_PHYSIOLOGY OF POISONING_ (_continued_).
EFFECTS OF THE VARIOUS VENOMS ON THE DIFFERENT TISSUES OF THE
ORGANISM.
The physiological effects of the various venoms are very different from
those that we have just described, when these toxic substances are
introduced into the organism otherwise than subcutaneously.
Their direct penetration into the blood-stream, whether by the bite
of the snake itself or by experimental intravenous injection, always
produces immediate results. With the venoms of VIPERIDÆ,
coagulation of the blood and, consequently, death are almost
instantaneous. With the venoms of COLUBRIDÆ, which, on the
contrary, destroy the coagulability of the blood, the toxic effects are
less rapid, but after the lapse of only a few minutes asphyxia ensues
and the death-struggle is very short.
Absorption by the serous membranes is slower, but is nevertheless
effected much more quickly than when it takes place in the subcutaneous
cellular tissue. When cobra-venom is injected into the peritoneal
cavity of a rabbit or a guinea-pig, the local effects upon the serous
membrane are almost _nil_. No leucocytic exudation is observed; death
supervenes before this has had time to take place. The venoms of
VIPERIDÆ, on the contrary, produce, directly after their
introduction into the peritoneum, an enormous afflux of sanguinolent
serosity; the capillary vessels of the serous membrane, immediately
becoming distended, allow the blood to filter through their walls, and
the animal succumbs after a few minutes, or a few hours, according to
the dose injected, with the peritoneum full of blood.
When deposited upon the mucous membranes of the eye, vagina, or
urethra, all venoms, those of COLUBRIDÆ like those of
VIPERIDÆ--but the latter with greater intensity--cause very
acute inflammation, comparable to that produced by jequirity; the
capillaries become distended, allow leucocytes to exude _en masse_,
and, as for instance upon the eye of the rabbit, a purulent ophthalmia
soon establishes itself.
Certain species of _Sepedon_ (COLUBRIDÆ), common on the
West Coast of Africa, especially in Senegambia and in the hinterland
of Dahomey, and to which the name _Spitting Snakes_ has been given,
possess the faculty of projecting little drops of venom to a distance
by forcibly expelling the air from their lungs, and the natives assert
that this venom, when it happens to come into contact with the eyes,
causes blindness. This is true to a certain extent, in so far as it
produces attacks of purulent ophthalmia which are often serious; but
these attacks, like those provoked experimentally in animals, can be
cured in a few days when properly treated.
When absorbed by the _digestive_ tract, the venoms of
COLUBRIDÆ often produce no ill-effects. It is otherwise with
those of VIPERIDÆ. The venom of _Lachesis_, for example, if
administered in sufficient doses, sets up acute inflammation of the
gastric mucous membrane, and the animals speedily succumb with attacks
of gastro-intestinal hæmorrhage, even before it has been possible for
the toxic effects upon the nerve-cells to become apparent.
These facts explain the contradictions that are to be found in the
works of different investigators upon this subject. It is affirmed
by some writers that venom can be swallowed without danger, and they
even advise the sucking of venomous wounds in order to hinder its
absorption. Others, including Sir Joseph Fayrer, Richards, and Weir
Mitchell, have killed pigeons and fowls by making them ingest venom
of _Vipera russellii_, or _Crotalus_. C. J. Martin, in experimenting
upon rats with the venom of _Pseudechis_ (COLUBRIDÆ), has
succeeded in keeping these animals alive for a whole week by providing
them every day with a ration of bread and milk mixed with a dose of
venom one hundred times greater than the lethal dose for a subcutaneous
injection. This innocuousness of the venoms of COLUBRIDÆ,
which I have frequently been able to establish by causing them to
be ingested by different animals, is explained by the fact that the
pancreatic juice and the ptyalin of the saliva very rapidly modify the
proteic substances to which these venoms owe their toxicity, so that
this disappears. No trace of them is found in the fæces.
The glandular secretions of persons bitten by venomous snakes, and
those of animals inoculated with doses of venom calculated to kill only
after a few hours, are not infrequently found to be toxic. In the case
of the urine in particular this has been shown to be so.
Observations have also been recorded by C. Francis[18] and Sir Joseph
Fayrer with reference to the passage of venom through the mammary
gland. In the year 1893 a poor Mussulman woman died at Madras from the
bite of a Cobra. She was nursing her child at the time, and the latter
succumbed in its turn a few hours later, with all the symptoms of
poisoning, although it had not itself been bitten, and had been suckled
by its mother only once since the bite.
The _histological lesions_ produced by snake poisoning have been
particularly well studied by Hindale,[19] Karlinski,[20] Nowak,[21]
Louis Vaillant-Hovius,[22] and Zeliony.[23]
(1) ACTION UPON THE LIVER.
