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Report on the Physiological Action of Organic Chemical Compounds.

By BENJAMIN WARD RICHARDSON, M.A., M.D., F.R.S. THE plan I have heretofore followed, of passing under review the practical results of the labours chronicled in previous Reports, cannot be carried out this year. The review itself would now become so comprehensive that it would occupy all the time allowed for the reading of the Report to the exclusion of the new matter to be brought forward. I shall therefore proceed at once to the description of new research.

CALORAL HYDRATE. It is two years since the substance called chloral hydrate (the physiological properties of which had been previously discovered by Liebreich) was introduced into this country at the Norwich Meeting of this Association. During the first year of the employment of chloral hydrate the enthusiasm connected with the learning of its value prevented, in some degree, all fair criticism as to its real values and dangers. The year immediately past has afforded time for calmer and more judicial observation, greatly, as I think, to the advantage of the public, since it has given to the professors of medical art the opportunity of learning that the new agent placed in their hands, blessing as it is to humanity, is not an unalloyed blessing, but one that has engendered a new and injurious habit of narcotic luxury, and has added another cause to the preventible causes of the mortality of the nation.

Recognizing these truths, I have felt it a duty to devote some part of the labours of this Report to the elucidation of questions which have become of public, not less than of scientific importance, and to these I would now ask attention.

1. I have endeavoured to ascertain what is a dangerous and what a fatal dose of chloral hydrate. The conclusion at which I have been able first to arrive on this point is, that the maximum quantity of the hydrate that can be borne, at one dose, bears some proportion to the weight of the animal subjected to its influence. The rule, however, does not extend equally to animals of any and every class. The proportion is practically the same in the same classes, but there is no actual universality of rule. A mouse weighing from three-quarters of an ounce to an ounce will be put to sleep by one quarter of a grain of the hydrate, and will be killed by a grain. A pigeon weighing twelve ounces will be put to sleep by two grains of the hydrate, and will be killed by five grains. A guineapig weighing sixteen ounces will be put by two grains into deep sleep, and by five grains into fatal sleep. A rabbit weighing eighty-eight ounces will be thrown by thirty grains into deep sleep, and by sixty grains into fatal sleep.

The human subject, weighing from one hundred and twenty to one hundred and forty pounds, will be made by ninety grains to pass into deep sleep, and by one hundred and forty grains into a sleep that will be dangerous.

From the effects produced on a man who had of his own accord taken a hundred and twenty grains of the hydrate, and who seemed at one period to be passing into death, I was led to infer that in the human subject one hundred and forty grains should be accepted as dangerous, and one hundred and eighty as a fatal dose. Evidence has, however, recently been brought before me which leads me to think that, although eighty grains would in most instances prove fatal, it could, under very favourable circumstances, be recovered from.

Dr. Hills, of the Thorpe Asylum, Norwich, has, for example, favoured me with the facts of an instance in which a suicidal woman took no less than four hundred and seventy-two grains of the hydrate dissolved in sixteen ounces of water, and actually did not die for thirty-three hours. Such a fact, ably observed as it was, is startling ; but it does not, I think, militate against the rule that one hundred and forty grains is the maximum quantity that should, under any circumstances, be administered to the human subject.

2. A second point to which my attention has been directed is, what quantity of hydrate of chloral can be taken with safety at given intervals for a given period of time, say of twenty-four hours. To arrive at some fair conclusion on this subject, I calculated from a series of experiments the time required for the development of symptoms from different doses of the hydrate, the full period of the symptoms, and the time when they had entirely passed away. Great difficulties attend this line of investigation ; but I may state, as a near approximation to the truth, that an adult person who has taken chloral in sufficient quantity to be influenced by it, disposes of it at the rate of about seven grains per hour. In repeated doses, the hydrate of chloral might therefore be given at the rate of twelve grains every two hours fa twenty-four hours, with less danger than would occur from giving twelre times twelve (144) grains at once; but I do not think that amount ought, except in the extremest emergencies, to be exceeded even in divided quantities.

3. A third point to which I have paid attention is, the means to be adopted in any case when, from accident or other cause, a large and fatal dose of chloral hydrate has been administered. I can speak here with precision. It should be remembered that this hydrate, from its great solubility, is rapidly diffused through all the organism. It is in vain, consequently, to attempt its removal by any extreme measures after it has fairly taken effect. In other words, the animal or person under chloral, like an animal or person in : fever, must go through a distinct series of stages on the way to recovery or death; and these stages will be long or short, slightly dangerous or intensely dangerous, all but fatal or actually fatal, according to the conditions by which the animal is surrounded. One of the first and marked effects of the chloral is reduction of the animal temperature; and when an animal is deeply under the influence of the agent, in the fourth degree of narcotism of Dr. Snow, the temperature of its body, unless the external warmth be carefully sustained, will quickly descend seren and even eight degrees below the natural standard. Such reduction of temperature is itself a source of danger; it allows condensation of fluid on the bronchial pulmonary surface, and so induces apnea, and it indicates a period when the convulsion of cold (a convulsion which sharply precedes death) is at hand.

