mixtures than we calculate, but we seem to manage OK. I guess if we went to Bristol we would notice the difference, and, of course, if the temperature changes then we have to adjust for that too. Still if you watch the patient you will know if you are giving the right amount whatever the figures say.’
So off I went to help Doug. It was quite a challenge really - an anaesthetic agent and a paediatric circle neither of which I had ever used before, and a vaporiser that I was only just beginning to get the hang of. Still Doug was in his second year of anaesthesia at Denver so at least he would be familiar with the apparatus even if he was unfamiliar with handling small babies. Between us we would be fine.
I breathed the infant down with nitrous oxide and Fluoromar and when he was deep enough I slipped a tube between his cords. Then we reduced the concentration of Fluoromar and assisted his breathing to be sure that his carbon dioxide level did not rise, which would have increased the bleeding and have made the surgery more difficult. Fluoromar turned out to be not so very different from other anaesthetic agents with which I was familiar.
The surgeon was a most amusing fellow. He spent the whole time pretending to be Jimmy Durante. I laughed and laughed at him and his antics.
‘He's an real clown,’ I said to Doug, ‘but is he really going to keep it up all morning.’
‘Keep what up?’
‘Why, the Jimmy Durante act.’
Doug looked at me in amazement.
‘He's not taking off Jimmy Durante. That is the way he talks normally.’
It was my turn to be amazed.
‘You don't mean that, do you?’ I asked incredulously. ‘Do people really talk like that?’
‘Why, sure they do, if they come from Brooklyn.’
I listened to the surgeon with renewed interest. He really did talk like that! And I had always thought that Jimmy Durante was making up an accent almost like Stanley Unwin inventing a language. I felt fairly foolish but I don't think the surgeon realised my faux pas.
Both the anaesthesia and the operation went well. I was pleased with everything and felt that I had passed my first real test in the mile high city. Doug kept very precise records of what was happening and it was not till we were talking afterwards that I came to understand that to a large degree I had pinched the case from him, because I had done most of the work myself instead of supervising him while he did it. This was not the old fashioned apprenticeship system that I was used to, where the lads sat at the feet of the master picking up crumbs of wisdom; this was a formal training programme
I was on call the following Thursday and I supervised the anaesthesia for my first kidney transplant. I was quite a dab hand by now with Fluoromar and already knew how to make the most of it to eke out the amazingly small doses of curare that they used in Denver; they rarely exceeded a total of 12mg even in a long ordinary case but if it was a transplant two doses of 3mg seemed to be their limit. However, as the Fluoromar did not drop the blood pressure too much you could push it a bit so that there was some relaxation of the muscles; as the kidney was put into the recipient outside the peritoneum you did not need a great deal of relaxation anyway.
Some while later, perhaps it was a couple of months, Ted said
‘The transplant surgeons are going to start up the liver programme again. They have a man with a huge liver that they want to skeletonise.’
‘Skeletonise? What on earth do you mean?’
‘Oh, they want to free it up from its adhesions so that it will be easy to take out if they get a donor liver. Mobilise it is what they mean. In the past they have sometimes found that a liver has become available but it has taken too long to get the old one out, so where it looks to be a big problem there free it up in advance.’
The operation was not as it simple as I had imagined it would be. Every time they moved the liver, dislocated would be a better word, the blood pressure fell precipitously; this was probably due to kinking of the vena cava but there was also a tremendous amount of bleeding. The operation took six hours; most of this time was spent in controlling the blood loss. We had to give more him than fifty pints of blood and plasma.
At the end of the surgery we turned off the Fluoromar and the nitrous oxide. Five minutes later the patient opened his eyes and pulled the endotracheal tube out of his mouth unaided.
‘Your operation is all over, Mr Bird. You have done very well. How are you feeling?’
‘I'm fine. thank you.’
Great stuff, this Fluoromar.
Next day I was helping one of the residents with give the anaesthetic for a kidney transplant. I told him what Derek had said about the flammability of Fluoromar.
‘Gee, that’s sure a surprise. I expect we would be all right at the moment though, as I have been adding only 2% for the last five minutes.’
‘Well, let’s put it to the test.’
So I took a 20 cc syringe from the drawer of his equipment cart, put a large needle on it and took a sample from inside the circuit by thrusting the needle straight through the rubber tubing and pulling back the plunger till it nearly came out of the barrel.
‘I'll take it outside, put a match to it and see what happens.’
When I put the match to the open end of the syringe the gas inside exploded with a soft pop. It reminded me of the experiments that we did in chemistry lessons at school with hydrogen. The pop here and now was certainly not so loud or powerful as it had been with the hydrogen but the ritual and the result were similar enough.
I told Dave about it. He laughed.
‘Why, I remember Derek doing that when he was here. Still nobody uses the diathermy inside the circuit, you know, and anything that leaks into the room will immediately be diluted with air and so it will be below the danger level. I don’t think you need worry, John.’
