Halothane. F3C-CHBrCl. Trifluoro-chloro-bromo-ethane. Trade name: Fluothane. An almost colourless volatile liquid with a distinctive, pleasant odour; non-flammable and non-explosive.
I hurried across the park to the library. Would the Gazette be there yet? I hoped so. It had been so exciting to get my short article accepted for the fortnightly hospital journal, though by the time I sent it off the humour was too familiar to me and it no longer seemed to be funny. Perhaps it had never been funny in the first place, I thought gloomily. Still no-one would know it was me who had written it, so it would not matter, would it? I liked the nom de plume, Nevill Clunes, that I had chosen but it had had nothing, consciously at least, to do with any Shakespearean actors as the editor had assumed. I swung the door of the library open and went in. No, the Gazette had not arrived. Perhaps it would come after lunch? Yes, maybe. I was more disappointed than I cared to admit.
As I had half an hour before the ward round I sat down and flicked through the pages of the British Medical Journal. There was an extremely interesting article on Motor-Cyclists, Crash Helmets and Head Injuries. I learnt that crash helmets had become compulsory for Army motor-cyclists in 1941, but that less than one third of civilian motor-cyclists wore them, though they should all be encouraged to do so, as wearing helmets led to a significant reduction in the risks of severe and complicated skull fractures.
There were several other interesting articles which I read, some of which I found frustrating because I only half understood them. Still the more I read the more I would learn.
I put the BMJ down and picked up the British Journal of Anaesthesia. I had so enjoyed my time giving anaesthetics last year that I often looked at this journal. Here was something interesting: a Dr Johnstone from Manchester was describing the effects of a new anaesthetic agent on the cardiovascular system. I skipped to the end and read the summary:
(1) Fluothane - a new nonexplosive volatile anaesthetic agent - has been administered to 500 patients...
Fluothane, eh? That was a lovely word, wasn’t it? Sounded so elegant and graceful. I wondered who had invented such a lovely name.
(2) Smooth and rapidly reversible anaesthesia has been maintained in all cases by the continuous administration of Fluothane vapour, using a Boyle’s vaporiser and a gas flow of ten litres a minute with 50 per cent oxygen and nitrous oxide.
A Boyle’s vaporiser? That would be the glass bottle on the anaesthetic machine where you usually put ether or Trilene.
(3) Cardiovascular changes suggestive of depression of the sympathetic activity have been consistently observed... the shock syndrome has been completely absent in all cases.
No shock syndrome? That sounded a good thing
(4) There has been a complete absence of salivary, mucous, and bronchial secretions in all cases throughout the period of anaesthesia. Nausea, vomiting and retching during recovery have been absent in over 90% of the patients.
That was marvellous. Fancy only 10% of patients being sick; that was much less than after ether or Trilene.
I looked up at the clock on the wall. Good heavens, it was nearly two o’clock. I put the journal down and hurried away so as not to be late for the ward round. I was still thinking about halothane when the one-eyed consultant physician, who happened also to be dean of the medical school, asked me my name. Unfortunately I misunderstood him; I thought he was asking for the name of the patient that had been allotted to me, a pleasant young man from Malaya.
‘Boon Leong Ooi, sir’ I replied.
He raised his eyebrows in surprise and his blacked-out monocle fell from his bad eye. He looked at me closely for a moment, then turned to the student next to me and asked him his name.
I realised my mistake, but it was too late, he had already moved on. I felt very foolish.
I was in the Wills library again, browsing rather than studying. What wonderful places libraries are. In the Proceedings of the Royal Society of Medicine (which sounded very grand, if somewhat pompous) I came across another paper about Fluothane. It was by two doctors from Oxford and they described their observations on using the drug in 500 cases.
At the end of their paper there was some discussion: here was Dr Johnstone from Manchester again and he was now reporting that he had used Fluothane for 1,200 operations and it had been very successful. It was not irritating to breathe like ether, and it was not explosive either. The blood pressure did fall a bit and the breathing was sometimes rather shallow.
But a certain Dr Cecil Gray from Liverpool did not seem impressed with the new agent:
Fluothane appears to possess every property we consider bad in an anaesthetic drug: tachypnoea combined with reduction in tidal volume, ...
He means rapid shallow breathing. I wonder why he didn’t say so.
...hypotension and sensitization of the heart to adrenaline are all extrememly undesirable effects which the speakers have assured us are produced by this drug, and yet, to a man, they still regard it as a valuable agent. It is probable that the facts that it is non-explosive, non-inflammatory and produces rapid induction and recovery of anaesthesia will give it a small place in anaesthetic practice but I find it difficult to conceive that it will replace any of the agents at present at our disposal.
That seemed pretty final. What a pity It was time there was a good non-explosive anaesthetic. Perhaps they would find one one day - or perhaps Dr Gray would be proved wrong.
‘We are quite up-to-date here, you know,’ said the anaesthetist who welcomed me to Musgrove Park Hospital, where I was to start my new post as Senior House Officer in Anaesthetics. ‘We use all the latest things, including Fluothane.’
I was suitably impressed. I had heard that Fluothane was now being used quite commonly in many hospitals throughout the country - though as yet only occasionally at Guy’s, and then only by senior anaesthetists; it was, after all, a very expensive drug as it had cost ICI over two million pounds to develop it.
He showed me the vaporizer that they used. It had been adapted from the standard Trilene vaporizer on the Boyles machine by fitting a longer scale with more markings on it beside the lever.
‘The numbers are quite arbitrary,’ he explained. ‘But you get to know how far to move the lever after a bit of practice. It is difficult to tell exactly what concentration you are using, though it is easy to decide whether you are giving too little or too much of the stuff; just watch the patient closely’
‘You mean each patient acts as his own bio-assay?’ I asked.
‘I expect you’re right,’ he replied rather vaguely. ‘Of course, how much Fluothane you get from any given position of the lever depends an awful lot on how long the vapourizer has been switched on; after a few minutes the halothane gets amazingly cold and the gas that flows through it does not pick up so much vapour.’
I soon got the hang of it. I found that Fluothane was especially useful for heavy muscular patients, though it was it was not as good as Trilene for frail old ladies, as it sometimes dropped their blood pressures alarmingly. Still it certainly did have a place in the armamentarium of the modern anaesthetist, along with ether, cyclo and Trilene. I would certainly aim to get expert with all of them.
Catterick Camp, Yorkshire
When I arrived at Catterick I prided myself on being an anaesthetist with a variety of agents at his fingertips, but by the time I left early in May 1964 I was using Fluothane almost to the exclusion of the other volatile anaesthetics, and was also by this time calling it by its approved name ‘halothane’ rather than by its trade name.
One day Derek said:
‘Why don’t we try out the halothane-ether azeotrope and see how well it works.’
