Source: Snow, John. London Med. Gazette, vol. 42,  Aug. 25, 1848, pp. 330-35 (part 4).

On narcotism by the inhalation of vapours

By John Snow, M.D.

Vice-President of the Westminster Medical Society.

[Part 4]

On bromoform, bromide of ethyle, and Dutch liquid--General results of the experiments--The strength of narcotic vapours in the inverse ratio of their solubility in the blood.

Description of the physiological effects of chloroform.

Bromoform.

This is a volatile liquid of the same composition as chloroform, except that three atoms of bromine occupy the place of the same proportion of chlorine. It is made in the same way as chloroform, bromide of lime being used instead of chloride. I have repeatedly made it, but have never succeeded in obtaining more than a few grains in a purified state, although I used an ounce of bromine in making the bromide of lime on each occasion; consequently it is very expensive. It is extremely fragrant, having an odour that is, in my opinion, much pleasanter than that of chloroform or any other of this class of substances with which I am acquainted. It boils at about 184? Fah.; but, as its vapour is twice as heavy as that of chloroform, it is in point of fact nearly as volatile as that liquid. It is very pleasant to inhale, but I have never breathed in more than a few grains at a time, and, therefore, cannot speak of its operation on the human subject. Its effects on animals closely resembles those of chloroform.

The two following experiments will serve to illustrate the action of bromoform, and to determine the quantity in the blood.--

Exp. 35.--A common mouse was placed in a jar containing 400 cubic inches, in which three grains of bromoform had been diffused. In the course of four or five minutes it became unsteady in its walking, and ceased to regard objects in its way. It did not get further affected, except to become rather sluggish, and, when removed at the end of twenty minutes, was capable of voluntary motion. It did not regard a slight pinch, but flinched when the soft part of its foot was pinched severely. It recovered gradually and was pretty well re-established in half an hour.

Exp. 36.--Another mouse was placed in the same jar with six grains of bromoform: it was more quickly affected, and, at the end of five minutes, all voluntary motion had ceased, and it lay breathing naturally and rather deeply. It was removed at the end of a quarter of an hour, and did not stir on being pinched. It began to recover voluntary motion in ten minutes, but staggered at first. In a little more than half an hour it had recovered.

In the first of these experiments the second degree of narcotism was caused by three-quarters of a grain of bromoform to each 100 cubic inches of air. The specific gravity of the vapour of bromoform is stated, in Thompson’s Chemistry of Organic Bodies, to be 8.785 which gives 0.275 of a cubic inch as the quantity of vapour that three-quarters of a grain would yield; and I find that fifteen cubic inches of this vapour are contained in 100 of air saturated with it at the temperature of 100?; consequently the air of the jar contained 0.275 ÷ 15 = 0.0183, or nearly one fifty-fourth part of what it would take up if saturated at 100?, and according to the principles explained in a former part of these papers,* (* Vol. xli. p. 850 [first page of Part 1]) the blood of the mouse would contain just the same proportion--one fifty-fourth of what it could dissolve. In the other experiment, the fourth degree of narcotism was produced by twice the quantity--a grain and a half to each 100 cubic inches, which, by the same computation, gives about one twenty-seventh part of what the blood would take up. These proportions are nearly the same as in the case of most of the substances previously examined. I have not ascertained the exact solubility of bromoform, and consequently cannot compute the absolute quantity in the blood, but it resembles chloroform in being very sparingly soluble.

I have not heard that any one else has examined the effects of the vapour of bromoform; but Dr. Glover men- [330/331]tions an experiment in his valuable paper "On Bromine and its Compounds,"* (*Edin. Med. and Surg. Jour., Oct. 1842) in which bromoform in the liquid state was introduced into the stomach of a rabbit, with the same results as in other experiments with similar bodies: these were death, with congestion of the lungs and stomach.

Bromide of Ethyle.

Bromide of ethyle, or hydrobromic ether, is a very volatile liquid, boiling, as I have found, at 104?. It has a pleasant but somewhat pungent taste and smell. It was discovered by Serullas in 1827, and is formed by the action of phosphorous on a solution of bromine in alcohol. I am not aware that its physiological effects have been examined except in a few experiments which I have performed with its vapour. I will cite two of them to illustrate its effects. The bromide of ethyle was made by myself.

Exp. 37.--Eight grains of bromide of ethyle were introduced into a jar containing 400 cubic inches, and the vapour which instantly resulted was equally diffused by moving the jar. A mouse was then put in. In about four minutes it began to stagger and fall over, and was quite regardless of external objects. It did not get affected beyond this extent, except that it became rather feeble. It was taken out at the end of a quarter of an hour, having the power of voluntary motion, but rolling over in its attempts to walk. It flinched with severe, but not with slight pinching. In ten minutes it had pretty well recovered.