‘All right, I’ll try not to!’
The daily seminar at 7am was always a problem for me. It seemed unreasonable to start work at such an unsociable hour. One morning I fell asleep during the presentation and when, at 7.15, the professor asked ‘Are there any comments?’, I dropped a loud snore into the silence; Ted fell off his chair laughing.
Afterwards, I said to him
‘I am sorry that I missed the talk. Was it something I should know about?’
‘No, nothing important. Gee, it was worth staying awake just to hear you snoring. You looked really guilty when you woke up.’
‘I don’t now about guilty, but I was certainly embarrassed. Do you think Bob was put out about it?’
‘No, of course, he wasn’t. He realises that no Englishman wakes up before nine in the morning.’
‘Well, it’s positively uncivilized to have meetings as early as seven o’clock.’
‘Why, John, it’s the early bird that gets the worm.’
‘Only if the worm is silly enough to be early as well.’
Just then Dave came into the room.
‘I’ve just been looking this quarter’s figures for the agents we’ve used. We sure are using a lot more Penthrane than we did last year.’
‘That’ll be Doug’s influence He swears by it. ‘
‘Yes, he’s just told me that he used it for a gallbladder on Monday and the patient didn’t need any other analgesia till Tuesday lunchtime.’
‘Sounds even better than Trilene.’
‘Do you have figures for previous years available? If so, I would love to look at them.’
‘Why, sure. I’ll get them out for you later on this morning.’
He was as good as his word.
‘Here you are, John. These are the figures since 1962. Of course, this year’s are based only on the first nine months.’
‘I’s a pleasure.’
That evening I plotted them out:
So methoxyflurane was the only agent whose use had increased substantially over the last three years. That would make a good talking point when I got home. (How was I to know that nobody would be interested?) And how amazing that as late as 1964 they were using so much cyclopropane and so little halothane. Of course, being a mile up in the sky might make some difference, but it still surprised me. Perhaps, it had something to do with the fact that the first case report of jaundice after halothane had come from Denver.
To Isabel's great amusement I started at Southmead on April Fool's day. What a mixture of pride and anxiety; I was proud of my new job, but anxious that I would acquit myself adequately. University jobs seemed such awkward things. I knew I would be judged by some people on the research that I did, by others on the amount and quality of the clinical work that I undertook, and yet I myself felt that my ability and enthusiasm as a teacher should be the most important thing. Surely that was what universities were about?
My clinical programme had five half-day sessions in the operating theatres each week which would provide me with a ready-made framework while I sorted myself out. There were no students at the moment but it would not be long before they arrived. I was looking forward to organising their tuition and galvanising them into an interest in the things in anaesthesia that I found so exciting.
In the meantime I would plan some research around the kidney transplants that Humphrey would be doing. It would be fun to get into transplant work again. It was strange that the Ohio Chemical Co had not replied to my letter from Denver asking them to send me some Fluoromar when I got back to England. I would have to get some from somewhere; after all I had never seen anything else used as the anaesthetic for a kidney transplant. I would write to them again. I would also have to get hold of a copper kettle. In any case a copper kettle would be useful as a standard against which to calibrate other pieces of equipment.
Some weeks later a message came from the post room that there was a parcel from America for me. When I opened it I found that they had sent me ten bottles of Fluoromar. Unfortunately my copper kettle had not yet arrived. By the time it did come, I had got used to anaesthetising the transplants with halothane, opiates and a dose of relaxant small enough for the patient to recover by redistribution. It was amazing how irrelevant Fluouromar seemed now to me on this side of the Atlantic. Of course, it could only mean that I had been overimpressionable in Denver.
The bottles stayed unused in the cupboard for eight years. Occasionally I showed then to a younger colleague who had never seen, or even heard of, Fluoromar. Then one hot summer’s day I decided to get rid of them. I took the bottles outside to the football field, unscrewed the caps and scattered the volatile liquid to the winds.
‘John, we are going to have a symposium on training at the SW Society meeting in November. Alistair Spence is going to talk on the problems of anaesthetic training in the UK, and Peter Reilly is going to criticise our system from an Australian viewpoint. Would you like to talk about what the training in Denver was like? It would make a nice contrast.’
Luckily, before I had left Denver I had asked one of the residents to give me a copy of the cases he had done, so that would be a useful talking point.
I would start by mentioning the precordial and the oesophageal stethoscope.
The Americans listen to every breath and every heart-beat during an anaesthetic.
I guessed the typical English anaesthetist would respond by saying
Oh, yes; but, of course, they give such dangerous anaesthetics!
And yet surely it was true that the stethoscope applied to the chest, or inserted down the oesophagus, was the most reliable, and the most informative, monitor we possess. After all , it told us about changes in the heart rate and rhythm, the intensity of the heart sounds, the respiratory rate, depth and pattern, and about the presence or absence of bronchospasm or secretions in the bronchi. It also helped in the diagnosis of an air embolus, a disconnected ventilator or a fall in cardiac output. What is more, it yielded this information continuously despite distractions and without conscious effort on the part of the anaesthetist. It was also cheap and simple.
