Anaesthesia, 1992, Volume 47, pages 1-2
Editorial A golden jubilee to celebrate ‘A purified extract of curare (Intocostrin) has been administered intravenously to 25 patients under light general anesthesia. In each case temporary but complete muscular relaxation was rapidly produced with apparently no harmful effect’. Fifty years ago, Griffith and Johnson [I] thus summarised the results of their historic clinical trial of Intocostrin (Squibb), the first relaxant to be used with posological reliability. Their first patient was treated on Friday, 23 January 1942, in the Homeopathic Hospital, Montreal. Their report was free of drama and sensationalism. If there were any excitement in the operating theatre on that day, it is, perhaps, suggested in the description of an abdomen, ‘as soft as dough’. Nevertheless, a revolution in the treatment of the patient undergoing surgery had started, hardly less radical than that which followed the clinical trials of ether by Clark of Rochester, New York and Crawford Long of Jefferson County, Georgia which took place almost exactly a century earlier. It is fitting in this jubilee year to review the events which led up to that climactic experiment in Montreal and to examine its effects. That first paper was typical of Harold Griffith, a quiet and rather shy man. He sought neither fame nor greatness, but he was indeed to achieve both and to receive international acclaim and distinction. With characteristic humility and commendable honesty he has related how, 2 years previously, when Dr Louis H. Wright of New York, suggested to him that curare might be useful in anaesthesia, he ‘laughed at the idea’[2]. Then he thought about it for more than a year and, after further persuasion by Wright, he succumbed. The story leading to such a denouement on that Friday in Montreal was an example of how many discoveries in medicine are the result of prodromal events which have demanded imagination and courage. In 1938-39, on the suggestion of McIntyre [3], Professor of Physiology and Pharmacology at the Nebraska School of Medicine, Dr Bennett had demonstrated the removal of the traumatic effects of convulsive therapy by a prophylactic dose of a curare preparation which had been extracted from a known plant source in McIntyre’s laboratory. It was standardised by acetylcholine antagonism, using the frog gastrocnemius preparation. Bennett later used Intocostrin and his results were reported in January 1940 [4]. It must have been around that time that Wright made his suggestion to Griffith. Another remarkable man, in a story featuring several such, was Richard Gill [5]. He played a key role. In 1932, Gill developed multiple sclerosis. Whilst in a severe relapse and suffering painful muscle spasms, he developed an obsessional interest in the therapeutic potential of the South American arrow poison. He had studied the Indians’ method of preparing it and the materials used whilst he was working for a rubber company on a station in the Ecuadorian rain forest. His obsession resulted, in 1938, in an expedition to Ecuador of 6 months’ duration. He returned with a huge consignment of the plants which became the source from which
0003-2409/92/010001+ 02 %03.00/0
McIntyre prepared his extract and Squibb their Intocostrin. In recalling these events, however, it should not be forgotten that there had been attempts before Griffith to use curare during anaesthesia: by Lawen [6] in Leipzig, in 1912, and in London, in 1928, when de Caux, at the North Middlesex Hospital, used an aqueous extract of curare to supplement nitrous oxide, oxygen anaesthesia [7]. Like other physicians of the time, who attempted to use the arrow poison in the treatment of various convulsive and spastic conditions, they were frustrated by the unpredictable effect of their preparations. However, we in Britain cannot claim to have been quickly off the mark. During the war communications were difficult and American anaesthetic journals were not easily obtained and, when this new development was rumoured or confirmed, it was far from easy to obtain Intocostrin. It is certainly tantalising to recall that Harold King, a chemist working in London in the Medical Research Institute, published a paper in 1935, announcing his successful extraction from tube curare of its active principle, the crystalline alkaloid d-tubo curarine [8]. It was in fact July 1945 before the first papers on the use of curare in anaesthesia appeared ip the British medical press. Mallinson [9] described a series of 40 patients to whom he had given Intocostrin during anaesthesia. In the same issue of the Lancet, Griffith [2] reviewed his experiences with