Whether we are dealing with the venoms of VIPERIDÆ or
COLUBRIDÆ, the anatomo-pathological processes are alike, and
the changes produced are more or less profound, according to the degree
or the slowness of the intoxication.
The liver is more affected than any other organ. In cases in which
death has quickly followed the injection of the venom, the protoplasm
of the cells is merely cloudy, or granular, and the granulations
readily take a stain in their periphery, though the interior remains
uncoloured. If, on the contrary, the animal has survived for some
hours, the protoplasm becomes condensed in certain parts of the cell,
leaving vacuoles, the limits of which are not well defined. A portion
of the cellular protoplasm is necrosed and destroyed. In these cases
the nuclei have already undergone a change; although their contours
may be well defined, we discover in their interior only a very little
chromatin in the form of small granulations, and the nuclear fluid
takes a feeble stain with basic colours, since it contains a little
chromatin in solution.
When the protoplasm of the hepatic cells has suffered more pronounced
lesions, the changes in the nuclei are also more marked; the quantity
of nuclear chromatin diminishes and slowly loses its property of taking
stains, in proportion as the protoplasm of the hepatic cells undergoes
necrosis; finally, in the hepatic cell, there remains nothing more than
a small quantity of granular protoplasm without a nucleus (Nowak).
In certain cases we find extensive areas of fatty degeneration, or
small foci in which the hepatic tissue is absolutely destroyed. In the
case of the dog it may even happen that the microscopic structure of
the parenchyma has entirely disappeared. The arrangement of the hepatic
cells in lobules can no longer be distinguished; the trabeculæ are
ruptured and broken asunder, and we find nothing more than a confused
agglomeration of cells floating in the extravasated blood.
In animals which have lived for a long time after being poisoned,
lesions of the bile-ducts are also found. The epithelial cells have
undergone fatty degeneration, or else, in the case of small animals,
the ducts appear infiltrated with small mononuclear cells, which
penetrate between the epithelial cells of the canaliculi. Sometimes
also the latter cells are distended, and enclose large vacuoles.
Venom thus produces in the liver lesions of _fatty degeneration_, or
_necrosis_, and an infiltration of the bile-ducts by lymphatic cells.
(2) ACTION UPON THE KIDNEY.
The changes in the kidney are also very extensive. The three portions
of the glomerulus often exhibit lesions; the vessels of the tuft
show ectasia; their walls are sometimes ruptured, and the blood is
extravasated into the capsular cavity. The latter is filled with a
granular exudation, which varies in amount with the slowness of the
intoxication. The epithelial lining of _Bowman’s capsule_ is swollen;
the nucleus stains badly (Vaillant-Hovius).
In the _tubuli contorti_ the lesions in the cells greatly resemble
those seen in the liver. Granulations and vacuoles appear, and the
nucleus becomes diffuse. The lumens of the tubules are filled with
necrosed cells, and the _branches of Henle_ are found to be similarly
obliterated.
In the _straight tubes_ and in the _collecting tubes_ the epithelium
is sometimes detached in its entirety. Some of these canals are
obliterated by granular cylinders or by accumulations of epithelial
cells.
The vessels met with in the parenchyma of the kidney are always greatly
distended, and sometimes they are torn, whence there results the
formation of small foci of interstitial hæmorrhage. In many cases the
extravasated blood also destroys the parenchyma.
(3) ACTION UPON THE SPLEEN, HEART, AND LUNGS.
In the spleen, Nowak merely found a little fatty degeneration, and only
in cases in which the lesions in the liver and kidneys were very far
advanced. The same applies to the muscular fibres of the heart. This
organ exhibits, above all, hæmorrhagic infiltrations in its peripheral
portion, rarely in its substance.
The lungs are the seat of more important lesions. We find in them a
multitude of little infarcts. Around these the capillary vessels are
extremely dilated, and the pulmonary vesicles have become very small.
All these lesions of the visceral organs strangely resemble those
observed in the case of individuals who have died from _yellow fever_.
This observation has been made by several scientists, among others
by Sanarelli, and it is this perhaps that has suggested to some
(Dyer, of St. Louis, R. Bettencourt, of São-Paulo[24]) the idea of
treating--without much success, however--yellow fever by the antitoxin
of venom.
(4) ACTION UPON THE STRIATED MUSCLES.
The changes in the _striated muscles_ in places at which venom has been
injected do not present any specific character. The muscular fibres
already become necrosed half an hour after the injection; the diseased
tissue becomes permeated with an albuminous mass rich in fibrin, and
the blood is extravasated. A few hours later we observe, between the
bundles of degenerate muscle fibres, polymorphous leucocytes. The
number of these latter constantly increases, and attains its maximum
after one or two days. The muscular nuclei become distorted, appear
long or angular, and assume the aspect of myoblasts (sarcoblastic
muscle cells). In the protoplasm of the myoblasts we frequently find
particles of broken-down muscle, and globules of fat.