Next I would describe the American anesthesiology resident.
He is a self-confident young person. This self-confidence stems from the social climate, which expects him to have an opinion worth stating and which respects neither age nor status, but only ability, knowledge of the facts and acquaintance with the literature.
Of course, there were also the relative lack of competition, the simplicity of the career structure and the freedom from prolonged financial insecurity.
Then how about
The teaching staff are full-time teachers, neither being employed to give the routine anaesthetics, nor having to contend with the distractions of private practice.
That would rock the boat splendidly! And what about Bunker’s remark
The British must be very slow. It takes them six years.
Now what were the main features of the Denver training programme?
Well, brevity, for a start.
Next, an emphasis on the acquisition of good habits, especially continuous monitoring and meticulous record-keeping.
Then, experience of a wide variety of techniques and types of case.
Also, the avoidance of apprenticeship as practised in the UK,
and finally systematic theoretical instruction.
When I got home that evening I searched around until I found the list of cases and techniques that Doug had sent me. It made interesting reading:
Cases anaesthetised during a two-year residency:
Superficial (orthopaedic, ENT, herniae, vaginal, etc) ......................544
Non-cardiac thoracic .......................................................................25
Cardiac and Vascular ......................................................................94
Obstetric ........................................................................................ 36
Techniques and agents used to anaesthetise these cases
Halothane (+/- relaxants) ..............................................................257
Cyclopropane (+/- relaxants)........................................................ 207
Methoxyflurane or Fluoroxene (+/- relaxants) ................................177
Nitrous oxide (+/- relaxants, +/- IV adjuvants)................................106
Diethyl ether .................................................................................28
Cardiopulmonary bypass .............................................................55
Surface cooling ...........................................................................11
When I considered how haphazard, and how prolonged, my own training had been, it was remarkable that a young man could pack such a variety of experience into two short years. Admittedly the number of cases was relatively small, but he had personally administered the anaesthetics. I had had to wait till my seventh year as an anaesthetist before I was exposed to anaesthesia for cardiac surgery , and then I was only helping the consultant, not orchestrating and administering the anaesthetic myself. Of course, it was not really seven years as a trainee, because in the army they had made use of me rather than trained me; not that I could grumble as there had been lots of time for study and I had passed both parts of the FFA whilst serving my Queen and country.
I looked again at Doug’s list. Slightly more halothane than cyclo. And then the two ethers that I had not met till I had arrived in the Mile High City, and which between them had accounted for than a fifth of his general anaesthetics. Lots of spinals and some epidurals, altogether 12% of his cases. And 55 bypasses and 11 hypothermias! Without radical changes the British system of training could never hope to match this variety of experience in such a short time.
We in the UK have a lot to learn from the Americans about efficiency in the training of our junior staff. Let’s hope we will!
Yes, that should do it.
‘John, there is an eighteen month old baby with a plastic bead stuck in one of its bronchi. They want to scope it at seven o'clock. I’d be grateful for some help.’
That sounded great fun. How should we do it? Well, after my experience in Denver it seemed to me that methoxyflurane would be the best thing. I would take the child down with gas-oxygen-halothane and then change over to methoxyflurane. When he was nicely settled I would pop in a laryngoscope and spray his cords and trachea liberally with local anaesthetic. The surgeon would be able to do his bronchoscopy without any hurry as the child would lie still for ages while excreting the methoxyflurane.
In the event it worked brilliantly. The surgeon fiddled round for nearly half an hour to get the bead out; the child lay there unprotesting , and breathing quietly.
‘Great stuff, this Penthrane,’ I said to the world at large. ‘We should use it more often.’
As it happened, this was the very last time I used methoxyflurane as the main agent in an anaesthetic, largely because of the lack of suitable vaporisers on the anaesthetic machines, and later because of the worry about renal toxicity. We did try it as an analgesic in labour, once the Cardiff inhaler became available; it was quite good really, but no-one liked the smell, and it did not catch on. In any case, the risk of kidney damage eventually caused the use of this agent to be abandoned altogether.
‘John, would you like to present something at the journal club?’ I was asked.
‘Yes, certainly. I have just been reading Edmond Eger’s paper on isoflurane which was in Anaesthesiology last month. Its a very good review, and I think it may be important.’
‘Good. I’ll put you down for it.’
‘And I’d better read it again.’
So I got journal off the library shelf and made a photocopy of it. I smiled ruefully at the thought of the notice that I had above my desk:
I MUST NOT CONFUSE
PHOTOCOPYING AN ARTICLE
ACTUALLY READING IT.
