NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
12
This, then, completes the observations which bear on the question at present
under consideration, namely, the cause of the symptoms and of death following
rapidly on either the subcutaneous or intravascular injection of daboia venom.
Later on we shall present some experiments made with a view to ascertain
the cause of the symptoms and of death in the chronic cases of this intoxication.
Let us now consider the conclusions to which the data contained in the three
series of experiments collated above seem to point.
It would appear, from our observations, that when death rapidly follows
an injection of daboia poison, made either subcutaneously or directly into the
blood stream, more or less extensive intravascular clotting is always found on
careful post-mortem examination performed immediately after death. Further,
it would appear, that, even when a dose which just fails to cause death from intra-
vascular thrombosis is given intravenously, the animal presents none at all or
only very slight symptoms. In the case of subcutaneous injection, however, as
we shall see later, a dose which fails to cause rapid death by intravascular clot-
ting may, in some cases, produce serious symptoms of chronic intoxication and
death. A study of our experiments will show, also, that the larger the quantity
injected, whether given subcutaneously or directly into the blood stream, the
more rapidly do symptoms come on, the more quickly does death follow and the
more extensive and solid is the clotting found on post-mortem examination.
Such, then, being the facts of the case the question evidently resolves itself
into the consideration as to whether intravascular thrombosis, which we have
seen is found in all cases, can be brought forward as an adequate explanation of
the symptoms observed and of the rapidly fatal result which follows. Now, the
objective symptoms which follow thrombosis or embolism of the pulmonary
arteries or their main branches are well known in man and are similar to those
which we have described above. 1 6
Whether these symptoms are ultimately refer-
able to asphyxia or to cerebral anæmia is a question which is under dispute, but
which does not concern us at present. In our opinion, therefore, there can be
no doubt that the extensive intravascular clotting, especially the thrombosis
of the pulmonary arteries, is the cause of the symptoms and of the rapidly fatal
result which follows in these acute cases of daboia intoxication. Now, the
symptoms which we have noted in all our experiments, viz., restlessness and
difficulty in preserving equilibrium, gasping and laboured respiration, followed
by violent general convulsions, are the symptoms which were observed by
Cunningham 1 7
i n h i s e x p e r i m e n t s . A s w e h a v e m e n t i o n e d b e f o r e , t h i s o b s e r v e r
holds the opinion that these symptoms are entirely due to a direct irritant action
of the venom on the central nervous system, and that the cause of death is also
this action of the poison on the nerve centres. The reasons for his belief
are put forward in the publication already referred to. A study of this
13
paper will show, however, that this opinion is based solely on the observer's
interpretation of the symptoms preceding death, and that the post-mortem exami-
nations were quite inadequate in number and detail. In the one or two instances
in which he records having made a post-mortem examination, he found the blood
of the heart in a fluid condition, and he further noted that it remained unclotted.
We have ourselves noted this same phenomenon occurring in conjunction with
an extensive thrombosis of the portal vein and the pulmonary vessels ( vide
monkeys 1, 2, 3, 4, 5, and 6) . It is evident, then, that Cunningham either did
not observe, or attached no importance to, the more or less extensive intravascular
clotting which we have described and which, in our opinion, has a most important
bearing on the question at issue. In view of these facts and considerations
it appears to us, therefore, that Cunningham's hypothesis, that the symptoms
and death in these cases are due to a direct irritant action of the venom on the
central nervous system, is not substantiated and will have to be discarded.
We have seen above that one milligramme of daboia venom when injected
directly into the blood stream of a monkey causes almost instantaneous death.
If, then, the cause of death is, as Cunningham holds, due to a direct action of
the venom on the nerve centres, especially on the centres of the medulla, the
rapidity of the onset of the phenomena observed being due to the poison being
at once carried by the blood stream to these centres, we should expect a
similar result following the introduction directly on to the medulla of a larger
amount of venom than one milligramme.
Such an experiment was made as follows :—
Monkey 8.—With the head fully flexed, the posterior occipito-atlantoid liga-
ment was exposed. Through this 2 milligrammes of daboia venom in 1 c.c. of
sterile saline solution were injected into the spinal canal, that is, directly on to
the medulla. No immediate symptoms followed this injection. A few hours after-
wards the animal appeared dull, lethargic and inclined to lie down. These are
symptoms which are usually observed in chronic cases when the poison is injec-
ted subcutaneously. These symptoms, however, soon passed off, and next day
the monkey was apparently all right, eating and drinking well. No further symp-
toms developed and an uninterrupted recovery followed.