‘Remind me exactly what an azeotrope is,’ I replied. ‘I did read about it once but I’ve forgotten all about it. It’s a lovely word, whatever it is.’
‘Oh, you know, an azeotrope is a mixture of liquids that evaporates so that the composition of the mixture remains constant. With halothane and ether you need roughly one part ether to two parts halothane. It doesn’t have to be exact as the mixture is self-correcting.’
‘Self-correcting? What do you mean by that?’
‘Well if you have a bit too much halothane then the halothane evaporates more quickly than the ether till they end up at the azeotropic mixture.’
‘And if you have too much ether? Does that sort itself out as well?’
‘Certainly, it does. The mixture is self-correcting from either direction.’
‘Is it still flammable?’
‘No. That’s the whole point of it. It is more analgesic than halothane alone and yet won’t burn at the concentrations you use in clinical practice.’
‘Sounds too good to be true’
So we tried it out. It worked well enough. The patients certainly shivered less while they were waking up in the recovery ward than they did after halothane alone, but the smell of ether made me uneasy when the diathermy was being used; it was difficult not to imagine that we were about to blow ourselves up
‘I don’t think this stuff will catch on,’ said Derek. ‘Not now that we have reliable temperature and flow compensated vaporisers for halothane. Still it was fun to try it out.’
Some fifteen minutes after the list had finished, Norman, the surgeon who during the war had walked the length of Italy to avoid capture by the German forces, put his head round the door.
‘Thank you very much, John,’ he said. He disappeared once more.
The theatre sister told me later that he had said to her as he passed:
‘I had to come all the way back from the car park just to say thank you to him; he’s such a sensitive young man.’
I was quite taken aback; the words of Rabbie Burns came to mind:
O, wad some Pow’r the giftie gie us
To see oursels as other see us.’
Sensitive young man, indeed!
Royal Infirmary, Bristol
‘Are you coming to the deathwatch meeting tonight? There’s a case of liver failure after laryngectomy. The physicians are saying that it was probably halothane hepatitis.’
I looked up at my fellow registrar, another John as it happened. The ‘deathwatch’ was the name they gave to the monthly meeting where the clinical staff, who looked after the patients while they were still alive, got together with the pathologists, who were the people who examined them once they were dead. Its real name was the clinicopathological meeting, but it was always known irreverently as the deathwatch. It was a very good idea to get a meeting like this set up because everyone learnt something that might prove useful in the care of patients at a later date.
‘I’ll try and get there’ I replied, not really sure that I would manage it. Isabel would be hoping that I would stay home. I was on duty in the hospital two nights in every five and on call from home on a third night so it was very hard on her if I went out on one of my few free evenings. Nevertheless I knew that when the time came I would feel obliged to go to the meeting, and anyway it was sure to be interesting; I knew that there were people around the world who were saying that halothane could occasionally cause liver failure, but it was so rare that it was difficult to take it seriously. Anyway, it would not be so bad as it might have been because my twenty four tour of duty as ‘first call’ anaesthetist for emergencies finished at one o’clock lunchtime and I could spend the afternoon and early evening at home. In any case tomorrow’s patients would have to be seen so I would have to come back to the hospital at some time. Still it would be good to see the kids who were often asleep in bed by the time I got home, and to give Isabel a break from them. They were such a handful, especially the baby, and Isabel would be exhausted with looking after them, poor love.
I was tired myself, of course, as it had been a busy night. We had finished the last case in the theatre, an appendicectomy, at four in the morning. After bacon and eggs, which were delivered from the main kitchen (a fine tradition that probably does not still exist) I had played squash with Chris till twenty past five. We had gone off to bed exhausted but exhilarated.
Now it was time now to go to the casualty department to do the ‘pus list’. What happened was that over the previous twenty four hours they collected all the abscesses that needed incising to drain out pus and got them to come back at twelve noon so that they could all be done one after another. Sometimes there were only a couple of patients, or even none at all, but it varied a lot from day to day. It was a fairly good arrangement as it meant the first call anaesthetist usually could sleep during the morning and recover to some extent from the rigours of the previous night. It also allowed the patients to be properly prepared for an anaesthetic by getting them to starve themselves for four or five hours beforehand.
As it turned out there was only one patient waiting. He was a powerfully built labourer with an abscess on his backside.
I checked the machine and mixed up some thiopentone which I injected into a vein on his forearm. I switched on the halothane glancing slightly apprehensively at the Goldman vaporizer which was of very simple design and not capable of giving a really good dose of halothane, a safety feature perhaps, but one that could create problems when you had a tough customer to deal with who needed more than 2% halothane to get him deep enough. If you had several cases the problem became even worse because the vaporizer got cold and then gave out even less halothane than it had done at the start. Really it was time, I muttered to myself, that they had a proper Fluotec vaporizer in the casualty department like they had everywhere else, except the dental hospital, of course. Despite my foreboding everything went smoothly, the abscess was duly incised, and I was off to lunch a few minutes later, the smell of halothane and pus soon drowned by the smell of institutional cooking.
When I got home I found Isabel trying hard not to laugh. Apparently she had just said to Katy, now three years old, that she had been very naughty and that she was going to be smacked. Katy had tossed her head back, put her hands on her hips and said:
‘Well, come on then.’
Isabel was not pleased when I told her that I felt that I should go to the meeting that evening.
‘But, John, you have hardly been home this week. Do you really have to go?’
‘I think I ought to, dear. One of the cases is a man who died of jaundice after a halothane anaesthetic and Fen will be expecting us all to be there.’
The meeting was already crowded when I arrived but I managed to find a seat next to Derek. Looking around I was surprised how many people in the room were not known to me even though I had been working in the United Bristol Hospitals for sixteen months now; older members of the departments of Medicine and Pathology I guessed. I knew the younger ones, of course, from the day-to-day business of the hospital but the consultants in anything else but surgery and anaesthetics were rather distant figures.
The meeting was called to order by the chairman, who was one of the pathologists, banging his gavel on the table.
‘Good evening and thank you all for coming. We have some interesting cases for you tonight so I think we should make a start.’
The first two presentations were rather obscure medical problems which failed to make me forget I had been up most of the night before. Eventually it was time for the ENT registrar to present his case.
‘Sixtysix year old man... developed a hoarse voice eighteen months ago following bronchitis... diagnosed as cancer of the larynx a year ago but refused surgery at this time... given radiotherapy instead... developed stridor one month ago and was admitted to hospital for further radiotherapy and also tracheotomy... on the 17th of this month he underwent total laryngectomy which took over four hours to complete and during which he received several pints of blood... the anaesthetic included halothane but was entirely unremarkable and though there was considerable blood loss the blood pressure did not fall below sixty at any time...’
‘That’s rubbish’ Derek muttered in my ear. ‘I heard that the blood pressure was well below sixty for at least ten minutes.’
