HUMPHRY DAVY'S RESEARCHES ON NITROUS OXIDE

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1 Brit. J. Anaesth. (1972), 44, 291 HUMPHRY DAVY'S RESEARCHES ON NITROUS OXIDE F. F. CARTWRIGHT Researches Chemical and Philosophical, chiefly concerning Nitrous Oxide and its Respiration, By Humphry Davy, Superintendent of the Medical Pneumatic Institution. Such is the full title of the most astonishing book in the history of anaesthesia, and one of the more astonishing in the whole history of medicine. Written by a lad aged only 21, who had studied chemistry for less than three years, the 580-page work contains the results of a meticulous investigation into the then known compounds of nitrogen, their preparation, chemical properties and analyses; describes methods of preparing nitrous oxide; details the effect of the gas on animals and the postmortem appearances of animals killed in it; records the sensations produced by inhaling nitrous oxide in varying quantities and dilutions; contains analyses of expired breath after inhalations of common air, nitrous oxide, and other gases, and explains the effect of these upon the blood; and suggests how nitrous oxide may be employed in medicine. Humphry Davy, the young author of this work, was born at Penzance in South Cornwall on December 17, 1778, the eldest son of Robert Davy. Robert Davy took possession of the family farm at Varfell in the parish of Ludgvan in 1784, leaving Humphry at Penzance under the guardianship of John Tonkin, a surgeon. Humphry received his education at the Penzance Grammar School but made so little progress that he was removed to a school at Truro in The headmaster, Dr Cardew, later wrote: "He was not long with me; and while he remained I could not discern the faculties by which he was afterwards so much distinguished; I discovered, indeed, his taste for poetry, which I did not omit to encourage". Robert Davy died in 1794 when Humphry was 16 and, on Tonkin's advice, the boy was apprenticed to John Bingham Borlase, the leading surgeon of Penzance. At this time Humphry Davy was both ill-educated and idle, paid little attention to his master's business, and spent his leisure in shooting, fishing, and playing billiards. He was a dreamer, sometimes intoxicated by words, by the calm blue waters and raging storms of Mounts Bay, by the grandeur of the Cornish coast. Always he dreamed of a great future for himself. He might have ended his days in the nightmare world of schizophrenia, but in the autumn of 1797 he came face to face with reality. There could be no fine career open to one lacking in education and so he set himself an exacting syllabus ranging through a wide variety of subjects from theology to anatomy. At the same time he decided that he was not content to remain an unqualified surgeon in a remote Cornish town; he would go to Edinburgh, study medicine, and qualify as a physician. In the winter of , about three months after starting his course of self-instruction, Davy started to read chemistry. His only books were Nicholson's Dictionary and Lavoisier's Elements in the English translation by Robert Kerr. He had no reagents or apparatus except such drugs as he could obtain from the apothecary shop and the primitive glass or metal ware he could improvise from household utensils. One of his most treasured possessions was an enema syringe, given to him by a shipwrecked French surgeon, from which he was able to fashion an air-pump. With this he managed to extract and analyze the gas contained in the bladders of seaweed, finding it to have the same properties as common air. In spring 1798, only three months after taking up chemistry, Davy came to the conclusion that the great A. L. Lavoisier had unaccountably neglected light when considering the nature of heat. Davy started a series of experiments designed to prove that light is ponderable matter, capable of entering into chemical combinations. His fallacious experiments, and the absurd theory which he built upon them, introduced Davy to the three men who were to set his feet on the road to fame. Davies Giddy, afterwards Davies Gilbert, who followed Humphry Davy in the chair of the Royal Society, is supposed to have first noticed young Davy making extraordinary grimaces in the doorway of Borlase's shop. On enquiry he was told that the boy was fond of chemical experiments, but he took no action until urged by Gregory Watt, son of the great engineer, who came to lodge with Davy's F. F. CARTWRIGHT, F.F.A.RX.S., Department of the History of Medicine, King's College Hospital, Denmark Hill, London, SE5 9RS.