Intocostrin and ‘a new preparation, d-tubocurarine’ and ended his review with the modest opinion that ‘it will probably have a permanent place in anaesthesia’. Since the summer of 1944, as the result of a fraternal relationship with ’Medical Officers of an American Bomber Squadron, stationed at Burtonwood, work had been proceeding on Merseyside, using at first Intocostrin and very soon, as supplies of the American preparation dried up, tubocurarine [lo]. In January 1946, a series of abdominal and thoracic operations in which tubocurarine was used was described to a meeting of the Liverpool Medical Institution and a larger series of over 1000 cases presented to the Section of Anaesthetics of the Royal Society of Medicine 3 months later [I I]. In the early days, curare was considered just as another useful tool in the anaesthetist’s bag which would help to avoid the embarrassing protrusion of the abdominal contents on closure of the abdomen. Some of the writer’s generation will remember the use of a tablespoon by the surgeon on occasions when the patient was ‘too light’! Now, not only was the tablespoon banished but so also was that bane of the anaesthetist, laryngeal spasm. From the patient’s viewpoint, the benefits were manifest. Severe attacks of pneumonia, sometimes fatal, which not infrequently used to follow upper abdominal operations, became rare, provided that full recovery of respiratory function was achieved, if necessary by the use of the antidote neostigmine. Failure to assure this, before returning patients to the ward, accounted for the dire results reported in 1953 from 10 University Hospitals in the United States [12]. But the most beneficial effect of curare was to make
@ 1992 The Association of Anaesthetists of Gt Britain and Ireland
1
2
Editorial
deep anaesthesia a thing of the past. As early as 1944, Knight noted that the use of curare ‘helps us to realise that deep general anaesthesia is more damaging and more shock producing than even the trauma of surgery’ [13]. Rapid recovery became the norm as did absence of the toxic effects of anaesthetic drugs. Circulatory disturbances were minimised. Indeed, in the 1940s and 1950s, a change occurred in the practise of anaesthesia of a magnitude which, must be difficult for the practitioner of today fully to imagine. An enormous amount of research has been carried out during these 50 years and many synthetic relaxant drugs produced as subsitututes for tubocurarine. It is, perhaps, fair to suggest that two may be regarded as markers for future development: suxamethonium, introduced in 1951, because of its short action, and the more recently produced atracurium, the first relaxant to have a mode of degradation independent of hepatic and renal functions. So, there can be no question that patients benefited directly from the event of January 1942, but there were other very important effects which were of indirect benefit to them. Instead of being limited to thoracic units IPPV became a feature of daily practice with farreaching results in the treatment of paralytic conditions such as poliomyelitis, severe neuropathies and myasthenic conditions. With better understanding of blood gas and electrolyte disturbances the way was paved towards intensive therapy. The respiratory management of the paralysed patient demanded the pursuit of knowledge of respiratory physiology and of pharmacology of a standard which was daunting to many anaesthetists of the time. Anaesthesia had developed from a clinical art into a clinical science. When, in 1946, the National Health Service was being planned, there was serious debate, in the corridors of power, as to whether practitioners in some specialties would merit consultant status and the grade of Senior Hospital Medical Officer was created. Anaesthesia was one such specialty. In the opinion of the writer, it is reasonable to suggest that a main factor which led to a decision in favour of the consultant grade for anaesthetists was this change from empiricism to science, a change which extended the horizons of both anaesthetists and surgeons. Education in the basic sciences thus became imperative. A two-part Diploma in Anaesthetics replaced the one-part examination and there arose the compelling need for a qualification of the same standard as that of a Fellowship in a Royal College. There was strong support from senior surgical colleagues and from anaesthetists [ 141. The threat to the future of the specialty was finally removed