No chance this time of just stuffing it in a drawer and forgetting it. I would need to study it thoroughly. Now is as good a time as any, I reminded myself, so I got on with it. It was a well written and informative article, that was a pleasure to read. I began to make some notes:
Physically stable ( as E; contrast H )
Low blood sol ( < E < H )
Myocardium OK ( contrast E & H )
Less adren. arrythmias ( <E >H )
No seizure ( as H; contrast E )
Potentiates relaxants ( as E; contrast H )
CBF & ICP &endash; ( < H or E )
Minimal biodegrad ( 1/10 E; 1/100 H ) - so L & K toxicity rare
BP falls ( E > I > H )
PR rises ( as E ; contrast H )
Pungent ( as E ; contrast H )
Resp falls; ( as E & H )
MH ( as E & H )
Uterus relax ( as E & H )
Cost ++ ( I >> E >> H )
Less clinical experience
Not a mutagen, teratogen or carcinogen
Cf to ‘balanced ‘ anaesthesia -
No ‘stiff chest’
No postop relapse (contrast opiates & relaxants)
BP controllable & myocard work not increased
Rapid recovery; less nausea
Isoflurane-O2 as easy as isoflurane-N2O-O2
Major role in the future delivery of anesthetic care ( E.E. II )
That seemed to cover everything. It would make a good handout, but perhaps it needed some information about other inhalational agents, just for comparison. What about MAC, and molecular weight, boiling point, vapour pressure, oil/ gas and blood/gas partition coefficients? I remembered that I had compiled a table of data about various inhalational agents may years before and I searched around until I found it. It only took a few minutes to look up the extra data on enflurane and isoflurane and add them to produce a new table:
VP 20 C
I hoped no-one would ask me for the references for all this data. I would not be able to produce them as I had collected in bits and pieces over the years from a variety of sources and anyway they might have been superceded by new figures for all I knew. Still they would do for comparison.
Now what was there on this table that would be worth drawing attention to? Well, first of all the striking correlation between MAC and oil/gas partition coefficient - though enflurane and isoflurane did throw a slight spanner in the works as they had different MACs even though their oil/gas figures were the same; perhaps this was due to the convulsant properties of enflurane. Then there was the amazingly high blood solubility of diethyl ether which made it such a slow agent, though a safe one. This quirk of ether upset the nice inverse relationship between potency and speed of induction, whereby the agents at the top of the list were weak but fast, and those at the bottom were potent but slow. Isoflurane, like halothane and enflurane, was near enough the bottom to be usefully potent, but also far enough away not to be depressingly slow. And the vapour pressure of isoflurane was virtually the same as that of halothane; that must mean you could use the same vaporiser.
What else should I add? Cost, perhaps? It would emphasise just how expensive isoflurane was, and how cheap was Trilene - cheap, potent and poorly volatile, ideal really from an economist’s point of view. Compatibility with soda-lime? All the ethers, including isoflurane and enflurane, scored here, but these last two were the only liquids on the list that did not need stabilizers added to them. Then there were all the pharmacological properties like sensitization of the myocardium to adrenaline - cyclo, fluoroxene, DEE and isoflurane were the good drugs here - or the effect on systemic vascular resistance - cyclo and DEE increasing it while the other vapours , especially isoflurane, decreased it; and then what about dysrhythmias when the CO2 was raised, or even when it wasn’t, - isoflurane scored particularly well here compared to the other smellies. And then there was the degree of metabolism - isoflurane scored heavily again by being far the least metabolised, while Trilene and MOF were worst. Yes, I would add these to my handout.
Then finally, though it had nothing at all to do with isoflurane, I could not resist adding at the top, above the MAC values
Helium weaker than ..... ..................the anti-anaesthetic effect of pressure
Neon balances ............................................''.....................''.......................
Hydrogen stronger than ............................''.....................''.......................
Oxygen...................................MAC calculated from lipid solubility 15 atmospheres
Carbon dioxide ..................................''....................''..................... 1.7 atmospheres.
If on the night no-one was interested in isoflurane, at least this would give me something else to talk about.
It was the divisional meeting once again.
‘Abbott say they will give us some vaporisers for enflurane if we will undertake to buy six bottles a month.’
‘That sounds like sharp practice to me.’
‘Not at all; just sound business sense. They think that if we use it more, we will get to like it, and they know that we won't use it if we haven't enough vaporisers.’
‘I think we should accept their offer.’
‘But will we use six bottles a month? And what will happen to them if we don’t? Can we sell them on to someone else?’
‘Oh, I think we will use six bottles all right. We were getting through four a month when they lent us just one vaporiser.’
‘Yes, but was it any better than halothane?’
‘Oh, I think so. A bit slower at induction, perhaps, but it gives a lovely steady maintenance without any VEs or nodal rhythm, and not much respiratory straining in response to surgery.’
‘Yes, but how much do six bottles cost?’
‘I don’t think we should worry too much about the cost. We are meant to be a teaching hospital and ethrane ought to be available so that our juniors can learn to use it. It is going to be an important part of anaesthesia in the future.’
‘Not necessarily, if isoflurane becomes available.’