This single experiment, therefore, would appear to support our contention,
that the symptoms and rapid death seen in acute cases of daboia poisoning are
not due to any direct action of the poison on the central nervous system. It
points, rather, to the conclusion that daboia venom contains no element similar
to the toxic albumose of cobra poison, which acts directly on the nerve centres
of the cord and medulla. To this question we shall return.
Chronic intoxication from daboia venom.
We may now pass on to the consideration of some observations we made on
the pathology of cases of daboia poisoning, in which either a fatal result is delayed
14
for some time after the injection or, even after grave symptoms, recovery
ultimately takes place. These observations were made principally on monkeys,
although a few rabbits, fowls, pigeons and rats were also used. It was found,
however, that the symptoms could be better seen and studied in the monkey
than in any of those animals. The following observations, therefore, apply,
for the most part, to cases of chronic intoxication in the monkey.
The symptoms which are observed in chronic cases of daboia poisoning
may be divided into local and general. At the site of inoculation a few hours
after the injection a more or less extensive subcutaneous hæmorrhage developed.
Around this, especially at the dependent part, a considerable œdema soon made
its appearance. After some time the local condition in some cases underwent
resolution, but in other cases the parts sloughed, and on separation of the slough
a large irregularly shaped ulcer was left. In other cases we have seen
a rapidly-spreading gangrenous condition supervene on this local hæmorrhage.
This condition soon ended in death. In some instances a simple subcutaneous
abscess developed at the site of injection. These several conditions depend, of
course, on the nature of the bacteria which become planted in the tissues already
damaged and devitalised by the hæmorrhage and cedema.
As regards the general symptoms, they are as a rule very indefinite and
somewhat difficult to interpret. In a few severe cases hæmaturia was ob-
served, while in one instance there was an actual hæmorrhage from the bowel.
General œdema was not observed, although in some cases a considerable œdema
of the penis and scrotum took place. The animals appeared depressed, dull
and lethargic, and refused food. The external surface of the body was
markedly cold to the touch, indicating considerable cardiac depression.
Rapid emaciation soon appeared, and in the prolonged cases a profound
anæmia and lethargy developed. In no instance did we observe either convul-
sions or paralysis or other symptoms which might point to any direct action
on the central nervous system.
The post-mortem appearances varied in different cases. If life was pro-
longed for some days, with the exception of the local lesion, whatever that
might be, no macroscopic lesion was seen. In cases in which gangrene
developed the local condition was the chief, if not the only, pathological change
apparent to the naked eye.
When death occurred within 24 to 48 hours after-the injection of the poison,
it was noted that post-mortem rigidity was completely absent, and that the bloody
extravasation around the site of inoculation was well marked. In some cases
hæmorrhage around and into the substance of one or both kidneys was observed ;
and in the intestine small submucous hæmorrhages were sometimes found. In
these cases, also, blood taken from the heart showed a marked diminution of
coagulability, while, when any vessels were cut across, fluid blood flowed readily.
15
We have seen above that at the post-mortem examination of animals in
which death has rapidly followed on the injection of daboia venom, although
intravascular clotting is a prominent feature, the fluid blood collected from the
heart remained uncoagulated, and that in some instances most of the blood was
in this condition, the clots being small and difficult to find (e.g., monkeys 1, 2
and 3). From a consideration of this fact, and of the symptoms and post-mortem
lesions noted above as occurring in cases of chronic daboia intoxication, it
seemed to us not unlikely that these symptoms might be accompanied by, or even
might be dependent on, a considerable deficiency in the coagulation of the blood.
With a view of further investigating this hypothesis the following experiments
were made :
—
Deficiency of blood coagulability in chronic cases of daboia
venom intoxication.
The method adopted in all our observations to estimate the coagulation
time of the blood was that elaborated by Professor Wright of Netley.1 8
A s o u r
observations were always made at a uniform temperature, viz., the day tempera-
ture of the laboratory in the months of November, December and January,
which in Bombay varies very little from day to day, it was found unnecessary to
make use of the device described by the inventor for maintaining the tubes
at a standard temperature. The results obtained may therefore be considered
as comparable with each other.