I offer these explanations in order to indicate the first favourable condition for the recovery of an animal or man from the effects of an extreme dose of chloral hydrate. It is essential that the body of the animal be kept warm, and not merely so, but that the air inspired by the animal be of high temperature. The first effort to recovery, in short, should consist in placing the animal in a warm air. This fact is perfectly illustrated by experiment on the inferior animals. In the pigeon an air of 95° Fahr. is most favourable, in tho rabbit an air at 105° to 110°, in the dog the same. In man the air to be breathed should be raised and sustained at 90° Fahr. at least*.

# I have no doubt it will be found, as the chronicle of deaths from chloral hydrate in. creases, that the mortality from the agent will be greatest when the thermometrical readings are the lowest, and vice versa.

The next thing to be remembered in the recovery of persons under the fatal influence of chloral hydrate is to sustain the body by food. I find that under even deep sleep from the narcotic, although the process of waste is less than is common under natural conditions of rest, there is still a very considerable waste in progress, which, if not made up, is against recovery. I find also that the digestive and assimilating powers, though impaired during sleep from chloral, are not arrested, but may be called into fair action with so much advantage, that if two animals be cast into deep sleep by an excessive quantity of the narcotic, and one be left without food and the other be artificially fed on warm food, one fourth of the chance of recovery is given to the animal that is supplied with food. In the human subject warm milk, to which a little lime-water has been added, is the best food. Milk is very easily administered mechanically, and it should be administered in the proportion of half a pint every two hours*.

4. The fourth point to remember is to sustain the breathing; in the inferior animals the question of life or death can be made to turn on this pivot. But the artificial respiration must be carried out with great gentleness; it must not be done by vehement movements of the body or compressions of the chest, but by the simple process of inflating the lungs by means of small bellows, through the nostrils. I have devised, in the course of the researches conducted chiefly for the Association, various instruments for artificial respiration, viz. a small double-acting bellows, a small syringe, and a double-acting india-rubber pocket-bellows; but I have lately made an observation which leads to a simpler method still, i. e. I merely attach to a single hand-bellows a nostril-tube, and gently inflate the lungs, letting the elasticity of the chest-wall do the work of expiration. A little valve near to the nostril-tube effectually stops all back currents from the lungs into the bellows. For the human subject, five charges of air from the bellows should be given at intervals of five seconds apartt.

There is another subject of public interest connected with the employment of chloral hydrate. I refer to the increasing habitual use of it as a narcotic. As there are alcoholic intemperants and opium-eaters, so now there are those who, beginning to take cħloral hydrate to relieve pain or to procure sleep, get into the fixed habit of taking it several times daily and in full doses. I would state from this public place, as earnestly and as forcibly as I can, that this growing practice is alike injurious to the mental, the moral, and the purely physical organization, and that the confirmed habit of taking chloral hydrate leads inevitably to confirmed disease. The digestion gets impaired; natural tendency to sleep and natural sleep are impaired; the blood is changed in quality, its plastic properties and its capacity for oxidation being reduced; the secretions are depraved; and, the nervous system losing its regulating, controlling power, the muscles become unsteady, the heart irregular and intermittent, and the mind uncertain and irritable. To crown the mischief, in not a few cases already the habitual dose has been the last, involuntary or rather unintentional suicide closing the scene.

I press these facts on public notice not a moment too soon, and I add to them the facts, that hydrate of chloral is purely and absolutely a medicine, and that whenever its administration is not guided by medical science and experience, it ceases to be a boon, and becomes a curse to mankind.

* This question of feeding is applicable to all forms of accidental narcotic poisoning. In every such case the poisoning is a distinct process, and the recovery turns largely on the sustainment of the animal force by supply of food and of external warmth.

† Dr. Richardson exhibited the different instruments described.

ANHYDROUS CHLORAL. The hydrate of chloral, of which I have treated above, is made from another substance, called anhydrous chloral, by the addition to the latter of a certain proportion of simple water. Anhydrous chloral was discovered by Liebig in 1832, and is formed by the process of passing chlorine through absolute alcohol. It is a colourless oily fluid, of specific gravity 1502, at 64° Fahr. It boils at 93° Cent. (199° Fahr.); its composition is C, HCI, 0, and its vapour-density, taking hydrogen as unity, is 73. It dissolves in ether, alcohol, and hydride of amyl.

