On chloroform and other anæsthetics: their action and administration

by John Snow

AMOUNT OF VAPOUR OF CHLOROFORM ABSORBED TO CAUSE THE VARIOUS DEGREES OF NARCOTISM.

Before proceeding to describe the mode of administering chloroform, it is desirable to treat of the quantity of it which produces its different effects. Without alluding to the facts and experiments which prove that all narcotics produce their effects by being absorbed into the circulating fluid, and so reaching the nervous system on which they act, it is only necessary to mention the following circumstances to show that this is the case as regards chloroform. In some experiments in which I assisted Dr. Sibson, we found that the vapour of chloroform produced its effects after both the pneumogastric nerves had been divided, exactly the same as before. Chloroform can be detected by means of chemical tests exhaling in the breath of those who have just previously inhaled it. It can also be detected in the urine after inhalation, and very readily in all the tissues of animals that have been killed by it, for several days after death.

The quantity of chloroform in the blood in the different degrees of narcotism might be estimated approximatively from the amount used in inhalation, but I devised some experiments in 1848 for ascertaining the quantity with accuracy.[^[52]] The experiments were based on the following circumstances.

When air containing vapour is brought in contact with a liquid, as water or serum of blood, absorption of the vapour takes place, and continues till an equilibrium is established; when the quantity of vapour in both the liquid and air, bears the same relative proportion to the quantity which would be required to saturate them at the temperature and pressure to which they are exposed.

This is only what would be expected to occur; but I verified it by numerous experiments in graduated jars over mercury. The intervention of a thin animal membrane may alter the rapidity of absorption, but cannot cause more vapour to be transmitted than the liquid with which it is imbued can dissolve. The temperature of the air in the cells of the lungs and that of the blood circulating over their parietes is the same; and, therefore, when the vapour is too dilute to cause death, and is breathed till no increased effect is produced, the following formula will express the quantity of any substance absorbed:—As the proportion of vapour in the air breathed is to the proportion that the air, or the space occupied by it, would contain if saturated at the temperature of the blood, so is the proportion of vapour absorbed into the blood to the proportion the blood would dissolve.

The manner in which the experiments were performed, was to place a small animal in a glass jar, so large that it formed a capacious apartment for it, and held much more air than it could require in the course of the experiment. The jar was covered with a closely fitting lid, and a carefully weighed portion of chloroform was allowed to diffuse itself through the air of the jar. The experiments were continued till the chloroform produced no further effect. I shall pass over a number of tentative experiments, and adduce only a few of those which were made after I had ascertained the quantities requisite to produce the desired effect. The results obtained in these experiments were entirely due to the degree of dilution of the vapour; for the quantity of chloroform employed was, in every instance, more than would have killed the animal in a much shorter time than the experiment lasted, if it had been conducted in a smaller jar. It is assumed that the proportions of vapour and air remain unaltered during the experiment; for the quantity absorbed must be limited to what the animal can breathe in the time, which is so small a part of the whole that it may be disregarded.

Experiment 1. A guineapig and a white mouse were placed in a jar holding 3,000 cubic inches, and fifteen grains of chloroform were introduced by a tube in the lid of the jar, which was closed immediately by a screw. The chloroform fell on some blotting paper suspended in the jar, and in a minute or two was converted into vapour and diffused through the air in the jar. The animals were allowed to remain half an hour, and were unaffected by the chloroform, except that they appeared to be a little less brisk than usual, during the first two or three minutes after their removal.

Experiment 2. A guineapig was placed in the same jar, and twenty-two and a half grains of chloroform were introduced in the same manner as before, being three-quarters of a grain to each hundred cubic inches of air. In two or three minutes the chloroform was converted into vapour and diffused through the air in the jar. Six minutes afterwards the guineapig began to stagger, and soon afterwards was unable to keep on its legs. It was kept for half an hour in the jar, but did not become further affected. It was occasionally quiet, but always tried to walk when disturbed by moving the jar. When taken out, it flinched on being pricked, and it tried to walk, although unable to support itself on its legs. It recovered from the effects of the chloroform in three or four minutes.

