NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
List of numbers of Scientific Memoirs by Officers of the Medical and
Sanitary Departments of the Government. of India (New Series)
published previous to the present issue.
.No. Standardisation of Calmette's Anti-Venomous Serum with Pure Cobra Venom: the
Deterioration of this Serum through keeping in India, by Captain G. Lamb,
I.M.S., and Wm. Hanna, Esq., M.B. Price As. 3 or 4d.
No. 2. Malaria in India, by Captain S. P. James, I.M.S. Price Re. 1-8 or 2s. 3d.
No. 3. Some Observations on the Poison of Russell's Viper (Daboia Russellii), by Captain
G. Lamb, I.M.S., and Wm. Hanna, Esq., M.B. Price As. 5 or 6d .
No. 4. On the Action of the Venoms of the Cobra and of the Daboia on the Red Blood
corpuscles and on the blood plasma, by Captain G. Lamb, I.M.S. . Price As. 8 or 9 d .
No. 5. Specificity of Anti-Venomous Sera, by Captain G. Lamb, I.M.S. Price As. 3 or 4d.
No. 6. First Report on the Anti-Malarial Operations in Mian Mir, 1901–03, by Captain
S. P. James, I.M.S. Price As. 12 or 1 s . 2d .
No. 7. Some Observations on the Poison of the Banded Krait (Bungarus Fasciatus), by
Captain G. Lamb, I.M.S. Price As. 8 or 9 d.
No. 8. A Preliminary Report on a Parasite found in Patients suffering from Enlargement
of the Spleen in India, by Lieutenant 8. R. Christophers, I.M.S . Price Re. 1-8
or 2s. 3d.
No. 9. Second Report of the Anti-Malarial Operations at Mian Mir, 1901—03, by Lieutenant
S. R. Christopher, I.M.S. Price As. 10 or 1s.
No. 10. Specificity of Anti-Venomous Sera (Second Communication), by Captain G. Lamb,
I.M .S. Price As. 8 or 9d .
No. 11. On a Parasite found in persons suffering from Enlargement of the Spleen in India
—Second Report, by Lieutenant S. R.. Christophers, I.M.S. Price Rs. 2 or 3s.
No. 12. On the Morphology, Teratology, and Diclinism of the Flowers of Cannabis, by
Major D. Prain, I.M.S. Price As. 14 or 1 s . 4d.
No. 13. Oriental or Delhi Sore, by Captain S. P. James, I.M.S. Price As. 10 or 1s.
No. 14. On a Parasite found in the White Corpuscles of the Blood of Dogs, by Captain S. P.
James,
I.M.S. Price As. 10 or 1s.
No. 15. On a Parasite found in persons suffering from Enlargement of the Spleen in India
—Third Report, by Lieutenant S. R. Christophers, I.M.S. Price As. 10 or 1s.
No. 16. The Specificity of Anti-Venomous Sera with special reference to a Serum prepared
with the Venom of the Daboia Russellii, by Captain G. Lamb, I.M.S. Price
As. 6 or 7 d.
No. 17. Snake-Venoms in relation to Hæmolysis, by Captain G. Lamb, I.M.S. Price As. 6
or 7 d .
No. 18. Hæmogregarina Gerbilli, by Lieutenant S. R. Christophers, M.B., I.M.S. Price
As. 10 or 1s .
No. 19. On Kala Azar, Malaria and Malarial Cachexia, by Captain S. P. James, M.B., I.M.S.
Price Re. 1-4 or 1 s . 11d .
No. 20. Serum-Therapy of Plague in India; Reports by Mr. W. M. Haffkine, C.I.E., and
various officers of the Plague Research Laboratory, Bombay, by Lieutenant-
Colonel W. B. Bannerman, M.D., B.Sc., F.R.C.S. , I.M.S.
Price As. 14 or 1s .
4 d.
No. 21. On the Standardisation of Anti-Typhoid Vaccine, by Captain George Lamb, M.D
I.M.S. (Director, Pasteur Institute of India ), and Captain W. B. C. Forster ,
M.B., .D.P.H. , I.M.S. Price As. 6 or 7d.
CONTENTS.
CHAPTER I.
INTRODUCTION
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CHAPTER II.
THE NATURE OF TETANUS INFECTION AND HOW IT IS BROUGHT ABOUT .