2 292 BRITISH JOURNAL OF ANAESTHESIA mother in autumn Giddy had been a pupil, and Watt was a patient, of the notable Dr Thomas Beddoes of Bristol who, until 1793, had held the post of Lecturer in Chemistry at the University of Oxford. Davy's theory of light roused Beddoes' interest. By Giddy's advice, Watt took Davy's papers to Beddoes, when he consulted him while passing through Bristol on the way from Penzance to his father's home at Birmingham in April Davy had meanwhile embarked on another research. We must presume that sometime in the early spring of 1798 either Giddy or Gregory Watt lent Humphry Davy a copy of Considerations on the Medicinal Powers and the Production of Factitious Airs, written by Thomas Beddoes in collaboration with James Watt. One of the appendices to this voluminous work is a paper by Samuel Latham Mitchill, Professor of Chemistry, Natural History and Agriculture in the College of New York. The ponderous title suffices to explain his remarkable theory: Remarks on the Gaseous Oxyd of Azote or of Nitrogene, and on the effect it produces, when generated in the stomach, inhaled into the lungs, and applied to the skin. Being an attempt to ascertain the true nature of Contagion, and to explain thereupon the phenomenon of Fever. Mitchill, who had undoubtedly confused nitrous oxide with marsh gas, set out to prove that "dephlogisticated nitrous air", prepared and first described by Joseph Priestley in , was miasma, the principle of contagion and the cause of plague. Just as Lavoisier's apparent failure to explain the nature of light had urged Davy to experiment, so Mitchill's absurd theory impelled him to put it to practical test. When considering light, Davy's own ill-conceived and uncontrolled experiments led him to conclusions further from the truth than Lavoisier's suppositions. But Mitchill's theory was more easily disproved by simple tests. Davy submitted mice to the influence of the impure gas obtained by reducing nitrous gas with metal; he hung strips of lean meat in it and found that the meat did not putrefy more quickly than in air; he exposed wounds to it without causing sepsis; he breathed it himself without ill result. Davy thus proved, beyond reasonable doubt, that Priestley's dephlogisticated nitrous air could not be the principle of contagion or miasma. Gregory Watt brought this work to the notice of Thomas Beddoes at a critical moment. Beddoes had for some years been interested in the potential value of the gases in the treatment of disease. He had raised a sum of about 3000 by subscription and was now ready to embark on his project of opening a small hospital for a full trial. An enthusiastic and not over-discriminating experimenter himself, he was deeply impressed by the ingenuity of Davy's work. During the summer of 1798, he wrote to Davies Giddy asking whether Davy might be a suitable person to take charge of his projected hospital and laboratory, a proposal which Giddy commended. There were a number of difficulties to be overcome, not least of which was Beddoes' obstinate refusal to enter into a contract or name a salary. Davy hesitated, but the temptation of working in one of the bestequipped laboratories in England could not be resisted. On October 5, 1798, Humphry Davy, only 19 years old, arrived in Bristol to assume his duties as Superintendent of the Pneumatic Medical Institution. The Institution opened for the reception of outpatients on March 21, 1799, in two houses at the upper or northwest corner (now Nos. 6 and 7) of Dowry Square in the Hotwells district of Bristol. Davy repeated his experiments with nitrous oxide in Beddoes' presence. The gas obtained by Priestley's method was very impure, heavily contaminated with nitrogen and residual nitrous gas. It could be prepared in only small quantities and the process of reduction took many days. Priestley had been puzzled because he found that a brightly burning flame was enlarged in the gas, yet mice quickly died in it. Davy confirmed the first finding and disproved the second. He discovered that mice seemed first to become excited, then to fall asleep. When taken from the jar, sleeping but still breathing, they quickly recovered. The enlargement of the flame and the excitement of the mice interested Beddoes, who formed the opinion that nitrous oxide must be allied to oxygen in its effect upon the body, if not in its chemical properties. A staunch Brunonian, he regarded oxygen as a potent stimulant indicated in such diseases as were classed as asthenic in John Brown's System of Medicine. Nitrous oxide must therefore also be a stimulant. At the end of April 1799 Beddoes wrote to his friend Dr Erasmus Darwin of Birmingham that "something extraordinary has been made out at the Institution", adding that he would say no more because it was too early to decide upon the importance of the discovery. He referred to Davy's inhalation of pure nitrous oxide. We do not know how Davy came to hear of Berthollet's experiments, but it seems likely that James Watt drew his attention to them. Berthollet had found that a gas much purer than Priestley's dephlogisticated nitrous air could be

