FOOTNOTES:
[2] Journal of Physiology, Vol. XXIV, 1899, p. 99.
[3] Johns Hopkins Hospital Reports, Vol. I, 1896.
[4] Loc. cit.
[5] Deutsch. Med. Wochenschr., XV, 1899.
[6] Amer. Journ. Physiol., Vol. VI, 1902.
[7] Pflüger’s Archiv, VI, 1872; VIII, 1874.
[8] Johns Hopkins Hospital Reports, I, 1896.
[9] Arch. f. exp. Path. u. Pharm., Bd. 23-24.
[10] De Motu peristaltic. intest. Treviris, 1750.
[11] Über das Hemmungsnervensystem f. d. peristal. Bewegungen d. Darmes, Berlin, 1857.
[12] Sitzungsb. d. k. Akad. d. Wissensch. Wien, 1864, Bd. 1.
[13] Untersuchung. z. Naturl. d. Mensch. u. d. Thiere; 1881; Bd. XIII.
[14] Arch. f. d. gesammte Physiologie, Bd. LXI, 1895, S. 359.
[15] Centralbl. d. Medicin. Wissensch., S. 209, 1868.
[16] Verhandl. d. K. K. Leop. Carol. Akad. d. N., Bd. 19, 1860.
[17] Lehrbuch der Physiologie, 10th Ed., p. 360.
[18] Zeitsch. f. Biologie, Bd. 22, 1886, p. 195.
[19] Arch. f. d. ges. Physiol., Bd. 63, 1896, p. 425.
[20] Arch. di Fisiologia, 1904, I, 413.
[21] Arch. internationales de Physiologie, 1905, Vol. III, II, p. 156.
CHAPTER II.
The Subcutaneous and Intravenous Injection of Saline Purgatives.
Although it has long been known that many of the vegetable purgatives act as well when introduced into the circulation as when taken by mouth, it has generally been stated that saline purgatives are inactive when injected either subcutaneously or intravenously. It has even been claimed that they have the opposite effect, causing constipation. Claude Bernard,[22] however, states that sodium sulphate causes purgation when introduced into the circulation, although he gives no experiments to support the assertion. Buchheim[23] believed that intravenous injection of purgative salts produced no purgation. Rabuteau[24] stated that the injection of a large amount of sodium sulphate into the blood caused constipation in a dog, an experiment which he took to prove that the strong solution outside the intestine withdrew fluid from the lumen by its endosmotic power. Headland[25] advanced the view that all medicines act after being absorbed into the blood, and that saline cathartics are first taken up into the circulation and stimulate the intestine in being later excreted by the intestinal glands. Carpenter reported an experiment in which he obtained a purgative action by introducing magnesium sulphate into the stomach after this organ had been separated from the intestine by a ligature. It was further found by Vulpian[26] that small doses of magnesium sulphate, but not of sodium sulphate, acted as purgatives when injected subcutaneously. Hay[27] gives an excellent resumé of the literature on this subject. Although he considers it already proven that purgatives do not act when injected subcutaneously or intravenously, he has made a number of experiments to confirm this idea. He was unable to obtain any purgative effect in dogs and cats by the introduction into the blood of 10% Na2SO4 or 20% MgSO4. With the subcutaneous injection of these salts, however, a purgative action was sometimes produced. This he attributed to the local irritation of the injection. It will be noted that the conditions of these experiments are by no means ideal. Hay injected directly into the blood a solution of Na2SO4, which is approximately twice as strong as a solution of this salt isosmotic with the blood would be. Similarly a solution of MgSO4 isosmotic with the blood would be about 4% (m/6 Soln MgSO4 + 7 H2O = 4.1 g. in 100 c.c.). Hence the solution which Hay introduced directly into the circulation was five times as concentrated as an isosmotic solution. Although it is not clear just what abnormal conditions would be brought about by the injection of such concentrated solutions, it is certain that the normal action of the salt could not be expected under these circumstances. This is further shown by the fact that Hay did obtain a purgative action in some cases when he injected the salt solutions subcutaneously. Here the injury caused by the concentrated solution was only local, and the salt itself was absorbed in small quantities and in more dilute solution into the blood.
In a large number of experiments which have yielded quite constant results I have been unable to confirm the idea generally held and supported by Hay that subcutaneous and intravenous injections of saline purgatives do not exert a purgative action. I have quite constantly found that with proper conditions these salts do produce increased peristalsis and also an increased secretion of fluid into the intestine when introduced directly into the circulation or under the skin. In most cases also an actual passage of faeces was observed.
