NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
Medical,Officers of the Army of India.
41
During life sanguinolent evacuations very frequently are conspicuous symptoms,
and on post-mortem examination sanguinolent effusions will constantly be
found, not merely in the immediate neighbourhood of the site of introduction of
the venom but extending thence in diffuse fashion over wide areas. In the case
of fowls which die in consequence of repeated injections of venom into the
subcutaneous tissue of the thighs, sero-sanguinolent effusions are ordinarily
present, extending thence over the whole flanks and up as far as the origins of
the wings ; the phenomena being, in fact, almost precisely identical with those
which attend the subcutaneous injection of relatively large quantities of virulent
comma-bacilli in similar sites.
From the results of the foregoing and similar experiments it is quite clear
that, whilst in the case of any sample of cobra-venom we are dealing with a ma-
terial in which we can readily determine that the amount constituting a mini-
mal lethal dose bears a simple relation to weight, in that of any sample of
Daboia-venom, it has always to be taken into account that we are dealing with
one in which the relation of lethality to quantity is more complicated, not mere-
ly because of the presence of two distinct toxic principles, but because the-pro-
portions which these bear to one another may vary very considerably, and
because the action of one of them is liable to be affected by the manner in which
it enters the system. In the case of any sample of cobra-venom we have only
to ascertain the weight constituting a minimal lethal dose ; in that of Daboia-
venom we have to ascertain the weights containing the minimal lethal doses of
two perfectly distinct toxic principles, and, further, under what conditions one of
the latter is capable of producing its maximal effects. Having once ascertained
that a given amount of cobra-venom is lethal we know that, however it be intro-
duced into the system, it will cause death ; in the case of Daboia-venom we
have in the first place to ascertain what amounts of it contain lethal doses of
two distinct toxins, and then, in regard to one of these, to determine how it
must be introduced into the system to produce its full effects.
It now remains to consider the phenomena attending the immediate intro-
duction of relatively large doses of the venom into the system as compared with
those which have been previously shown to follow the introduction of large
doses of cobra-venom.
Experiment LVIII.— 1 0
- 4 4 A . M .
A f o w l r e c e i v e d a s u b c u t a n e o u s i n j e c t i o n
of 0.01 gramme of dried venom (of which 0.00 3 was sufficient to cause general
convulsions and death within ten minutes when administered in 1 c.c. of water)
in 1c . c . o f w a t e r .
Strong local muscular action attended the injection and the bird presently
sat down, making conspicuous swallowing movements once or twice.
10-47 A.M. It began suddenly to jerk its head about from side to side and then at
once passed into furious general convulsions, shrieking loudly, and
with widely expanded and fluttering wings.
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Scientific Memoirs by
10-48 A.M. Dead. Comb and wattles bright red. Death occurred in tetanic spasm
with the wings widely expanded and curved, and the legs rigidly ex-
-tended, and this position was permanently retained.
Experiment LIX. —11-10 A.M.A fowl was bitten in the thigh by a large,
fresh Daboia.
11-12 A.M. Violent general convulsions set in.
11-13 A.M. Dead.
Experiment LX. —10-18 A.M. A fowl was bitten by a large, fresh Daboia.
It at first appeared to be restless and excited, jerking its head about in a
peculiar way.
10-19 A.M. Furious general convulsions set in and half a minute later death occurred.
The next two experiments illustrate the effects following the bite of a
Daboia as compared with those attending the bite of a cobra.
Experiment LXI.—(a) 10-18 A.M. A fowl was bitten in the thigh by a
large, fresh Daboia.
It remained at first standing motionless and making swallowing movements.
10-19 A.M. It suddenly staggered backwards and passed into furious opisthotonic
convulsions.
10-20. A.M. Dead.
( b ) 10-37 A.M. A fowl was bitten in the thigh by a large, fresh cobra.
It remained standing on the uninjured leg for a short time and then sat down.
10-44 A.M. Beginning to gape and to inspire gaspingly.
10-43 A.M. The head beginning alternately to droop forward and to be elevated
suddenly with each inspiration.