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CHAPTER III
THE EFFECTS OF QUININE ON ANIMALS SUCH AS RABBITS AND GUINEA PIGS WHEN GIVEN—
(a) Hypodermically
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(b) By the mouth .
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(c) Intravenously .
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CHAPTER IV.
REMARKS PRELIMINARY TO A DETAILED EXAMINATION OF THE EXPERIMENTS RECORDED IN THE NEXT
CHAPTER.
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CHAPTER V.
A SERIES OF EXPERIMENTS RECORDED IN TABLES I TO XIX
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The following are among the subjects discussed in this chapter:
The influence of quinine in bringing about infection when animals are inoculated with " washed
tetanus spores":
( a) Spor es gi ven bef or e qui ni ne.
( b) Spor es gi ven af t er qui ni ne.
(c) Spores given same time as quinine.
The influence of cold in bringing about infection when animals are inoculated with " washed
tetanus spores."
The influence of quinine when given hypodermically and away from the site of infection in
tetanus in establishing a focus where tetanus bacilli germinate and are found after death.
The absence of tetanus infection from the blood and internal organs of animals suffering from
acute tetanus.
The presence of tetanus spores in the intestinal contents of man and animals.
Latent tetanus infections (" washed tetanus spores " remain localised at the site of injection in
animals for months).
CHAPTER VI.
TETANUS ANTITOXIN AS A PROPHYLACTIC WHEN IT IS NECESSARY TO GIVE QUININE HYPODERMICALLY
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59
CHAPTER VII.
CONCLUSIONS.
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60
The Relation of Tetanus to the Hypodermic
or Intramuscular Injection of
Quinine.
CHAPTER I.
Introduction.
EVERY now and again we are confronted with the observation that cases of
tetanus occur after the hypodermic or intramuscular administration of quinine,
even in circumstances where every possible care has been taken to ensure sterility
of the syringe and fluid injected. When an accident of this nature occurs it is only
natural that the patient's friends and the public should feel inclined to throw the
blame on the operator, and reproach him with having used a contaminated syringe,
or contaminated solution, or with not having sufficiently cleansed the skin before
introducing the needle.
In some cases it is possible that one or the other of these precautions may have
been overlooked but there are facts which clearly account for cases of tetanus
supervening after quinine injections, where none of the precautions mentioned
has been omitted.
At first sight it would seem impossible when given a sterile syringe, sterile
quinine solution, and sterile skin at the site of inoculation, to produce tetanus,
and so it would be except for the fact that there are people who harbour in their
bodies tetanus spores, which may lie dormant either in a recently- healed up wound
or abrasion, or possibly in an old healed up injury long since forgotten. There
are also many healthy individuals who harbour tetanus germs in their intestinal
tracts. Tetanus spores being extremely resistant and capable of surviving under
very adverse conditions for many years, it follows that they are not likely to
give up their disease-producing qualities by remaining in a resting stage when
stowed away in the tissues, and as a matter of fact we know from experiments on
animals (see table XIII) that they can remain alive and retain their virulence in
the tissues for seven months at least, and very possibly for years. Tetanus
spores have also been proved to remain alive and virulent on a rusty nib for as
long as 18 years. Compared with this test of their vitality, the shelter which
they find in the tissue of an animal would not be likely to reduce their pathogenic
capabilities should conditions for germination become favourable.
In a latent tetanus-spore infection there are many conditions, in addition to
the hypodermic injection of quinine, which would favour the growth of the spores,
B 2
2
but as these conditions have no direct connection with quinine as a favouring
agent it will be necessary to mention only a few of them.
.
It has long been known that in campaigns where soldiers are subjected to
great faligue coupled with extremes of heat and cold many cases of tetanus occur.
Here the depressing influences of fatigue, in conjunction with great heat or great
cold, would diminish the resistance in those who harboured infection.
Fournier Pescay1 states, " On several occasions when men had marched all
day under a blazing sun in Spain, a number were attacked on the following day
with generalised tetanus."
Baron Larrey2 states, " In the Austrian Campaign in 1809, the wounded who
happened to be most exposed to the cold and damp air of the freezing nights in.
