NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
2
studied the physiological action of cobra venom, consider that it owes its lethal
property principally, if not entirely, to its action on the central nervous system,.
that it is, in fact, a primary neurotropic poison, Cunningham 1 2
c o n t e n d s t h a t
cobra venom acts primarily as a blood poison, and that its action on the
nervous system is quite secondary to the changes which it produces on
the blood. It is not, however, our intention in the present paper to enter into
this discussion. Again, there is much difference of opinion as regards the exact
physiological cause of death resulting from the injection of viperine poison.
Thus, Martin13 states, as a result of his researches with the poisons of Pseudechis
and Hoplocephalus curtus, that he believes that all rapid deaths from viperine
poison are due to extensive intravascular clotting. These snakes, however,
classed morphologically amongst the colubrine snakes, resemble more the
vipers as regards the nature and action of their poison. This opinion is upheld
by the researches of Weir. Mitchell 14 with the poison of Crotalus. Cunningham15,
on the other hand, as a result of his experiments with the poison of a true viper,
viz., Daboia Russellii, puts forwards the opinion that, when this venom causes
rapid death, it does so entirely by a direct action on the central nervous system.
He looks upon its primary action as being that of a strong nervous irritant. It
may be noted in passing that the symptoms preceding rapid death, as described
by Martin in the case of the Australian snakes, are practically identical with the
symptoms which Cunningham noticed in similar cases of daboia venom intoxica
-tion. In view of the fact that Martin's hypothesis is based on experiments made
with the venom of snakes which are not true vipers and the poison of which,
he admits, is probably related in its physiological action to both the poison of
the cobra and the poison of the viper, and in view of Calmette's statements
mentioned above, it would appear necessary that further research should be
made with the venom of a true viper with the object of controlling those obser
-vations and statements. It was, then, with this object in view that the experi
-ments which we have now to present were begun. At a later date a consider
-able extension of the originally intended scope of the research had to be made.
Unfortunately an interruption occurred in the work through the departure of
one of us from India. The present publication, therefore, may be looked upon'
as a preliminary note only, which it is hoped will soon be further extended.
With this object experiments are now in progress in this laboratory.
The material which was used in all our experiments was pure, dry and fresh
daboia venom. This was collected during a period of some months from, on an
average, six full sized living snakes. The poison was obtained by firmly compress
- i n g t h e g l a n d s , c a r e b e i n g t a k e n t o k e e p t h e f a n g s o v e r a w a t c h - g l a s s b y m e a n s
3
of a piece of string passed behind them. After collection the venom was
rapidly desiccated over lime. When the poison had been thoroughly dried, it
was added to the general stock, which was preserved in an air-tight tube protected
from light. Before the venom was weighed a considerable quantity of it was
reduced to an impalpable powder, and again dried over sulphuric acid. In this
way it was found possible to obtain a poison of a uniform strength for all
experiments made at different times, thereby ensuring observations which could
be compared with each other.
Rapid death—the result of daboia. poison intoxication.
T h e f i s r s t t h r e e s e r i e s o f e x p e r i m e n t s , w h i c h w e r e c o r d , w e r e m a d e w i t h t h e
view of directly controlling Cunningham's observations as to the cause of death,
w hen this takes place rapidly after either the subcutaneous or intravenous injec-
tion of daboia venom.
In the first series pigeons were employed, and the injections were made
subcutaneously. It was found convenient to make use of these birds, as the
minimum lethal dose of daboia venom, when injected subcutaneously, was found
to be much smaller for them than for the other laboratory animals with which
experiments were performed.
Sterile normal saline solution was used to dissolve the venom, the solution
being of such a strength that I c. C . =2 milligrammes of the dried venom.All
injections were made subcutaneously in the pectoral region. The time of the
onset of symptoms was carefully noted, as also the moment when death took
place. A careful post-mortem examination was made immediately after death.
SERIES I.—Experiments in which daboia venom was. injected
subcutaneously into pigeons.
Pigeon I —Received 5 milligrammes of venom. In 45 seconds violent
convulsions with respiratory difficulty set in. The bird died 30 seconds later,
viz., I minute and 15 seconds after receiving the poison.
Post-mortem examination.—Heart had stopped beating. The blood in the
portal vein was clotted solid. There were large clots in all the chambers of the
heart, while the pulmonary arteries were the site of extensive thrombosis.