The vapour of anhydrous chloral is irritating and painful to an extreme degree when it is inhaled, and the substance has consequently not attracted attention as a subject for physiological study. Having, however, a pure specimen of it prepared by Dr. Versmann, I thought it was worth while to make a research with it. The results have proved worthy of the trouble ; in fact I have rarely derived from so simple an investigation so rich a practical result. It would be inferred d priori that anhydrous chloral in the liquid state would be, like its vapour, a powerful irritant to the skin and mucous membrane. I soon found, however, that this was not the fact, that I could apply the fluid freely to my own skin and to the tongue without injury, and that the caustic action is extremely mild, even when the substance is applied to a moist surface. If a quarter grain of it (anhydrous chloral) be placed upon the skin of the frog in a dry atmosphere, there is a rather quick absorption, followed by the formation of a white film of the hydrate of chloral beneath the skin, which film soon disappears by absorption, the symptoms following the absorption being the specific narcotic symptoms of chloral hydrate. The animal soon falls into a deep sleep with complete muscular exhaustion.

If in higher animals, birds and rabbits, anhydrous chloral be injected subcutaneously, the same phenomena are indicated, the quantities for producing the specific effects being the same as are required for the hydrate.

It is clear from these observations that anhydrous chloral, when brought into contact with the exposed surfaces of the body, abstracts water from the part with which it is in contact, becomes converted into the hydrate, and is directly absorbed into the body, producing the same symptoms as the prepared hydrate produces when it is introduced into the organism.

As anhydrous chloral is soluble in amyl hydride, ether, and many other volatile fluids, I tried whether any of it could be carried over with the vapour of amyl hydride, and whether, if it were administered in this way, it would produce prolonged narcotism by being transformed into the hydrate in the lungs and taken up into the blood.

The result of the experiment was to show that in frogs, guinea pigs, and pigeons general narcotism can be so induced, and that the narcotism is prolonged far beyond what follows from the simple inhalation of amyl hydride. But I observed that when the solution used contained so little as twenty minims of anhydrous chloral to an ounce of the hydride, the vapour given off was irritating to breathe; and when I breathed it myself I found it caused drsness of the throat and a sense of constriction, which lasted several minutes. A weaker solution than that named is too slow in its action, and I therefore can hardly at this moment recommend that anhydrous chloral should be administered by inhalation. It is possible, nevertheless, that in course of time the agent may be found serviceable when administered in the manner described. It is probable that much smaller quantities, administered for a much longer time, would be serviceable in sustaining a slight narcotism. It is probable that in some chronic diseases of the throat or bronchial passages, where the effect of a local narcotic would be desirable, this mode of practice may find favour from its success. Again, it may be that in disease of the lungs themselves, where there is loss of structure (cavity), anhydrous chloral may be inhaled in minute quantities with advantage. I name these points in order to call the attention of fellow physicians to the mode of administration I have ventured to suggest.

Connected also with anhydrous chloral is another reasonable suggestion ; I mean the plan of applying the agent as a narcotic caustic to unnatural growths and ulcerating fungoid surfaces. I find that by applying the fluid to my arm freely there is destruction of the epidermis (scarf skin), so that without any pain the epidermis peels off, almost dry, at the point where the fluid has been placed ; and that when on this exposed surface some of the fluid is applied, the true skin is in turn affected, so that in a day or two what the ancients called an issue may be developed, the tissues destroyed coming away in the form of scales. The surgeon will at once see the practical utility of an agent possessing these properties, and he may in some instances subcutaneously inject the fluid if the outward employment of it be too slow.

It is a very curious experiment to subject freshly drawn blood to anhydrous chloral, and to observe microscopically the changes that ensue. The action of the chloral is to extract water both from the liquor sanguinis and the corpuscles, and to form crystalline chloral hydrate. Into this formation the shrinking corpuscles sink, while the fibrine remains free from precipitation ; but if water be added, so as to dissolve and remove the hydrate that has been formed, the corpuscles are to some extent restored, and the fibrino coagulates and separates in the usual way.

METACHLORAL. Under favouring conditions anhydrous chloral is converted into an insoluble substance, to which the name of “ metachloral" has been applied. The change sometimes occurs spontaneously, as it has done in a specimen now on the table ; but it is always effected when chloral is brought into contact with sulphuric acid. Dr. Versmann has made for me some beautiful specimens of metachloral by this last-named process.

Metachloral is a white substance, easily reducible into a fine powder, but insoluble in water and in alcohol. It is isomeric with chloral itself, being merely different in respect to physical condition. When it is treated with an alkali it yields, as chloral does, an alkaline formate and chloroform. These facts led me to ask whether, in the animal body, metachloral would undergo decomposition and produce specific narcotic effects ; and here, again, a series of results were obtained of great interest. Administered to birds in the form of pilule, and to other animals either in the same form or in suspension in gum emulsion, the metachloral, so insoluble in water, is found to undergo solution in the animal secretions, and to produce the same narcotic effects as the chloral hydrate, viz. narcotism, muscular prostration, and decrease of animal temperature.

In the pigeon from ten to fifteen grains are sufficient to take full effect. The animal in the course of an hour becomes drowsy, and in an hour and a half is in a perfect sleep, from which, nevertheless, it may be roused, to fall back again into sleep with great rapidity: the sleep lasts from three to four

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