when, in 1948, a Faculty of Anaesthetists was formed within the Royal College of Surgeons. There is to be a commemorative meeting in Montreal from 21-24 May 1992. In the half-century, there has been significant clinical and scientific work performed in the field of relaxants on this side of the Atlantic and it is to be hoped that a strong representation from the United Kingdom will be able to attend and make a worthy contribution. Griffith was affectionately known as ‘Uncle Harold’. It is thanks to his daring that there is indeed much for anaesthetists, surgeons and patients to celebrate in this 50th year. T. C. GRAY
6 Ravens Meols Lane,
Formby, Liverpool L37 4DF
References [I] G R I ~ T HHR, S JOHNSON GE. The use of curare in general anesthesia. Anesthesiology 1942; 3 418-20. HR. Curare as an aid to the anaesthetist. Lancet [2] GRIFFITH 1945; 2 74-5. [3] MCINTYRE AR. Curare. Its history, nature and clinical use. Chicago: University of Illinois Press: 192. [4] BENNETTAE. Preventing traumatic complications in convulsive shock therapy by curare. Journal of the American Medical Association 1040; 1 1 4 322-4. [5] HUBBLE RM. The Gill-Merrill expedition. Anesthesiology 1982; 57: 519-26. [6] LAWENA. Ueber die Verbindung der Lokal-anasthesie mit der Narkose, iiber hohe Extraduralanasthesie und epidurale Injectionen anasthesierenderLosungen bei tabischen Magenkrisen. Beitrage zur klinischen Chirurgie 1912; 80: 168-89. [7] WILKINSON DJ. Dr F.P. de Caux updated. Proceedings of the History of Anaesthesia Society 1988; 4 4-17. [8] KINGH. Curare alkaloids 1. Tubocurarine. Journal of the Chemical Society 1935; 57: 1381-9. [9] MALLINSON FB. Curare in anaesthesia. Lancet 1945; 2 75-6. 101 GRAYTC. Luck was a lady. In: ATKINSON RD,BOULTON TB, eds. The history ofanaesthesia. London; Royal Society of Medicine: 1989: 16. II] GRAYTC, HALTONJ. A milestone in anaesthesia? (dTubocurarine Chloride). Proceedings of the Royal Society of Medicine 1946; 39:400-8. 121 BEECHER HK, TODDDP. A study of the deaths associated with anesthesia and surgery. Annals of Surgery 1954; 140: 2-35. 131 Knight RT. The use of curare in anesthesia. Minnesota Medicine 1944; 27: 667-8. [ 141 Association News. Anaesthesia 1948; : 74-8 I .
Editorial notices
-
Manuscripts must be submitted in accordance with the internationally recognised Uniform requirements for manuscripts submitted to biomedical journals (British Medical Journal 1979: 1: 423 5). Details will be found in the Notice to Contributors to Anaesthesia at the end of this issue.
Editorial A golden jubilee to celebrate ‘A purified extract of curare (Intocostrin) has been administered intravenously to 25 patients under light general anesthesia. In each case temporary but complete muscular relaxation was rapidly produced with apparently no harmful effect’. Fifty years ago, Griffith and Johnson [I] thus summarised the results of their historic clinical trial of Intocostrin (Squibb), the first relaxant to be used with posological reliability. Their first patient was treated on Friday, 23 January 1942, in the Homeopathic Hospital, Montreal. Their report was free of drama and sensationalism. If there were any excitement in the operating theatre on that day, it is, perhaps, suggested in the description of an abdomen, ‘as soft as dough’. Nevertheless, a revolution in the treatment of the patient undergoing surgery had started, hardly less radical than that which followed the clinical trials of ether by Clark of Rochester, New York and Crawford Long of Jefferson County, Georgia which took place almost exactly a century earlier. It is fitting in this jubilee year to review the events which led up to that climactic experiment in Montreal and to examine its effects. That first paper was typical of Harold Griffith, a quiet and rather shy man. He sought neither fame nor greatness, but he was indeed to achieve both and to receive international acclaim and distinction. With characteristic humility and commendable honesty he has related how, 2 years previously, when Dr Louis H. Wright of New York, suggested to him that curare might be useful in anaesthesia, he ‘laughed at the idea’[2]. Then he thought about it for more than a year and, after further persuasion by Wright, he succumbed. The story leading to such a denouement on that Friday in Montreal was an example of how many discoveries in medicine are the result of prodromal events which have demanded imagination and courage. In 1938-39, on the suggestion of McIntyre [3], Professor of Physiology and Pharmacology at the Nebraska School of Medicine, Dr Bennett had demonstrated the removal of the traumatic effects of convulsive therapy by a prophylactic dose of a curare preparation which had been extracted from a known plant source in McIntyre’s laboratory. It was standardised by acetylcholine antagonism, using the frog