Source: Snow, John. London Med. Gazette, vol. 41, May 19, 1848, pp. 850-54 (part 1).
On narcotism by the inhalation of vapours
By John Snow, M.D.
Vapours when inhaled become absorbed. Method of determining the quantity in the blood in different degrees of narcotism. Experiments on animals for this purpose, with chloroform and with ether.
It is generally admitted that ether and chloroform, when inhaled, are imbibed and enter the blood, and this has been proved, as regards ether, in more ways than one. That substance has been detected in the blood of animals that have inhaled it; and I have proved its absorption as follows:--I passed a tame mouse through the quicksilver of a mercurial trough, into a graduated jar containing air and ether vapour, and, after a little time, withdrew it through the mercury, and introduced it, in the same manner, into a jar containing only air. On withdrawing it, and waiting till the air cooled to its former temperature, I found that the mercury had risen considerably in the first jar, and become depressed to some extent in the second; vapour of ether having been absorbed from one jar and part of it exhaled into the other.
M. Lassaigne* (*Comptes Rendus, 8 Mars, 1847; and Med. Gaz. vol. xxxix. p. 968.) endeavoured to ascertain the proportion of ether in the blood in etherization, by comparing the tension of the vapour of serum of the blood before and after inhalation, with that of an aqueous solution of ether in certain known proportions. This method would, no doubt, indicate the quantity of ether in the serum at the time it was examined; but part of the ether would escape from the blood, in the form of vapour, as soon as it came in contact with the air in its exit from the body. He made the quantity of ether in the blood to be 0.0008, or one part in 1250.
Dr. Buchanan† († Med. Gaz. vol. xxxix. p.717.), by considering the quantity of ether expended in inhalation, and making allowance for what is expired, without being absorbed, considered the quantity in the blood of the adult in complete etherization to be not more than half a fluid ounce; and this is, I believe, a pretty correct estimate.
I consider, however, that I have found a plan of determining more exactly the proportions of ether and of other volatile substances present in the blood in the different degrees of narcotism. It consists in ascertaining the most diluted mixture of vapour and of air that will suffice to produce any particular amount of narcotism; and is founded on the following considerations, and corroborated by its agreeing with the comparative physiological strength of the various substances.
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. If, for instance, the liquid contains one per cent, and would require ten per cent to saturate it, the air will contain three per cent if thirty per cent be the quantity that it could take up. This is only what would be expected to occur; but I have 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 plan which I adopted to ascertain the smallest quantity of vapour, in pro-[850/851] portion to the air, that would produce a given effect, was to weigh a small quantity of the volatile liquid in a little bottle, and introduce it into a large glass jar covered with a plate of glass; and having taken care that the resulting vapour was equally diffused through the air, to introduce an animal so small, that the jar would represent a capacious apartment for it, and wait for that period when the effects of the vapour no longer increase.
Experiments with Chloroform
I will first treat of chloroform, and, passing over a number of tentative experiments, will adduce a few of those which were made after I had ascertained the requisite quantities. The effects produced 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.
Exp.1.--A Guinea pig was placed in a jar, of the capacity of 1600 cubic inches, and the cover being moved a little to one side for a moment, 8 grs. of chloroform were dropped on a piece of blotting paper suspended within. The animal remained in the jar twenty minutes, and was not appreciably affected any part of the time.
Exp.2.--The same Guinea pig was placed in the same jar, on another occasion, and 12 grs. of chloroform were introduced in the same manner, being three-quarters of a grain for each 100 cubic inches. In about six minutes it seemed drunk. It was allowed to remain for seventeen minutes, but did not become more affected; occasionally it appeared to be asleep, but could be disturbed by moving the jar. On being taken out it staggered, and could not find the way to its cage at first, but it recovered in two or three minutes.
Exp.3.--Two grains of chloroform were put into a jar containing 200 cubic inches; it was allowed to evaporate, and the resulting vapour equally diffused by moving the jar; and then the cover was withdrawn just far enough to introduce a white mouse. After a short time it began to run round continuously in one direction. At the end of a minute it fell down and remained still, excepting a little movement of one or other of its feet now and then. It remained in the same state, and was taken out at the end of five minutes: it flinched on being pinched, tried to walk directly afterwards, and in a minute or so seemed to be completely recovered.
Exp.4.--A Guinea pig was placed in the jar of 1600 cubic inches’ capacity, and 20 grains of chloroform were introduced, as in the two first experiments, being a grain and a quarter for each 100 cubic inches. In two minutes the Guinea pig began to be altered in its manner. At the end of four minutes it was no longer able to stand or walk, but crawled now and then. After seven minutes had elapsed it no longer moved, but lay breathing as in sleep. It was taken out at the end of a quarter of an hour. It moved its limbs as soon as it was touched, flinched on being pinched, and in four minutes was as active as usual.
