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% Na_{2}SO_{4} or 20% MgSO_{4}.
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 Na_{2}SO_{4}, which is approximately twice
as strong as a solution of this salt isosmotic with the blood would
be. Similarly a solution of MgSO_{4} isosmotic with the blood would
be about 4% (m/6 Sol^_n_ MgSO_{4} + 7 H_{2}O = 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 BaCl_{2} 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. BaCl_{2} is
usually given subcutaneously. Its action is very constant. When given
to rabbits I have found that 2 c.c. m/6 solution BaCl_{2}, 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 BaCl_{2} 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 BaCl_{2} + 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
BaCl_{2}.
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 CaCl_{2} 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 Na_{2}SO_{4} 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 BaCl_{2} 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 BaCl_{2} 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 BaCl_{2} 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
BaCl_{2} given subcutaneously, and a smaller quantity is sufficient
to produce purgation. Boehm[28] gives as the lethal dose of BaCl_{2}
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 BaCl_{2} 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 (Na_{2}HPO_{4}) 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 BaCl_{2} 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
BaCl_{2}. 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 BaCl_{2} 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 BaCl_{2}, must be given intravenously to produce
this effect. If 1 c.c. m/8 BaCl_{2} 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 BaCl_{2} 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 BaCl_{2} 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 BaCl_{2} 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 MgSO_{4} 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.
FOOTNOTES:
[22] Leçons sur les effets des substances toxiques et médicamenteuses,
Paris, 1857.
[23] Arch. f. physiol. Heilkunde, 1854.
[24] Gaz. Méd. de Paris, 1879.
[25] Action of Medicines, 1867.
[26] Gazette Médicale, 1873.
[27] Journal of Anatomy and Physiology, Vol. XVI, 1882, and XVII, 1883.
[28] Arch. f. exp. Path. u. Pharm., Bd. 3, 1875, p. 215.
[29] MACCALLUM, J. B.: Journal of Exp. Zoology, Vol. I, No. 1, 1904.
Preliminary Report, University of California Publications, Physiology,
Vol. I, No. 10, p. 81, 1904.
[30] Arch. di Fisiologia, 1904, I, 413.