‘Well, you should say so then,’ I whispered back, but Derek just shrugged his shoulders; after all he hadn’t actually been there at the time so he couldn’t be sure about it.
The ENT registrar continued:
‘Four days postoperatively the patient became jaundiced and drowsy... blood urea 65mg%... white blood cells 12,800, mostly polymorphs... SGOT greater than 120... Coombs test weakly positive... deteriorated slowly and died two days later on the sixth day after the operation.’
He sat down. There was a short pause. Then one of the physicians, a small plump bouncy man and a renowned expert in diseases of the liver, jumped to his feet.
‘This dangerous drug which poisons the liver... anaesthetists totally irresponsible in failing to admit the hazards of continuing to use halothane... surely time its use was abandoned.’
I could hardly believe my ears. I knew there was some controversy over the effect of halothane on the liver in a small number of patients, but ill effects such as liver failure were extremely rare and certainly much less common than with some of the drugs that the physicians themselves prescribed quite happily. The amazing tirade against halothane went on for nearly five minutes but when I tried later to recall the substance of what had been said I found that I could not remember anything but seemingly mindless invective. Apparently I was not alone. One of the pathologists, a splendidly eccentric man with a piece of black ribbon round his neck, stood up.
‘I congratulate the learned doctor on his fine speech but I would like to remind him that mere oratory is no substitute for facts. Before the discussion proceeds any further could we please have some facts?’
There was general laughter.
‘What facts would you like?’
‘Well, for example, can you tell us what has happened to the incidence of infective hepatitis over the last twenty years?’
‘Certainly. It has halved.’
He sounded so sure of what he was saying that I quite believed him.
It came as a complete surprise when, two days later, as I was getting dressed, I heard the local news on the wireless:
The Medical Officer of Health for the City and County of Bristol has issued statistics concerning communicable diseases in the region.... measles... mumps... chickenpox... and finally... reports that the incidence of infective hepatitis has more than doubled over the last ten years.
Doubled? DOUBLED? DOUBLED!
I have never forgotten the way that the meeting had been misled. It was to colour my attitude towards ‘experts’ for many years to come. It certainly did not help to persuade me that I should stop using halothane.
The afternoon seminar had been a good one; before it finally broke up Bob had something to say:
‘There are only a few bottles of halothane left and there will be no more delivered till the end of the month as this quarter’s budget for halothane has already been spent. So, please, only use it when you think it is really indicated, or we will run out altogether.’
I was fascinated to hear this. At home halothane was by this time almost universally considered the volatile anaesthetic of choice, with the exception of a few diehards who still used ether for tonsillectomy in children and those folk who still found Trilene useful for superficial surgery which did not require relaxation; to suggest that halothane would not be available would be unbelievable the hospital would grind to a halt. Yet here in Denver it was seriously suggested that there might be no halothane for two or three weeks, simply because there was no money left to buy it. This was a philosophy that was entirely new to me, but then I had been surprised when we arrived in Denver some months earlier to see the notice in the casualty department stating unequivocally ‘EMERGENCY ROOM. MINIMUM CHARGE $5’. Still I could see that they would manage all right without halothane. Even though they never used Trilene they had plenty of other things they could use. I asked Dave about it afterwards.
‘Dave, what percentage of patients in Denver actually get halothane at the moment?’
‘I can’t tell you off hand, but I could easily find out. As you know we keep carbon copies in the department of every anaesthetic that we give. Last year’s figures will already be available. I’ll ask the seceretary to get them out for us.’
A few days later he produced the figures from 1962 to 1966. They made fascinating reading: amongst the general anaesthetics halothane had worked its way up from 22% in 1962 to 35% in 1966, whilst cyclopropane had fallen from 50% to 28%; the crossover of these two agents had occurred only during the last year.
‘Was that anything to do with the National Halothane Study?’ I asked.
I was referring to the study, published early in 1966, which had looked at all anaesthetics given over a four year period at 34 different American hospitals.
‘Why, sure. I think the National Halothane Study made folk less worried about halothane than they had been. Did you know that the Prof was one of the first people to report a case of unexplained jaundice after halothane.’
‘No, I didn’t know that. I don’t remember all the details of the Study, either. Can you remind me?’
‘Well, they looked at more than 850,000 anesthesias; more than a quarter of a million of these had been with halothane. They enquired closely into every death which occurred within six weeks of surgery. There were 82 cases of massive liver failure; of these only 9 could not be easily explained; 7 of these 9 had received halothane, but, despite this, the overall death rate after halothane was as good as any other agent and better than most. They concluded that postoperative liver failure was a rare occurrence and that halothane had a good overall record of safety, including operations on the biliary tract and gall bladder. The possibility of extremely rare cases of halothane induced liver failure could not be excluded but was not confirmed either.’
I looked once more at the figures he had given me a few moments earlier. I saw that between 1962 and 1966 the use of ether in the department had fallen from from 12% to less than 3%; there were also numbers for fluroxene and methoxyflurane (see chapter 7) and nitrous oxide supplemented with various intravenous drugs, such as barbiturates, opiates and gammahydroxybutyric acid; Trilene was not mentioned at all. When regional anaesthesia rather than general anaesthesia had been used it had mostly been spinals, though epidurals were preferred in day cases, which seemed reasonable enough.
‘At home we are nothing like so versatile,’ I said. ‘These days it’s usually a choice between "flick the Fluotec" or "paralyse and puff". It’s probably because we can’t stop our surgeons using the diathermy that we use so much halothane.’
‘Why, that would certainly make a difference to us as well. Still it would be boring if we all did things the same way, wouldn’t it?’
‘I guess you are right. Of course, halothane is certainly the easiest of them to use, so perhaps it just proves that we’re constitutionally lazy.’
‘You said it, John. You said it.’
Southmead Hospital, Bristol
‘Sheila, there’s a paper in this week’s Lancet which suggests that the anaesthetic agents given during an operation may depress a patient’s immune system in the postoperative period. It seems a bit unlikely to me. After all, anaesthetics have to be reversible or they wouldn’t be any good, would they? The patients wouldn’t wake up.’
‘I suppose not. What exactly did they do?’
‘Well, they took lymphocytes from patients’ blood before and after surgery and looked to see how well they responded to to something called phytohaemagglutinin. Apparently this stuff acts as a stimulus for lymphocytes to start producing extra DNA and change into large blast cells, or is it the other way round?’
‘Both probably, I expect.’
‘Well, it seems that after an operation the lymphocytes don’t respond so well. They say it might in part be due to the anaesthesia.’
‘Do you think they are right?’
‘No, I shouldn’t think so. Anyway, we ought to look at it. We could culture some lymphocytes and expose them to halothane in the lab and see if they transformed all right afterwards.’
‘You would have to bubble the halothane out again before you tried to stimulate them.’
