Abstract

One hundred years after Morton's demonstration of the anaesthetic effects of ether, T. Cecil Gray revolutionized anaesthesia with his introduction of balanced general anaesthesia. Gray's technique involved i.v. induction, administration of a neuromuscular blocking agent (curare), tracheal intubation, controlled ventilation, maintenance of unconsciousness with a light inhaled anaesthetic (supplemented with opioids if necessary), and reversal of neuromuscular blocking agent at the conclusion of the anaesthetic. In the 65 yr since his seminal papers, our drugs have changed, and i.v. anaesthetics suitable for maintenance of anaesthesia have been introduced, but the basic principles of general anaesthesia today are those set forward by Gray 65 yr ago.

Editor's key points

  • In this beautifully researched article, the author illustrates the enormous contribution of T. Cecil Gray to modern anaesthetic practice.

  • Gray's innovations were often achieved through remarkable, brave, unconventional, and inspirational means. Self-experimentation and smuggling accompanied running clinical and academic departments and publishing world-changing research.

  • The Liverpool technique exists today, modified only slightly by modern pharmacology and pharmaceuticals.

Forty-six is a propitious year for anaesthesia. The discovery of anaesthesia is generally dated October 16, 1846, ‘Ether Day’, when William T. G. Morton successfully demonstrated the anaesthetizing properties of diethyl ether at Massachusetts General Hospital (MGH).1 Morton's demonstration was the culmination of much previous work, including the experiments by Horace Wells in 1844 on nitrous oxide that led to an unsuccessful demonstration at MGH in 1845,2 Crawford Long's use of ether in 1842,3 and Elton Romeo Smilie's use of ethereal tincture of opium in 1846.4

On March 1, 1946, 100 yr after the discovery of anaesthesia, T. Cecil Gray set forth the principles of modern anaesthesia to the world. In a lecture delivered to the Royal Society of Medicine,5,6 Gray and Halton explained the use of curare in ∼1000 cases. In a subsequent publication later that year, Gray and Halton described the use of muscle relaxation in ‘balanced anaesthesia’, based on ∼1500 patients:7

This is essentially a balanced anaesthesia. After induction the patient is maintained in a light plane by means of an intravenous barbiturate. The curarine produces relaxation and at the same time so reduces the amount of the barbiturate which has to be used that there is no delay in recovery. The exhibition of any of the inhalational agents is possible without causing laryngeal spasm. Their addition is useful when excessive manipulation or other factors arising during the operation demand a momentary deepening of the anaesthetic plane. Only minimal amounts of these agents are ever required. With very little experience the quantity of the barbiturate, the curarine, and the inhalational anaesthetic can be so estimated that no excessive amounts of any single one of them will produce a delay in post-operative recovery. … Experience has shown that this balanced technique results in far less post-operative morbidity than if the anaesthesia were either solely inhalational or solely intravenous. … {For reversal} prostigmine {pyridostigmine} 3–5 mg. with atropine gr. 1/50 (1.3 mg) has proved an effective combination. …

Gray's description introduces modern anaesthesia: an i.v. induction, a relatively ‘light’ maintenance of anaesthesia, typically with an inhaled gas, muscle relaxation as needed by the administration of a neuromuscular blocking agent, titration of the anaesthetic for ‘momentary deepening’ of the anaesthetized state, and the use of a cholinesterase inhibitor with a muscarinic antagonist for reversal. In the same lecture, Gray spelled out the dangers of curare:6

Curare should never be used by anyone who is not fully conversant with the care of the apnoeic patient. Anoxia appears easily and is more serious, especially when there is cardiac inefficiency. Despite laboratory evidence that the drug has no cardiac action, clinically there is no doubt that with this form of anaesthesia patients do not tolerate even a slight degree of anoxaemia. … Curare should not be used in cases of intestinal obstruction with distension, unless particular care is taken to avoid the uncontrolled regurgitation of the intestinal contents in these patients whose every natural protection has been removed. … The dosage may have to be modified in the presence of renal damage of any consequence. … Finally, this drug should not be used in cases suffering from myasthenia gravis. … {We offer} a grave and insistent warning to the inexperienced that we are dealing with one of the most potent poisons known.