Exp.5.--Three grains of chloroform were diffused in the jar of the capacity of 200 cubic inches, and a white mouse introduced. It was not affected at first, but in less than a minute became drowsy, and at the end of a minute appeared insensible, and did not move afterwards. It was allowed to remain two minutes longer; it breathed naturally, and its limbs were not relaxed. When taken out it was insensible to pinching; it began to recover voluntary motion in two minutes.
Exp.6.--The same mouse was placed in the same jar on the following day with 3.5 grs., being a grain and three-quarters for each 100 cubic inches. I[t] ran round as before, but fell down in less than a minute, and before the end of the minute ceased to move. It continued breathing in its natural rapid manner till nearly four minutes had expired, when the breathing became very feeble, and immediately afterwards appeared to have ceased. The mouse was taken out just as four minutes had elapsed. It began immediately to give a few deep inspirations at intervals, after which the breathing became natural; it was perfectly insensible to pinching, and did not stand [851/852] for three minutes. At the end of five minutes it seemed to be recovered, but it did not eat afterwards, and it died on the following day. The state of its organs will be mentioned farther on. The stoppage of respiration and impending death did not seem to be the direct effect of the vapour, but the result of continued and very deep insensibility.
Exp.7.--A white mouse was placed in the same jar, with 4 grs. of chloroform. At the end of a minute it was lying, but 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.
Exp.8.--The same mouse was placed in the same jar on the following day with 4.5 grs. of chloroform, being 2 ¼ grs. for each 100 cubic inches. It became more quickly insensible, and at the end of two minutes the breathing was beginning to be affected, when it was taken out. It recovered in the course of five minutes.
Exp.9.--A white mouse was put into this jar, after 5 grs. of chloroform had been diffused in it, being 2 ½ grs. to each 100 cubic inches. It was totally insensible in three-quarters of a minute; in a little more than a minute the breathing became difficult, and, before two minutes had expired, the respiration was on the point of ceasing, and it was taken out. The breathing remained difficult for five minutes, but in other five minutes the mouse recovered, and at the end of a quarter of an hour was very active.
It will be remarked that in these experiments, the mice became much more quickly affected than the Guinea pigs. The reason of this is, their quicker respiration and much more diminutive size. In the last experiment, the quantity of vapour was evidently sufficient to arrest the breathing by its direct influence.
It is evident from the second, third, and fourth of the above experiments, that about one grain of chloroform to each 100 cubic inches of air, suffices to induce the second degree of narcotism, or that state in which the correct relation with the external world is abolished, but in which sensation and ill-directed voluntary movements may exist. Now one grain of chloroform produces 0.767 of a cubic inch of vapour of the sp. gr. [specific gravity] 4.2 as given by Dumas; and when it is inhaled, it expands somewhat as it is warmed, from about 60° to the temperature of the body; 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 sp. gr. 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.
From the fifth experiment it appears that a grain and a half per 100 cubic inches of air is capable of producing the third degree of narcotism; and by the sixth and seventh experiments, it is shewn that from a grain and three-quarters to two grains causes a very complete state of insensibility, which cannot be long continued without danger; but I may remark, that four minutes in a mouse represents a much longer period in the human being, in whom the circulation and respiration are so much less rapid. I think we may take two grains as the average quantity capable of inducing the fourth degree,--the utmost extent of narcotism required, or that can be safely caused in surgical operations; and by the method of calculation above we shall get 0.0354, cr 1-28th, as representing the degree of saturation of the blood, and 0.0001228 the proportion by measure in the blood.
A greater quantity than this seems to induce the fifth degree of narcotism, embarrassing the respiration; and two and a half grains have the power of [852/853] directly stopping the respiratory movements. By calculation we obtain 0.0442, or 1-22nd, as the degree of saturation of the blood which has this effect.
Birds have generally a somewhat higher temperature than most mammalia, and therefore the following five experiments have been separated from the rest; but, in 13 and 14, the thermometer placed under the wing of the linnet, at the end of the experiment, indicated only 100°,--just the temperature in the groin of the Guinea pig when it was removed from the jar in the 4th experiment. These are the only occasions on which it occurred to me to apply the thermometer.