‘Yes, of course. Do you think the people in the cytogenetics lab would teach you how to culture lymphocytes?’
‘I am sure they would if I asked them nicely.’
‘The authors of this paper used a radioactive technique to assess the uptake of thymidine used by the lymphocytes to make new DNA but I don’t think that we could get into the radioactive scene. I think we could just look at them down a microscope.’
‘Would that be good enough?’
‘Oh, I think so. We would only be looking for gross changes. Dr Kauntz at Guy’s used to say about physical signs that if you couldn’t demonstrate them to your grandmother then they weren’t important. I know he was talking about enlarged spleens and livers and kidneys, not lymphocytes, but it’s the same thing really, isn’t it?’
‘I’ll take your word for it.’
‘We will need to bubble halothane in air, with 5% carbon dioxide added, of course, through half of the cell cultures and the same gas mixture without any halothane through the other half. I wonder what would be the best way to do it.’
‘We could use the Adams’ tonometers, couldn’t we?’
‘That’s a brilliant idea, Sheila.’
Adams’ tonometers were splendid glass vessels which had been designed for equilibration of blood samples with mixtures of gases at known temperatures for the measurement of their acid-base status. They would do splendidly for our halothane.
So Sheila went off and learnt how to culture lymphocytes while I sorted out the gases and the halothane.
A couple of weeks later we were ready for the experiment. We took some blood out of a vein at the bend of my elbow and Sheila separated out the white cells and suspended them in some culture medium. We split this suspension in two and then, as planned, bubbled 2% halothane in air with 5% carbon dioxide through one half of the mixture while we bubbled the same gas mixture but without halothane through the other half.
‘That’s a huge dose of halothane’, I said. ‘We never give that much to a patient. We often let them breathe 2% halothane, but we never equilibrate them with it. It’s nearly three times MAC. Still if the lymphocytes recover from that it’ll prove something, won’t it?’
‘Yes, I guess so.’
‘It’s funny to think that the cells inside that bit of glass were once part of me. Perhaps they are still part of me; after all they have my chromosomes inside them.’
‘That may not be anything to be proud of’
We left the equilibrated samples undisturbed for two hours, lying the tonometers on their side so that the cells would not get stuck in the holes of the sintered glass at the bottom.
We had another cup of coffee and discussed exactly how we would score the cells under the microscope. We decided that we would get someone to code the slides for us after Sheila had prepared and stained them so that there would be no possibility if there is no observer bias.
‘It’s time to bubble the halothane out again,’ Sheila said. ‘Let’s get on with it.’
We watched the gases bubbling a second time through the suspension of lymphocytes. When we were certain that we had removed all the halothane we took the mixtures, added the phytohaemagglutinin and put them in the incubator.
Seventy two hours later we harvested the cells and made slides and stained them. When we compared slides from the different groups we could not detect any difference between them. The lymphocytes which had received the halothane had transformed as beautifully as those which had not.
We persuaded some of our colleagues to let us have a sample of their blood and we repeated the experiment several times. Each time the result was the same: no obvious depression of the reponse.
‘I think we should assess the uptake of thymidine as well,’ Sheila said. ‘It would be a more sensitive test and tritiated thymidine has a short half life and only emits beta rays which cannot get out of a glass bottle, so it is pretty safe.’
I hoped she was right.
‘OK. I’m game.’
So we added some tritiated thymidine to a further set of cultures and made autoradiographs of the cells. Again we could not find any difference between cultures that had been bubbled with halothane and those that had not.
I was quite delighted by these experiments, and I could not resist submitting a ten minute paper went to the 10th Scandinavian Congress of Anaesthesiology in Lund in Sweden.
Lund proved to a beautiful city and the midsummer weather was splendid. When the time came to read my paper at the Congress I was very nervous, but at least I was talking in my native tongue which was more than the Swedes and the other Scandinavians were doing. I was very impressed with their command of English.
After the meeting Peter asked whether I was coming to supper in Malmö, which was about ten miles from Lund. We dined at a horrendously expensive restaurant. At the end of the evening, after a splendid meal and plenty of wine and akvavit the ICI representative insisted on settling the account.
Afterwards I said to Peter
‘Did you know that ICI would pick up the bill?’
‘No, of course I did not know, but it had occurred to me that they might.’
‘Peter, you’re incorrigible’
‘Well, they’re making a fortune out of halothane; they are still charging nearly £10 a bottle, even though they have had fifteen years to recoup their original development costs. It will do the shareholders no harm at all to feed us just this once.’
That was certainly one way of looking at it.
When I got back from Lund we wrote a letter to the Lancet, briefly reporting our findings. I ended it with these words
These results redemonstrate the reversibility of the action of halothane at a cellular level, and suggest that the reported postoperative depression of the lymphocyte response to PHA is not a direct result of inhalational anaesthesia.
That was what we had set out to see, but still I could not reasonably leave it there, so I added:
Indirect effects via the stress reaction or via the action of metabolites of anaesthetic agents are not excluded, nor are the effects, direct or indirect, from non-inhalational narcotics.
That seemed to cover everything. We were very excited when the Lancet wrote to say they would publish it. Sheila told all her aunts and uncles and on the expected day they all bought copies. Unfortunately our letter did not appear till the following week. Still when it did appear it looked splendid enough to us, though it has never been cited, as far as I am aware, in any other paper on the subject. I wonder if there is such a thing as a negative citation index?
‘Sheila, there’s a meeting of the Association of Anaesthetists in Exeter in August. They’ve written around asking for papers. I wonder if should I tell them something about the effect of halothane on the cell cycle. Chris is sure to have counted the slides by then.’
‘Sounds a good idea, but it will be difficult to send them a summary if you don’t know what the results are yet.’
‘Oh, it’s not like the Anaesthetic Research Society, you know. They only need a title at this stage.
‘Why don’t you do it then. We ought to have the Southmead branch of the University represented.’
‘I’ll just call it Anaesthesia at a Cellular Level. That’ll leave me free to say anything I want to. It’s only for ten minutes anyway.’
In the event Chris finished counting the slides in plenty of time but I began to worry that an Association meeting was not really the right place to talk about stages of the cell cycle. I decided to make it something of a mixture. How should I start? I picked up a pencil.
In the mid-60s there were some fanciful suggestions concerning the possible therapeutic value of inhalational anaesthetic agents, for instance in the treatment of neoplasia and in the provision of post-transplant immunosupression. These suggestions rapidly came to nothing and the emphasis has swung again towards consideration of the possible deleterious effects of anaesthetic agents at the cell level.
That was all right, wasn’t it? Set the scene anyway. I’d better mention Claude Bernard, hadn’t I? He really was a clever fellow, well ahead of his time.
Of course, there is nothing new under the sun. Claude Bernard reported the inhibition of phagocytosis by ether in 1875. I wonder what this must have meant to a patient in the days of deep anaesthesia and no antibiotics.