Spring, after having endured different degrees of very high temperature during the
day were almost all attacked with this disease which was prevalent only at this
season when the thermometer fell at night to half its daily maximum. The day
on which the battle of Bautzen was fought was very hot, and the following night
very cold ; next day there were 110 cases of tetanus. After Austerlitz, and Eylau
and during the retreat from Russia, there was scarcely a case of tetanus, the
temperature was very low but uniform."
Seidillot3 states, " Our wounded at Constantine in 1836, who were placed in
narrow corridors, and who had to endure hot days and frosty nights, were attacked
by tetanus in very large numbers."
It will be seen from the few quotations given that extremes of heat, cold, and.
fatigue, were clearly recognised as factors conducive to tetanus, and at a time
when nothing whatever was known about the causal micro-organism. Possibly
some of the wounded mentioned by the observers here quoted may have con-
tracted tetanus from the ground on which they lay, but the fact of such
an acute observer as Baron Laney associating the disease with extremes of heat
and cold is significant, and in the example given by Fournier Pescay the men were
not wounded at all.
Quinine, when given hypodermically to a spore-infected person would produce
favouring conditions for the production of tetanus in two ways
(1) By a paralysing effect on the phagocytes when given in large doses and
for some time.
(2) By destroying tissues at the seat of injection, and by this means pro-
ducing a suitable local anaerobic focus where a stray phagocyte carry-
ing tetanus spores might get stranded.
It will be seen from the experiments in this paper, that a hypodermic injection
of quinine in animals invariably destroys tissue at the site of injection, and dead
subcutaneous tissue would act in every way as a suitable medium for the germina-
tion of tetanus spores irrespective of how they found their way there.
3
In 1904, Vincent4 brought forward observations which proved that the physio-
logical action of quinine can prevent phagocytes from successfully coping with
tetanus spores ; and that quinine, heat and other depressing influences, diminish
the resistance to tetanus in animals inoculated with spores.
Small doses of quinine would increase the leucocytes, and probably also in
crease phagocytosis, but when large doses are given the paralysing effect of the
drug on leucocytes has to be taken into account. Further, there is another
condition to be taken into account when quinine is given hypodermically, viz .,
the malarial infection for which it is given; this would lower resistance to most
infections, tetanus included.
Many hearsay records might be mentioned in which tetanus is said to have.
followed the hypodermic administration of quinine, and no doubt many of these
are authentic, but in the absence of sufficient authority to vouch for their accuracy
one would not be justified in treating information of this kind with the respect due
to established facts.
It is a pity that medical men who have had to deal with such cases have not
been more eager to publish all details connected with them. Possibly the fact of
tetanus following any operation being looked upon as a misfortune which ought
not to have happened, may account for little being said on the subject, and for'
obvious reasons one can understand this being the case.
There are, however, a number of cases recorded.
Maclean5 mentions six cases as having occurred in India, the details of which.
were brought to his notice. These cases evidently made a deep impression on his,
mind, for he adds, " There is something revolting in a death brought about directly
or indirectly by a remedy intended to cure."
Manson6 issues a note of warning when he states, " Not only abscesses, slough-
ing and chronic painful indurations have sometimes followed the hypodermic.
injections, but also tetanus." Manson evidently believed that the quinine
had nothing to do with tetanus for he adds, " In these latter unfortunate
cases it was not the quinine that caused the tetanus ; it was the tetanus.
bacillus, and this tetanus was introduced either in a dirty needle, or in a fouled
solution."
Vincent7 mentions that the French in Madagascar had eleven cases of tetanus
following upon. injections of quinine and he also draws attention to a number of
cases reported, by other observers.
In India 10 cases occurring after injections of quinine have been brought to.
my notice. In one of these cases the tetanus bacillus was isolated by me from a
sample of the distilled water in which the quinine was dissolved, so that in this
particular case the quinine was evidently not altogether to blame, but it may have.
been conducive to infection by establishing favourable local conditions when the
4
same amount of tetanus-infected water might not have produced the disease given
with a morphia or cocaine injection.
We know that hypodermic injections of morphia, cocaine, strychnine, or
digataline are rarely (if ever) followed by tetanus. I cannot remember ever hear-
ing of a case of morphia injection giving rise to tetanus, and I am sure it is a method
of treatment more generally adopted than quinine injections. The syringes used
for morphia, cocaine, etc., are just as likely to be septic as those used for quinine,
so it cannot be altogether the cleanliness of the syringes used which accounts for
the difference.