Experiment 3. Another guineapig was placed in the same jar, and thirty grains of chloroform were introduced. In three or four minutes the chloroform had evaporated and diffused itself through the air in the jar. In two minutes afterwards the guineapig lay down, but stirred when the jar was moved. It was allowed to remain in the jar for half an hour, being asleep except when disturbed. When taken out it awoke and endeavoured to walk, but was unable to support itself at first. It flinched on being pricked. Recovered in three or four minutes.

Experiment 4. A cat was placed in the same jar, and the same quantity of chloroform was introduced. In three minutes it had evaporated, and, when ten minutes had elapsed, the cat began to stagger. Soon afterwards it was unable to support itself on its legs; and, when a quarter of an hour had elapsed, it seemed asleep, but raised its head when the jar was inclined. It remained apparently sleeping till the end of an hour, when it was taken out. It was unable to stand, but was sensible to the slightest pinch. It recovered gradually in the course of twenty minutes.

Experiment 5. Sixteen grains of chloroform were put into a jar holding 1,600 cubic inches, being one grain to each 100 cubic inches of air, as in the two last experiments. When it was converted into vapour, a white mouse was introduced, by moving the lid a little to one side for a moment. After running about for a minute and a half, it began to stagger and to lose power, but it continued to run with little intermission till three minutes had expired. After this it lay still, except when the jar was inclined, when it always endeavoured to maintain its balance and to walk. It also moved its limbs now and then, when not disturbed. It was removed at the end of ten minutes, when it tried to walk, but was unable. It did not flinch when its tail was pinched, but flinched, half a minute after its removal, on one of its toes being pinched. It recovered in two or three minutes.

Experiment 6. A guineapig was placed in the jar holding 3,000 cubic inches, and 37·5 grains of chloroform were introduced in the same manner as in the former experiments, being a grain and a quarter to each 100 cubic inches of air. The chloroform took three or four minutes to evaporate and diffuse itself in the jar; and by the end of this time the guineapig, which had been excited and running about, began to stagger, and in two minutes longer it was unable to walk, but endeavoured to keep its balance when the jar was inclined. At the end of a quarter of an hour it was lying still, but moved its limbs when it was rolled over by inclining the jar; but it made no voluntary effort. It was taken out when thirty-three minutes had elapsed. It moved its limbs as it was removed, though apparently not in a voluntary manner. Its limbs were not relaxed. It was quite insensible to pricking. It recovered in about ten minutes. The temperature in the axilla before it was put into the jar was 100° Fah., and immediately after its removal 96°.

Experiment 7. A guineapig was placed in the same jar, and forty-five grains of chloroform were introduced, being a grain and a half to each 100 cubic inches of air. In four minutes after the chloroform had evaporated, the guineapig was unable to walk. In half a minute more it seemed asleep, but there was a tremulous motion of the hind legs, which continued till ten minutes had elapsed. Afterwards it lay still, but winked now and then spontaneously. When rolled over by moving the jar, it made no voluntary effort. It was taken out twenty minutes after the chloroform had evaporated. It winked spontaneously, and also when the eyes were touched. It did not flinch when the ear was pricked, but flinched when the paw was pricked. The temperature in the axilla before the experiment was 100°, and immediately afterwards it was 96°. The guineapig recovered from the effects of the chloroform in ten minutes.

Experiment 8. A guineapig was put into the same jar, and 52·5 grains of chloroform were introduced, being a grain and three-quarters to each 100 cubic inches of air. The chloroform evaporated in the course of four minutes, at the end of which time the guineapig was altered in its manner, as if partially inebriated. In two minutes more it was becoming drowsy. A little while afterwards it was lying down. Six minutes after the evaporation of the chloroform was complete, the guineapig made no effort when turned over by inclining the jar, but only moved its feet, as it were automatically. At the end of nine minutes, it was lying quietly and breathing naturally. When fifteen minutes had elapsed it was in the same condition, and was removed from the jar. It cried and flinched on the foot being pricked. The temperature in the axilla was 97°. In five minutes after its removal it was fast recovering, and in ten minutes was quite recovered.