‘Now that really will be expensive.’
‘Let’s save isoflurane for another day.’
‘Another year, probably.’
‘OK, another year. Let’s stick to ethrane for the moment. Shall we take up Abbott’s offer or not?’
There was general agreement that we should, though I added
‘I’m not really sure that it is any better than halothane. I’ll probably stick with what I am used to.’
‘I didn’t realise your were such a reactionary, John.’
‘I’m not,’ I said testily, but of course I was. I remember telling the Abbott rep the following morning that I thought ethrane was quite irrelevant for modern anaesthesia.
Many months later, I asked James
‘Are you using much ethrane?’
‘Yes, I use it all the time. I hardly use halothane at all these days.’
‘Oh, I had better try it then.’
‘I should. You’ll find that you need to use high concentrations during induction. I often go above the 5% stop on the vaporiser, though it makes the patients salivate rather a lot.’
Soon, to my surprise, I, too, was hardly using halothane. Ethrane was so satisfactory once you got the patient settled, though I still used halothane for gas inductions in children. I began to wonder why I had been so reactionary about ethrane in the first place. Perhaps, partly it was due to the controversy about halothane and postoperative jaundice, for I had always felt the case against halothane had been thoroughly overstated, and in an emotional rather than a scientific manner. Still I should not have been so silly.
The divisional meeting had a distinct air of deja vu about it, but this time it was vaporisers for isoflurane, rather than ethrane, that were on offer. I was pleased that at last we were going to try out the stuff that Edmond Eger had said in 1981 was likely to play a major role in the future delivery of anesthetic care. It would certainly be interesting, even if it was expensive. Colin suggested putting notices on the vaporizers reminding people just how much isoflurane cost. It seemed a good idea at the time.
‘I am still using more ethrane than isoflurane, though I guess there is not really a great deal to choose between them except the cost. And perhaps isoflurane is more pungent.’
‘Well, I don't know about that,’ the young registrar said. ‘It seems to me that if you don't go above 2% isoflurane then you don't get any trouble from it being irritant to breathe.’
‘Doesn't that make the induction much slower? I usually go above that sort of level when I use it.’
‘It doesn't make all that much difference, and you save time in the end because they don't breath-hold and splutter. You can waste an awful lot of time that way.’
‘Well, with propofol that sort of thing isn't the problem that it used to be, as you can control the coughing easily by giving a bit more propofol. But I’ll try it out keeping the concentration down’
So I started using more isoflurane, resisting the impulse to turn the concentration up. I found that he was quite right. If you did not go above 2% everything went smoothly. It did not always take the patient quite deep enough, and then you might have to increase it slightly for a short while, but mostly it worked very well. I was not sure whether this was because of reduced irritation to the respiratory tract, or just because there was less saliva produced. However, isoflurane was still very expensive so I did not go over to it in a wholesale fashion - at least not at this time.
The new Ohmeda Excel machines were a godsend, once you got used to all the monitoring gadgets and the display modes, because now it was so easy to use the closed circuit and turn down the fresh gas flows that you could justify the use of isoflurane without having to worry about the cost. From this time on I largely abandoned the other volatile agents, except for gas inductions in children. Not, of course, that we were doing so many of those; EMLA had changed all that.
One fine October day Barry stopped me in the corridor.
‘John,’ he said, ‘I’ve had a letter from Arnold about a lady whose varicose veins we did a couple of months ago. Apparently she became jaundiced afterwards and he is asking what sort of anaesthetic she had, and could it be anything to do with it.’
‘I doubt it had anything to do with the anaesthetic,’ I replied, ‘ but I’ll get the notes out and see if there is anything in them.’
Later that day I spoke to Ed about it. He said:
‘I had a patient last year who was jaundiced after an ethrane anaesthetic, and we filled out a yellow card for the Committee on Safety of Drugs. However, once she got over the jaundice she started taking her Duphaston again and the jaundice came back.’
‘Duphaston? What on earth is that?’
‘Oh, its a progestogen. Apparently it does sometimes cause jaundice.’
‘Well, my lady was on Femulen, amongst other things. That’s a progestogen, too, and the data sheet does say that it should be withdrawn if jaundice occurs, though it doesn’t say that it causes the jaundice.’
‘Anyway, I should write to Arnold and tell him that it was nothing to do with your anaesthetic.’
‘I’ll do that. Actually, it was Robin who gave the anaesthetic, though I saw her preoperatively. It was one of those days where there was a shortage of vaporisers and we had ethrane in the anaesthetic room and isoflurane in the theatre. I’m sure that doesn’t matter, but, of course, it does mean I will have to look up the literature on both of them, instead of just one of them.’
‘I’ve got some of the papers on ethrane in my filing cabinet. I’ll get them for you.’