10-46 A.M. The head permanently depressed with the tip of the beak resting on
the floor of the cage.
10-47 A.M. Asphyxial convulsions setting in.
10-54 A.M. Dead.
Experiment LXII. —(a) 11-10 A.M. A fowl was bitten in the thigh by a
large, fresh Daboia, but the venom of only one fang entered the tissues.
11-12 A.M. Violent general convulsions set in.
11-13 A.M. Dead.
( b ) 11-31 A.M. A fowl was bitten in the thigh by a large, fresh cobra.
It remained at first standing on the uninjured leg, the tips of the toes of
the other one only touching the floor of the cage.
11-33 A.M. It sat down with the eyes closing, and the mandibles gaping with each
laboured, gasping inspiration. The head gradually drooped further
and further forward between each inspiration until the tip of the beak.
rested on the floor. Gradually the head fell over to one side and the
bird lay flat with extended neck, save when it occasionally roused
itself and suddenly threw up the head during inspiration.
11-36 A.M. General convulsions set in and recurred at short intervals.
11-41 A.M. Dead.
Medical Officers of the Army of India.
43
The following experiment illustrates the phenomena attending the direct
introduction of minimal lethal doses, of Daboia-venom on the one hand and of
cobra-venom on the other, into the circulation.
Experiment LXIII. —( a ) A sample of Daboia-venom was carefully tested
and the minimal lethal dose requisite to occasion general convulsions and death
ascertained to amount to between 0.005 and 0.004 gramme.
11-7 A.M. A fowl received an intrajugular injection of 0.005 gramme in
0.5 c.c. of distilled water.
Furious general convulsions set in before the bird could be put down and
death occurred immediately afterwards. The blood was of a dull brick-red
colour. It brightened in some degree on exposure to air, but was absolutely in-
coagulable.
( b ) 10-50 A.M. A fowl received an intrajugular injection of 0.0005 gramme
of dried cobra-venom, of which that amount constituted a minimal lethal dose.
No appreciable symptoms whatever manifested themselves until between
2 and 3 P.M., but they then began to appear, ran their normal course and
terminated in death between 7 and 8 P.M.
The phenomena which attend the mixture of various amounts of Daboia
-venom with blood outside the body are also, as the following experimental data
clearly show, quite district from those which attending the action of cobra-
venom.
Experiment LXIV.—A covered glass capsule having been carefully steri-
lised, a solution of 0.003 gramme of dried Daboia-venom of ascertainedly
highly lethal property, in 1 c. c. of sterilised distilled water, was introduced into
it, and 19.69 grammes of blood added directly from the throat of a fowl at
11 A.M.
The blood at once became of a vivid scarlet colour and rapidly underwent
coagulation, but the clot was persistently of an extremely soft, tremulous
consistence.
11-30 A.M. The blood consisted of a relatively small clot, vivid scarlet superficially
and darker red in substance, floating free in a large bulk of brilliant
scarlet opaque serum.
12 Noon. The serum had now deposited a scarlet sediment of blood corpuscles
and was of a muddy colour.
2 P.M. The clot was relatively very small, widely separated from the sides of
the vessel and floating free in the muddy serum. The deposit had
now lost its scarlet colour but portions of it, when exposed to the air,
rapidly re-gained it. There was no appreciable evidence of any
solution of corpuscles.
On the following day the clot was small and of a very dark plum colour,
and 11 c.c. of very dark, opaque plum-coloured serum surrounded it. Both
F 2
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clot and serum brightened considerably in colour on exposure to air. Many red
corpuscles were still well preserved.
Experiment LXV. —This was conducted in precisely the same fashion as
the previous one, 31 grammes of blood being added to a solution of 0.001
gramme of dried venom in 1 c. c. of distilled water at 11.25 A.M. The blood
very rapidly coagulated into a loose, tremulous, vivid-scarlet clot.
11-40 A.M. A large quantity of bright scarlet, opaque serum had already separated.
11-55 A.M. The clot was vivid scarlet on the surface and dull scarlet in substance.