Experiment 9. A guineapig was placed in the jar used in the last three experiments, and sixty grains of chloroform were introduced in the same manner, being two grains to each 100 cubic inches of air. In four minutes it was all converted into vapour, and the guineapig was beginning to be affected by it. In two minutes more it was unable to stand or walk. In five minutes from the time when the evaporation was complete, the guineapig showed no sign of sensibility when turned over by inclining the jar; the breathing was natural. At the end of ten minutes it was lying still, breathing gently forty times in the minute. At the end of fifteen minutes it was in the same condition. From seventeen to twenty minutes, it stretched out one of its hind legs several times, and was doing so when taken out, at the end of twenty minutes. It showed no sign of sensibility when pricked. The temperature in the axilla was 96°. It began to recover gradually in a minute or two, and recovered completely in from ten to fifteen minutes.

Experiment 10. A cat was placed in the same jar, and the same quantity of chloroform was introduced in the same manner. It became quite insensible in a few minutes after the chloroform was introduced; and it was allowed to remain for twenty-five minutes, when it was taken out. It was perfectly insensible to pricking, and its muscles were quite relaxed; it was breathing gently, and the pulsations of the heart were between sixty and seventy in the minute. It was immediately made the subject of another experiment of drowning whilst insensible, which need not be related in this place.

Experiment 11. Four grains of chloroform were put into a glass jar holding 200 cubic inches, and when it had evaporated and was diffused through the air in the jar, a white mouse was introduced, by momentarily removing the cover a little to one side. A minute after its introduction the mouse was lying, but it moved its legs for a quarter of a minute longer. When four minutes had elapsed, the breathing became slow, and it was taken out. It was totally insensible for the first three minutes after its removal, and recovered during the two following minutes.

Experiment 12. Thirty-two grains of chloroform were diffused through the air of a jar holding 1,600 cubic inches, being two grains to each 100 cubic inches, as in the last three experiments. A white mouse was introduced by moving the cover a little to one side for a moment. In one minute it was insensible, and did not make any effort on being rolled about by inclining the jar, but it moved its paws for half a minute longer. It remained insensible, breathing 160 times in the minute, till it was taken out at the end of five minutes. It was quite insensible to pinching. It began to walk in a minute or two. Its temperature before the experiment was 98°, and immediately afterwards was 92°. The temperature of the room was 68°.

Experiment 13. A guineapig was put into a jar holding 3,000 cubic inches, and 67·5 grains of chloroform were introduced on blotting paper suspended within the jar, being 2¼ grains to each 100 cubic inches. In four minutes, the chloroform had all evaporated, and the guineapig was becoming affected. In two minutes more, it was quite insensible. Eight minutes after the chloroform had evaporated, it was lying still, breathing forty times in the minute. During the next three or four minutes, it moved one or other of its legs occasionally. At the end of seventeen minutes, it was lying still, and the breathing was twenty-six in the minute. It was taken out at the end of twenty minutes quite insensible; in three or four minutes it began to try to walk, and in ten minutes, was quite recovered.

Experiment 14. Two white mice, one being full grown, and the other about three-quarters grown, were placed in the jar holding 1,600 cubic inches, and forty grains of chloroform were introduced on blotting paper, being two grains and a half to each hundred cubic inches. In two minutes, the chloroform had evaporated, and the mice were much excited. In another minute, they were unsteady in walking; and in a minute more, the old mouse was lying insensible, and breathing deeply and laboriously. In four minutes more, i. e., six minutes after the chloroform had evaporated, the young mouse was insensible also, but was moving one of its hind legs. In other four minutes, the young mouse was breathing by slow gasps, whilst the old one continued to breathe deeply as before. Three minutes later, i. e., thirteen minutes after the chloroform had evaporated, the old mouse had begun to gasp, and the young one was gasping only at intervals. They were removed, and recovered completely in ten minutes. The young one recovered most quickly. Their temperature, on being removed, was about 90°.

Experiment 15. A cat was put into the jar holding 3,000 cubic inches, and 82·5 grains of chloroform were introduced, being two grains and three-quarters to each hundred cubic inches. In five minutes, it had evaporated, and the cat began to stagger in its walk. In two minutes more, it was unable to stand. Five minutes after the chloroform had evaporated, the cat was breathing deeply, seventy-five times in the minute. At eight minutes, it was breathing less deeply, one hundred and seventeen times in the minute. Ten minutes after the chloroform had evaporated, the cat was quite insensible, and breathing one hundred and twenty-six times in the minute. It was now taken out. The temperature in the axilla was 98°. In half an hour after its removal from the jar, it had recovered its consciousness, but was still drowsy.