Now I could mention a little about the work we were doing on the effect of halothane on the cell cycle, though this would have to wait till Chris had done all the counting. Still I could reminisce about our study on lymphocytes:
Fame and appreciation came late to the lymphocyte, the cell we now recognise as occupying the key position in our defences against bacterial, fungal and viral pathogens, and as being of some importance in checking the development and spread of cancers.
That’s OK. Now something about transformation:
You will recall that before 1959 the lymphocyte was believed to be a mature cell awaiting sentence and death. In that year it was demonstrated that in fact the lymphocyte in culture could be stimulated to change or ‘transform’ into an actively DNA-synthesising blast cell capable of proceeding to division into two new cells.
Here I could show them a slide of a blast cell here alongside a normal lymphocyte, and also some of the autoradiographs after the tritiated thymidine. Tell them, too, about bubbling the halothane in and out. Yes, I could see a short talk taking shape.
The exposure to halothane was made upon the laboratory bench in order to avoid surgical trauma and increased cortisol levels.
Then tell them how we found the effects of halothane to be reversible and finish off with a snappy conclusion. Let me see; what could I say?
In summary, we have shown that if you bubble the halothane out, then blastoid transformation will occur if an appropriate stimulus is applied - or in the words of Milton: ‘no sooner blown than blasted’.
The meeting in Exeter was a great success, though this had absolutely nothing to do with my paper, nor indeed anything to do with halothane; it was largely because the firm that sold ‘Butterfly’ needles declared the bar open without cost to delegates for the entire two days.
Later I asked Isabel, ‘Who is it that makes Butterflies?’
‘God makes butterflies,’ she replied.
‘Rudolph is getting worse,’ I said to Isabel. ‘He can’t move his back legs at all now and his behind is horribly sore. I’ll have to put him down before Katy gets back from Hanover.’
I was talking about the white rabbit. Katy herself was away on the Bristol-Hanover Schools Exchange trip and would not be home for another ten days.
‘I quite agree, John. Put the poor thing down as soon as possible.’
‘I’ll do it this evening.’
As I drove to work I pondered on how to do the deed. I knew that sometimes vets used intraperitoneal thiopentone, but I did not fancy that at least not until I had anaesthetised him first. Clearly I needed some halothane. I would see if there was any in the lab left over after our recent experiments.
The traffic was jammed solid on the approach road to the roundabout at the top of Cribb’s Causeway and it looked likely to stay that way. I sat there as patiently as I was could. My thoughts wandered back to the rabbit. Katy would be so upset. I remembered how distraught she had been at the untimely loss of her last rabbit, the much loved Snowdrop. And now it was Rudolph I wondered how much halothane I would need. Let me see: 1 cc of liquid halothane evaporates to about 230 cc of vapour; a bucket holds about 10 litres; so 1 cc of liquid halothane put in a bucket would give about 230 cc of vapour in 10,000, which is 2.3%; so 5 ccs of liquid halothane would give me a bucketful of 11.5% halothane. That ought to be enough to put a sick rabbit to sleep.
I was startled out of my reverie by a horn hooting. The traffic ahead of me had moved on and the driver behind me was getting impatient. I waved my apologies, slipped the car into gear and moved forwards to the next hold up.
‘Is there any halothane left in the bottle, Sheila,’ I asked when I reached the lab.
‘How much do you want?’
‘Oh, just a few ccs; ten would be plenty. It is only to put a rabbit down.’
‘Put a rabbit down?’
‘Yes, and it’s not the first time I’ve been responsible for the death of a white rabbit, you know. A couple of years ago I let poor Snowdrop escape from her hutch and she got squashed on the A38.’
‘Do you mean me or the rabbit?’
‘The rabbit, of course.’
‘I thought as much. Well, I deserved some sympathy too, you know. It was a bitterly cold night, and I went out to give Snowdrop some extra straw. I lifted up the front of the hutch and I guess the door must have slid open, and then got stuck so that when I lowered the front of the hutch it stayed open. Anyway, to cut a long story short, in the morning I found poor Snowdrop squashed flat on the road. I tried to scrape her off with a spade but unfortunately she was frozen stiff and was stuck fast to the tarmac. The ice was too thick and the traffic too heavy to give me time to work at it properly, so I gave up. What do you think I did so that Katy wouldn’t be upset by seeing Snowdrop squashed like that when she went to school?’
‘Knowing you, John, I should think it was something pretty unlikely’
‘Not at all. I only did what any caring father would do: I went to the kitchen and got some gravy browning and poured it over the poor dead creature. When Katy saw it as we drove out of the gates at least she knew that it was not Snowdrop that had been so silly as to cross a busy road.’
Sheila laughed, but managed to find me some halothane.
That evening I carefully lifted Rudolph into a bucket, stroked the back of his neck and poured the halothane onto the straw I had put at the bottom of the bucket. Then I covered it with a small sheet of plywood that I had found in the garage.
Rudolph struggled for a moment or two and then was still. I waited for five minutes before I lifted the lid. Rudolph was unconscious. I injected the thiopentone into his belly.
Later I buried him in the garden.
‘Sheila, there is a fascinating article in New Scientist this week, all about actin and myosin you know, the special proteins you have inside your muscles to make them contract. It seems that we have similar proteins inside most of our nonmuscle cells too, including brain neurones and blood platelets.’
‘Platelets, eh? That’s interesting. Perhaps they’re the things that make blood clots retract.’
‘Yes, almost certainly they are. The article actually says that the peculiar phenomenon of clot retraction ... appears to account for their unusally high content of actin and myosin. Apparently actin and myosin don’t just occur in higher animals; they also play a part in the motility of primitive organisms such as slime mould amd amoeba.’
‘Slime mould? That sounds nasty What on earth is it?’
‘Oh, its some sort of unicellular creature that lives in slime, exactly as its name suggests. I first heard about it at the ARS a couple of years ago when I gave that terrible talk, which I hadn’t prepared properly, on ethylene and cell division; it makes me go hot and cold just to think about it. Anyway one of the other papers was from Northwick Park; it described how anaesthetic agents, includung halothane, produced a narcotic effect on slime mould; the mould lost its pseudopodia and stopped its normal directional streaming motion. They thought this showed an effect on microfilaments in the cytoplasm and suggested this might be important in the production of anaesthesia. Apparently colchine, which, as you know, affects microtubules, did not affect the slime mould, but some stuff called cytochalasin B, which affects microfilaments, did the same thing as the halothane.’
‘It seems a bit far-fetched to me to jump from this slime mould stuff to anaesthesia in man. It would probably be much better to look at clot retraction; at least platelets are warmblooded and human, not cold and slimy.’
‘Yes, that’s true. Let’s do it, then.’
