_THE PHYSIOLOGICAL ACTION OF SNAKE-VENOMS._
A.--PHYSIOLOGY OF POISONING IN MAN AND IN ANIMALS BITTEN BY
THE DIFFERENT SPECIES OF POISONOUS SNAKES.
(_Colubridæ; Viperidæ; Hydrophiidæ._)
The bites of poisonous snakes produce very different effects according
to the species of snake, the species to which the animal bitten
belongs, and according to the situation of the bite. It is therefore
necessary to take these various factors into account, in describing the
symptoms of poisoning in different animals.
When the quantity of venom introduced into the tissues by the bite of
the reptile is sufficient to produce fatal results--which is happily
not always the case--the venom manifests its toxic action in two series
of phenomena: the first of these is local and affects only the seat and
surroundings of the bite; the second, or general series, is seen in the
effects produced upon the circulation and nervous system.
It is remarkable to find how great is the importance of the local
disorders when the venomous reptile belongs to the _Solenoglypha_
group (VIPERIDÆ), while it is almost _nil_ in the case of the
_Proteroglypha_ (COLUBRIDÆ and HYDROPHIIDÆ).
The effects of general intoxication, on the contrary, are much more
intense and more rapid with the venom of _Proteroglypha_, than with
that of _Solenoglypha_.
In considering the usual phenomena of snake-poisoning in man, we must
therefore take this essential difference into account, and draw up
separately a clinical description of the symptoms observed after a
bite from a _Cobra_ (COLUBRIDÆ), for instance, and another
list of those that accompany a bite from _Lachesis_ or _Vipera berus_
(VIPERIDÆ).
The bite of a _Cobra_, even of large size, is not very painful; it is
characterized especially by numbness, that supervenes in the bitten
part, rapidly extends throughout the body, and produces attacks
of syncope and fainting. The patient soon experiences a kind of
lassitude and irresistible desire to sleep; his legs scarcely support
him; he breathes with difficulty and his respiration becomes of the
diaphragmatic type.
By degrees the drowsiness and the difficulty of breathing become
greater; the pulse, which at first is more rapid, becomes slower and
gradually weaker, the mouth contracts, and there is profuse salivation,
the tongue appears swollen, the eyelids remain drooping, and, after
a few hiccoughs frequently accompanied by vomiting and involuntary
emissions of urine or fæcal matter, the unfortunate victim falls
into the most profound coma and dies. The pupils react to luminous
impressions up to the last moment, and the heart continues to beat
sometimes for two hours after respiration has ceased.
All this takes but a few hours, most frequently from two to six or
seven, rarely more.
When the reptile by which the bite is inflicted is one of the
_Solenoglypha_, such as a _Lachesis_ for example, the seat of the bite
immediately becomes very painful and red, then purple. The surrounding
tissues are soon infiltrated with sanguinolent serosity. Sharp pains,
accompanied by attacks of cramp, extend towards the base of the limb.
The patient complains of intense thirst, and extreme dryness of
the mouth and throat; the mucous membranes of the eyes, mouth, and
genitalia become congested.
These phenomena often continue for a very long period, even for more
than twenty-four hours, and are sometimes accompanied by hæmorrhages
from the eyes, mouth, stomach, intestines, or bladder, and by more or
less violent delirium.
If the quantity of venom absorbed be sufficient to cause death,
the patient exhibits, a few hours after being bitten, stupor,
insensibility, and then somnolence, with increasing difficulty of
respiration, which ends by becoming stertorous. Loss of consciousness
seems complete a good while before coma appears. Asphyxia then ensues,
and the heart continues to beat for nearly a quarter of an hour after
respiratory movements have entirely ceased.
In certain exceptional cases death is very rapid; it may supervene
suddenly in a few minutes, even before the local phenomena have had
time to manifest themselves; in this case the venom, having penetrated
directly into a vein, has produced almost immediate coagulation of the
blood, thus causing the formation of a generalized embolism.
If the venom be introduced in a highly vascular region, or directly
into a vein, the result is almost invariably fatal. On the contrary,
if the derm be scarcely broken, or if the clothing has acted as a
protection, scarcely any absorption will take place. We are here
confronted with the same factors of gravity as in the case of bites
inflicted upon human beings by animals suffering from _rabies_.