It was now put into the jar again, and the same quantity of chloroform was introduced in the same manner as before. In five minutes, it had evaporated, and the cat was again insensible. In other five minutes, it was breathing rather deeply, forty-eight times in the minute. Twelve minutes after the chloroform had evaporated, the cat was breathing in the same manner, but sixty-eight times in the minute. The breathing afterwards became shallow and feeble, and half an hour after the chloroform had evaporated, it was eighty-eight in the minute. In five minutes more, the breathing ceased. The cat was taken out of the jar, and the stethoscope was applied to the chest. The heart could not be heard to beat at first, but in a short time, the cat gave a gasp, and the heart’s action returned, and the breathing became reestablished.

Experiment 16. Forty-eight grains of chloroform were put into a jar holding 1,600 cubic inches, being three grains to each hundred cubic inches, and when it was converted into vapour and diffused through the air in the jar, a white mouse was introduced. It ran about for a minute and a half, and then it was unable to move any longer. In nine minutes and a half, the breathing was getting very slow, and the mouse was immediately removed. Before it could be got out, it appeared to have entirely ceased to breathe, but it immediately began to gasp at intervals. In a minute, the breathing improved, and soon became natural. Three minutes after its removal, the mouse began to walk in a ring, and in seven minutes, it had quite recovered.

Experiment 17. A guineapig was placed in a jar holding 1,600 cubic inches, and fifty-four grains of chloroform were introduced on blotting paper, in the manner previously explained; being three grains and three-eighths to each hundred cubic inches of air. In four minutes, the chloroform had evaporated, and become diffused through the air in the jar, and the guineapig was drowsy. In three minutes more, it was lying apparently insensible, and breathing feebly, thirty times in the minute. After this, it kicked occasionally for a few minutes. When six minutes had elapsed from the time when the chloroform had evaporated, the breathing was very feeble, and apparently performed only by the diaphragm. From fifteen to eighteen minutes, I could hardly see whether the animal was breathing or not, and it was taken out of the glass at eighteen minutes, when the breathing appeared to have ceased. The stethoscope was applied to the chest, and the sounds of the heart could scarcely be heard at first, but the breathing returned in a few seconds, and the action of the heart improved. The guineapig gradually recovered, but it was not able to walk for twenty-five minutes.

Experiment 18. Sixty grains of chloroform were introduced into the jar employed in the last experiment, being three grains and three-quarters to each hundred cubic inches of air contained in the jar. When it had evaporated, and was diffused through the air, a white mouse was introduced, whilst the lid of the jar was moved a little to one side for a moment. It ran about at first, but suddenly ceased to run, and became insensible, at the end of three-quarters of a minute. It lay breathing deeply and rapidly till two minutes had elapsed, when the respiration became slow, and it ceased at two minutes and three-quarters after the mouse was introduced. It was removed at this time, and it gasped a few seconds afterwards; this gasp was soon followed by another; the gaspings became more frequent, and in a short time, the natural breathing was resumed. In five minutes, the mouse was able to walk.

The third, fourth, and fifth of the above experiments show that one grain of chloroform to each hundred cubic inches of air suffices to induce the second degree of narcotism, or that state in which consciousness and voluntary motion are disturbed, but not entirely abolished. Now one grain of chloroform produces 0·767 of a cubic inch of vapour at 60°, when its specific gravity is 4·2; and, when the vapour is inhaled, it expands somewhat, as it is warmed to the temperature of the lungs; but it expands only to the same extent as the air with which it is mixed, and therefore the proportions remain unaltered. But air, when saturated with vapour of chloroform at 100°, contains 43·3 cubic inches in 100; and

As 0·767 : 43·3 :: 0·0177 : 1.

So that if the point of complete saturation be considered as unity, 0·0177 or 1–56th, will express the degree of saturation of the air from which the vapour is immediately absorbed into the blood; and, consequently, also the degree of saturation of the blood itself.

I find that serum of blood at 100°, and at the ordinary pressure of the atmosphere, will dissolve about its own volume of vapour of chloroform; and since chloroform of specific gravity 1·483 is 288 times as heavy as its own vapour, 0·0177 ÷ 288 gives 0·0000614, or one part in 16,285, as the average proportion of chloroform by measure in the blood, in the second degree of narcotism.