‘It might be a easier to use clots from platelet-rich plasma rather than whole blood.’
‘Yes, I suppose so. It would be less messy, anyway.’
‘I was thinking that as it’s the platelets that cause a clot to retract, there wouldn’t be any point in confusing the issue with all the other blood cells.’
‘No, I suppose not. It would certainly be simpler than looking at contractile proteins in brain.’
Over the next few days I did some reading in the library. I learnt that up to 2% of the weight of platelets was actin and myosin, and that cytochalasin B was a fungal metabolite. I looked up the abstract of the paper given to the ARS on slime mould:
In 1968, Allison and Nunn proposed a possible mechanism of anaesthesia based on the interaction of inhalational anaesthetics with protein molecules, of which the effect on microtubules was an example.
I remembered that paper well. Not that I had read it when it was published in 1968, for I had missed it altogether at the time, but we had come across it later when we were studying ethylene (see chapter 8).
Currently, microtubules are believed to maintain the shape of cells, while microfilaments are related to functions requiring movement of cells or cell constituents. Microfilaments are protein structures located in the peripheral cytoplasm of most animal cells. Their actin-like nature is shown by their ability to bind heavy meromyosin to form distinctive ‘arrowhead’ structures seen in electron microscopy.
I tried to remember if they had taught me anything about ‘arrowhead’ structures when I was doing physiology at Cambridge. I couldn’t remember anything, but then, of course, the electron microscope had not been invented till the sixties.
Amoeboid movement in the cellular slime mould, Dictyostelium discoideum, is one form of cellular motility believed to be mediated by microfilaments.
It went on to discuss the group of substances called ‘cytochalasins’ which were produced by a fungus with an equally strange name and which were thought to be specific inhibitors of microfilament function. They had exposed slime mould to a variety of anaesthetics and had showed that the ‘narcotic’ effect they produced (rounding of the cell and loss of streaming motion) was mimicked by cytochalasin B but not by colchicine, nor, strangely enough, by diethyl ether which seemed to be odd man out among the six anaesthetics they had tried. Very curious!
We adjusted the concentration of platelets in the plasma so that it was constant. Then we put measured exact volumes of it into small glass bottles, which we had previously weighed, and added some calcium chloride solution which reversed the effect of the anticoagulant. When the clots had formed, we left them undisturbed at 37oC to give them time to retract. Sixty minutes later we removed the shrunken clots from the bottles, which we then weighed to see how much serum had been expressed by the clot as it had retracted. It was simple enough in principle but it needed all the concentration and care that Sheila could give it. She persuaded Des, one of the anaesthetic registrars, to lend her a hand; I was considered far too clumsy and impatient to be trusted.
We carried out the experiments in groups of seven to ten bottles at a time, depending on how many platelets we had available. Each experimental group had its own individual contols. The experimental treatments were with halothane, methoxyflurane, colchicine or cytochalasin.
When we studied our results we found that at clinical dose levels both halothane and methoxyflurane enhanced the retraction of the clots, though higher doses inhibited it, as also did colchicine and cytochalasin at high concentration, though the effect of colchicine was only transient.
‘So, Sheila,’ I said, ‘it looks as though inhibition of microfilament function may not be as important in the production of narcosis in man as those slime mould studies suggested. We’ll write it up and send it off to Nature.’
It took me a surprisingly long time to get the paper written. I found myself hunting for reasons to justify using platelets in the first place. The truth was that platelets had been easy to come by, and using them had fitted in well with the laboratory skills that Sheila possessed. I had a lurking fear that we had not been as scientific about it all as we might have been.
Finally it was finished. Des was by this time working in Exeter. I could not resist sending him a telegram: ‘Paper sent off to Nature this day. Fame is the spur’.
Within forty-eight hours the paper was back on the front door mat. It seemed that we were just one of ‘Nature’s rejects’. Still it had been presumptious of me to send it to Nature in the first place. I rewrote bits of it and then I put it in a drawer for several months.
It was summer 1975 before I sent it off to the American journal Anesthesiology. I was sure they would be interested. It was a shock some nearly three months later when they too rejected it. The editor wrote:
I regret that we are unable to accept for publication your paper ‘Enhancement of Human Platelet Clot Retraction by Halothane amd Methoxyflurane at Clinical Dose Levels’. The main reason is that the experimental model employed, the methods used in the study of this model, and the data derived from it are insufficient to support the inferences as to what to what it all means. The hypothesis that these data are relevant in terms of understanding the mode of action of inhalation anesthetics is couched in cautious terms and even with disclaimers, but nevertheless the hypothesis is presented, and the data must be adequate to prove or disprove the hypothesis. Caution and disclaimers cannot offset the fact that the material presented does not and, indeed, cannot either prove or disprove that a microfilament related process is critical in the mechanisms of anesthesia.
Well, John, put that in your pipe and smoke it! Of course, I knew that what he said was true enough; it was the very reason why I had put in the ‘caution and disclaimers.'
‘Sheila, that does it,’ I said. ‘He thinks I have been wasting my time and yours. It’s definitely time I went back to looking after old ladies in an NHS post rather than trying to mix clinical anaesthesia with basic research. I should have stuck to looking at straightforward clinical problems, and not allowed myself the luxury of wondering how anaesthetics worked. I’ll apply for the next NHS post that comes up at Southmead.’
Later I wrote to Cedric:
Enclosed is the summary that I promised you concerning our researches at Southmead. I am sorry about the delay. The truth is that I have been waiting to see if my currently depressed mood about my research activities would lift. You may remember that the first time that you came to Southmead I told you that I was not pleased with the way things were going. I have always been a peaks-and-troughs individual about my research, ...
This was not really true; always had a grasshopper mind, was nearer the mark.
... but this year the troughs have tended increasingly to run into one another.
Well, it was certainly true that I was seriously wondering if I was in the right job. Of course, if I had never tried a university post I would always have wondered whether I should have been an academic or not.
Anyway I am off to Sweden later this month where I will throw myself fully into clinical work for four weeks. It may be that I will feel quite differently when I return, but if not then I will probably apply for one of the two NHS posts that are coming up at Southmead... In the meantime I am sorry to be away from Bristol when you arrive, but the school fees have to be paid somehow.
It was my own fault really. If I had not got this inbuilt thing against doing private practice I would not have to go to Sweden during my holidays to earn extra money to pay the fees at Bristol Grammar School. Still at least the Swedish Health Service paid you much better than the NHS; it was a pity that both the Swedish and the UK tax people wanted their cut.