In experiments we are able to eliminate all these factors, and to
follow in an animal inoculated with a known quantity of venom the
whole series of phenomena of poisoning, the intensity of which can
be graduated. Let us see, then, how the various animals that it is
possible to make use of in laboratories behave with regard to venoms of
different origins.
B.--THE PHYSIOLOGY OF EXPERIMENTAL POISONING.
In the monkey, the first apparent sign of the absorption
of _Cobra_-venom, or of the venom of any other species of
COLUBRIDÆ, is a sort of general lassitude; the eyelids next
become half closed. The animal appears to be seeking a suitable spot
in which to rest; it gets up again immediately, and walks with a
jerky action; its limbs have a difficulty in supporting it. It is
soon attacked by nausea, vomiting and dyspnœa; it rests its head upon
the ground, raises it, trying to get breath, and carries its hand to
its mouth as if in order to pluck a foreign body from its throat. It
totters upon its limbs, and lies down upon its side with its face
against the ground. Ptosis increases, and complete asphyxia soon
supervenes. The heart continues to beat for some time after respiration
has ceased, and then stops in diastole.
Cadaveric rigidity very rapidly sets in, and persists for a long time,
even after putrefaction has commenced. During the last moments of
life the pupil remains very sensitive; the animal appears to retain
unimpaired its sense of hearing and sensibility to pain. The electric
excitability of the muscles of the face persists, but that of those
of the limbs and body almost entirely disappears. The application of
volta-faradic currents from the nape to the diaphragm produces no
respiratory movement when asphyxia begins to manifest itself. The
sphincters of the bladder and anus relax after a few spasms, which, in
case of males, frequently provoke the ejaculation of semen; the urine
and fæces immediately escape.
The autopsy reveals slight hæmorrhagic œdema at the point of
inoculation, and hyperæmia of all the viscera, especially of the liver
and spleen, with, very frequently, small hæmorrhagic patches on the
surface of these organs, and on that of the intestine and kidneys. The
serous membranes, especially the meninges, endocardium, pleuræ, and
peritoneum, exhibit ecchymoses; the lungs are besprinkled with small
infarcts, the more numerous the slower the intoxication. The blood
remains fluid and laccate.
* * * * *
In poisoning by the venoms of VIPERIDÆ, the hæmorrhagic
phenomena appear at the outset, and are more intense. Death is always
preceded by a period of asphyxia, indicating that the bulbar nuclei
of the pneumogastric nerve have become affected. At the autopsy,
however, the blood, instead of remaining fluid, is always found to
be coagulated into a mass in all the vessels; it afterwards gradually
becomes redissolved in six or eight hours, and then appears laccate, as
after poisoning by _Cobra_-venom, but darker.
* * * * *
All mammals exhibit the same symptoms after inoculation with lethal
doses of venom. The same applies to birds; but in the latter the
period of asphyxia is much longer, probably on account of the reserves
of air accumulated in their air-sacs and pneumatic bones. They gape
like pigeons that are being suffocated, rest the tip of the beak on
the floor of the cage, and frequently have convulsive spasms of the
pharynx, accompanied by flapping of the wings. Small birds and even
pigeons are extremely sensitive to venom; fowls are more resistant.
Frogs, thanks to their cutaneous respiration, succumb very slowly. I
have seen some survive for thirty hours after being inoculated with a
quantity of venom which, when subcutaneously injected into a rabbit,
causes death in ten minutes.
* * * * *
Lizards and chameleons succumb very rapidly. Grass Snakes and
non-venomous snakes in general withstand doses of venom that in
proportion to their weight are fairly large; nevertheless, as indeed we
shall see in the sequel, they do not possess any real immunity. It is
only poisonous snakes that are unaffected by enormous doses of their
own venom, as has already been shown by Fontana, Weir Mitchell, and
Viaud Grand Marais. They are, however, quite capable of being poisoned
by snakes belonging to altogether different species; strong doses of
_Crotalus_- or _Lachesis_-venom are fatal to Cobras or Kraits, and,
when several poisonous snakes are shut up together in the same cage,
they are not infrequently seen to kill each other as the result of
repeated bites.
Fishes, which are particularly sensitive to the venom of
HYDROPHIIDÆ, readily succumb to inoculation with other venoms,
such as that of the Cobra. At Saigon, in 1891, I made experiments upon
the action of this latter venom on two specimens of the fighting
fishes, that the natives of Annam rear in aquariums in order to witness
their combats and make bets on them. The fishes died five hours after
intramuscular inoculation with a dose which kills a pigeon in twenty
minutes.