Exp. 38.--Another mouse was placed in the same jar with sixteen grains of bromide of ethyle. In two minutes it had ceased to move, not having shewn any signs of excitement. It lay motionless, breathing at first deeply, afterwards more naturally. It was removed at the end of a quarter of an hour, and was found to be totally insensible. In five minutes it began to move, but rolled over in its first attempts to walk. Twenty minutes after its removal, it appeared to have recovered from the effects of the vapour.

Connected with the great volatility of this liquid is the increased quantity of it required to be present in the air to produce a given effect,--in accordance with the law which requires that the blood must be impregnated to a certain extent relatively to what it could imbibe. In one experiment I performed with this substance, one grain to each 100 cubic inches of air produced no appreciable effect whatever on a mouse confined for twenty minutes in it, although with that quantity of several less volatile bodies complete insensibility would have been induced.

In experiment 37 two grains to each 100 cubic inches of air produced the second degree of narcotism; and in the following experiment four grains produced the fourth degree. The specific gravity of the vapour of bromide of ethyle is, I find 3.78, the atom being represented by two volumes. Two grains will consequently occupy 1.706 cubic inches in the form of vapour. At the temperature of 100? the vapour of bromide of ethyle almost excludes the air, and occupies 92.8 per cent of its place. So 1.706 ÷ 92.8 gives 0.0183, or nearly one fifty-fourth, as the relative saturation of the blood with this vapour for the second degree of narcotism; and there would be twice as much, or one twenty-seventh, for the fourth degree.

I have not ascertained by direct experiment how much bromide of ethyle serum will dissolve, but I find that water dissolves about one-sixtieth of its volume of it; and as the solubility of liquids of this kind is nearly the same in water as in serum, this may safely be taken as the standard;--when, if we consider the average quantity of serum in the human body to be 410 fluid ounces, as in a former part of these papers, and make the kind of calculation there made, we shall find that one fluid drachm and ten minims is the average quantity that there would be in the blood of a human subject in the second degree of narcotism; and two drachms and twenty minims in the fourth degree.

Dutch Liquid.

In recent works on chemistry this substance is called the hydrochlorate of chloride of acetyle. It is formed by the combination of equal volumes of olefiant gas and chlorine. It has a taste at once sweet and hot, and a pungent ethereal odour. It boils at 180?, [331/332] and not at 148?, as Dr. Simpson states in some brief remarks on it in the Edinburgh Monthly Journal for April last, where he informs us that its vapour, when inhaled causes so great irritation of the throat that few persons can persevere in inhaling it long enough to produce anæsthesia; but that he had, however, “seen it inhaled perseveringly until this state, with all its usual phenomena, followed; and without excitement of the pulse or subsequent headache.” My experiments with it have been confined to animals; and the two following will serve as a sample of them:--

Exp. 39.--One grain and a half of Dutch liquid was diffused through the air of a jar containing 400 cubic inches, and a mouse was introduced. After ten minutes had elapsed it began to stagger in its walk, and it continued to do so till it was removed at the end of half an hour. It was occasionally lying still, but always began to walk in an unsteady manner when the jar was move. It was sensible to pinching on its removal, and in a quarter of an hour had recovered from its inebriation. It continued well.

Exp.40.--A mouse was put into the same jar after three grains of Dutch liquid had been diffused in it. It began to stagger sooner than that employed in the last experiment; and at the end of ten minutes had ceased to move, without having had any struggling or rigidity; and it was not disturbed on the jar being moved. It lay breathing naturally till it was taken out at the end of half an hour, when it was found to be totally insensible to pinching. In ten minutes after its removal it began to move, but rolled over in its efforts to walk; when half an hour had elapsed it appeared to have recovered entirely form the narcotism, but was less lively than before; and two or three hours afterwards it was observed to be suffering with difficulty of breathing, and it died in the course of the day. The lungs were congested and of a deep vermilion colour, probably the result of inflammation, occasioned by the irritating nature of the vapour. The right cavities of the heart were distended with dark-coloured coagulated blood. The same appearances were met with in another mouse that died in the same way after breathing this vapour.

In the first of these two experiments the second degree of narcotism was effected by three-eights of a grain of vapour to each 100 cubic inches of air; and as the specific gravity of this vapour is 3.4484, three-eights of a grain must occupy 0.35 of a cubic inch. I find that air, when saturated with vapour of Dutch liquid at 100?, contains 17.5 per cent., and therefore 0.35 ÷ 17.5 gives 0.02, or one-fiftieth, as the relative saturation of the blood in this degree. In the other experiment the fourth degree of narcotism was caused by twice as much vapour, or three-quarters of a grain to each 100 cubic inches, and, consequently, the blood would contain twice as much, or one twenty-fifth part of what it would hold in solution if saturated. I have ascertained that Dutch liquid requires about 100 parts of water for its solution, and taking its solubility in the serum to be the same, the blood would contain one part in 5000 in the second, and one part in 2500 in the fourth degree of narcotism, which in the human subject would be, on an average, 46 minims and 92 minims respectively.