Several methods were used in testing the action of the salts and it was found that the results could best be studied by observing the loops of intestine directly. In rabbits under the influence of morphine (5 c.c. 1% solution morphine hydrochlorate subcutaneously) the abdominal cavity was laid open and the loops of intestine carefully protected from loss of heat and moisture while under observation. In other cases they were observed under the surface of normal sodium chloride solution, a method devised by van Braam-Houckgeest and used by him in a long series of experiments. In the NaCl solution the intestines normally remain almost quiet and the effect on them of stimulating agents can be readily determined. In addition to this method many experiments were made in which animals were kept in separate cages, some acting as control animals, others for experiment. The amount and character of the faeces were observed during several hours after the administration of the purgative and compared with the control animals. The solutions used were made up as fractions of molecular solutions. Thus to obtain a solution of sodium citrate, for example, approximately isosmotic with the rabbit’s blood, one-sixth molecular weight of the salt in grams (including water of crystallization) was dissolved in 1,000 c.c. distilled water. This gave an m/6 solution, which was taken to be approximately isotonic with the blood. The injections were made usually with a hypodermic needle into the marginal vein of the rabbit’s ear, or into the jugular vein. Subcutaneous injections were made under the loose skin of the back. In most of these experiments small rabbits weighing from 1,200 to 1,500 grams were used.
In studying the purgative action of these salts, two criteria may be considered, namely, the actual passage of faeces, and secondly merely the increase of peristalsis and secretion not necessarily accompanied by defaecation. The former is of course the object of purgation, and unless a salt produces an actual passage of faeces it cannot strictly be termed a purgative. When this has been established, however, it is of much greater advantage to use the other criterion in studying the action of the solutions on the intestine. Any salt which in small doses produces an increased peristalsis will with a more prolonged action and perhaps larger doses produce actual purgation. Therefore in the first rough test as to the action of the salts I have used the actual passage of faeces as the criterion of the action. In this case no morphine is given the animal and its intestines are not exposed as in the other experiments where the movements are directly watched. In these tests the animals were kept in boxes, the bottom of each of which was covered by a large sheet of paper. During a certain time preceding the injection of any solution the animals were watched and the faeces collected and weighed. Half of the animals were kept as controls, and the rest subjected to injections of various solutions. The average weight of the normal faeces was compared with the weight of the faeces passed during the same time by the animals receiving the injections. The faeces were collected and weighed each hour during the first six hours following the first injection. The chief purgative effect usually took place during the first two hours. Although there was considerable individual variation in the rabbits, there was found to be a constant increase in the amount of faeces following the subcutaneous or intravenous injection of one of the salts. This amount varied from two to six times the average normal weight. Sometimes the increase was much greater and in many cases the nature of the faeces was much changed. The normal faeces of the rabbit consist of dry hard definitely formed masses. Following the purgative, they become soft and unformed, and may as in the case of NaF and BaCl2 be semifluid.
The amount of sodium citrate, sulphate, or tartrate necessary to produce purgation is about the same in each case: 10 c.c. m/6 solution injected subcutaneously, followed 10 minutes later by a second injection of 5 c.c. of this solution and 10 minutes after this by a third similar injection, usually produces well marked passages of faeces. Sometimes the result is obtained with a single injection, but a prolonged action of the salt seems to be more favorable. With sodium fluoride and barium chloride much smaller doses are necessary. Sodium fluoride is more poisonous than the citrate or sulphate, but if injected slowly as much as 10 c.c. m/6 solution can be safely introduced under the skin. This produces in a little over an hour well marked purgation, usually with the passage of soft or semifluid faeces. Barium chloride is a well known saline purgative among veterinary surgeons, who always administer it intravenously or subcutaneously. In order to purge a horse weighing 1,000 pounds, O.75 g. BaCl2 is usually given subcutaneously. Its action is very constant. When given to rabbits I have found that 2 c.c. m/6 solution BaCl2, injected under the skin always produces a well marked purgative action with the passage of large quantities of semifluid faeces. When injected intravenously it is better to mix the BaCl2 with about five times its volume of m/6 NaCl. The injection of 1 c.c. of a mixture of 1 c.c. m/6 BaCl2 + 5 c.c. m/6 NaCl produces purgation and a passage of semifluid faeces. This action is much more rapid than with NaF.