1.15 P.M. The preparation now consisted of a large quantity of muddy serum with
a red deposit of corpuscles, and a relatively small clot floating free in
it. The clot where exposed to the air was bright scarlet, and where
submerged plum-coloured.
Twenty-four hours after the beginning of the experiment the clot was wide-
ly shrunken away from the sides of the vessel and, where not submerged, of
a dull red colour. It floated in 15 c. c. of dark plum-coloured serum, which on
exposure to the air in thin layers became bright brick-red. The surfaces
of the clot also on exposure to air brightened to a dull scarlet. Many red cor-
puscles remained still intact.
Experiment LXVI.— Two capsules, a and b, were sterilised as usual. A
solution of 0.01 gramme of dried Daboia-venom in 1 c.c. of distilled water and
23.69 grammes of blood were introduced into a at 10-40 A.M., and a solution of
0.01 gramme of dried cobra-venom in 1 c.c. of distilled water and 22.59
grammes of blood into b at 10-42 A.M.
a. The blood very rapidly formed a very loose soft, tremulous coagulum
of a vivid scarlet colour. The clot retained its soft consistence until the exuda-
tion of serum began to take place shortly after 11 A.M.
11-23 A.M. The blood now consisted of a soft clot floating almost free in a large
quantity of opaque, scarlet serum. The surface of the clot was vivid
scarlet and the sides of it bright plum-coloured.
12 Noon. The corpurcles in the serum had now subsided to form a scarlet deposit
beneath a muddy fluid. The clot was now widely shrunken from the
sides of the vessel and its surface was still bright scarlet.
2 P.M. The surface of the clot, which now floated free in a large quantity of
muddy serum, was still bright scarlet and there was no appreciable
evidence of any solution of red corpuscles.
On the following day the surface of the clot was plum-coloured mottled
with deep red, and the substance plum-coloured. It floated in 13 c. c. of
opaque, muddy, plum-coloured serum. On exposure to air the surfaces of the
clot brightened to a dull red. The red corpuscles were apparently thinned and
wanting in substance, but a very large number of them were still readily recog-
nisable.
Medical Officers of the Army of India.
45
b. The blood rapidly formed an even, firm, coagulum the surface of which
soon became bright scarlet but presently after wards began to darken rapidly.
11-23 A.M. The surface of the coagulum was dark red and its substance deep
plumcoloured. No free serum was yet present.
1 P . M .
T h e s u r f a c e a n d s u b s t a n c e o f t h e c o a g u l u m w e r e a l m o s t b l a c k , f r o m
the intense darkness of the red colour which they possessed. There
was a little, limpid, dark-red serum present, but the clot was every
where closely adherent to the sides of the vessel.
2 P.M. The characters of the specimen remained as before. The bodies of
the red corpuscles were almost universally dissolved, leaving their
nuclei free.
On the following day the clot was throughout of such an intensely deep
lake colour as to be apparently black, and was everywhere closely in contact
with the sides of the vessel. Only 1 c. c. of serum was present, transparent and
of a deep lake colour in thin layers but in mass appearing black and opaque, only
the nuclei of the red corpuscles remained recognisable.
The above experimental data are surely sufficient to demonstrate that
Daboia-venom is entirely unlike cobra-venom in its nature and action and that
the two poisons differ from one another in the following respects :
—
1. The minimal lethal dose of normal cobra-venom is very much smaller
than that of Daboia-venom.
2. But a minimal lethal dose of normal, potent Daboia-venom is much
more rapidly fatal than a minimal lethal dose of the most potent cobra-venom.
3. The manifestation of the action of minimal lethal doses of normal
cobra-venom, even when directly introduced into the circulation, is preceded by
a prolonged latent period which lasts for some hours, but the symptoms of the
action of minimal lethal doses of Daboia-venom of normal quality make their
appearance in any case very rapidly, and in cases of direct introduction into the
blood-vascular system, are developed instantaneously. In other words, the
phenomena attending the action of minimal lethal doses of cobra-venom are
essentially those of the action of a ferment-poison whilst the symptoms following
corresponding doses of normal Daboia-venom are those characteristic of the
action of direct nervous irritants such as strychnia.