Many invertebrates, such as leeches, crayfish, and gastropod molluscs
(snails), are killed by inoculation with very small quantities of venom.
C.--DETERMINATION OF THE LETHAL DOSES OF VENOM FOR DIFFERENT
SPECIES OF ANIMALS.
It is very difficult to specify, even within broad limits, the dose
of venom necessary to kill a human being. The quantity of poison
introduced by the bite of a venomous snake depends, as has already
been stated, upon a large number of factors, and, very fortunately,
this quantity is not always sufficient to cause death. Thus in India,
that is to say in the region in which snakes are most numerous and
most dangerous, the mean mortality seems scarcely to exceed 35 to 40
per cent., so far as it is possible to judge from official statistics.
But, by experimenting upon animals, and commencing with known doses of
venom, which has first been dried and then dissolved again in always
the same quantity of physiological saline solution or sterile distilled
water, we can determine exactly, _for each kind of venom, and for each
species of animal_, the minimum lethal dose _per kilogramme of animal_.
The entire series of data collected by investigators who have devoted
themselves to this study may be summed up as follows:--
Minimal doses lethal in twenty-four hours for a _guinea-pig_ weighing
from 600 to 700 grammes:--
_Colubridæ._
Venom of _Naja tripudians_ 0·0002 gramme
“ _Bungarus cæruleus_ 0·0006 “
“ _Naja haje_ 0·003 “
_VIPERIDÆ._
Venom of _Vipera berus_ 0·04 gramme
“ _Vipera russellii_ (_Daboia_) 0·001 “
“ _Lachesis lanceolatus_ 0·02 “
“ _Lachesis mutus_ (_Surucucu_) 0·02 “
“ _Lachesis neuwiedii_ (_Urutù_) 0·02 “
“ _Lachesis flavoviridis_ 0·007 “
“ _Ancistrodon contortrix_ 0·015 “
_Cobra_-venom. Dose lethal in twenty-four hours for different animals:--
Dog 0·0008 gramme per kilogramme
Rabbit 0·0005 “ “
Guinea-pig 0·0004 “ “
Rat 0·0001 “ 150 grammes
Mouse 0·000003 “ 25 “
Frog 0·0003 “ 30 “
Venom of _Bungarus cæruleus_ (Common Krait), according to Elliot,
Sillar, and Carmichael.[15] Minimal lethal doses for:--
Frog 0·0005 gramme
Rat 0·001 “
Rabbit (by subcutaneous injection) 0·00008 “ per kilogramme
Rabbit (by intravenous injection,
according to G. Lamb) 0·00004 “ “
Venom of _Enhydrina valakadien_ (according to Elliot and Fraser).[16]
Minimal lethal doses per kilogramme:--
Rat 0·00009 gramme
Rabbit 0·00006 “
Cat 0·0002 “
Venom of _Enhydris curtus_:--
Rat 0·0005 to 0·0006 gramme per kilogramme
Venom of _Notechis scutatus_ (syn. _Hoplocephalus curtus_; the Tiger
Snake of Australia):--
Rabbit (by intravenous injection,
according to Tidswell) 0·00006 gramme per kilogramme
Venom of _Vipera russellii_ (Daboia):--
Rabbit (by intravenous injection,
according to G. Lamb) 0·00005 gramme per kilogramme
Venom of _Lachesis gramineus_ (Green Pit-Viper, India):--
Rabbit (by intravenous injection,
according to G. Lamb) 0·002 gramme per kilogramme
Venom of _Crotalus adamanteus_ (Californian Rattle-Snake):--
Rabbit (by intravenous injection,
according to McFarland, G. Lamb,
and Flexner and Noguchi) 0·00025 gramme per kilogramme
It will have been seen from the foregoing figures, that the respective
sensitiveness of the dog, cat, rabbit, guinea-pig, rat, mouse, and
frog, with regard to the same venom, is in no way proportional to the
weight of these animals.
The species mentioned are, per unit of weight, more or less resistant
to intoxication; and, on experimenting with other animals, as for
instance the monkey, pig, ass, and horse, we find that the monkey is
much more susceptible to intoxication than the dog, and that the ass
is extremely sensitive (0·010 gramme of Cobra-venom is sufficient to
kill it), while the horse is less so, and the pig is by far the most
resistant.