It is evident, from the experiments numbered 9 to 12 inclusive, that two grains of chloroform to each hundred cubic inches of the inspired air cause a state of very complete insensibility, corresponding with what I have designated the fourth degree of narcotism; and by the method of calculation employed above we get 0·0354, or 1–28th, as representing the degree of saturation of the blood, and 0·0001228 the proportion by measure in the blood.

In experiments 6, 7, and 8, in which quantities of chloroform were employed intermediate between one and two grains to each hundred cubic inches of air, a moderate amount of insensibility was induced, corresponding very much with the state of patients during operations under chloroform.

The experiments from 13 to 18 show that quantities of chloroform, exceeding two grains to 100 cubic inches of air, have a tendency to embarrass and arrest the function of respiration, if the inhalation is continued. I have not yet been able to determine satisfactorily the exact proportion of chloroform which requires to be absorbed to arrest the respiration of animals of warm blood. I believe there is a definite proportion which has this effect, but there are two reasons why it is not so easy to ascertain it, as to ascertain the proportion which causes the minor degrees of narcotism. In the first place, the breathing often becomes very feeble before it ceases, so that the animal inhales and absorbs but very little chloroform, and remains on the brink of dying for some time. In the next place, the temperature of the body falls in a deep state of narcotism, especially in small animals; and, as the temperature falls, the amount of chloroform which the blood can dissolve from any given mixture of air and vapour increases.

Judging from the experiments numbered 14 to 18, three grains of chloroform to each hundred cubic inches of air must be very nearly the quantity which has the power of arresting the breathing when the temperature of the body is 100°; and as three grains of chloroform produce 2·3 cubic inches of vapour, and air at 100° is capable of taking up 43·3 per cent. of its volume, it follows that the blood must contain between 1–18th and 1–19th as much chloroform as it is capable of dissolving, at the time when the respiration is arrested. In the 14th experiment, the breathing of the two mice was on the point of being stopped by two and a half grains of chloroform in each hundred cubic inches of air, but during the thirteen minutes which the mice breathed the vapour, their temperature fell to about 90°. Air, when saturated with the vapour of chloroform at this temperature, contains 35 per cent., and two grains and a half of chloroform yield 1·917 cubic inches of vapour; so by a calculation similar to that made at page 68, the mice at the time when the breathing was about to cease must have absorbed 1–18th part as much chloroform as their circulating fluids were capable of dissolving.

The reader will have observed that, in the experiments related above, the mice became much more quickly affected than the guineapigs and cats. The reason of this is their quicker respiration and circulation, and much more diminutive size. Little birds, such as linnets and sparrows, are also very quickly affected by chloroform. Frogs are more slowly affected, owing to their languid respiration, unless the vapour to which they are exposed is very strong.

They can, however, owing to their low temperature, be rendered insensible by proportions of vapour too small to affect animals of warm blood; and as they have no proper temperature of their own, the amount of vapour (in proportion to the air in which they are placed) that will affect them, depends entirely on the temperature of that air.

The following experiment was several times performed on frogs with the same result, the temperature of the room being about 55°, as it was in winter.

Experiment 19. 4·6 grains of chloroform were diffused through the air of a jar of the capacity of 920 cubic inches, and a frog was introduced. In a few minutes, it became affected, and at the end of ten minutes, was quite motionless and flaccid; but the respiration was still going on. Being now taken out, it was found to be insensible to pricking: it recovered in a quarter of an hour.

In a repetition of this experiment, in which the frog continued a few minutes longer in the vapour, the respiration ceased, and the recovery was more tardy. On one occasion, the frog was left in the jar for an hour, but when taken out, and turned on its back, the pulsations of the heart could be seen. In an hour after its removal, it was found to be completely recovered.