So I wrote to Arnold pointing out that the anaesthetic had been uneventful with no hypoxia, hypotension or hypercarbia; that hepatotoxicity from inhalational agents in the absence of other causal factors was an extremely rare event; that a review in 1986 of 43 million enflurane anesthetics had revealed only 15 cases where postoperative jaundice was ‘unexplained’, and that this was considered too small an incidence to suggest an association between enflurane and liver damage; that as far as isoflurane was concerned a review in 1987 had concluded that there was not a reasonable likelihood of an association between isoflurane and postoperative liver impairment; and incidentally that the only case of ‘?halothane hepatitis’ I had ever had had turned out to be a large stone in the common bile duct!
Later I had a letter from him telling me that tests had now shown that she had had infectious mononucleosis. Which only goes to prove that common things commonly occur!
One morning I was speaking to James Clapham. I asked him if he could get me any information about the relative usage of enflurane and isoflurane. He promised to do what he could, and some weeks later I had a nice letter from one of the Abbott managers, giving me some data about market trends. Although data post-1989 was not to hand, he said the situation had largely stabilised.
Other ................................................Remaining % ................................................(IV, Regional, etc)
These figures were totals from all manufacturers, e.g. Abbott, Anaquest, ICI etc., though I guessed that cost alone would ensure that halothane still had a strong position in the third world. Also I wondered if we would soon be using the two new agents, desflurane and sevoflurane; these had been reviewed in the British Journal of Anaesthesia nearly two years ago now, but I had heard little of them since. The author of this review had titled it ‘DESFLURANE AND SEVOFLURANE: INHALATION ANAESTHETICS FOR THIS DECADE?’, though I remembered that he had hedged his bets:
Further work needs to be performed with both agents before their likely place in anaesthetic practice can be stated with confidence.
Nevertheless, he had been very impressed with the stability and the lack of toxicity of desflurane:
In the case of desflurane, however, a major advance in anaesthesia may be in the offing.
Was he right? Only time would tell!
I opened the envelope and out fell yet an another advert from Pharmacia promoting Suprane, which was their trade name for desflurane. I knew desflurane was a more highly fluorinated methyl ethyl ether than isoflurane, but I could not remember its exact formula. I turned the pages of the booklet looking for the answer, but did not find it in the text. There was, however, on page 12, a beautifully clear photo of a bottle of Suprane and I could read on the label ‘1,2,2,2 - tetrafluoroethyl difluromethyl ether’. So there were only two hydrogen atoms left in the molecule, and no chlorine at all. No wonder it needed a heated vaporiser and was so little metabolised - and so expensive. I read the introduction:
In comparison with isoflurane SupraneR offers improved controllability, a more rapid emergence, better quality of recovery and lower metabolism.
Controllability? Surely that was not a real word! I would have to ask Neville.
‘Do you think we should be using desflurane at Southmead?’ I asked the room at large.
‘Oh, I don’t think the advantages are going to be worth the cost,’ Tony replied. ‘That’s the one that needs a heated vaporiser, isn’t it?’
Fiona looked round, and said
‘I have heard that the recovery time is amazingly short - perhaps even too short for comfort sometimes, if the vaporiser needs filling.’
‘Ah, well, we’ll see what happens.’
I resolved to look up the papers quoted in the booklet as claiming better quality of recovery[1,2] to see if they really added up to something , but I have not got around to it yet. I wondered whether we would see it at Southmead before the end of the year.
When I got back to the office once the afternoon list had finished, there were more papers in my in-tray. The first two were swiftly ‘filed in the usual place’; but beneath them was a ‘read and pass down the line’ letter which caught my attention: National contract for the supply of anaesthetic gases. As it was not about gases at all , but about volatile liquids, this heading was somewhat misleading. Nevertheless the news it contained was most welcome. As a result of changing from regional to national contracts the price of both isoflurane and ethrane had been reduced by 15%, and Abbott was going to continue to let us use their vaporisers for free, instead of making the NHS pay rent, or even buy them, which would have cost more than £6 million.
‘David, this letter says that the price of enflurane and isoflurane are the same, £29 a bottle. If that is so I can’t see why anyone would want to use enflurane at all.’
‘You have forgotten, John, that the bottles are of different sizes. That makes a huge difference.’
‘Oh, yes, of course. How stupid of me. I know perfectly well that enflurane bottles are 250ml, but isoflurane bottles are only 100ml. It just shows how long it is since I had to fill a vaporiser for myself.’
A couple of days later an advert arrived from Abbott for their latest inhalational agent, sevoflurane, which had just been given a U.K. licence. I knew sevoflurane was a fluorinated methyl isopropyl ether. I remembered also how Robert Macintosh, sometime in the 1930s, had said that we did not need any new agents, just that we should learn how to administer what we already had in the best way possible. He was wrong , of course, the new agents since then had made a tremendous difference to anaesthetic practice and outcome. This was especially true of halothane, even though now it was being displaced by enflurane and isoflurane. Whether we needed anything better than isoflurane, and whether, indeed, either desflurane or sevoflurane was that improvement, I was not at all sure; but then I remembered how reactionary I had been at the introduction of enflurane and isoflurane. Still the advantages of sevoflurane did seem a bit marginal, even if the advert did have a man playing a violin with the words ‘In tune with day case anaesthesia’ on it.