The same weight of dry Cobra-venom, let us say 1 gramme to be precise,
will enable us to kill 1,250 kilogrammes of dog, 2,000 kilogrammes of
rabbit, 2,500 kilogrammes of guinea-pig, 1,430 kilogrammes of rat, or
8,333 kilogrammes of mouse.
The lethal dose for a horse being, as I have ascertained by my own
experiments, about 0·025 gramme, 1 gramme of dry Cobra-venom will
therefore suffice to kill 20,000 kilogrammes of horse.
Assuming that man, in proportion to his weight, possesses a resistance
intermediate between that of the dog and that of the horse, we may
consider that the lethal dose for a human being is about 0·015 gramme.
It follows, therefore, that 1 gramme of venom would kill 10,000
kilogrammes of man, or, let us say, 165 persons of an average weight of
60 kilogrammes.
Another extremely important fact, which must not be lost sight of,
is that differences of toxicity, which are often considerable, are
exhibited by the venoms of different specimens of the same species of
snake, or by the venom of the same snake collected at different times.
I have found, for instance, in the case of the specimens of _Naja_ and
_Lachesis_ reared in my laboratory, that, according to the length of
time that the animals had been without food, and to the nearness or
otherwise of the moulting period, the venom was more or less active,
and that on evaporation it left behind a more or less considerable
quantity of dry extract. In certain cases, immediately after the moult
and after a prolonged fast, the venom was _ten times_ more active than
after a plentiful meal or before the moult.
The figures given above must therefore not be regarded as determining
the minimal lethal doses of the different venoms, except in a purely
comparative way, and they must be considered only as data useful
to know when it is desired to experiment upon animals with these
substances.
Variations of this kind are observed in the case of all species of
snakes. Thus Phisalix rightly insists upon the necessity of always
noting, besides the species of snake, the place of origin and the
season; for he has himself seen that, as regards French vipers,
those of the Jura, for example, produce in the spring a venom almost
devoid of local phlogogenic action; while vipers from the vicinity of
Clermont-Ferrand, though less toxic, produce much more serious local
effects.
On the other hand, it has been shown by Th. Madsen and H. Noguchi,
in a very interesting study of venoms and anti-venoms,[17] that,
when we examine the relation between dose and toxicity, we find
that the interval separating the moment of inoculation from that of
death diminishes only up to a certain point in proportion as the
dose is increased. In the case of the guinea-pig, with 0·0005 gramme
of Cobra-venom the interval is 3 hours 75 seconds; but after this,
an increase in the dose produces only a relatively inconsiderable
acceleration of death. There is therefore no strict ratio between the
dose inoculated and the time that elapses until death supervenes.
D.--EFFECTS OF VENOM IN NON-LETHAL DOSES.
When the quantity of venom introduced into the organism is insufficient
to cause death, the phenomena that precede and accompany recovery
differ very greatly according as the snake from which the venom was
derived belongs to the COLUBRIDÆ or VIPERIDÆ.
After a non-lethal bite from a Cobra or Krait, for example,
convalescence usually takes place very rapidly, and, apart from the
local œdema of the subcutaneous tissue surrounding the wound, which
in very many cases leads to the formation of a suppurating abscess,
no lasting injury to health is observed. The venom is eliminated by
the kidneys, without even causing albuminuria, and sensation gradually
returns, in twenty-four or forty-eight hours, in the part affected by
the original lesion.
If the bite has been inflicted by a Viperine snake, the local lesion,
which is much more extensive, almost always results in the formation
of a patch of gangrene. Hæmorrhages from the mucous membranes, and
sanguineous suffusions into the serous cavities, such as the pleura
or pericardium, may supervene more or less slowly. Pulmonary infarcts
are sometimes produced, as well as desquamation and hæmorrhage from
the kidneys, albuminuria, or hæmaturia. These lesions, which are more
or less severe, last for several days, and then slowly disappear after
a period of true convalescence. In many cases they leave behind them
traces which last for months and even years, and they then more or less
affect the health of the subjects according to the organs that were
most seriously affected.
In certain cases, in domestic animals such as dogs, and more rarely in
man, after recovery from the bite of a viper, total or partial loss of
sight, smell, or hearing, has been observed. Such results, however, are
fortunately exceptional.