Monkey 9—29-11-1900.—Blood coagulation time before injection was 3¼
minutes. At 3 P.m. received subcutaneously in pectoral region 3 milligrammes
of daboia venom,
30-11-1900.—Marked hæmorrhagic extravasation with œdema round the
site of inoculation. Considerable œdema of the scrotum and penis.
Blood coagulation time, 5¼ minutes.
1-12-1900 .—Bloody extravasation still marked. The œdema of penis and
scrotum has markedly increased.
Blood coagulation time, 11¾ minutes.
2-12-1900.—A small abscess has formed at the site of inoculation : œdema
of scrotum has considerably diminished.
Blood coagulation time, 6 minutes.
3-12-1900.—The scrotum still slightly œdematous.
Blood coagulation time, 4¾ minutes.
4-12-1900.—Œdema of scrotum practically gone.
Blood coagulation time, 4 minutes.
From this date the animal made an uninterrupted recovery. For the next
few days daily observations of the coagulability of the blood were made, the
coagulation time being found on each occasion to be about 4 minutes.
M o n k e y 1 0 — 3 - 1 2 - 1 9 0 0 . — T h e b l o o d c o a g u l a t i o n t i m e b e i n g 2 ¾ minutes, re-
ceived subcutaneously in the pectoral region 2 milligrammes of daboia
venom.
4-12-1900—There was a very large extravasation of blood around the site
of inoculation. The front of the chest was œdematous. The animal had the
appearance of being very ill, dull, lethargic and hardly able to stand up.
Blood coagulation time, 16 minutes.
5-12-1900.—The hæmorrhagic extravasation and œdema still very promi-
nent. The animal was very weak and ill, and was, in consequence, killed under
chloroform. Coagulation time of blood taken from the left ventricle was 12
minutes.
Large hæmorrhagic extravasations were found around the kidneys and also
a the substance of these organs, especially in the cortex. There were many
submucous hæmorrhages in the intestines.
Key 11—3-12-1900.—Blood coagulation time before inoculation was 2½
minutes. Received subcutaneously in the pectoral region 3 milligrammes of
daboia
venom.
4-12-1900.—Considerable extravasation of blood a round the site of injec-
tion. Slight ædema over the front of the chest. The general condition of the
animal is good, the general symptoms not being prominent. Blood coagula.
tion time, 5¾ minutes.
5-12-1900.—Bloody extravasation and œdema still present, although less
marked than on the previous day.
Blood coagulation time, 5½ minutes.
6-12-1900 —The œdema was practically gone. The animal appeared well
and fit.
Blood coagulation time, 6 minutes.
The œdema had completely disappeared by next day, when the blood
coagulation time was found to be 3¾ minutes.
No further symptoms developed, and the animal made a good recovery.
In this case the symptoms, both local and general, were never either pro-
minent or urgent.
Monkey 1
2—3-12-1900.—Blood coagulation time, 2¾ minutes. Received
subcutaneously in pectoral region 4 milligrammes of daboia venom.
4-12-1900.—The animal appeared dull and ill. There was a large hæmor-
rhagic extravasation around the site of inoculation, with several superficial
serous blebs. Blood coagulation time, 9¼ minutes.
5-12-1900.—Animal much better. There was some œdema over the front
of the chest.
Blood coagulation time, 5 minutes.
6-12-1900.—Œdema less than on previous day, and general condition much
improved.
17
Blood coagulation time, 3¼ minutes.
From this time the animal rapidly recovered. For the next few days the
blood coagulation time was about 4 minutes.
With a view of ascertaining how soon after the inoculation of the venom
this diminution of blood coagulability appeared, the following experiments were
made :
—
Monkey 13—11-12-1900.—Blood coagulation time, taken just before the
venom was injected, was found to be 3 minutes. At 4.15 P.M. received in the
right thigh, subcutaneously, 4 milligrammes of daboia poison.
At 5 P.M. no apparent symptoms, either local or general. Blood coagula-
tion time, 5 minutes.
At 9.30 P.M. slight œdema at site of inoculation. The part also is
evidently painful.
Blood coagulation time, 8½ minutes.
12-12-1900.—The animal this morning was dull and ill. There was consider-
able œdema of the leg and bloody extravasation around the site of inoculation.