In his lecture delivered on April 17th the following year to the Royal College of Surgeons of England,8 Gray definitively slammed the door shut on the practice of single-agent anaesthesia introduced by Morton 101 yr earlier:

Curare is used in anaesthesia for four purposes: This rationale calls for an entirely new conception of general anaesthesia. Many of our old ideas must give way to new. The age of deep anaesthesia with all its attendant evils has passed. The administration of heavy doses of the toxic anaesthetic agents to produce satisfactory operating conditions for the surgeon resulted in post-operative depression, shock, toxaemia often manifested by prolonged nausea and vomiting, and a high incidence of pulmonary complications. Now, when curare is used, the patients are given only minimal doses of the anaesthetic agents, just sufficient to keep them asleep. They are often awake at the close of the operation, are co-operative and fully conscious on return to the wards, they are able to cough effectively and breathe freely, facts which must reduce greatly the incidence of post-operative complications. They are for the most part singularly free from those unpleasant toxic sequelae which have always resulted from the administration of a general anaesthetic. …

  1. To provide, using only very light anaesthesia, the muscular relaxation which is required for abdominal surgery;

  2. To facilitate, in a light plane of anaesthesia, control of the respiration during thoracic operations;

  3. To ensure freedom from laryngeal spasm during any anaesthesia;

  4. To potentiate the anaesthetic agents so that light anaesthesia can be maintained with only minimal quantities.

As the induction of anaesthesia is always with an intravenous barbiturate and follows immediately on the administration of the full induction dose of curare the patient experiences no discomfort. … For prostigmine {pyridostigmine} to be effective it must be given in adequate dosage. 3–5 mg is the usual dose given together with atropine gr. 1/50 in order to overcome the undesirable parasympathomimetic effects. … Control of the respiratory exchange is essential when this substance is used in order to ensure that oxygenation is adequate and carbon dioxide eliminated. … Endotracheal intubation is, however, probably advisable as a routine. … In the doses which are recommended complete paralysis will not ensue and a lightening anaesthesia will be indicated by slight movement of a limb. … It must never be forgotten that {d-tubocurarine} is a very potent and dangerous drug and one having a profound and significant effect on the respiratory function. While the only two absolute contra-indications to its use appear to be the presence of myasthenia gravis or organic respiratory obstruction, it should never be used by those who are not used to dealing with the apnoeic patient.

Gray published two additional papers on curare in 1947, one describing its use in Caesarean section,9 and the other for use in head and neck surgery.10 In 1948, he described the use of curare in chest surgery,11 and factors that might cause idiosyncratic reactions to it.12 These papers, and the lectures delivered in 1946 and 1947, forever changed the practice of anaesthesia. Before 1946, we would have found the practice of anaesthesia terrifying, and indeed morbidity and mortality were unacceptably high.13,14 Gray's synthesis of hypnosis and muscle relaxation created a new paradigm for anaesthesia that we would recognize and comfortably practice (after asking for the right dosage of curare and thiopental, which many young anaesthesiologists have never used). In 1946, Gray explained the drugs, the size and timing of the doses, the methods signs for titration, the concurrent need for ventilation, the benefits, and the risks, of modern ‘balanced’ anaesthesia. On the basis of Gray's work, the practice of i.v. introduction, muscle relaxation, light general anaesthesia, controlled ventilation, and reversal of muscle relaxation with a cholinesterase inhibitor was known as the ‘Liverpool technique,’ because Gray was the head of anaesthesia at the University of Liverpool. Today that approach is more likely to be referred to as ‘the usual'.

