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.