These experiments demonstrate the fact that the intravenous or subcutaneous injection of saline purgatives do produce purgation and an actual passage of faeces. In order, however, to study the action of the salts more minutely another method was resorted to, namely, that of opening the abdomen and directly observing the loops of intestine. In a large number of experiments it is not difficult to become quite familiar with the movements normally present, and with the disturbances produced by such external influences as cooling, drying, etc. These influences can by proper precautions be practically eliminated.
By this method it was possible to study the influence of the salts on the two great activities of the intestine, namely, the muscular movements and the glandular activity. Their action on the secretion is treated of in a later chapter and can only be mentioned here. The increase of these two activities by means of a salt is the essential action of a purgative, and leads, if sufficiently prolonged, to purgation and to the passage of faeces. This passage of faeces does not take place so readily when the intestines are exposed and the animal is under the influence of morphine as it does in a normal animal. The exposure of the intestine for an hour or more apparently renders this action difficult, although not uncommonly the actual passage of faeces is observed under these circumstances. This is always the case with BaCl2.
In a rabbit with its intestines visible it was found that the injection of 1-2 c.c. m/8 or m/6 sodium citrate solution into the jugular vein of a rabbit brings about a very marked increase in the peristaltic movements, which begins from 1 to 2 minutes after the injection. The loops are set in active movements and become firm and rounded so that they seem to occupy a greater volume. The movements consist not only of swinging pendulum movements, but of real peristaltic waves which cause the contents of the intestine to move along the gut so that they may be watched through the thin walls. The morphine narcosis of the animal does not seem to interfere with this action of the salt.
When these salt solutions are administered subcutaneously they do not act at once, as in the case of intravenous injections. An interval of 10 to 15 minutes elapses after the subcutaneous injection before any influence on the intestine is noticed. The movements then begin as before, the peristaltic movements and pendulum movements gradually increasing in force. In addition to the greater time required for the action of the salt when administered in this way, it is also necessary to give a larger amount than in intravenous injections; 5-10 c.c. m/8 or m/6 solution of sodium citrate must be introduced subcutaneously in order to produce increased peristalsis.
If the solution be introduced into the stomach or intestine a similar increase in peristalsis is brought about, but only after a considerable interval. Usually no effect is obtained until 10 to 15 minutes after the injection of the salt into the lumen of the gut. The injection may be made by piercing the wall of the intestine or stomach with a hypodermic needle, and forcing the fluid into the lumen. The quantity of the solution necessary to produce increased peristalsis is about the same as when introduced subcutaneously. The movements begin not particularly in the part of the intestine containing the solution, but simultaneously in all parts.
To any one making these experiments there can be no doubt that the increased peristalsis is the direct result of the injection of the salt. It can be readily proven in the following way: As will be shown in a later chapter, the peristalsis and secretion caused by the saline purgatives can be inhibited by the administration of calcium or magnesium chloride. If now in a rabbit in which the intestine has been set into active motion by the intravenous injection of sodium citrate, a small quantity of m/6 CaCl2 be administered intravenously, all of these movements cease within a minute or two. A second injection of a slightly greater quantity of m/6 sodium citrate will overcome this action and cause active peristalsis to begin again. These actions cannot be due to anything but the solutions introduced.
It is evident also in watching the action of these salts that they produce increased peristalsis much more rapidly and powerfully when introduced intravenously than when placed in the lumen of the stomach or intestine. A much smaller dose also is required to produce this effect. They therefore cannot act because of their presence in the lumen of the gut, or because of their being subsequently secreted into the lumen. When introduced into the stomach or intestine they must first be absorbed into the blood before they can reach the muscular and glandular tissues upon which they act. They therefore act more slowly and only in larger quantities when administered in this way.
Experiments similar to the above were made with a number of salts, including sodium sulphate, fluoride, tartrate, phosphate and oxalate, barium chloride, and magnesium sulphate. It was found that intravenous and subcutaneous injections of all of these were active in producing a greater or less increase in peristalsis. Sodium sulphate acted in this respect very much as sodium citrate did. The latter, however, tended to produce muscular twitchings in the voluntary muscles, a phenomenon which will be spoken of later. Sodium sulphate on the other hand could be introduced into the blood in relatively large quantities without producing any evil effects. The action of sodium sulphate on the intestine was found to be somewhat less than that of sodium citrate; but almost constantly 2-3 c.c. m/6 Na2SO4 injected into the marginal vein of the ear caused a marked increase in the peristaltic movements of the intestine. I cannot at all agree with Hay and earlier writers who affirm that sodium sulphate injected intravenously produces no purgative effect. In all my experiments I have found it to have a very definite effect when introduced in this manner, and I can only attribute their results to the concentrated solutions used, or to other unfavorable conditions.