Blood coagulation time, 8 minutes.
13-12-1900.—To-day the animal was very ill ; the leg much swollen and
the seat of a spreading emphysematous gangrene. There was also slight
hæmaturia. It was killed.
Blood taken from the heart post-mortem had a coagulation time of 4
minutes. The only internal lesion observed was a slight hæmorrhage around
and into the pelvis of the left kidney. The right kidney appeared healthy.
We may ascribe the serious condition of this animal, before it was killed, to
gangrene of the leg, and not to the direct effect of the daboia poison.
Monkey 14—12-1-1901.— The blood coagulation time before the injection
of the poison was 3 minutes.
At 12.30 P.M. received subcutaneously in the pectoral region 4 milligrammes
of daboia venom. At 4 P.M. appeared to be very ill, dull and restless, and
lay down on the bottom of the cage. When roused, however, it became excited
and jumped about. At site of inoculation there was a certain amount of bloody
extravasation.
The blood was found to be quite incoagulable. The contents of tubes
filled from a vein of the ear were found, 22 hours afterwards, to be quite fluid.
13-1-1901. 10.30 A.M.—Was much better than on the previous evening ;
fairly active and sat upright in a corner of the cage. It was very violent when
attempts were made to catch it. The hæmorrhagic extravasation at the site of
inocualtion had not increased in size. Blood coagulation time, 3½ minutes.
3.30 p.m.—Blood coagulation time, 3 minutes.
14-1-1901.—The animal was quite well and lively. There was no œdema,
and the hæmorrhagic extravasation was disappearing.
18
Blood coagulation time, 3¼ minutes.
The observations detailed above may, for convenience, be tabulated as fol-
lows :—
TABLE IV.
The diminution of coagulability of the blood in chronic cases of
daboia venom intoxication in monkeys.
Animal.
Dose of
venom in
milligrs.
subcu-
taneously.
COAGULATION TIME OF BLOOD IN MINUTES.
REMARKS.
Before
i n j e c t i o n .
2nd day. 3rd day. 4th day. 5th day. 6th day.
Monkey 9
.
3
3 ¼
5 ¼
1 1 ¾
6
4 ¾
4
Symptoms severe with
much œdema.
Monkey 10
.
2
2 ¾
16
12
...
. . .
...
Very severe case : had
to be killed: several
hæmorrhagic extrava-
sations.
Monkey 11
.
3
2 ½
5 ¾
5 ½
6
3 ¾
...
Symptoms not severe ;
recovery rapid.
Monkey 12
.
4
2¾
9 ¼
5
3¼
4
4
Severe symptoms for
one day ; recovery
rapid.
Monkey 13
.
4
3
8
4
•••
. . .
. . .
Had to be killed on
account of emphyse-
matous gangrene.
Monkey 14
4
3
Blood
incoagul-
able 4
hours
after
injection.
3½
3
...
. . .
Very severe and urgent
symptoms soon after
inoculation; recovery
rapid
The data obtained from the above observations afford us a probable ex-
planation of the pathological symptoms seen in these chronic cases of daboia in-
toxication. Thus, the diminution of the coagulability of the blood, which
w e
h a v e
n o t e d i n a l l o u r c a s e s , i s n o d o u b t a f a c t o r i n t h e c a u s a t i o n o f t h e
hæmorrhages and œdema which are nearly always prominent symptoms. A
similar deficiency of blood coagulability has been brought forward by Wright1 9
as the pathological condition on which the excessive bleeding in hæmophlic
patients, the œdema of Bright's disease and the serous extravasations of urticaria
depend.
When we come to sift these data critically, it is apparent that in the cases
of animals in which both the general and local symptoms were prominent
19
and severe, the blood . coagulability was markedly deficient and remained
deficient for some time (monkeys 9 and 1 0
) , a n d e s p e c i a l l y w a s t h i s t h e
case in the latter animal, which had to be killed on account of the severity
of the symptoms. It would appear, however, from a consideration of these
two cases, in conjunction with the case of monkey 14, that in order that these
symptoms may become fully developed and so severe as to lead to an anticipation
of a fatal result, the blood coagulability must not only be greatly deficient but
must remain markedly deficient for some time after the injection. Thus, in
monkey 14 the blood a few hours after the injection remained unclotted " in vitro,"
and the animal was apparently moribund but next day this deficiency of blood
coagulability had passed off, and the urgent symptoms had disappeared. This
condition was also seen in the case of monkey 12 although in a much less,
degree.