I glanced at the summary I was sending to Cedric:
RESEARCH AT SOUTHMEAD
1. Cell Cycle Studies
We first became involved with cell cycle studies when we investigated the phenomenon of the hormonal effects of ethylene on plants (comparing them with the effects of anaesthetic agents). At this time Bruce was claiming that anaesthetics predominantly affected DNA synthesis, and Nunn that they predominantly affected metaphase. Using plant material we satisfactorily demonstrated that all phases of the cell cycle, including all phases of mitosis, were depressed by halothane.... We are currently looking at the possibility of using the papillae of human hairs as a source of rapidly dividing cells to study before, during and aftr clinical anaesthesia. If successful it would be a great step forward for us, as we have been looking for some time for a site at which to study cell division in patients themselves.
I liked that idea immensely, but I wondered if I would ever get around to doing it. Probably not.
2. Chromosome damage
Chromosome damage has not been demonstrated in cells that have been examined immediately after exposure to anaesthetic agents. However this is probably not the most appropriate time to look for it. In order to decide whether it was worth the effort of further studies in man we have looked quickly again at plants (which are easy to handle and have only a few chromosomes). We have just reported the detection of abnormal chromosome complements at the mitosis one after the mitosis that was exposed to halothane.It would seem, therefore, worthwhile to look again at mammalian systems, and we are appraoching the cytogeneticists to consider the feasiblity of further studies with human lymphocytes. A possible alternative mammalian soucre of lymphocytes would be the Wallaby, whose chromosome number is low (2u = 10) which would lead to greatly simplified methodology (other than getting the blood samples).
I did like the idea of using Wallaby cells. It appealed to the child in me.
3. Nonmuscle Contractile Proteins
Least said the better, eh? At the end of this bit I had written:
If further in vitro studies are to be attempted it would seem better to be more direct and use models containing mammalian brain actomyosin. It would, for instance, be interesting to compare the action of anaesthetics with that of cytochalasin B (an inhibitor of microfilament function) on uptake and release of transmitters by synaptosomes or brain slices.
Sounded very grand, I thought, but I knew there was no chance that I would ever get around to that sort of research now.
Some months later a new NHS consultant post at Southmead was advertised. I duly put in my application, in which I wrote:
My research activities have become progressively more directed towards the fundamentals of why anaesthetic agents work, and what their effects are at a cellular level. Interesting though this has been, I have slowly come to realise that a clinician cannot do this type of work as satisfactorily as someone totally committed to basic research. It is for this reason that I wish to adjust the emphasis off my work, and to concentrate more on patient care and teaching, although I feel sure that I will always continue to do some research.
I felt this was a critical time for me. I knew that if I did not get the post I would have to move, because it could only mean I had not got the support of my colleagues at Southmead; that would be something that I would not be able to live with if I stayed where I was. Iain, who was my only rival at the interview, said
‘I’m sorry to be competing against you, John, but I’m only doing it to make sure they realise I want the next job that comes up.’
‘That’s all right,’ I said. ‘By the way what’s your pulse rate doing? Mine’s is 106 per minute.’
He looked surprised at my question, but politely counted his pulse nonetheless.
It was a great relief to me when they did offer me the post; some months later Iain landed the next one as he had wanted.
I think Cedric was pleased to be getting me off his hands; after all I was a couple of months older than he was, and he was planning to fill my old position with younger blood.
He phoned me up and said he was bringing someone from Oxford over to Southmead to see the setup.
‘I’ll bring Peter over to Southmead for a look around. We’ll arrive about 2 o’clock.’
After lunch, while I waited for Cedric to arrive, I took a golf club down to the playing field and swung the club a few times. I had just hit an atrocious hook when Cedric’s car swung round the corner. It turned out that Peter was a keen golfer.
When they had gone, I said to Sheila:
‘He seems a nice young man, doesn’t he? I know I am the last of the ungifted amateurs as far as research is concerned; I hope Peter proves himself to be the first of the gifted professionals in this post.’
‘Oh, I’ll settle for a gifted amateur,’ she replied.
‘John,’ said Clive, ‘I’ve had a letter from one of the local GPs about a patient called Hubbard. He’s an old man with a bladder tumour we’ve been reviewing on and off since 1968. Do you remember him?’
I nodded. ‘Hubbard? Yes, that name is familiar. Isn’t he is the old chap who always feels queasy if he has an opiate premed? In his eighties, I think. He’s been fine since I stopped anyone giving him any unnecessary opiates. What about him?’
‘Well, apparently he got jaundiced three weeks after an anaesthetic at the end of 1977 and now he is jaundiced again. His GP wonders if it could have been related to halothane anaesthesia.’
Clive handed me the letter.
‘Halothane hepatitis, eh? I really don’t think there is such a thing, you know. Anyway I’ll get the notes out and see what the story adds up to.’
‘OK, John. See you on Friday.’
Although I asked for them straightaway the notes did not did not arrive from medical records till the Friday. I took them to theatre with me.
‘Clive, I’ve got Mr Hubbard’s notes here. I’ll have a look through them. Let me see now. His first anaesthetic in this hospital was in August 1968. He said at the time that anaesthetics in the past had always "‘turned his stomach", so he was given an epidural, but I see he was also given some Pethidine as a premed, and some more Pethidine intravenously during the operation, which is probably why he was sick afterwards. He has had thirteen anaesthetics in the last eleven years; till 1975 they always included an opiate of some sort, Omnopon or Pethidine or Fentanyl, and he was always sick; since then he has not had any opiate and he has not been sick. He has had two futher halothane anaesthetics since the episode of jaundice in 1977. These caused no problems, and listen to this: apparently he had an episode of jaundice thirty years ago and his gallbladder was removed. Even if he is jaundiced now, it is nine months since his last anaesthetic, so I think we can that rule out as a factor.
‘I’ll write to his doctor and suggest that he investigates him to see if he has a stone in his common bile duct.’
I heard later that the jaundice subsided after a few days and, in view of his age, he did not get any special X-rays at that time.
About four months later Mr Hubbard, breathless and semiconscious, was admitted to the hospital as an emergency; he was suffering from severe bronchopneumonia. Despite treatment he died after three days.
At post-mortem examination the diagnosis of bronchopneumonia was confirmed; the pathologist also found a stone, 1.5cm in diameter, in the lower common bile duct; the duct itself was markedly distended. Obviously it had intermittently been obstructing the flow of bile, so producing the episodes of jaundice.
So much for halothane hepatitis!
The Medical School building looked friendly enough in the bright sunlight. As I parked the car a pretty girl walked by and I felt my spirits, already high, lift higher.
When I entered the Medical School I met many old friends and soon we were drinking coffee, and talking and laughing. What a splendid thing it was to attend a have a day away from routine work The meeting I was going to attend was on Halothane and the Liver, the problem revisited; it was sure to be interesting.
The first speaker was from Flinders University in Australia. He reviewed the causes of jaundice occurring after operations and pointed out that anaesthetic drugs were probably way down the list. He presented some of his research using rats and guinea pigs and he made out a good case for there being a genetic predisposition for a patient to develop liver failure after halothane. Possibly the halothane was broken down in the body in an unusual way in some people and this might become more important if they were exposed to it on one or more previous occasions.