The injection of solutions of sodium fluoride produces very active movements, although only small quantities can be administered on account of its poisonous nature.
Barium chloride is even more poisonous and only the most minute doses can be given. It is, however, by far the most powerful of all these purgative salts. Its action is extremely rapid and violent. When given intravenously it is best to mix it with about five times its volume of m/6 NaCl solution. Thus 1 c.c. of a mixture of 5 c.c. m/6 NaCl + 1 c.c. m/6 BaCl2 injected into the circulation causes almost immediately most violent intestinal movements. The loops contract so that they resemble white firm cords. They rise up from one another so that they seem to stand erect and the squirming, twisting movements become extremely active. The intestinal contents are hastened on and can be watched through the thin walls moving rapidly from loop to loop. The actual passage of faeces takes place in a very short time. It begins with solid faecal masses, followed quickly by semifluid faeces. The quantity passed is sometimes very considerable. As will be shown in a later chapter, the injection of BaCl2 into the blood causes not only an extensive increase in the peristaltic movements, but brings about also an increase in the quantity of fluid secreted into the intestine.
The subcutaneous injection of 2-3 c.c. m/6 BaCl2 produces in 5-10 minutes an effect quite similar to that described for the intravenous injection of the salt. A rabbit weighing 1,200-1,500 g. does not, however, usually recover from a dose greater than 2.5-3 c.c. m/6 BaCl2 given subcutaneously, and a smaller quantity is sufficient to produce purgation. Boehm[28] gives as the lethal dose of BaCl2 when given intravenously for rabbits O.1-0.2 g., for cats 0.03-0.05 g., for dogs O.1-0.2 g. When given subcutaneously it is O.12-0.18 g. for rabbits and cats and O.3 g. for dogs.
When BaCl2 is taken into the stomach it is absorbed quite slowly, but its effects are similar to those described above. Active peristaltic movements and purgation result, and in many cases vomiting is seen in dogs.
It is clear from these experiments that all salts do not act equally on the intestine. Sodium chloride may be introduced in large quantities into the circulation without causing increased peristalsis or defaecation. Sodium oxalate and phosphate (Na2HPO4) exert only a slight action. Sodium phosphate, according to Bunge, increases the fluid in the intestine. Sodium tartrate produces quite active movements of the intestine and is considerably stronger in its action than either the oxalate or phosphate. Sodium citrate and sulphate as described above are quite constant and vigorous in their action, while barium chloride is by far the most powerful of all these saline purgatives. Sodium fluoride also acts very rapidly.
In addition to their action on the intestine, some of these salts affect the salivary gland. After the injection of BaCl2 there is often so great a flow of saliva that it falls in drops from the mouth. This phenomenon is not constant, however, and seems to follow only large doses. Sodium fluoride has sometimes the same effect. I have not noticed any influence exerted by the other purgative salts upon the salivary secretion. It is further of not infrequent occurrence to have a repeated evacuation of urine after the administration of BaCl2. Although this cannot be attributed to a direct increase of the secretion of urine, it is interesting to note in this connection some later experiments in which it was shown[29] that when the flow of urine in a rabbit had been well established by the injection of m/6 NaCl solution into the circulation, the addition of a minute quantity of BaCl2 to the NaCl solution caused a very considerable increase in the secretion of urine from the kidney. A quantity of not more than ¹⁄₈ c.c. m/8 BaCl2, must be given intravenously to produce this effect. If 1 c.c. m/8 BaCl2 be injected intravenously at one time the flow of urine suddenly stops. This seems to be due either to a sudden constriction of the musculature of the urinary passages and pelvis of the kidney by which the lumen is cut off, or to a similar constriction of the blood vessels of the kidney. In either case the action of BaCl2 in stopping the secretion is mechanical and has to do with its power of causing violent muscular contractions rather than with its capacity for increasing the secretory activity. Although there is apparently one action for BaCl2 on the flow of urine when given in small doses and quite the opposite action when it is given in larger quantities, the two actions are in reality quite distinct, one being exerted on the secretory cells of the kidney and the other on the musculature of either the urinary passages or of the blood vessels of the kidney.