Quinine being a protoplasmic poison is not likely to harbour living tetanus
spores before being dissolved, and the acidity of the tabloids used now-a-days
would not admit of any tetanus spores remaining alive in them. On numerous
occasions I have made anaerobic cultivations from quinine tabloids, but have never
succeeded in isolating tetanus bacilli.
Before entering into the details of the subject matter of this investigation, it
is necessary first of all briefly to describe the nature of a tetanus infection, and to
mention a few leading points connected with tetanus bacilli, their spores, and toxine ;
then to place on a sure footing the effects of quinine on the animals (guinea pigs)
chiefly used in the experiments which follow.
After this has been done the influence of quinine in bringing about infection
in the varying conditions in which tetanus spores and tetanus cultures were used
in guinea pigs and monkeys will be discussed in the order in which these experi-
ments are given in the various tables, and also the remaining experiments, includ-
ing those in which quinine was not given.
Finally the uses of tetanus antitoxin as a remedy in averting tetanus when it
is necessary to give quinine hypodermically will be considered, and a summary of
conclusions arrived at will be given.
5
CHAPTER II.
The Nature of Tetanus Infection.
When a wound becomes infected with tetanus it means that tetanus spores
have been introduced ; and in the majority of cases it also means that other micro-
organisms have been introduced at the same time.
The kinds of wounds most likely to be followed by tetanus are those in which
the tissues have been crushed and soiled with earth, or dust and dirt from roads;
also deep punctured wounds produced by contaminated spikes of wood, metal, or
other instruments.
The tetanus bacillus, which is the causal organism of tetanus, requires anaero-
bic conditions before it can germinate and produce the disease. These anaerobic
conditions are more likely to be found below the surface of contaminated crushed
wounds, than in any other class of surface wound ; but there are no wounds,
no matter how superficial and trivial, in which conditions favourable for the
development of tetanus may not become established.
When other bacteria besides tetanus spores have gained entrance to a wound
anaerobic conditions are more likely to be produced, because many of the
germs that commonly contaminate wounds use up the oxygen in their vicinity,
and this would favour the growth of any tetanus spores introduced at the
same time. In such a wound, crushed and dead tissue would act a s a suitable
medium for the multiplication of bacteria (including tetanus germs), whereas in
punctured wounds anaerobic conditions would certainly be found immediately
below the surface from the outset.
A complete description of the tetanus bacillus will be found in all standard
text books on bacteriology, and on this account it will be necessary to enter into
only a few of the details connected with its life-history, especially those details
which have a direct bearing on the experiments given further on, carried out with
tetanus spores and quinine.
The tetanus bacillus is a spore-forming germ which produces extracellular
toxines ; and it is to these toxines that all the symptoms of tetanus are due. It
was first described by Nicolaier in 1884, and is often referred to as Nicolaier's bacil-
lus. This observer produced tetanus in mice and guinea pigs by injecting them
with garden earth, and when symptoms set in he was able to communicate the
disease to other animals by using pus from the site cf injection.
About the same time Carle and Rattone proved that the pus and secretions
from tetanus wounds in man would cause tetanus when inoculated into animals.
These experiments were the first proofs of the infectious nature of tetanus.
6
Kitasato, in 1889, was able to obtain the bacillus in pure culture. He took
advantage of the fact that the spores of tetanus are very resistant to the action of
heat, and can withstand boiling for from 3-5 minutes. When a mixture containing
tetanus spores and other germs (whether spore-forming or not) is boiled in a water
bath for 2 or 3 minutes, or in many cases only just heated up to boiling point, and
then removed, in the majority of cases the tetanus spores are not injured, and all
other contaminating bacteria are killed off. When these tetanus spores are trans-
ferred to a suitable medium, and placed under anaerobic conditions at a tempera-
ture of 37°C., they germinate and a pure culture is the result.
In shape the bacillus resembles a small pin or drumstick, which means that
when fully grown it is a small thin rod in which the spore forms at one end, and
gives it a characteristic shape. During the first day or two of its life in a suitable
medium it is a thin motile rod, then after from 24 to 48 hours spores begin to form.