‘Does sevoflurane have a trade name?’
‘No, apparently they realised that no-one ever calls isoflurane Forane, so they thought they would save themselves the trouble of thinking one up.’
‘I’m sure that was sensible. In the fifties we used to call halothane by its trade name, Fluothane, but after a few years the Fluothane was dropped altogether except on the bottle it came in. Anyway, what would they have called it? Something like Sevane, I expect.’
Some weeks later it was the autumn meeting of the Society of Anaesthetists of the South West Region which was held at Redwood Lodge. I chaired the AGM before handing over to Noel, who was the new president. Then we went off to visit the trade exhibition.
I talked first to the Pharmacia rep, a very attractive young lady. We chatted about desflurane, and I mentioned that Fiona was the person at Southmead who had a special interest in anaesthesia for day case surgery. She said she would make a point of contacting Fiona, and went on to tell that they had a new intravenous agent coming out in about eighteen months.
‘It’ll have to be a pretty remarkable to displace Propofol,’ I said. ‘Or very much cheaper. Can you tell me anything more about it?’
‘No, not yet. I only know it is in the pipe line.’
I moved on to the Abbott stand and chatted to James Clapham.
‘I’m glad I’ve seen you,’ he said. ‘I thought you might be interested in this pamphlet as I know you are interested in how much the different anaesthetics around are used. This has some data on it.’
‘Oh, thank you.’
I looked at the thin booklet he held out: Current Anaesthetic Practice by the ‘Anaesthesia Review Group’. I wondered who on earth they were.
‘While I am here tell me all about sevoflurane,’ I added.
‘Of course. Well, it’s just been given its U.K. licence, though it’s been used in Japan since 1990. Over two million patients have been given it so far. It has a pleasant smell and gives a fast smooth induction and recovery. We think it may prove especially valuable for day case anaesthesia and paediatric anaesthesia.’
‘So its not irritating to breathe?’
‘No, not at all.’
‘Sounds too good to be true.’
He laughed. We both remembered how reactionary I had been when enflurane had come on the market.
Later I browsed through the booklet he had given me. I discovered that the Anaesthesia Review Group was a collection of seven anaesthetists from various places scattered throughout the UK, but there was not one not from Bristol, which was a surprise. The group had sent out questionnaires to 2,987 British based consultant anaesthetists, and they had had 932 replies (31%). Not a very satisfactory response, I thought, but apparently the Review Group considered it surprisingly good. I wondered whether I personally would have published the results if I had had only 31% of my questionnaires returned.
Data for 1985-89 are from the previous section (1992), adjusted to exclude cases where volatile agents were not used. Data for 1995 are from Current Anaesthetic Practice, Survey and Report, Aug. 1995.
Their findings were presented by some brightly-coloured diagrams, which were mostly in 3-D. This was OK in the pie charts, but it was rather confusing in the bar charts; were you meant to read the back or the front of the bar? Certainly the 3-D effect did not add anything to the information, so I wondered why they had bothered with it. There was one pie chart which showed the volatile agents the respondents used when maintaining anaesthesia with a closed circuit. Isoflurane, at 71%, was the most popular, which did not surprise me; it seemed to be the obvious choice. Enflurane was next at 24%, with halothane only 3%, and desflurane 2%. I decided to make a chart showing these results together with those from the previous section. The result is seeen in the chart on the opposite page
It was difficult to know how much reliance to put on these figures, but surely they reflected the overall trend over the last ten years. I wondered what the next ten years would show. Desflurane scored heavily for its lack of biotransformation and sevoflurane for its lack of pungency; both were rapid in and out, making them very suitable for day case anaesthesia and out-patient anaesthesia, but at present their high cost might make them slow to displace isoflurane for routine anaesthesia. As I said before: only time will tell.
Desflurane has not yet made an appearance at Southmead, but sevoflurane is by now well established as the agent of choice for gas inductions, though Iain refuses to place it in the same class as cyclopropane. While I agree there was something very satisfactory with trickling cyclo gently and unobtrusively beneath a child’s nose, the ‘single breath induction’ with sevoflurane (8%)-nitrous oxide- oxygen described in the latest issue of Anaesthetic Annotations is certainly quicker than the ‘three to six breaths’ needed with a 6 litre bag of cyclopropane (50%) mixed with nitrogen and oxygen.
 Sadove et al in 1955[a] compared EVE with DVE and DEE. They summarised the clinical properties of these drugs as follows:
Ethyl vinyl ether
Nausea & vomiting
‘Ether eye’ (post-ether conjunctivitis) was reported to be commoner with EVE than with other ethers, though the reason for this is not clear. Also, in deep anaesthesia, ‘running movements’ are frequently seen, similar to those observed when divinyl oxide (divinyl ether) is being administered: this suggests that these running movements are in some way related to the unsaturated vinyl molecule. These movements promptly disappear on withdrawal of the agent and consequent lightening of the plane of anaesthesia. Thus they are easily differentiated from incipient convulsions. I did not use either of these agents enough myself to become aware of this abnormal muscular activity, though it sounds intriguing!