Decades later, Gray described how he procured the d-tubocurarine for his seminal work:15

I cannot refrain from recalling how, frustrated by an inability in the last year of the war to obtain more than the occasional vial of the American preparation ‘Intocostrin', we {Halton and Gray} both remembered the little tubes of white powder we had used as students in physiology experiments. We found it labelled ‘Curarin' by Burroughs Wellcome. With the connivance of Dr Gregory, then Lecturer in the Department and now its Professor, every ampoule was commandeered from the Department of Physiology, autoclaved, and dissolved in pint bottles of normal saline to a dilution of 15 mg ml−1, was infused into patients. This appears to have been the first use of the pure alkaloid d-tubocurarine chloride. Had the Committee on the Safety of Drugs existed and had we the refined conscience on the dangers and ethics of human experimentation of later years, several consequent developments might have been delayed for a very long time; this would also have been the case if the American Food and Drug Regulations had been in evidence when Harold Griffith revolutionized anaesthesia by the use of ‘Intocostrin'.

Gray's account above omits a few delightful details, which have been supplied by Ballance16 in his tribute to Gray:

Gray proceeded to begin the pioneering work on curare, assisted by John (also known as Jack) Halton. John had two jobs—as anaesthetist to the thoracic surgical department at Clatterbridge Hospital and as a Medical Officer to the Royal Air Force. His latter employment put him in touch with the mess (social club) and doctors at the United States Air Force (USAF) base at Burtonwood near Warrington, Lancashire. Here, he learnt of the work of Harold Griffith in Montreal in using curare as a muscle relaxant, the first occasion being in January 1942, and the publication of a paper which popularized its use. Cecil and John persuaded the USAF to fly over some crude extract of Chondrodendron tomentosum which they put to use, initially experimentally on themselves, then on patients.

Gray and Halton initially used a preparation of curare, ‘intocostrin', that was neither available nor approved in England. Their supply of intocostrin was smuggled into England by the United States Air Force. They first tested it on themselves (ponder that for a moment) and then on patients. When they ran out of intocostrin, they enthusiastically ‘commandeered’ the supplies of crystalline d-tubocurarine from the department of physiology, autoclaved it, dissolved it in saline, and gave it to patients. All of this was done without a hint of research oversight or informed consent. As a journal editor, I cannot imagine the outcry among reviewers, editors, and readers, if these shenanigans were reported in a submission today. However, 70 yr ago, this is how clever and dedicated physician scientists pursued their investigations. Our patients are better off for it.

The road to modern anaesthesia

After Morton's demonstration of the anaesthetic effects of ether in 1946, and Simpson's subsequent demonstration of the anaesthetic effects of chloroform in 1947,17 the use of inhaled anaesthetics for induction and maintenance was the only form of anaesthesia available. Gray18 described this single-agent anaesthesia as ‘the old blunderbuss form of anaesthesia'. A few years later after Morton's demonstration, 1853, Wood19 introduced subcutaneous administration of morphine. There was little advance in the provision of general anaesthesia until the 1930s, when Lundy20 at the Mayo Clinic introduced evipal (an i.v. barbiturate) and thiopental.

Lundy21 is credited with introducing the concept of ‘balanced anaesthesia'. However, in Lundy's view, the ‘balance’ was created by the combination of general anaesthesia to alter the level of consciousness and regional anaesthesia to block pain conduction. This is a very different concept than the concept of balanced anaesthesia introduced by Gray in 1946. In our modern lexicon, we would refer to Lundy's balanced anaesthesia as a ‘combined regional/general anaesthetic', and the combination of hypnotics, relaxants, and opioids recommended by Gray as a ‘balanced anaesthetic'.

In the 1930s, in a seemingly unrelated branch of pharmacology, scientists were exploring the poisonous substance curare. In an excellent review, Raghavendra explains how curare, called ‘flying death’ by the Spanish invaders, was brought to England in the 18th century.22 It was quickly discovered that curare did not kill animals, provided they were ventilated. The definitive work was done by Claude Bernard, who demonstrated that curare acted on the neuromuscular junction.23 Interestingly, it appears that Bernard began his experimentation in 1844,24 exactly when Wells began his work with nitrous oxide.