In an old culture the rod part of the germ disappears and only the small round
spores remain. In this spore condition tetanus germs are widely distributed in
nature. They are found in almost every sample of rich garden earth, and in the
manure of many animals, especially the herbivora. It is quite the exception to
find them absent from the intestinal tracts of horses. On this account one would
expect to find them on roads and streets soiled with the excreta of horses and cattle,
and especially on the floors of stables, and in manured garden soil, and in the soils
of almost every inhabited locality. Tetanus spores have also been found in
commercial gelatine, and in ligatures made from the gut of sheep, both of
which are prepared from animals which harbour tetanus spores in their intestinal
tracts. The fact of their occasional presence in gelatine has led to fatal results
in the use of this material as a subcutaneous injection to control obstinate
hæmorrhage.
O n n u m e r o u s o c c a s i o n s I h a v e i s o l a t e d t e t a n u s b a c i l l i f r o m g a r d e n e a r t h ,
stable floors, and stable manure, and in four cases out of ten examined, from
human fæces. Some years ago when visiting a well-known horse repository in
London I picked up a. little earth and dust from the yard where the horses were
shown for sale, and from this material I had no difficulty in obtaining a rich growth
of tetanus bacilli.
The spores of tetanus when swallowed by horses, cattle, and other animals,
(and probably also by man on uncooked vegetables and salads, which have been
grown on manured soils) find in the intestinal tract anaerobic conditions where
they can germinate, and are then passed out with the excreta, and distributed
in the spore stage here, there, and everywhere.
It is not known whether tetanus spores can find in the soil conditions suitable
for germination, or whether it is absolutely necessary in order to prevent extinc-
tion that they should pass through a stage of development in the intesti-
nal tract of animals. Possibly there are localities in which they can develop, as
7
for instance, in the swamps of some of the Pacific islands, where the natives are-
said to poison their arrows with tetanus by dipping them in the mud of these swamps.
We know that there are other spore-forming anaerobic germs which germinate in
earth, and possibly tetanus bacilli may do so in some particular soils.
Irrespective of whether tetanus bacilli can germinate in the soil, or in other
situations not connected with man or animals, the fact remains that the spores
can survive for many years under most adverse conditions. Probably there are
no other known pathogenic spores which have the same resisting powers, and as
the disinfection of tetanus means the destruction of spores, it is necessary to
know something about their resisting powers. Some strains are more resistant
than others. The less resistant strains are destroyed in a Koch's steam steriliser
at 100°C in 5 minutes ; but on the other hand there are strains which require
2½ hours in steam at 100°C, before they are destroyed.
According to Theobald Smiths8 , t h e s p o r e s o f s o m e s t r a i n s r e s i s t b o i l i n g f o r 4 0
to 70 minutes, and steaming in a Koch's steriliser for 2½ hours, but not for 3 hours.
Roseneau,9 from experiments which he has carried out, states that it is neces-
sary when sterilising tetanus-infected solutions to boil for not less than 2 hours,
or to steam in a Koch's steriliser for a similar time. He also advises steam under
pressure as the most reliable disinfectant for tetanus spores.
In an autoclave the spores are destroyed in 15 minutes at a temperature of
120°C., and in 20 minutes at a temperature of 115°C., 5 per cent. carbolic acid re-
quires 15 hours, and 2 per cent. tricresol, or lysol, 2 hours. A solution of corrosive
sublimate of the strength 1 in 1000 requires several hours, but when hydrochloric
acid is added to the solution to the extent of ½ per cent. it kills tetanus spores in
30 minutes.
As an example of what one has got to expect when dealing with tetanus-
infected material, the following history of the life of tetanus spores on two rusty
nibs is interesting and instructive.
In 1891 two steel nibs were dipped in a tetanus culture in Paris, and then placed
in a sterile test tube, which was plugged with cotton wool and fitted with a rubber
cap. The test tube containing the two nibs came into my possession at the Pas-
teur Institute of India, Kasauli, in the Spring of 1900, and had not in the meantime
been tampered with, but presumably kept in a dark cupboard, screened from light.
In 1902 I happened to require a tetanus culture for experimental purposes, so I
removed one of the nibs from the test tube, placed it in atube of sterile broth under
anaerobic conditions, and grew a pure culture of tetanus. This culture was virulent
for guinea pigs in small doses.
The other nib remained in the original test tube, plugged with cotton wool
only, and in a cupboard which was often open, until December 1909, when I took
it out, placed it in a tube of broth, and under anaerobic conditions grew a pure-