4. Normal Daboia-venom gives rise to well-marked local muscular action
at the site of introduction, but normal cobra-venom does not do so. In some
exceptional cases, however, a certain amount of local muscular action follows the
subcutaneous injection of solutions of cobra-venom, so that it appears to be possi-
ble that the nerve-irritant constituent which is the cause of death in acute in-
toxication by Daboia-venom may be a normal constituent of cobra-venom also.
Even if it be, however, the maximal amount of it which is present is too small to
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give rise to any thing save local effects, and, hence, in so far as the lethal proper-
ties of the venom are concerned, it is of no practical importance.
5, The phenomena attending the administration of sub-lethal doses so long
as these are capable of producing any appreciable effects, of minimal lethal
doses, and of excessive doses of cobra-venom are essentially alike, but in the case
of normal Daboia-venom this is not the case, as sub-lethal doses, where they
produce any appreciable effect, are followed by symptoms indicative of the
action of one toxic principle, and minimal lethal and excessive doses by symp
- t o m s i n d i c a t i v e o f t h a t o f a n o t h e r .
6. In the phenomena normally attending the action of cobra-venom there
is no distinct evidence of the action of anything but a single toxin, whilst in the
case of Daboia-venom there is the most unequivocal evidence of the presence
of two distinct lethal toxins, one acting as a direct nervous irritant and the
other giving rise to septic changes in the blood.
7. The toxin in cobra-venom acts cumulatively ; in the case of Daboia-
venom the toxin which causes nervous irritation cannot act cumulatively whilst
that which induces septic phenomena does so.
8. Dilution of minimal lethal doses of cobra-venom in no way affects
their potency, whilst dilution of minimal lethal doses of normal Daboia-venom
ordinarily renders them incapable of causing death because it renders the ner-
vous irritant toxin incapable of acting upon the nervous centres, whilst the
septic one, as a rule, is only lethal when it enters the system in relatively large
amounts.
9. The symptoms attending the action of the septic factor in Daboia-venom,
although it is capable of acting cumulatively and is apparently unaffected by
dilution, are perfectly distinct from those attending the action of cobra-venom,
for, whilst in cases of intoxication by cobra-venom respiratory and nervous symp-
toms indicative of defective oxygen-supply constitute the characteristic pheno-
mena, in cases of chronic Daboia-poisoning such phenomena are entirely ab-
sent and are replaced by symptoms indicative of a tendency to abnormal escape
of blood-constituents from the blood-vascular system. Farther, in the case of
death from the action of cobra-venom the blood is characterised by its intense-
ly dark colour and by the fact that it coagulates rapidly and firmly unless ex-
cessive doses of venom have been directly introduced into the system, or life
has been artificially prolonged so as to give the ferment-action full time to
operate; whereas in the case of death from the action of Daboia-venom it is
of a peculiar dull brick-red colour and normally quite incoagulable, even when
death has been induced almost instantaneously by the direct intravenous injec-
tion of minimal lethal doses.
There are certain points in connection with the action of Daboia-venom
which appear to merit special consideration. These are, first, the phenomena
Medical Officers of the Army of India.
47
attending the dilution of minimal lethal doses of the constituent which acts as
a nervous irritant ; second, the fact that in certain cases the blood retains its
coagulability after death ; and, third, that the properties of the venom appear nor-
mally to vary at different times of year.
The only apparent explanation of the phenomena attending dilution of
minimal lethal doses is that the material which acts as a direct nervous
irritant is either very rapidly excreted or very rapidly decomposed, so that
in the case of minimal lethal doses a delay in absorption may prevent the
accumulation of enough of it within the circulation to occasion fatal irrita-
tion of the nervous centres. When a minimal lethal dose is subcutaneously
injected in 3 in place, of 1 c. c. of water it may be assumed that, other
things being alike, the absorption of the total mass of venom will be propor-
tionately delayed and, with this, the time for its partial excretion or decom-
position proportionately increased. Whether the phenomenon is actually de-
pendent on very rapid excretion or very rapid decomposition must in the
meantime remain an open question, but it appears not to be inprobable that de-
composition is the essential factor, seeing that there are various facts which
clearly indicate an extreme instability in the constitution of the material. Dr.