The first of the experiments related above (page 60), showed that an atmosphere containing half a grain of chloroform to each hundred cubic inches, produced scarcely any appreciable effect on animals of warm blood; but the following calculation explains why this quantity acts so energetically on the frog, and proves that this creature is affected by chloroform according to the same law as animals of warm blood. The vapour is absorbed into the blood and lymph of the frog at the temperature of the external air, whose point of relative saturation therefore remains unaltered, both in the lungs and in contact with the skin of the animal; and as half a grain of chloroform produces 0·383 cubic inches of vapour, and air at 55° contains, when saturated, 10 per cent. of vapour; 0·0383, or 1–26th, expresses the degree of saturation of the air, and also of the blood of the frog. And this is a very little more than the quantity (0·0354 or 1–28th) which was calculated above to be the greatest amount which could be absorbed with safety into the blood of the mammalia. It must be observed, however, that the pulmonary respiration of the frog was arrested by this proportion of 1–26th as much chloroform as the blood would dissolve, whilst we calculated that it required about as much as 1–18th to arrest the breathing of animals of warm blood. It must be remembered, however, that the pulmonary respiration of frogs is a process of swallowing air, which only goes on when the creature is comparatively active. In the torpid state, the respiration takes place only by the skin, and the frog never breathes with the aid of the same muscles and nerves as mammalia and birds.

By warming a frog, together with the air in which it is placed, it is, in accordance with the law explained above, rendered comparatively proof against an amount of chloroform which would otherwise render it insensible.

Experiment 20. A frog, which had been a few days previously subjected to the experiment just narrated, was put into the same jar, which was placed near the fire, till a thermometer inside marked 75° Fah.; 4·6 grains of chloroform were then introduced, and diffused through the air in the jar. The jar was kept for twenty minutes, with the thermometer indicating the same temperature within one degree. For the first seventeen minutes, the frog was unaffected; and only was dull and sluggish, but not insensible, when taken out. Air at 75°, when saturated with vapour of chloroform, contains 22 per cent., and therefore the 0·383 per cent. of vapour, which at 55° was capable of saturating the fluids of the frog to the extent of 1–26th of what they would dissolve, was, at 75°, capable of saturating them only to the extent of 1–57th.

At one of Dr. Wilson’s Lumleian Lectures, at the College of Physicians, on March 29th, 1848, I had the honour of performing some experiments, and making some remarks, on chloroform, and I combined together two experiments on frogs and small birds, in a way which shows how entirely the effects of a narcotic vapour depend on the quantity of air with which it is mixed, and on other physical conditions.

Experiment 21. I introduced a chaffinch, in a very small cage, into a glass jar holding nearly 1,000 cubic inches, and put a frog into the same jar, covered it with a plate of glass, and dropped five grains of chloroform on a piece of blotting paper suspended within. In less than ten minutes, the frog was insensible, but the bird was not affected.

Experiment 22. I then placed another frog and another small bird in a jar containing but 200 cubic inches, with exactly the same quantity of chloroform. In about a minute and a half, they were both taken out,—the bird totally insensible, but the frog not appreciably affected, as from its less active respiration it had not had time to absorb much of the vapour.

The blood in the human adult is estimated by M. Valentin to average about thirty pounds. M. Valentin’s experiments were so conducted that this quantity must include the extra vascular liquor sanguinis, as well as the blood actually contained within the vessels. On this account, his estimate is all the better fitted for calculating the amount of chloroform absorbed, since this medicine, when inhaled gradually, passes by exosmosis through the coats of the bloodvessels into the fluid in which the tissues are immediately bathed. The above quantity of blood would contain 26 pounds 5 ounces of serum, which, allowing for its specific gravity, would measure 410 fluid ounces. This being reduced to minims, and multiplied by 0·0000614, the proportion of chloroform in the blood required to produce narcotism to the second degree (see page 68), gives 12 minims as the whole quantity in the blood. More than this is used in practice, because a considerable portion is not absorbed, being thrown out again when it has proceeded no further than the trachea, the mouth and nostrils, or even the face-piece. But I find that if I put twelve minims into a bladder containing a little air, and breathe it over and over again, in the manner of taking nitrous oxide, it suffices to remove consciousness, producing the second degree of its effects.

To induce the third degree of narcotism, or the condition in which surgical operations are usually commenced, would require that about 18 minims should be absorbed by an adult of average size and health, according to the above method of calculation; and to induce the deep state of insensibility, which I have termed the fourth degree of narcotism, would require 24 minims; whilst to arrest the function of respiration would require that about 36 minims should be absorbed.