gastrocnemius preparation. Bennett later used Intocostrin and his results were reported in January 1940 [4]. It must have been around that time that Wright made his suggestion to Griffith. Another remarkable man, in a story featuring several such, was Richard Gill [5]. He played a key role. In 1932, Gill developed multiple sclerosis. Whilst in a severe relapse and suffering painful muscle spasms, he developed an obsessional interest in the therapeutic potential of the South American arrow poison. He had studied the Indians’ method of preparing it and the materials used whilst he was working for a rubber company on a station in the Ecuadorian rain forest. His obsession resulted, in 1938, in an expedition to Ecuador of 6 months’ duration. He returned with a huge consignment of the plants which became the source from which
0003-2409/92/010001+ 02 %03.00/0
McIntyre prepared his extract and Squibb their Intocostrin. In recalling these events, however, it should not be forgotten that there had been attempts before Griffith to use curare during anaesthesia: by Lawen [6] in Leipzig, in 1912, and in London, in 1928, when de Caux, at the North Middlesex Hospital, used an aqueous extract of curare to supplement nitrous oxide, oxygen anaesthesia [7]. Like other physicians of the time, who attempted to use the arrow poison in the treatment of various convulsive and spastic conditions, they were frustrated by the unpredictable effect of their preparations. However, we in Britain cannot claim to have been quickly off the mark. During the war communications were difficult and American anaesthetic journals were not easily obtained and, when this new development was rumoured or confirmed, it was far from easy to obtain Intocostrin. It is certainly tantalising to recall that Harold King, a chemist working in London in the Medical Research Institute, published a paper in 1935, announcing his successful extraction from tube curare of its active principle, the crystalline alkaloid d-tubo curarine [8]. It was in fact July 1945 before the first papers on the use of curare in anaesthesia appeared ip the British medical press. Mallinson [9] described a series of 40 patients to whom he had given Intocostrin during anaesthesia. In the same issue of the Lancet, Griffith [2] reviewed his experiences with Intocostrin and ‘a new preparation, d-tubocurarine’ and ended his review with the modest opinion that ‘it will probably have a permanent place in anaesthesia’. Since the summer of 1944, as the result of a fraternal relationship with ’Medical Officers of an American Bomber Squadron, stationed at Burtonwood, work had been proceeding on Merseyside, using at first Intocostrin and very soon, as supplies of the American preparation dried up, tubocurarine [lo]. In January 1946, a series of abdominal and thoracic operations in which tubocurarine was used was described to a meeting of the Liverpool Medical Institution and a larger series of over 1000 cases presented to the Section of Anaesthetics of the Royal Society of Medicine 3 months later [I I]. In the early days, curare was considered just as another useful tool in the anaesthetist’s bag which would help to avoid the embarrassing protrusion of the abdominal contents on closure of the abdomen. Some of the writer’s generation will remember the use of a tablespoon by the surgeon on occasions when the patient was ‘too light’! Now, not only was the tablespoon banished but so also was that bane of the anaesthetist, laryngeal spasm. From the patient’s viewpoint, the benefits were manifest. Severe attacks of pneumonia, sometimes fatal, which not infrequently used to follow upper abdominal operations, became rare, provided that full recovery of respiratory function was achieved, if necessary by the use of the antidote neostigmine. Failure to assure this, before returning patients to the ward, accounted for the dire results reported in 1953 from 10 University Hospitals in the United States [12]. But the most beneficial effect of curare was to make
@ 1992 The Association of Anaesthetists of Gt Britain and Ireland
1
2
Editorial