Pigeon 2 —Received 4 milligrammes of venom. The same symptoms as
noted in Pigeon z began 45 seconds after the injection of the poison and were
followed by death r minute and 20 sec onds after the bird received the
venom.
A 2
4
Post-mortem examination.—The heart had stopped beating. The blood in
both auricles and pulmonary vessels was clotted solid, as was likewise the blood
in the portal system of veins.
Pigeon 3—Received 3 milligrammes of venom. No symptoms appeared
for about 2½ minutes ; then convulsions accompanied by laboured respiration
began. Death took place 3 minutes and 20 seconds after the injection of the
poison.
Post-mortem examination.—The heart had stopped beating. The blood
in the portal vein was clotted solid. Large thrombi were found in the chambers
of the heart and also blocking up the pulmonary vessels.
Pigeon 4—Received 2 milligrammes of venom. Three minutes after receiv
- i n g t h i s d o s e t h e b i r d a p p e a r e d t o b e r e s t l e s s . A m i n u t e l a t e r i t f e l l d o w n i n
violent convulsions, accompanied by gasping and difficulty of breathing. Death
took place 4 minutes and 20 seconds after inoculation with the poison.
Post.mortem examination.—The blood in the portal system of the veins was
firmly clotted. There were large clots in the heart. The pulmonary vessels
were completely blocked by solid thrombi.
Pigeon 5—Received I milligramme of venom. Symptoms began in this
case 4 minutes after the injection of the poison. They were of exactly -the
same nature as noted in the previous cases. Death took place in about
minute after the onset of the symptoms, i.e., 5 minutes after the injection of
the poison.
Post-mortem examination.—Solid clotting was found throughout the portal
system. Large thrombi were present in the heart and completely filled the
pulmonary vessels.
Pigeon 6—Received 0 . 8 milligramme of venom. Four minutes after this
injection the bird became very restless, then convulsions set in. Death soon
followed, viz., in 5¼ minutes after inoculation with the poison.
Post-mortem examination.—The blood in the portal vein was clotted solid.
Large clots were found in both the auricles and ventricles, while the pulmonary
arteries were blocked with thrombi.
Pigeon 7—At 11-8 A.M. received 0 6 milligramme of venom.
11-13 A.M.—Appeared dull and depressed ; its breathing was laboured,
while its power of balancing itself seemed deficient.
11-15 A.m.—Fell down in severe and violent general convulsions, which in
half a minute ended in death, viz., in about 7¾ minutes after the venom had
been injected.
5
Post-mortem examination. —Blood in the portal vein was clotted solid.
Large clots filled the inferior vena cava, auricles and pulmonary vessels.
Pigeon 8—11-17 A.M.—Received 0. 6 milligramme of venom.
11-22 A.m.—Appeared to be dull and unable to stand. Breathing some-
what laboured.
11-25 A.m.—Violent general convulsions set in, which ended fatally in
about half a minute, i.e., about 8½ minutes after the injection of the poison.
Post-mortem examination.— Blood in the portal vein was clotted solid.
Large thrombi were found in the heart, pulmonary vessels and inferior vena cava.
Pigeon 9—11-32 A.M.—Received 0.4 milligramme of venom.
11-38 A.M.—Appeared dull and unable to stand.
11-41 A.m.—Fell down in violent convulsions and breathed with great
difficulty.
1 1-42 A.M.— Died 10 minutes after the injection.
Post-mortem examination.—Small threads of clot were found in the portal
vein : the superior mesenteric vein was free from any clots. Small clots were
found in the auricles and blocking up the branches of the pulmonary arteries.
These thrombi were all small and might easily have been overlooked if the exa-
mination had been a cursory one.
Pigeon 10—10-53 A.m.—Received 0.4 milligramrne of venom.
11-3 A.M.—Appeared dull and ill. Fell down, but was able to rise on being
excited.
11-10 A.M.—Still ill, but has had no convulsions.
No further symptoms developed, and the bird gradually recovered.
Pigeon 11.—This was a rather smaller bird than the others.
11-51 A.M.—Received 0.3 milligramme of venom.
11-56 A.M.— Dull and depressed with quickened respiration.
12 noon.— Fell down in convulsions and died immediately, i.e., in 9½
minutes after the injection.
Post-mortem examination.— There were small clots in the portal vein and
its tributaries. The auricles were full of solid clot. Several small thrombi were
found in the ventricles and also blocking up the pulmonary vessels.
Pigeon 12—12-8 p.m.—Received 0.2 milligramme of venom.