Bernard and others worked with crude mixtures of poison brought from the Amazon jungles. It was not until the 1935s that the structure of d-tubocurarine was determined by King.25 Concurrently, in hopes of finding a cure for his own multiple sclerosis, an American, Richard Gill, went on an expedition to Equador to obtain large samples of curare from the native inhabitants.26 He returned with ∼25 pounds of preparation, primarily from the Chondrodendron tomentosum plant. He turned these over to Squibb company in hopes they could make a usable formulation. Squibb produced a standardized although impure, preparation called intocostrin. Intocostrin did not benefit Gill, but was found to be useful in suppressing fractures during electroconvulsive therapy.27

On January 23, 1942,28 Harold Griffith, an anaesthesiologist at the (ironically named) Homeopathic Hospital in Montreal, and Enid Johnson, a resident, gave the first i.v. dose of curare to a patient undergoing anaesthesia. Remarkably, controlled ventilation was not required. Griffith and Johnson noted in July 1942 that ‘It has not been necessary to administer artificial respiration or stimulants in any of our cases'.29 The next clinical report was in 1945, when Whitacre and Fisher attributed to curare some useful properties, such as ‘whenever there is evidence of inadequate spinal anaesthesia, or when it is wearing off too soon, 20 mg doses of curare are given and then repeated every five minutes until the desired effect is obtained'.30 The mind boggles!

In following year, Gray brought it all together: muscle relaxation with curare (he was convinced it had no anaesthetic properties), thiopental, occasional use of opioids, an inhaled anaesthetic (usually nitrous oxide), and reversal with an anticholinesterase. Modern anaesthesia was born.

Subsequent contributions

Gray's contributions in 1946 were not limited to clinical observations on the use of curare. He undertook animal experiments at the time, reporting on the effects of curare in a canine Starling heart–lung preparation.8 In a subsequent human volunteer trial, he demonstrated that curare does not potentiate thiopental drug effect, as had been alleged by others based on animal studies.31 He later turned to the ganglionic blocking properties of curare.32 Low doses of inhaled anaesthetics were an intrinsic part of Gray's technique. Gray rarely observed intraoperative awareness, despite limiting his anaesthetic to 70% nitrous oxide in oxygen. He investigated whether the hyperventilation he used helped him administer light general anaesthetics without risking awareness. In a study in the Lancet, Gray demonstated that hyperventilation, in and of itself, produces EEG changes similar to those that accompany inhaled anaesthetics.33

Gray noted from his earliest work with curare that the classic signs of anaesthetic depth defined by Guedel were of no use with his new balanced anaesthetic approach. He introduced a new concept, ‘differential disintegration of the nervous system’ to characterize anaesthesia.34 With this approach, the anaesthesiologist separated the state of anaesthaesia into distinct tasks, each associated with specific drugs and endpoints. ‘Disintegration’ divided anaesthesia into paralysis, narcosis, and control of autonomic reflexes.

Gray devoted energy to investigating novel pharmaceuticals. The first was Win 2747, a novel relaxant that left him unimpressed.35 His subsequent investigation into the mercifully short-lived methyl-n-propyl ether ended with a wonderful example of blunt honesty:36

There appears to be only one outstanding and possibly valuable property exhibited by methyl-n-propyl ether as opposed to the di-ethyl homologue. That is the well-marked state of analgesia which it produces in low concentrations. This property could not be utilized to produce analgesia in conscious patients because the odour makes the drug unacceptable to them.