deep anaesthesia a thing of the past. As early as 1944, Knight noted that the use of curare ‘helps us to realise that deep general anaesthesia is more damaging and more shock producing than even the trauma of surgery’ [13]. Rapid recovery became the norm as did absence of the toxic effects of anaesthetic drugs. Circulatory disturbances were minimised. Indeed, in the 1940s and 1950s, a change occurred in the practise of anaesthesia of a magnitude which, must be difficult for the practitioner of today fully to imagine. An enormous amount of research has been carried out during these 50 years and many synthetic relaxant drugs produced as subsitututes for tubocurarine. It is, perhaps, fair to suggest that two may be regarded as markers for future development: suxamethonium, introduced in 1951, because of its short action, and the more recently produced atracurium, the first relaxant to have a mode of degradation independent of hepatic and renal functions. So, there can be no question that patients benefited directly from the event of January 1942, but there were other very important effects which were of indirect benefit to them. Instead of being limited to thoracic units IPPV became a feature of daily practice with farreaching results in the treatment of paralytic conditions such as poliomyelitis, severe neuropathies and myasthenic conditions. With better understanding of blood gas and electrolyte disturbances the way was paved towards intensive therapy. The respiratory management of the paralysed patient demanded the pursuit of knowledge of respiratory physiology and of pharmacology of a standard which was daunting to many anaesthetists of the time. Anaesthesia had developed from a clinical art into a clinical science. When, in 1946, the National Health Service was being planned, there was serious debate, in the corridors of power, as to whether practitioners in some specialties would merit consultant status and the grade of Senior Hospital Medical Officer was created. Anaesthesia was one such specialty. In the opinion of the writer, it is reasonable to suggest that a main factor which led to a decision in favour of the consultant grade for anaesthetists was this change from empiricism to science, a change which extended the horizons of both anaesthetists and surgeons. Education in the basic sciences thus became imperative. A two-part Diploma in Anaesthetics replaced the one-part examination and there arose the compelling need for a qualification of the same standard as that of a Fellowship in a Royal College. There was strong support from senior surgical colleagues and from anaesthetists [ 141. The threat to the future of the specialty was finally removed
when, in 1948, a Faculty of Anaesthetists was formed within the Royal College of Surgeons. There is to be a commemorative meeting in Montreal from 21-24 May 1992. In the half-century, there has been significant clinical and scientific work performed in the field of relaxants on this side of the Atlantic and it is to be hoped that a strong representation from the United Kingdom will be able to attend and make a worthy contribution. Griffith was affectionately known as ‘Uncle Harold’. It is thanks to his daring that there is indeed much for anaesthetists, surgeons and patients to celebrate in this 50th year. T. C. GRAY
6 Ravens Meols Lane,
Formby, Liverpool L37 4DF
References [I] G R I ~ T HHR, S JOHNSON GE. The use of curare in general anesthesia. Anesthesiology 1942; 3 418-20. HR. Curare as an aid to the anaesthetist. Lancet [2] GRIFFITH 1945; 2 74-5. [3] MCINTYRE AR. Curare. Its history, nature and clinical use. Chicago: University of Illinois Press: 192. [4] BENNETTAE. Preventing traumatic complications in convulsive shock therapy by curare. Journal of the American Medical Association 1040; 1 1 4 322-4. [5] HUBBLE RM. The Gill-Merrill expedition. Anesthesiology 1982; 57: 519-26. [6] LAWENA. Ueber die Verbindung der Lokal-anasthesie mit der Narkose, iiber hohe Extraduralanasthesie und epidurale Injectionen anasthesierenderLosungen bei tabischen Magenkrisen. Beitrage zur klinischen Chirurgie 1912; 80: 168-89. [7] WILKINSON DJ. Dr F.P. de Caux updated. Proceedings of the History of Anaesthesia Society 1988; 4 4-17. [8] KINGH. Curare alkaloids 1. Tubocurarine. Journal of the Chemical Society 1935; 57: 1381-9. [9] MALLINSON FB. Curare in anaesthesia. Lancet 1945; 2 75-6. 101 GRAYTC. Luck was a lady. In: ATKINSON RD,BOULTON TB, eds. The history ofanaesthesia. London; Royal Society of Medicine: 1989: 16. II] GRAYTC, HALTONJ. A milestone in anaesthesia? (dTubocurarine Chloride). Proceedings of the Royal Society of Medicine 1946; 39:400-8. 121 BEECHER HK, TODDDP. A study of the deaths associated with anesthesia and surgery. Annals of Surgery 1954; 140: 2-35. 131 Knight RT. The use of curare in anesthesia. Minnesota Medicine 1944; 27: 667-8. [ 141 Association News. Anaesthesia 1948; : 74-8 I .
Editorial notices
-
Manuscripts must be submitted in accordance with the internationally recognised Uniform requirements for manuscripts submitted to biomedical journals (British Medical Journal 1979: 1: 423 5). Details will be found in the Notice to Contributors to Anaesthesia at the end of this issue.