12-16 P.M.—Appeared slightly dull.
No further symptoms were observed, and the bird rapidly recovered.
6
This series of experiments can be conveniently tabulated as follows :
—
TABLE I.
Subcutaneous injection of daboia venom in pigeons.
Animal.
Amount of
venom in
milligrammes.
Time of onset of
symptoms.
Results.
Post-mortem examination.
Pigeon 1 ...
5
45 seconds
Died in 1¼ minutes
Extensive and solid in-
travascular clotting.
Pigeon 2
...
4
45 seconds
Died in 1¼ minutes
Extensive and solid in-
travascular clotting.
Pigeon 3
.
.
3
2½ minutes
Died in 3¼ minutes
Extensive and solid in-
travascular clotting.
Pigeon 4.
.
.
2
3 minutes
Died in 4¼ minutes
Extensive and solid in-
travascular clotting.
Pigeon 5
.
.
1 4 minutes
Died in 5 minutes
Extensive and solid in-
travascular clotting.
Pigeon 6
.
.
0 . 8 4 minutes
Died in 5¼ minutes
Extensive intravascular
clotting.
Pigeon 7
.
0 . 6 5 minutes
Died in 7¾ minutes
Extensive intravascular
clotting.
Pigeon 8
.
.
0 . 6 5 minutes
Died in 8½ minutes
Extensive intravascular
clotting.
Pigeon 9
.
.
0 . 4 6 minutes
Died in 10 minutes
Slight intravascular
clotting.
Pigeon 10 .
.
0 . 4
10 minutes
Recovered
......
Pigeon 11
.
.
0 . 3
5 minutes
Died in 9¼ minutes
Extensive intravascular
clotting.
Pigeon 12 . .
0 . 2
8 minutes
Recovered
......
It will be expedient now to draw attention in passing to the fact that, as
regards the nature and character of the symptoms and the changes in the blood
found post-mortem in the cases collated above, there was no difference ob-
served between the cases in which a minimum lethal dose of the poison was
injected and those cases in which a much larger quantity was given. The
larger, however, the amount of venom injected the more rapidly did the symp-
toms appear, and the sooner did death take place. In these cases, also, the
thrombosis was more extensive and more widespread and the clots were larger
and more solid than in those instances in which the minimum lethal dose, or a
quantity only slightly in excess of the minimum lethal dose, was given.
Before proceeding to consider further the experiments detailed above, it
would be well to set forth the observations which were made when the venom
7
was directly injected into the blood stream. We shall then be in a position
to critically sift the data of all the experiments at one and the same time.
In the second and third series of experiments, which bear on the question
under discussion and in which the venom was injected directly into the blood
stream, monkeys and rabbits, respectively, were the animals used. The dried
venom was dissolved in sterile normal salt solution, the strength of the solution
being, unless otherwise stated, 0.1 per cent.
The post-mortem examinations were made immediately after death.
SERIES 11.—Experiments in which daboia venom was injected directly into
the blood stream of monkeys.
Monkey 1—Received into the left femoral artery 2.5 milligrammes of venom.
The animal was under chloroform at the time. Gasping and laboured breathing
soon set in. Death took place 5 minutes after the injection.
Post-mortem examination.— This was not complete. The blood in the
right ventricle was fluid. A quantity of blood collected in test tubes remained
unclotted. Small clots were found in the portal vein and in the auricles.
Monkey 2—Received 2 milligrammes into a vein of the upper limb. No an
æs-thetic was administered. Breathing stopped almost immediately after the injec-
tion. It very soon began again, although it was now laboured and accompanied
by much gasping. Death took place in about 3 minutes after the injection
of the venom. Two minutes before death the brachial artery was opened and
blood collected from it in a small test tube. This blood remained uncoagulated.
Post-mortem examination. —Small thready clots were found in the heart and
portal vein. Unfortunately the pulmonary arteries were not examined. Fluid
blood collected from the heart in a test tube remained uncoagulated.
Monkey 3— Received into a vein of the upper limb 1 milligramme of venom.
Death, preceded by gasping and convulsions, took place 3 minutes after
the injection.
Post-mortem examination.— Immediately after the breathing had stopped
the brachial artery was cut across. Blood flowed freely from it. This blood
collected in a small test tube remained unclotted.
Small clots were found in the auricles and portal vein. Unfortunately the
pulmonary vessels were not opened.
In these three experiments, which were undertaken with another object in
view, the post-mortem examinations were unfortunately incomplete. In all
cases, however, signs of intravascular clotting were obtained, and for this reason
they are included in this series.