3 HUMPHRY DAVY'S RESEARCHES ON NITROUS OXIDE 293 prepared by heating ammonium nitrate. Watt certainly advised Davy how to obtain the salt from easily available raw materials. Davy's first inhalations of nitrous oxide made a great impression upon Beddoes' too credulous mind. "The scene exhibited was the most extraordinary I ever witnessed", he wrote. After the first moments of surprise, it was impossible not to recognize the expressions of the most ecstatic pleasure. I find it entirely out of my power to paint the appearances, such as they exhibited themselves to me. I saw and heard shouting, leaping, running and other gestures, which may be supposed to be exhibited by a person who gives full loose to feelings excited by a piece of joyful and unlooked-for news. No exhaustion or languor or uneasy feeling took place. Beddoes was, of course, describing the excitement stage of anaesthesia and, in the majority of subjects, this was the deepest stage to be reached. Their incoordinated and sometimes wild movements led Beddoes to the conclusion that nitrous oxide "may be regarded as a more powerful form of oxygen gas". Since Davy's muscles contracted apparently independently of his volition, nitrous oxide must possess the power of "renovating excitability". The flaccid, useless muscles of a paralyzed patient would contract under its influence. So the first use of nitrous oxide in medicine was as a stimulant in cases of paralysis. In the summer of 1799 Davy's new Theory of Light appeared in Contributions to Physical and Medical Knowledge, principally from the West of England, the first and only number of Beddoes' proposed quarterly journal. The theory was treated with derision. It is apparent from his notebooks that Davy was not only furiously angry with his critics but so bitterly disillusioned that he believed his career to be ended before it had begun. As his initial fury diminished and as his own doubts of his theory increased, it became urgently necessary to redeem himself by another piece of work, to show the scientific world that he was a new Lavoisier. The means of redemption lay at hand. Urged on by the enthusiasm of Beddoes, he contributed a sensible, well-argued paper on the subject of nitrous oxide to Nicholson's Journal. Encouraged by its reception, he started to plan on a more ambitious scale. At the beginning of December he visited London and discussed his project with J. Johnson, the well-known medical and scientific publisher. On his return two weeks later, Davy set seriously to work. Never again would he found a theory on "a few coarse experiments". Everything must be carefully considered, checked, repeated. For the rest of the winter and spring, Humphry Davy lived almost continuously in the laboratory at Dowry Square, working far into the night. From April until June 1800, he sifted his evidence and cast the rough notes in his commonplace books into a narrative form. He had his reward when his book appeared only a month later, at the end of July His work was reviewed favourably and at length in all the leading scientific journals. His name was made and, paradoxically, this very success may have entailed a great loss to medicine. Humphry Davy abandoned his projected career as a physician; after his appointment to the Royal Institution, London, in March 1801, he performed no more serious experiments with nitrous oxide. Thus it was that Humphry Davy's Researches came to be written. Now we must consider the work itself. There is only one edition (although John Davy included it in die eight-volume limited edition of his brother's writings) and it may be surmised that not many copies were printed, for it is a rare book today. A few short extracts have been copied and recopied into every history of anaesthesia, but the whole is virtually unknown and a large amount of valuable work has passed unnoticed. Davy divided his book into four Researches, the first two dealing with chemistry and the second two with physiology. The first Research described his analyses of nitric acid and nitrous gas, and the methods of preparing nitrous oxide; in the second he writes of the combinations of nitric oxide and of its decomposition. The third and perhaps the most interesting Research is entitled Relating to the Respiration of Nitrous Oxide and other Gases. This treats of respiration in general, the effect of nitrous oxide on fish, insects and animals, and of the action of nitrous oxide on the blood. Davy's statistics are valueless unless corrected because he accepted Lavoisier's estimate of 27 per cent for the oxygen content of the air. Further, he was not sure whether air was a simple mixture of oxygen and nitrogen or a compound. He produced evidence to show that "the oxygene and nitrogene of atmospheric air exist in chemical union" but this compound or loose combination was very easily broken down:... the whole compound atmospheric air, passing through the moist coats of the vessels, is first dissolved by the serum of the venous blood and, in its condensed state, decomposed by the affinity of the red particles for its oxygene; the greater part of the nitrogene being liberated unaltered. He also accepted the teaching that atmospheric air is the only medium which will support life and that animals die when submitted to oxygen.