[a] Sadove MS, Wyant GW, Cletcher JO Jnr. Ethyl vinyl ether: pharmacological and clinical evaluation. Curr. Res. Anesth. Analg. July-Aug 1955.
 Virtue RW, Payne KW. Postoperative death after Fluothane. Anesthesiology, 1958; 19: 562.
 When Dundee presented his observations on Fluoromar[a] to the Royal Society of Medicine in December 1956, he said:
A comparison of the properties of Fluoromar and its effects in man with those of other ethers....... does not reveal any outstanding advantage over drugs already available in British anaesthetic practice. Had it been completely non-inflammable, it would have been very useful; had it been less easy to produce apnoea and hypotension, it might have been the drug of choice for the inexperieinced or occasional anaesthetist. As it stands there does not seem any point in introducing the drug into this country.
Curiously it was at this very meeting that Cecil Gray made his memorably incorrect prediction about the future of Fluothane in anaesthesia - see chapter 6/1957. Dundee, though , was certainly right about Fluoromar.
[a] Dundee JW. Some observations on Fluoromar. Proc. Roy. Soc. Med. 1957; 50:191-193.
 Spence AA. Some basic problems in training in anaesthesia. Anaesthesia Points West, 1969; 2: 17-18
 Reilly PF. A criticism of British anaesthetic training. Anaesthesia Points West, 1969; 2: 21-22.
 Bunker JP. Education in anesthesiology. New York and London: Columbia University Press, 1967; page 71.
 Committee on Anesthesia, National Academy of Sciences, National Research Council, Special report. Anesthesiology, 1971; 34: 505.
 Jones PL. Brit. J. Anaesth. 1971; 43:190.
 Eger E. II. Isoflurane: a review. Anesthesiology, 1981; 55: 559-576
 Halsey MJ. Structure-activity relationships of inhalational anaesthetics. In: Halsey MJ, Millar RA, Sutton JA, eds. Molecular mechanisms in general anaesthesia. Edinburgh: Churchill Livingstone, 1974; 3-15.
 I cannot remember who said this to me. Do drop me a line if it was you.
 I recently came across, tucked away inside an old journal, a letter dated 13th March 1962 from the Senior Administrative Medical Officer of the South Western Regional Hospital Board to the Hon. Secretaries of the Medical Staff Committees of General Hospitals. It shows that there is nothing new under the sun:
The Ministry of Health has written to me on the subject of drug costs and remarked on the increasing use of the gas (sic) halothane, which is itself relatively expensive. I am informed that the cost of its administration to patients could be greatly reduced if a closed circuit system were used in place of a semi-closed or open circuit.
With cyclopropane, too, cost was often quoted as a reason for use of the closed circuit; for example, the first edition of Synopsis of Anaesthesia in 1947 says that
cyclopropane must be used in a closed machine with carbon dioxide absorption owing to the high cost of the gas - about 2s and 9d. per gallon..
Pursuing the theme that there is nothing new under the sun, we should recall that John Snow[a], in 1850, anaesthetised animals by means of a closed circuit using caustic potash as the absorbent.
 Eutectic Mixture of Local Anaesthetics.
[a] Snow J. On narcotism by inhalation of vapours. Lond. Med. Gazette, 1850; 11:749 and 12: 622.
 Eger EI II, Sumckler EA, Ferrell LD, et al. Is enflurane hepatotoxic? Anesth. Analg. 1986; 65:21
 Stoetling RK, Blitt CD, Cohen PJ, et al. Hepatic dysfunction after isoflurane. Anesth. Analg. 1987; 66:147.
 Jones RM. Desflurane and Sevoflurane: Inhalation anaesthetics for the next decade? Brit. J. Anaesth.1990; 65: 527-36.
 Tsai SK, Lee C, Kwan W-F. Recovery of cognitive functions after anaesthesia with desflurane or isoflurane with nitrous oxide. Brit. J. Anaesth. 1992; 69:255-258..
 Ghouri AF, Bodner M, White PF. Recovery profile after desflurane-nitrous oxide versus isoflurane-nitrous oxide in outpatients. Anaesthesia 1991; 74:419-424.
 Anaesthetic Review Group. Current Anaesthetic Practice, Survey and Report, Aug. 1995. Sherfield-on-Loddon: RRAssoc, 1995.
 Webster NR. History teaches us to keep open minds. Anaesthetic Annotations. 1996; Issue 4, Sept.
 Bourne JG. Nitrous oxide in dentistry. Its dangers and alternatives. London: Lloyd-Luke (Medical Books) Ltd. 1960; p117
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