Exp.10.--4.6 grs. of chloroform were put into a jar containing 920 cubic inches, by sliding the glass which covered it a little to one side. The jar was moved about to diffuse the vapour; and thus each 100 cubic inches of air contained half a grain. A hen chaffinch was introduced, by again momentarily sliding the cover a little to one side. In less than two minutes it seemed rather unsteady in its walking at the bottom of the jar, but no further effect was produced, although it remained twenty minutes; when taken out, indeed, it did not seem affected. This experiment was repeated on the same bird, and on another chaffinch, and also on a green linnet, with the same result; that is, no decided effect was produced.
Exp.11.--9.2 grs. of chloroform were diffused through the air in the same jar, being one grain to each 100 cubic inches; and a chaffinch was put in. In less than two minutes it staggered about, and in two and a half minutes fell down, but still stirred. It did not get further affected, although it remained ten minutes. Sometimes it seemed perfectly insensible, but always stirred when the jar was moved, and occasionally it made voluntary efforts to stand. On being taken out it seemed sensible of its removal; it flinched on being pinched, and quickly recovered.
Exp.12.--A chaffinch was placed in the same jar with 11.5 grs., being a grain and a quarter for each 100 cubic inches. In less than a minute it began to stagger, and shortly afterwards was unable to stand, but moved its legs and opened its eyes occasionally. It did not get further affected after two minutes had elapsed, although it remained three minutes longer. It seemed aware of its removal, but was not sensible to being pricked. In attempting to walk when placed on the table, immediately after its removal from the vapour, it fell forwards at every two or three steps. In a minute or two, however, it was able to walk.
Exp.13.--A green linnet was put in the same jar, with 13.8 grs., being a grain and a half to each 100 cubic inches. In a minute it was unable to stand, and in half a minute more ceased to move. It remained breathing naturally, and kept its eyes open. It was taken out at the end of ten minutes, was insensible to having its foot pinched, and began to recover voluntary motion in three minutes.
Exp.14.--Was performed on the same linnet, two or three days before the last, with a grain and three-quarters of chloroform to each 100 cubic inches, in the same jar. It was affected much in the same way as detailed above, but was longer in recovering voluntary motion after its removal, at the end of ten minutes.
It will be perceived that these results coincide as nearly as possible with the effects of the same quantities on the Guinea pigs and mice; and I found that when the quantity of chloroform exceeded two grains to the 100 cubic inches, birds were killed very rapidly.
It occurred to me that if this method of ascertaining the amount of vapour in the blood were correct, then a much more dilute vapour ought to suffice to produce insensibility in animals of cold blood; and that experimenting on them would completely confirm or invalidate these views.
The following experiment has been performed on frogs several times with the same result, the temperature of the room being about 55°.
Exp.15.--4.6 grs. of chloroform were diffused through the jar of 920 cubic inches capacity, as in Exp. 10. In the course of a few minutes the frog began to be 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, but recovered in a quarter of an hour. In a repetition of this experiment, in which the frog continued a few minutes longer, the respiration also ceased, and [853/854] the recovery was more tardy. On one occasion the frog was left in the jar for an hour, but when taken out and turned over, the pulsation of the heart could be seen. In an hour after its removal it was found to be completely recovered.
Now the vapour is absorbed into the blood of the frog at the temperature of the external air, whose point of saturation, therefore, remains unaltered; and as half a grain of chloroform produces 0.383 cubic inches of vapour; and air at 55° will contain, 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 little more than 0.0354, or 1-28th, which we considered as the greatest quantity that could with safety exist in the blood. But frogs are able to live without pulmonary respiration, by means of the action of air on the skin: consequently this experiment coincides exactly with the others, and remarkably confirms the accuracy of this method of determining the amount of chloroform in the blood.
At the College of Physicians, on March 29, when I had the honour of shewing the effects of chloroform at Dr. Wilson’s Lumleian Lectures, and briefly explained these views, I conjoined the last experiment and the 10th in the following manner. I introduced a chaffinch, in a very small cage, into a glass jar holding nearly 1000 cubic inches, and put a frog into the same jar, covered it with a piece of glass, and dropped 5 grs. of chloroform on a piece of blotting paper suspended within. In less than ten minutes the frog was insensible, but the bird was unaffected. Then, in order to shew that the effects depended entirely on the dilution of the vapour, another frog, and another small bird, were placed 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.
As the narcotism of frogs, by vapour too much diluted to affect animals of warm blood, depends merely on their temperature, it follows that, by warming them, they ought to be put into the same condition, in this respect, as the higher classes of animals; and although I have not raise their temperature to the same degree, I have found that as it is increased, they cease to be affected by dilute vapour that would narcotize them at a lower temperature.
Exp.16.--I placed the jar holding 920 cubic inches near the fire, with a frog and a thermometer in it; and when the air within reached 75°, 4.6 grains of chloroform were diffused through it. 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.
(To be continued)
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