8
Further, they seem to show that the intravascular clotting, which, as we shall
see from our later experiments, is present in all cases of rapid death following
the intravenous injection of daboia venom, can be easily overlooked. They also
show that the fluid blood collected either before or after death remains uncoagu-
lated. It is obvious, therefore, that without a very complete and thorough post
-mortem examination undertaken immediately after death the cause of the symp-
toms and of the fatal result might be passed over.
Monkey 4—Received into a vein of the upper limb 2 milligrammes of
venom. The pupils immediately became widely dilated and the breathing
laboured and gasping. Then slight convulsions set in. Death took place
minute after the injection.
Post-mortem examination. —The brachial artery was cut across at the
moment of death : no blood flowed from the wound. The portal vein was filled
with an extensive solid clot. The pulmonary vessels were blocked with clots,
while a large thrombus occupied the aorta.
Fluid blood taken from the ventricles remained uncoagulated.
Monkey 5—Received rapidly into the brachial vein 2 milligrammes of
venom.
Death, preceded by gasping and slight convulsions, took place 1 minute
after the injection.
The brachial artery was cut across just before death. No blood flowed
from the cut artery.
Post-mortem examination.— Solid clots were found in the portal vein, supe-
rior and inferior venom cavæ, aorta and pulmonary vessels.
The heart contained fluid blood, which collected in a test tube remained
unclotted.
Monkey 6 —Received 2 milligrammes of venom into the brachial artery.
The solution was run in slowly, 2 minutes being occupied in the operation,
The animal died at the moment the total amount had been injected. Death
was preceded by much gasping and slight convulsions.
Post-mortem examination. —Extensive and solid clotting was found through-
out the portal system, also in the pulmonary vessels and aorta. The right
ventricle contained a small thrombus.
Fluid blood collected from the heart remained uncoagulated.
Monkey 7 —Received 1 milligramme of venom into the left cephalic vein.
Death took place 1½ minutes after the injection. It was preceded by much
gasping and laboured respiration. Convulsions were not marked.
Post-mortem examination. —Solid clotting was found in the portal vein and
inferior vena cava. The pulmonary vessels were blocked with thrombi. Small
clots were found in the chambers of the heart.
9
This series of experiments is tabulated as follows :—
TABLE II.
Intravascular injection of daboia venom in monkeys.
A n i m a l .
Amount of
venom in
milli grammes.
Time of onset of
sympoms.
Result.
Post-mortem examination.
Monkey 1 . .
2.5
...
Death in 5 minutes. Post-mortem incomplete;
but evidence of throm-
bosis.
Monkey 2
.
.
2
Immediate.
Death in 3 minutes. Post-mortem incomplete.
Evidence of clotting.
Monkey 3
.
.
1
. . .
Death in 3 minutes. Post-mortem incomplete.
Evidence of intravas-
cular thrombosis.
Monkey 4
.
•
2
Immediate.
Death in 1 minute. Extensive and solid clot-
ting in vascular sys-
tem.
Monkey 5
.
.
2
Immediate.
Death in 1 minute.
Very extensive and solid
intravascular thrombo-
sis.
Monkey 6.
2
Immediate.
Death on completion
of injection.
Extensive and solid in-
travascular clotting
throughout.
Monkey 7
. .
1
Immediate.
Death in 1½ minutes. Extensive and solid in-
travascular clotting.
The third series of experiments, in which the venom was injected intrave-
nously into rabbits, was undertaken both with the object of demonstrating the
intravascular thrombosis, which we have seen takes place in the monkey, and
also with the object of ascertaining the minimum amount of daboia venom per
kilo. of weight which would bring about this intravascular clotting. This was a
preliminary step to some experiments, to be detailed later on, which were made
with a view of testing the potency of Calmette's anti-venomous serum in prevent-
ing this clotting effect of daboia venom. The solution of venom was prepared
of the same strength as in Series 2, viz., 0.1 per cent.
All injections were made into the marginal vein of the ear.
SERIES III .—Experiments in which daboia venom was injected intravenously
into rabbits.
Rabbit 1—1,240 grammes—Received 0.325 milligramme of venom, i.e., 0.26
milligramme per kilo. Death, preceded by violent convulsions and much gasp-
ing, took place 2 minutes after the injection.