General results of the experiments.

We have now seen the result of this experimental inquiry into the action of eight volatile substances, viz.: chloroform, ether, nitrite of oxide of ethyle, bisulphuret of carbon, benzin, bromoform, bromide of ethyle, and Dutch liquid. We find that the quantity of each substance in the blood, in corresponding degrees of narcotism, bears a certain proportion to what the blood would dissolve-–a proportion that is almost exactly the same for all of them, with a slight exception in the case of benzin, which I believe is more apparent than real. The actual quantity of the different substances in the blood, however, differs widely; being influenced by their solubility. When the amount of saturation of the blood is the same, then it follows that the quantity of vapour required to produce the effect must increase with the solubility, and the effect produced by a given quantity must be in the inverse ratio of the solubility, as I announced some time ago.* (*Medical Gazette, March 31. This rule holds good [332/333] with respect to all the substances of this kind that I have examined; including, in addition to those enumerated in this paper, bichloride of carbon, iodide of ethyle, acetate of oxide of ethyle, nitrate of oxide of methyle, acetate of oxide of methyle, pyroxilic spirit, acetone, and alcohol. The exact proportion in the blood, in the case of the three last mentioned [italicized in the table below], cannot be ascertained directly by experiments of the kind detailed above; for, being soluble to an unlimited extent, they continue to be absorbed as long as the experiment lasts: but from the large quantity of these substances that is required to produce insensibility, they confirm the rule stated above in a remarkable manner.

This general law, of course, does not apply to all narcotics; not, for instance, to hydrocyanic acid, but only to those producing effects analogous to what are produced by ether, and having, I presume, a similar mode of action. I am not able at present to define them better than by calling them, that group of narcotics whose strength is inversely as their solubility in water (and consequently in the blood). In estimating their strength, when inhaled in the ordinary way, another element has to be taken into the account, viz., their volatility; for that influences the quantity that would be inhaled. By multiplying together the number of parts of water that each substance requires for its solution, and the number of minims of each substance that air will hold in solution at 60?, we get a set of figures expressive of the relative strength of each, when breathed in the ordinary way; and by another method of calculation the time might be expressed, in minutes and seconds, that it would take, on an average, to render persons, breathing in the usual way, insensible by each substance: but I shall here confine myself to enumerating the bodies I have examined in two columns; arranging them, in the first column, in the inverse order of their solubility, which is the direct order of their actual potency; and in the second column, in the order in which they stand after their volatility is taken into the account, which is the order of their potency when mixed with air till it is saturated at any constant temperature.

Bisulpheret of Carbon

Bisulpheret of Carbon

Bichloride of Carbon

Chloroform

Chloroform

Bichloride of Carbon

Bromoform

Bromoform

Benzin

Bromide of Ethyle

Dutch Liquid

Benzin

Iodide of Ethyle

Iodide of Ethyle

Bromide of Ethyle

Dutch Liquid

Nitrate of Oxide of Ethyle

Oxide of Ethyle (Ether)

Nitrate of Oxide of Methyle

Nitrate of Oxide of Ethyle

Oxide of Ethyle (Ether)

Nitrate of Oxide of Methyle

Acetate of Oxide of Ethyle

Acetate of Oxide of Ethyle

Acetate of Oxide of Methyle

Acetate of Oxide of Methyle

Acetone

Acetone

Pyroxilic Spirit

Pyroxilic Spirit

Alcohol

Alcohol


The general law, stated above, respecting the solubility of these liquids in the blood, applies also, with certain modifications, to a number of bodies which are gaseous at ordinary temperatures, and there are several important conclusions to be deduced from it. But before proceeding further in the attempt to give a general history of narcotic vapours and gases, and to determine what substances should be included in the list or otherwise, it will be well for me to describe, more particularly than I have done, the nature of the narcotism produced by the class of bodies we are considering, of which chloroform may be properly be taken as the type. I shall, therefore, next proceed to give the best description that I can of the effects of chloroform, having especially in view the practical importance of the agent; and shall make all the remarks that I am able to include in a brief space, on the administration of chloroform in surgical operations, medicine, and midwifery.

Description of the effects of Chloroform.

I may premise, that in applying the term narcotic to chloroform and other volatile substances, I employ it in the extended sense in which it is used by writers on materia medica and toxicology, who make it include all the substances which act on the nervous system; and I apply the term narcotism to designate all the effects of a narcotic, [333/334] as I am entitled to do by strict etymology, and do not confine it, as the practice has generally been, to express a state of complete insensibility. I do not object to the term anæsthetic, but I use that of narcotic as being more comprehensive, and including the other properties of these vapours as well as that of annulling common sensibility.