He was somewhat more tactful in his assessment of laudolissin, noting that ‘It is considered, as a result of the observations made during this trial, that laudolissin is not a perfect substitute for d-tubocurarine chloride'.37 He was more impressed by mepivacaine, which he found better suited for dental procedures than lidocaine.38 Using his canine Starling heart–lung preparation, Gray also  investigated the effects of inhaled anaesthetics (ether, cyclopropane), thiopental, and novel relaxants (gallamine, decamethonium, and Win 2747) on cardiac output.39

Gray also was interested in physiology, looking at the physiology of cardiac output,40,41 hyperventilation,33,42,43 and hypothermia.44–47 He viewed hypothermia as a very dangerous technique, but one that conferred upon some patients the only hope of surviving temporary circulatory arrest, particularly infants with congenital heart disease.48 On the basis of both human and animal data, he identified 28°C as the critical temperature below which ‘serious cardiac irregularity’ threatened survival.44 These activities led to advances in cardiovascular anaesthesia, including Gray's recommended anaesthetic technique for mitral valve surgery.49

Gray's last major scientific contribution took him full circle back to curare. In 1959, Churchill-Davidson described the use of electromyography to measure the effects of curare on muscle contraction.50 This led to the use of responses to single twitch or tetanic stimulation to assess neuromuscular block. In 1968, Roberts and Wilson51 at the University of Liverpool described the use of the train-of-four stimulus in assessing myasthenia gravis. Ali and colleagues52–55 demonstrated in volunteers, and then in patients, that the ‘train-of-four’ could be applied to assess the effects of curare, and also residual paralysis from incomplete reversal. These studies also examined the utility of tetanic stimulation and post-tetanic facilitation in assessing muscle paralysis. The innovation in the train-of-four was that it was self-calibrating. Gray demonstrated that the ratio of the force of the first twitch to the force of the fourth twitch provided as much information as the ratio of the force of the first twitch to the force of a control twitch administered before induction. The standard monitor for neuromuscular block, four stimuli given at 0.5 s intervals, is based on the recommendations by Ali and colleagues. This was T. Cecil Gray's final contribution to the scientific literature.

The life of T. Cecil Gray

Thomas Cecil Gray was a true Liverpudlian, born in 1913 ‘in a room above a public house in Scotland Road, Liverpool'.16 Following a 2 month stint as a monk,16 he attended the University of Liverpool, where he studied medicine. After graduating as a General Practitioner, he decided to study anaesthetics, eventually earning a ‘Diploma in Anaesthetics’ under the mentorship of RJ Minnett.16 Suffering from asthma, he spent very little time with the British armed forces during World War II, returning to Liverpool, where he quickly turned to the study of curare.

Gray must have been continually exhausted between 1946 and 1948, given what he accomplished during these years. In addition to his work with curare, Gray established the Department of Anaesthesia at the University of Liverpool in 1947 (http://en.wikipedia.org/wiki/Thomas_Cecil_Gray, accessed April 1, 2011). He was concerned at the poor level of training in anaesthesia, and in 1948 initiated a 1 yr programme of specialist training in anaesthesia in his department at Liverpool [Professor T. Cecil Gray. Physician who revolutionized the practice of anaesthesia with what became known as the ‘Liverpool Technique'. The Times (obituary). February 2008]. He remained active in registrar training throughout his career. He subsequently became Dean of the School of Medicine in 1970, eventually retiring in 1976 (http://en.wikipedia.org/wiki/Thomas_Cecil_Gray, accessed April 1, 2011).

In 1948, Gray and E. Falkner Hill became coeditors of the British Journal of Anaesthesia (BJA), resurrecting it from an understandably neglected state during World War II to the esteemed journal it has become today.56 Gray continued to edit the BJA until 1963, making him the second longest serving editor (after Joseph Bloomfield, who served as the editor from 1929 to 1948). Riding and Hunter summarized Gray's contribution to the BJA in an elegant obituary in this journal:57

Gray was an outstanding editor. He would go to great trouble to help an author if he believed the basic content was worthy of publication. At that time, the principles of manuscript presentation, now regarded as normal, were little understood and there were few able to instruct the aspiring author. … Gray was remarkably skilled at achieving desired changes to manuscripts without upsetting senior personages unused to constructive criticism. … This often required much attention to English language style and presentation and again he excelled at the task.