In addition to their action on the intestine and in some cases the kidney and salivary gland, these salts produce an interesting condition of the voluntary muscles. As mentioned above, Loeb was able to produce muscular twitchings in the muscle of a frog by immersing the muscle in solutions of these various salts. He also produced muscular twitching in a living frog by injecting sodium citrate into the dorsal lymph sacs. I have found that a subcutaneous injection of 10 c.c. m/1 sodium citrate produces in a rabbit well marked twitchings of the muscles all over the body. These are very noticeable in the gluteal region. They begin almost immediately in the neighborhood of the injection, but only after an interval of 20 to 25 minutes on the opposite side of the body. If the animal be placed on the floor it moves with a peculiar incoördinated gait. The hind legs are dragged and very little headway is made. If the rabbit be held up by the ears, the feet tremble, and if touched the legs jerk away violently and usually become rigid. There are sometimes tetanus-like contractions of the limbs, and occasionally general convulsions of greater or less severity. In one rabbit I gave daily injections of 5 c.c. m/1 sodium citrate subcutaneously throughout one month. For some time after the injections had been discontinued the hypersensitiveness seemed to persist. It seemed possible from this that a chronic state of increased irritability might be produced. No conclusion, however, can be drawn from this one experiment since the irritation caused by the repeated injections might have had some influence. It is a subject which is of interest for further experiment, on account of the similarity such a chronic condition bears to the various chronic hypersensitive conditions found in human beings.
In looking over the experiments made by various investigators on this subject it will be noticed that their results are inconstant and contradictory. This can only be the result of imperfect technique and unfavorable conditions, or of the adoption of a criterion of the action of the salt, which is uncertain. As mentioned above, the solutions used in many cases were not at all those most favorable for introduction into the blood. The very concentrated solutions used by Hay rendered the conditions obviously unfavorable. If in addition to watching for the actual passage of faeces these experimenters had observed the intestines directly the results would of necessity have been more uniform.
My own experiments have given quite uniform results, so much so that the production of increased peristalsis in rabbits by the intravenous injection of one of the saline purgatives has come to be a class experiment with the students in the medical school here. The increased secretion into the intestine produced by the same means requires greater care in protecting the loops from loss of heat and moisture. For any one to convince himself that a salt may act as a purgative when injected subcutaneously or intravenously it is only necessary to introduce a small amount of BaCl2 into the blood or under the skin of a rabbit. The evacuation of large quantities of semifluid faeces and the violent intestinal movements leave no room for doubt as to the action of the salt. The fact that the intravenous and subcutaneous administration of this salt as a purgative by veterinarians is in general use should be sufficient proof.
The milder salts such as sodium citrate and sulphate must, as stated above, be given in larger quantities, and a more prolonged action is necessary.
As will be described in detail in the next chapter, the application of solutions of these salts, isosmotic with the blood, to the peritoneal surfaces of the intestine cause not only increased peristalsis and increased secretion of fluid into the intestine but also bring about an evacuation of faeces. This fact alone proves that it is not necessary to introduce the purgative salt into the stomach or intestine. The action on the intestine in this case takes place more rapidly than in any other method of administration. The solution seems to be directly absorbed through the peritoneal covering and to come into contact with the muscles and glands, and perhaps the nerves of the intestine. These tissues are immediately set into activity.
In the intravenous or subcutaneous injections of the salts it is necessary to mention a peculiarity of magnesium sulphate. This salt of course acts as a purgative because it is a sulphate and not on account of the presence of magnesium. As shown later on, magnesium chloride has an effect quite opposite to this. In injecting MgSO4 into the blood the greatest care must be taken because of its peculiarly poisonous nature when rapidly absorbed. Rabbits frequently die suddenly from an injection of a relatively small quantity. This fact has been mentioned by a number of authors, and is repeated here only as a warning against its too rapid injection, possibly in human beings.
It may be mentioned here also that Bottazzi[30] has found that the intravenous injection of an extract of the small intestine containing secretin causes not only a well marked increase in the secretion of fluid into the intestine, but also produces increased peristaltic activity. It at the same time increases the pancreatic secretion.