All these changes resemble those observed as the result of the action
of a host of other muscle poisons, especially the irritant or caustic
chemical substances.
(5) ACTION UPON THE NERVOUS CENTRES.
It is extremely difficult to determine with any degree of precision
the nature of the lesions produced by venoms in the _nervous system_.
The intensity of these lesions depends in the first place upon the
length of time that has elapsed between the introduction of the venom
into the organism and death. It depends, secondarily, in a large
measure, upon the origin of the venom. That of the VIPERIDÆ
acts almost exclusively upon the blood by coagulation, and exhibits
only a very slight degree of toxicity as regards the nerve-cell.
That of the COLUBRIDÆ, on the contrary, produces manifest
changes in the chromatic substance. Nissl’s bodies are completely
disintegrated, and transformed into a granular mass. In the majority of
the stichochromes neither the form of the bodies nor even the reticulum
is distinguishable. The nuclei are opaque, the nucleoli swollen and
broken up. The dendrites often become irregular and contracted (Ewing
and Bailey,[25] G. Lamb[26]).
It was found by Bailey that the majority of the cells of the anterior
cornua of the medulla are normal, but that a small number of them
exhibit indications of acute granular degeneration; a few cells were
found to have lost almost all their chromatic substance.
From the physiological point of view it is perfectly clear that
Cobra-venom especially affects the bulbar centres, and particularly
the nuclei of origin of the pneumogastric nerve. We observe in the
first instance the gradual suppression of the functions vested in the
nerve-cells that are found in connection with the vagus nerve, the
spinal accessory, and the hypoglossal. Later on the excitability of the
nerve-endings in the muscles is found to have been destroyed, and this
action presents great similarity to that of curare.
The venoms of VIPERIDÆ, when injected in very weak doses,
exercise a paralysing action upon the reflex excitability of the
medulla. But it is open to question whether these effects are
not exclusively due to the lesions of the blood, which are here
all-predominant; for no histological modification is observed in the
cells of the central nervous system.
I have made a number of experiments with a view to discovering whether
the cerebral, bulbar, or medullary substance of animals susceptible
to the action of Cobra-venom (rabbit, guinea-pig, fowl) possesses
the property of _fixing_ this venom as it fixes the toxin of tetanus
(Wassermann and Takaki). I found that, on pounding up a little of the
pulp of the cerebral hemispheres or bulb with doses of venom lethal in
two hours for the control animals, the injection of the mixture, well
washed and centrifuged in order to free it from all excess of non-fixed
venom, always caused death, but with a retardation of from four to ten
_hours_. We see, therefore, that partial fixation of the venom upon
the nervous elements really takes place, but we cannot conclude from
this that these elements exercise an antitoxic function, any more than
in the case of tetanus, for animals that receive cerebral emulsions in
one thigh and the dose of venom lethal in two hours in the other thigh,
succumb at the same time as the controls.
Major Rogers has made similar experiments with the venom of _Enhydrina_
(HYDROPHIIDÆ), and has obtained the same result on employing
the cerebral hemispheres of the pigeon.[27]
Flexner and Noguchi,[28] on their part, have compared, by aid of
the method of intra-cerebral injections, the toxicity of the venom
of _Crotalus_ with that of the venom of the _Cobra_. On employing
Cobra-venom heated to 75° C., they found that the convulsive and
paralytic effects were immediate, contrary to what takes place after
subcutaneous or intraperitoneal injections, but that the dose of venom
necessary to produce death was the same (0·1 milligramme for the
guinea-pig) as when the injection is made in the peritoneum or beneath
the skin.
With the venom of _Crotalus_ heated for half an hour at 75° C., which
contains but very little _neurotoxin_ and has lost all its hæmorrhagic
properties, 0·5 milligramme introduced directly into the brain of the
guinea-pig only produces transitory and non-lethal effects; while, if
fresh venom be employed, 0·05 milligramme is sufficient to cause death
in three hours, with severe hæmorrhagic lesions. Now this dose is
twenty times smaller than the minimal lethal dose for a subcutaneous
injection.
It is evident that the harmful matter, in the particular case of
_Crotalus_-venom, is not the _neurotoxin_, but an altogether different
substance, termed by Flexner and Noguchi _hæmorrhagin_, which acts upon
the elements of the blood and upon the endothelium of the blood-vessels.
We shall meet with this substance again in almost all VIPERINE
venoms, and shall study it further on.