4 294 BRITISH JOURNAL OF ANAESTHESIA Oxygene, which is capable of being respired for a much greater length of time than any other gas except common air, finally destroys life; first producing changes in the blood, connected with new living actions. But Davy was obviously not certain. He was puzzled by the fact that mice sometimes lived longer in the poisonous oxygen than when confined in vessels of innocuous air. Temptingly he writes: I design very shortly to repeat these experiments and to make others on the comparative consumption of oxygene and atmospheric air by the larger quadrupeds. Whatever may be the results, I hope to be able to ascertain from them why pure oxygene is incapable of supporting life. There is no record that he performed these experiments; had he done so, he must have come to the conclusion that his confined animals died from asphyxia and not from oxygen poisoning. During his experiments for this third Research he discovered the essential fact, which was to be lost again for over a century, that whole blood can be saturated at one and the same time with nitrous oxide and with oxygen: To human blood that had been saturated with nitrous oxide whilst warm and consequently agitated for some four or five minutes to prevent its uniform coagulation, oxygene was introduced; the red purple on the surface of it immediately changed to vermilion and, on agitation, this colour was diffused through it. On comparing the tinge with that of oxygenated blood, no perceptible difference could be observed. No change of volume of the oxygene introduced had taken place, and consequently no nitrous oxide had been evolved from the blood. The present writer is indebted to Sir Harold Hartley for pointing out to him that Davy was the first man clearly to understand that carbon dioxide is carried in the venous blood, although the fact had been half suspected by Lavoisier among others. The reasoning which led Davy to this belief is muddled but his conclusion is definite. After breathing air, he found an average of 5.6 cubic inches of carbon dioxide in his exhaled breath. In the third Research he writes "there is consequently every reason to believe that it [carbon dioxide] is wholly or partially liberated from the venous blood through the moist coats of the vessels". Davy's fourth Research is the one from which all the familiar quotations have been taken an indication of the extent to which his work has been neglected. It is in the form of a rough diary, covering the whole period of his self-experiments with nitrous oxide between March 1799 and June 5, But others beside Davy inhaled the gas. Beddoes had surrounded himself with a quite remarkable circle of friends; most of these breathed nitrous oxide and recorded their experiences. Davy lets fall the reason. He tells us, in the section on respiration, that accurate experiment is not possible when under the influence. "Whenever I breathed pure nitrous oxide in the mercurial airholder, after a complete and voluntary exhaustion of my lungs, the pleasurable delirium was very rapidly produced." Nitrous oxide owed its popularity to this "pleasurable delirium" rather than to a general interest in scientific experiments. It was a new experience; in most cases the person breathing the gas could not correlate his sensations with any past event. Davy strove to explain this fact. In one of his rough notebooks there is the striking phrase "like blind men who use the language of sight". He expanded this notion in Researches: When pleasures and pains are new or connnected with new ideas, they can never be intelligently detailed unless associated during their existence with the terms standing for analogous feelings. I have sometimes experienced from nitrous oxide, sensations similar to no others, and they have consequently been indescribable. This has often been likewise the case with other persons. Of two paralytic patients, who were asked what they felt after breathing nitrous oxide, the first answered, "I do not know how, but very queer". The second said: "I feel like the sound of a harp". Probably in the one case, no analogous feelings had ever occurred. In the other, the pleasurable thrillings were similar to the sensations produced by music; and hence, they were connected with terms formerly applied to music. Davy often draws attention to a phenomenon which was not uncommonly experienced by patients under the old-fashioned "straight gas". I existed in a world of newly connected and newly modified ideas. I theorised; I imagined that I made discoveries. When I was awakened from this semidelirious trance by Dr Kinglake, who took the bag from my mouth, indignation and pride were the first feelings produced by the sight of the persons about me. My emotions were enthusiastic and sublime; and for a minute I walked round the room perfectly regardless of what was said to me. As I recovered my former state of mind, I felt an inclination to communicate the discoveries I had made during the experiment. I endeavoured to recall the ideas. They were feeble and indistinct; one collection of terms, however, presented itself: and with the most intense belief and prophetic manner, I exclaimed to Dr Kinglake: "Nothing exists but thoughts! The universe is composed of impressions, ideas, pleasures and pains!" Of the many descriptions written (or dictated) by those who inhaled nitrous oxide, that which most repays reading is by one who can justly be termed a Master of Words. Peter Mark Roget attached himself to the Pneumatic Institution soon after qualifying from Edinburgh. In retirement, Roget devoted himself to the study of ideas expressed as words and compiled his Thesaurus. Here is a slightly abridged account of his own description of breathing nitrous oxide:

5 HUMPHRY DAVY'S RESEARCHES ON NITROUS OXIDE 295 The first effect was that of making me vertiginous, and producing a tingling sensation in my hands and feet; I seemed to lose the sense of my own weight, and I imagined I was sinking into the ground. I then felt a drowsiness gradually steal upon me, and a disinclination to motion; even the actions of inspiring and expiring were not performed without effort; and it also required some attention of mind to keep my nostrils closed with my fingers. I was gradually roused from this torpor by a kind of delirium, which came on so rapidly that the air-bag dropt from my hands and I suddenly lost sight of all the objects around me, they being apparently obscured by clouds, in which were many luminous points. I felt myself totally incapable of speaking, and for some time lost all consciousness of where I was or who was near me. My whole frame felt as if violently agitated; I thought I panted violently; my heart seemed to palpitate and every artery to throb with violence; I felt a singing in my ears: all the vital motions seemed to be irresistibly hurried on as if their equilibrium had been destroyed and everything was running headlong into confusion. My ideas succeeded one another with extreme rapidity, thoughts rushed like a torrent through my mind, as if their velocity had been suddenly accelerated by the bursting of a barrier which had before retained them in their natural and equable course. The Lakeland poets also breathed nitrous oxide. Samuel Taylor Coleridge and Robert Southey recorded their impressions. Southey's words are of importance in the history of anaesthesia. He says in Researches that he suffered from dizziness, fullness of the head, and a fear of falling. "When I took the bag from my mouth, I immediately laughed. The laugh was involuntary but highly pleasurable." He inhaled nitrous oxide on many occasions and finally concluded that "the sensation is not painful, neither is it in the slightest degree pleasurable". There is a strange anomaly here, for Southey wrote to Davy, in a letter of August 3, 1799: "You still, I suppose, go on working with your gaseous oxide, which, according to my notions of celestial enjoyment, must certainly constitute the atmosphere of the highest of all possible heavens." In autumn 1799 Thomas Beddoes published a small pamphlet, Notice of Some Observations made at the Medical Pneumatic Institution, and described Robert Southey's sensations : "In a second experiment, he felt pleasure still superior and has since poetically remarked that he supposes the atmosphere of the highest of all possible heavens to be composed of this gas." On December 10, 1844, the advertisement of Gardner Quincy Colton's exhibition of the effects of nitrous oxide appeared in the Hartford Courant. This advertisement contains the words: "No language can describe the delightful sensations produced. Robert Southey (poet) once said that the atmosphere of the highest of all possible heavens must be composed of this gas." Thus Southey's words form the concrete link which binds the Pneumatic Institution with the introduction of anaesthesia by Wells and Morton. Perhaps the most interesting part of the story to the modern anaesthetist is Davy's discovery of the analgesic power of nitrous oxide. The steps by which he was led to this discovery can be traced in Researches but some additional information is to be found in his two remaining "commonplace" books. John Davy wrote that his brother suppressed much of his evidence, thinking that it might share the fate of his Theory of Light. The two rough notebooks, although they obviously only form part of his original records, do not bear out John Davy's statement. The contents consist of accounts of experiments and trial passages for the finished book. But there remains a little interesting material which Davy did not include in his published work. The account which here follows is taken from both sources, and these will be indicated by [Notebook] and [Researches]. Davy started by sharing Beddoes' opinion that nitrous oxide is a stimulant. "I imagined that I had increased sensibility of touch; my fingers were pained by anything rough, and the tooth edge produced from slighter causes than usual" [Researches]. For this reason nitrous oxide was used at the Institution in the treatment of paralysis; it was a