On the other hand, it would appear that in those instances in which there
is no great deficiency of the blood coagulability, the symptoms are neither well
marked nor urgent and recovery is rapid (monkey 11 ) ,
A study of these facts, therefore, justifies the conclusion that the patholo-
gical symptoms in chronic cases of daboia intoxication depend for the most part
on the deficiency of the blood coagulability, and that the greater this deficiency
the more urgent and pronounced are the symptoms, especially the hæmorrhages
and œdema ; and that if this deficiency be at all prolonged the more likely will
the case be to have a fatal result. Should, however, the deficiency quickly pass
off, the symptoms which have not had time to become fully developed quickly
subside, and rapid recovery takes place. The manner in which this diminution
of blood coagulability is brought about is a problem on which our experiments
throw no light.
We do not intend in this paper to enter into the question of the hæmolytic
action of daboia venom. This question and its significance in connection
with the facts which we have already detailed, viz., the extensive intravascular
clotting seen in cases of rapid death from daboia venom, and the diminution of
blood coagulability, as observed in chronic cases, we shall postpone for another
publication.
The diminution in the blood coagulability is more marked when there is
injected directly into the blood stream a quantity of venom which just fails to
produce death by intravascular thrombosis. Further, after such an injection
no larger quantity of venom can cause the extensive clotting which we have
seen to result from intravascular inoculation of even small amounts of the poison.
These facts were demonstrated by the following experiments : —
Monkey 15.—The animal was anæsthetised with a mixture of chloroform
and ether. The left brachial artery was then laid bare, and having been clamped
with bull-dog forceps was cut across.
C 2
20
At 3-9 P.M., 1 milligramme of daboia venom in 1 c.c. sterile normal salt
solution was slowly injected into the cephalic vein.
A minute after this injection the animal stopped breathing and was ap-
parently dead. Respiration, however, soon started again. It was at first gasp-
ing and then of regular rhythm.
3-11 P.M.— A specimen of blood taken from the brachial artery in a small
test. tube was not coagulated after 24 hours.
3-25 P.M.—A second specimen of blood, taken in the same manner as the
first, also remained unclotted after 24 hours.
3-25 P.M.—One milligramme of venom was injected into the cephalic vein.
3-30 P.M.—A third sample of blood, again taken from the brachial artery
as before, also showed no signs of clot after 24 hours.
Between 3-35 and 3-42 P.M. 2 . 25 milligrammes of venom were injected
into the cephalic vein.
3-50 P.M.—The animal showed no symptoms. Allowed to recover from
the anæsthetic it was quite lively and apparently none the worse for the injec-
tions. It was now killed with chloroform. No intravascular clotting could be
found in any vessel although careful search was made. A specimen of blood
collected from the heart immediately after death was uncoagulated after 2
4
hours.
In this case 4.5 milligrammes in all of daboia venom were injected directly.
into the blood stream in a space of 33 minutes. It will be remembered that in
our former experi ment s 1 mi l l i gramme, i nj ect ed di rect l y i nt o t he bl ood st ream
in two monkeys, caused extensive intravascular clotting, (vide, monkeys 3 and 7).
Monkey 16.—Was not anæsthetised.
2-58 P.M.—Received into the left cephalic vein 0 .4 milligramme of daboia
venom dissolved in 0 .4 c.c. of sterile normal salt solution.
The corneal reflex was lost immediately after injection of the poison but
returned in 1 minute. The breathing remained good and regular.
At 3-4 P.M.—Blood coagulability was tested by means of Wright's coagu-
lation tubes. The blood remained unclotted after 1 hour.
3-12 P.M.—Received into the left cephalic vein 1 milligramme of venom.
No symptoms followed this injection.
3-29 P.M.—Received into the right cephalic vein 4 milligrammes of daboia
venom.
The corneal reflex was again lost for 1 minute. The breathing remained
regular. The blood drawn soon after the injection did not coagulate.
This animal died during the night. In the morning a post-mortem examin-
ation was made. The only lesion seen was a small hæmorrhage around the
left suprarenal capsule. The blood in the heart was quite fluid and collected
into a test tube remained unclotted after 24 hours.