Post-mortem examination. —Extensive and solid clotting was found through-
out the portal system of veins and also in the inferior vena cava. The heart
contained small thrombi, while the pulmonary arteries and their branches were
completely blocked with clots.
B
10
Rabbit 2— 2,030 grammes—Received 0.4 milligramme of venom, i . e., 0.2
milligramme per kilo.
General convulsions soon set in and ended in death, which took place
3 minutes after the injection of the poison.
Post-mortem examination. —The blood in the portal vein and in the inferior
vena cava was clotted solid. Both auricles were filled with large thrombi, while
the pulmonary arteries were completely blocked with clot.
Rabbit 3—2,500 grammes—Received 0.3 milligramme of venom, i. e., 0.12
milligramme per kilo.
Convulsions with gasping soon followed this dose.
Death took place 4½ minutes after the injection.
Post-mortem examination. —The blood in the portal vein was clotted solid.
Large thrombi were found in alt the chambers of the heart, while the pulmonary
arteries were blocked with firm clots.-
Rabbit 4—2,500 grammes—Received 0.3 milligramme of venom, i. e., 0.12
milligramme per kilo.
Convulsions and difficulty of breathing were, as usual, the prominent
symptoms. Death occurred in about 4 minutes after the injection.
Post-mortem examination. —The blood of the portal vein and inferior vena
cava was firmly clotted, while the pulmonary arteries were blocked by an exten-
sive thrombosis.
Rabbit 5—1,250 grammes—Received 0.125 milligramme of poison,
i. e., 0.1 milligramme per kilo.
At first this animal showed no symptoms. The coagulation time of the
blood was tested about 4 minutes after the injection by means of Wright's
coagulometer. It was found to be 3½ minutes, that is, practically normal.
Seven minutes after the administration of the poison violent convulsions,
accompanied by gasping respiration, set in and ended in death a minute after
their onset.
Post-mortem examination. —Extensive thrombosis was found throughout
the body, but was especially marked in the portal system of veins, the inferior
vena cava and the pulmonary arteries. There were also some small clots found
in the chambers of the heart.
Rabbit 6—1,250 grammes.—Received 0.125 milligramme of venom, i.e., 0.1
milligramme per kilo. This rabbit, also, for a short time showed no symptoms.
Death, which took place 6 minutes after the injection, was immediately pre-
ceded by violent general convulsions and gasping respiration.
Post-mortem examination. —The portal vein and the inferior vena cava
contained extensive firm clots. Thrombi were also found in the cavities of the
heart and plugging up the pulmonary arteries and their branches.
II
Rabbit 7—1,400 grammes—Received 0.1 milligramme of venom, i.e.,
0.075 milligramme per kilo.
Symptoms were again delayed in this instance till about 5 minutes after
the injection. Convulsions and laboured respiration then set in and ended in
death 2 minutes after their onset.
Post-mortem examination.—The blood in the portal vein and the inferior
vena cava was clotted firmly. Clots were present in all the chambers of the
heart, but were firmer and larger in the auricles. The pulmonary vessels were
blocked by thrombi.
Rabbit 8—1,250 grammes—Received 0 .093 milligramme of venom, i. e.,
0.075 milligramme per kilo.
This animal showed no symptoms at any time and seemed not to be
affected at all by the poison. The blood coagulation time was taken half an
hour after the injection and was found to be reduced to 6 minutes, the normal
coagulation time of a rabbit being about from 2 to 3 minutes.
This third series of experiments is tabulated as follows : —
TABLE III.
Intravascular injection of daboia venom in rabbits.
Animal.
Weight in grammes.
Amount of venom
in milligrammes
per kilo.
Result.
Post-mortem examination.
Rabbit 1..
1,240
0.26
Died in 2 minutes. Extensive and solid in-
travascular clotting.
Rabbit 2..
2,030
0 . 1 2
Died in 3 minutes. Extensive and solid in-
travascular clotting.
Rabbit 3..
2 , 5 0 0
0.12
Died in 4½ minutes. Extensive and solid in-
travascular clotting.
Rabbit 4
.
2,500
0.12
Died in 4 minutes. Extensive and solid in-
travascular clotting.
Rabbit 5..
1,250
0.1
Died in 8 minutes. Extensive intravascular
clotting.
Ra b b i t 6 . .
1,250
0.1
Died in 6 minutes. Extensive intravascular
clotting.
Rabbit 7..
1,400
0.075
Died in 7 minutes. Extensive intravascular
clotting.
Rabbit 8...
1,250
0.075
No symptoms.
B2