The second speaker was a world renowned expert on liver diseases from King’s College Hospital in London. I was most interested to see and hear him as I had often read articles he had written, which usually had taken a strong stand about the dangers of halothane as a liver poison. I felt a slight animosity stirring inside me, but I knew that it was stupid of me to allow it to happen. As the talk progressed I began to realise that I was indeed listening to a real expert who was setting out his views clearly and unemotionally. The Liver Unit where he worked had dealt with 53 cases of unexplained liver failure after halothane between 1968 and 1985. In the world literature there were, up to 1982, 690 cases who had been labelled ‘halothane hepatitis’, of whom 338 (49%) had died. During this time, I thought to myself, there had been more than fifty million halothane anaesthetics given, so that the incidence was remarkably low. The figure of one in twenty or thirty thousand cases was being bandied around but quick calculation ( 50 million / 338) made the incidence of death from liver failure after halothane more like 1 in 150,000 probably safer than travelling from London to Glascow on the motorway Anyway, I guessed it probable that halothane was only one of a number of factors involved in the story.
The next speaker was an immunologist, also from King’s College Hospital. He told us about experiments in which he and his colleagues had exposed white rabbits to 1% halothane for 45 minutes. After allowing them to recover fully, so that breakdown products of halothane could be formed, they had killed them and chopped up their livers to use as a source of ‘halothane antigen’. Apparently many patients with halothane hepatitis had antibody in their serum which reacted with the rabbit liver cells. He reckoned this test would be a valuable aid to the diagnosis of halothane hepatitis.
I wondered about it. I remembered reading a similar claim in the early seventies (or was late sixties?) about lymphocytes from patients who had had halothane hepatitis transforming when exposed to halothane in culture, but this had not proved to be reliable. My thoughts at this stage started to wander away from halothane towards on sherry and lunch, but I made an effort to listen to the discussion that followed. Finally, Cedric, from the chair, summed up by saying
‘I think this morning our discussions and presentations have led us to the inescapable conclusion that halothane can cause a specific immnologically identifiable hepatic injury, leading to fulminant hepatic failure.’
I suppose I was convinced, after all I had to be, but it was certainly extraordinarily rare I had been using halothane for twenty seven years now and I had never seen a case. I wondered how many halothane anaesthetics I had given; if my average was 20 a week that made over 27,000. Cedric continued
‘Clearly, if we anaesthetists totally cease to use halothane we should no longer see this entity. However, in doing so we will deny millions of patients an economically and medically appropriate anaesthetic. This then is the dilemma we face.’
Very nicely put. Now, surely, it was time for lunch.
The afternoon session began with a paper by one of the consultants from the BRI, Brian, who had organised the meeting and whose wife Jean had taught Katy at school. He spoke about current practice in the use of volatile agents. He had sent out a questionnaire to colleagues in the SouthWest and in Cardiff. During 1984 nad 1985 the cases where halothane had been used had varied from 58% to 75%. While most of the people who had replied to his questionnaire recognised that there was a ‘repeat halothane’ problem, one of them regarded the literature on the subject as hysterical. I could not help but agree with him.
In the summary at the end of his talk Brian said:
Halothane is a popular, safe and enormously successful anaesthetic agent, and has brought comfort to millions of patients. While the vast majority of anaesthetists accept the problem of repeat exposure to halothane, considerable controversy surrounds the nature of the problem and methods for its prevention. The fact that some 5000 people will die as a result of road accidents this year has not prevented me, nor any of the speakers, from using private transport. Similarly, I think halothane will continue to have a role in anaesthetic practice, although a modified one, despite its unfortunate and very small risk of serious liver dysfunction.
The next two speakers dealt with the alternatives to halothane that were available, including intravenous agents. Next came a paper on the legal aspects of halothane anaesthesia, which was fascinating. Then there was a final discussion and a final summing up by Alistair, the professor in Edinburgh. A thoroughly stimulating and useful day.
When I got home I told Isabel all about it.
‘I can see that the days of halothane are numbered,’ I said. ‘It’s a pity really; it’s such a splendid drug.’
Over these last six years the use of halothane at Southmead has fallen by 90%, though it still retains a place in our armamentarium. Its low cost, relative to the newer agents ethrane and isoflurane, ensures that it will continue to play a major role in the provision of anaesthesia in countries where costs are paramount. Our local ICI representative occasionally whispers to me that it may even now be making a comeback in the UK, but I doubt it. Still ICI can console itself with the amazing success of Diprivan, its new intravenous anaesthetic, which must surely be keeping the shareholders happy and good luck to them too.
 Nevill Clunes. Shakespeare and the medical profession. Guy’s Hospital Gazette, 1956.
 Johnstone, M. The human cardiovascular response to Fluothane anaesthesia. Brit. J. Anaesth., 1956; 28: 392.
Bryce-Smith R., O’Brien HD. Some observations on Fluothane. Proceedings of the Royal Society of Medicine, 1957; 50: 193.
 Cecil Gray is renowned, together with G Jackson Rees, for the introduction of the ‘Liverpool technique’ of anaesthesia in which narcosis, analgesia, relaxation were obtained by the use of selective drugs, and could be varied independently. Gray later redefined these components as narcosis, reflex suppression and relaxation[b]. Later he became Professor of Anaesthesia at Liverpool, Dean of the Medical School there, and was knighted for services to medicine. He was, nevertheless, quite wrong in his prediction about halothane!
[a] Gray TC, Rees GJ. Brit. J. Anaesth., 1950; 22: 83.
[b] Gray TC. Ir. J. Med. Sci., 1960; 419: 499.
 These figures are discussed more fully in chapter 7, 1967.
 Bunker JP, Forrest WH, Mosteller F, Vandam LD. The National Halothane Study, US Government Printing Office, Washington DC, 1969.
 Virtue RW, Payne KW. Post-operative death after Flothane. Anesthesiology, 1958; 19: 562.
 Riddle PR, Berenbaum MC. Postoperative depression of the lymphocyte reponse to phytohaemagglutinin. Lancet, 1967, April 8th: 746
 Adelstein R. Actin and myosin in non-muscle cells. New Scientist, 1974, 7th February: 346.
 Wiklund RA, Allison AC. The effects of anaesthetics on the motility of Dictyostelium discoideum: evidence for a possible mechanism of anaesthesia. Brit. J. Anaesth.,1972; : 622.
 Allison AC, Nunn JF. Effects of general anaesthetics on microtubules. Lancet, 1968 ii: 1326.
 The proceedings of this symposium, Halothane and the Liver; the problem revisited, was subsequently published by the Sir Humphry Davy Department of Anaesthesia, Bristol Royal Infirmary, 1986.
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