To facilitate the description, I divide all the effects of chloroform short of the abolition of life, into five degrees. I use the term degree in preference to stage, as, in administering chloroform, the slighter degrees of narcotism occur in the latter stages of the process, during the recovery of the patient, as well as in the beginning.

The division into degrees is made according to symptoms, which, I believe, depend entirely on the state of the nervous centres, and not according to the amount of anæsthesia, which I shall give good reason for believing depends very much on local narcotism of the nerves.

In the first degree I include any effects of chloroform that exist while the patient possesses perfect consciousness of where he is, and what is occurring around him. As the sensations caused by inhaling a small quantity of chloroform have been experienced by nearly every medical man in his own person, I need not attempt to describe them. They differ somewhat with the individual, but may be designated as a kind of inebriation, which is usually agreeable when induced for curiosity, but is often otherwise, when the patient is about to undergo an operation: in such cases, however, this stage is very transitory. Although it is the property of narcotic vapours to suspend the functions of different parts of the nervous system in succession, yet they probably influence every part of that system from the first, but in different degrees.

I have found that my vision became impaired when inhaling chloroform, whilst I should have thought it as good as ever, had it not been that the seconds pointer disappeared from the watch on the table before me; and I could only discover it again by stooping to within a few inches within it. Common sensibility becomes also impaired, so that the pain of disease, which is generally due to a morbid increase of the common sensibility, is in many cases removed, or relieved, according to its intensity. And hence it is that patients are able to inhale chloroform and ether, without assistance, for the relief of neuralgia, dysmenorrhœa, and other painful affections; the latter, which acts less rapidly, being the best adapted for this kind of domestic use--chloroform being perhaps not perfectly safe. The sufferings attendant on parturition, when not unusually severe, may generally be prevented, as stated by Dr. Murphy,* (* Pamphlet on chloroform in the practice of midwifery.) without removing the patient’s consciousness; but I have met with no instance in which the more severe kind of pain caused by the knife was prevented, whilst complete consciousness existed, except in a few cases, for a short time, as the patients were recovering from the effects of the vapour, having just before been unconscious.

In the second degree of narcotism, there is no longer correct consciousness. The mental functions are impaired, but not altogether suspended. Generally, indeed, the patient neither speaks nor moves, but it is possible for him to do both; and this degree may be considered to be analogous to delirium, and to certain states of the patient in hysteria and concussion of the brain; and it corresponds with that condition of an inebriated person, who is not dead drunk, but in the state described by the law as drunk and incapable. It is so transitory, however, that the patient emerges to consciousness in a very few minutes at the farthest, if the chloroform is discontinued. This degree, any more than the others, cannot properly be compared to natural sleep, for the patient cannot be roused at any moment to his usual state of mind. Persons sometimes remember what occurs whilst they are in this state, but generally they do not. Any dreams that the patient has, occur whilst he is in this degree, or just going into, or emerging from it, as I have satisfied myself by comparing the expressions of patients with what they have related afterwards. There is generally a considerable amount of anæsthesia connected with [334/335] this degree of narcotism, and I believe that it is scarcely every necessary to proceed beyond it in obstetric practice, not even in artificial delivery, unless for the purpose of arresting powerful uterine action, in order to facilitate turning the fœtus. For, on the one hand, obstetric operations are less painful than those in which the knife is used, and, on the other, it is not so necessary that the patient should be perfectly motionless during their performance, as when the surgeon is cutting in the immediate vicinity of vital parts.* (*Mr. Gream and Dr. Wm. Merriman, who have done me the honour of quoting from my essays on ether and chloroform, in their pamphlets, have applied to midwifery, what I meant to apply only to delicate and serious surgical operations, and have grounded objections on the supposed necessity of producing a deep state of narcotism.) There is sometimes a considerable amount of mental excitement in this degree, rendering the patient rather unruly; but a further dose of the vapour removes this by inducing the next degree of narcotism, and there is less difficulty from this source with chloroform than with ether, since its action is more rapid, and two or three inspirations often suffice to overcome the excitement. Very often, however, the patient is quiet, and to a certain extent tractable in this degree, and if sufficient anæsthesia can be obtained, there are certain advantages in avoiding to carry the narcotism beyond it for minor operations, especially tooth-drawing, as I shall explain when I enter on the uses and mode of applying chloroform, at the end of this sketch of its physiological effects. The patient is generally in this degree during the greater part of the time occupied in protracted operations; for, although, in most cases, it is necessary, as I have formerly stated, to induce a further amount of narcotism before the operation is commenced, it is not usually necessary to maintain it at a point beyond this.

(To be continued)

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