case of this kind which gave Davy his first inkling that the gas might have effects other than of causing flaccid muscles to contract. The entry is not dated but the sequence places it at about August 1799: Albert M. Much afflicted with rheumatism. Pain when he began to respire. First feelings very pleasant accompanied with laughter, then thrilling in the fame leg which occasioned tremulous motion. Thrilling in both legs which had involuntary motions general very pleasant feeling. Ten minutes pain has not yet returned [Notebook]. On December 23, 1799, Davy designed an experiment to show whether the "debility" following intoxication with alcohol would be increased or decreased by inhalations of nitrous oxide. He drank a full bottle of strong wine in less than eight minutes. "On December 23 I breathed after a terrible drunken fit a large quantity of gas 2 bags and two bags of oxygen. It made me sick" [Notebook]. But he published a much longer and more informative account in which he states that, during his period of "debility", he inhaled seven quarts of a very pure sample of nitrous oxide for two and a half minutes: I was unconscious of headache after the third inspiration... immediately after the exhilaration had disappeared, I felt a slight return of the headache; it was

6 296 BRITISH JOURNAL OF ANAESTHESIA connected with transient nausea.... The experiment proved that debility from intoxication was not increased by excitement from nitrous oxide. The headache and depression, it is probable, would have continued longer if it had not been administered. [Researches.] So we come to the famous incident of the infected wisdom tooth: In one instance, when I had headache from indigestion, it was immediately removed by the effects of a large dose of the gas, though it afterwards returned, but with much less violence. In a second instance, a slighter degree of headache was wholly removed by two doses of gas. The power of the immediate operation of the gas in removing intense physical pain, I had a very good opportunity of ascertaining. In cutting one of the unlucky teeth called denies sapientiae, I experienced an extensive inflammation of the gum, accompanied with great pain, which equally destroyed the power of repose and of consistent action. On the day when the inflammation was most troublesome, I breathed three large doses of nitrous oxide. The pain always diminished after the first four or five inspirations; the thrilling came on as usual, and uneasiness was for a few minutes swallowed up in pleasure. As the former state of mind however returned, the state of organ returned with it, and I once imagined that the pain was more severe after the experiment than before. [Researches.] Davy was puzzled by "the state of mind" as opposed to "the state of organ". He appears to have believed that he would be able to solve the eternal problem of pleasure and pain, if only he could reason out this strange attribute of nitrous oxide. In one of his trial passages he gives us something which may be described as the first theory to account for the phenomenon of anaesthesia: Almost all powerful emotions have been originally connected either with pain or pleasure, hence pain or pleasure will produce them and the kind will be influenced by the existing association. Sensible pain is not perceived after the powerful action of nitrous oxide because it produces for die time a momentary condition of other parts of the nerve connected with pleasure. [Notebook.] During the late spring of 1800 Davy was struggling to solve this problem, writing a trial essay on pleasures and pains of intellect, when he seems to have been quite suddenly struck by an idea. He broke off his essay and, boxing the words between two lines as though he regarded them as of special importance, he wrote across the page: "removing physical pain of operations" [Notebook]. Later he expanded this idea and when, in Researches, he rather hesitantly mentioned a few uses to which nitrous oxide might be put, he included that wellknown sentence which may be regarded as the first suggestion of a practicable means of anaesthesia: As nitrous oxide in its extensive operation appears capable of destroying physical pain, it may probably be used with advantage during surgical operations in which no great effusion of blood takes place. At last, after over a century and a half, Humphry Davy's Researches Chemical and Philosophical is to be republished in facsimile form as part of the bicentenary of Joseph Priestley's discovery of nitrous oxide. It is hoped that enough has been said in this short appreciation of Davy's work to whet the appetite for more. Here is one of the books which should be read by every anaesthetist. FACULTY OF ANAESTHETISTS OF THE ROYAL COLLEGE OF SURGEONS OF ENGLAND SCIENTIFIC MEETING To commemorate the Bicentenary of the discovery of Nitrous Oxide will be held at the College on May 5 and 6, 1972 Tickets: 1 per head per day. Refreshment Tickets: 1.25 per head per day Full details available from Faculty Office towards the end of March 1972