In 1948, Gray was also the founding member of the Faculty of Anaesthetists of the Royal College of Surgeons. His public service also include work with the Royal Society of Medicine, where he served as the President of the Section of Anaesthetics in 1955, and the Association of Anaesthetists of Great Britain and Ireland, where he served as the president in 1957.

In his later years, Gray developed a great interest in the history of anaesthesia. Not surprisingly, one of his first historical reviews described the considerable contributions made by British investigators in the development of neuromuscular blocking agents.58 Interestingly, he only mentions his own contributions in passing (‘British anaesthetists were introduced to the use of curare in anaesthetic practice by Gray and Halton in 1946’), focusing, instead, on the contributions of others. He subsequently reviewed the contributions of the Liverpudlians to anaesthesia,59 starting with an account of James Currie, who studied hypothermia in the late 1700s, and David Waldie, who suggested that Simpson consider trying chloroform in his obstetric patients.

Anyone interested in historical writing should read Gray's entertaining assessment of ‘Whatever happened to Felix Yaniewicz?’60 Yaniewicz was a Liverpool dentist who constructed an apparatus to deliver ether. On January 11, 1847, just 2 weeks after the first use of ether at the University of London, Yaniewicz delivered the first anaesthetic in Liverpool. Gray describes life in Liverpool at the time of Yaniewicz. He constructs how Yaniewicz's immigrant past, and the dissmissive attitudes of Liverpool physicians towards dentists, destined this distinguished Polish dentist to have a single moment of glory and then vanish from history.

Gray was also determined that Harold King's work be recognized.61 King was responsible for purifying and characterizing the structure of the dextro isomer of curare from the crude preparations brought back by explorers to South America. There were several different preparations of curare in the museum, and King chose the poison packaged in bamboo tubes, hence the name ‘tube curare’. King also developed decamethonium, one of the first depolarizing neuromuscular blocking agents, and hexamethonium, one of the first drugs available to lower arterial pressure. King also contributed fundamental work on the structure of cholesterol that led to the synthesis of vitamin D, corticosteroids, the steroidal neuromuscular blocking agents (e.g. vecuronium), and the steroidal anaesthetics (e.g. althesin). Gray was clearly annoyed at the timid response of his colleagues to King's discovery, observing that ‘it is galling to appreciate that tubocurarine was available to anaesthetists who, certainly since the advent of cyclopropane in the early 1930s, were skilled in controlling pulmonary ventilation. It took the courage of Harold Griffith in 1942 to take the first step to revolutionise anaesthesia and surgery'.

Gray passed away on January 26, 2008. His obituaries cited his work with curare, his introduction of the train-of-four, and his history of training and service that spanned a half-century. Many mentioned the ‘Liverpool technique’, most without recognizing how Gray's innovations became the standard approach to general anaesthesia, modified only by the introduction of novel hypnotics, relaxants, and sugammadex.

Young anaesthesiologists associate Liverpool with the most innovative and influential rock and roll band in history. It would do well to remember that 20 yr before the Beatles, Liverpool was also the home of one of the world's most innovative and influential anaesthesiologists T. Cecil Gray.

Conflict of interest

None declared.

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Comments

1 Comment
Date Error
27 July 2011
Oliver R Dearlove (with Vimmi Oshan)

Dear Sir, 17 July 2011

Dr Shafer is mistaken when he refers to the first use of ether in 1946 on page 99 of his article. It was one hundred years earlier (1). Sir James Young Simpson's description of chloroform as an anaesthetic agent was also one hundred years earlier than stated, although there is debate about the date of publication around Nov 1847. (2)

Yours sincerely Vimmi Oshan MB BS FRCA

Oliver R Dearlove M.A.,M.B., BChir.,F.R.C.A.

1. Bigelow H J Insensibility during surgical operations produced by inhalation . Boston Medical and Surgical Journal 1846 35 309-316

2.Crane P F J Y Simpson's early articles on chloroform Bull N Y Acad 1986 62 903-99

Conflict of Interest:

None

Submitted on 27/07/2011 8:00 PM GMT