Wall's experiments unequivocally showed that an exposure to temperatures which
in no way affected the septic potency of the venom was sufficient to render it
entirely inert as a nervous irritant. * Indeed, as he was unaware that in any
case the septic phenomena may be induced without the induction of any save
purely local nervous irritation by means of the cumulant employment of minute
doses, he regarded preliminary heating of the venom as an essential step to-
wards their study uncomplicated by the others. But it is not merely exposure
to excessive temperatures which alters the properties of the venom in this way ;
for, during the moist, warm weather which prevails in Calcutta during the rainy
season, a similar loss of nerve-irritant property almost invariably occurs in any
specimens of venom which are not most carefully protected from all exposure
to ordinary atmospheric air. Even when kept in carefully stoppered bottles, un-
less these be continuously retained in an artificially desiccated atmosphere they
lose greatly in nerve irritant property, whilst retaining septic potency un-
impaired. This loss of power came out very clearly in the case of a peculiarly
potent sample of dried venom which had been employed in experiments during
the course of the winter of 1894, and subsequently set aside in a stoppered
bottle for some months. In its original state its potency was such that 0.003
gramme when administered in one 1c.c. of water invariably induced fatal general
convulsions in fowls of about 1 kilo in weight within ten minutes subse-
quent to administration, but when it was again tested during the course of the
* Op. cit.
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autumn, doses of 0.003 and 0.006 gramme failed to give rise even to any signs
of local nervous irritation, and doses of at least 0.012 gramme were necessary
in order to induce fatal general convulsions. The instabilty of the material is
further indicated by the results which attended the following experiments on
the action of the albumin and globulin which my friend, Dr. Warden, was
good enough to separate from a sample of venom of ascertainedly high neurotic
property, and which show that during the course of the treatment to which it
had been exposed the venom had lost all power as a general nervous irritant.
Experiment LXVII. —A fowl received a subcutaneous injection of 1 c.c. of
a solution of the albumin, that is, an amount equivalent to 0.01898 gramme of
the original dried venom. Strong local muscular action occurred, but no symp-
toms of central nervous irritation supervened. The bird presently sat down and
passed into the condition of watchful immobility characteristic of the action
of the septic toxin, but after some time these symptoms wore off and recovery
occurred.
Experiment LXVIII. —A fowl received injections of 2 c.c. of the same
solution of the albumin which was employed in the previous experiment with
similar results.
Experiment LXIX. —A fowl received a subcutaneous injection of 1c.c. of
solution of the globulin of the same strength as the solution of the albumin em-
ployed in the previous experiments.
No local or general symptoms indicative of the action of either toxic prin-
ciple of the venom occurred.
It is more difficult to find an explanation for the variability in the phenomena
presented by the blood in respect to coagulability in cases of death caused by the
action of the poison. In almost all cases a condition of absolute incoagulability
is present, but now and then an exception occurs in which the blood although
presenting the peculiar and characteristic brick-red colour, associated with the
action of the poison, coagulates slowly and partially. Wall affirms that this re-
tention of coagulability only presents itself "where an animal dies almost instan-
taneously from the convulsions, and also when it dies after a very long interval
from exhaustion."* Had it been an invariable rule that coagulability should be
present in such cases the phenomenon might have been simply accounted
for on the assumption that the loss of coagulability was entirely owing to the
action of the septic factor in the venom. On this theory the occurrence of coa-
gulation in cases of almost instantaneous death might be credited to the absence
of sufficient time for the induction of any important changes in the blood, and
the parallel phenomenon in cases where death is very greatly delayed to the oc-
currence of partial recovery of normal properties in it. It would, however, at
first sight appear to be a fatal objection to any such explanation that even in
* Op. cit.