Dec,
riflinal ^rlitlps. A NOTE
ON
TETANUS,"
"QUININE WITHOUT AND SOME REMARKS
ON TETANUS AND By
SIR DAVID
QUININE.
SEMPLE, m.d.,
lt-col.,
Director, Central Research Institute, Kasauli.
In the Indian Medical Gazette for September 1911, an article by Major F. "A. Smith, j.m.s., Quinine without appeared under the heading author the which in rightly emphasises Tetanus," the question of administration of quinine as being of fundamental importance to medical practitioners in malarious countries. is to the effect that Major Smith's experience much ignorance and many fallacies exist as to the method of administering quinine; and he is also of opinion that a recent publication by " On the Relation of Tetanus to the me Hypodermic or Intramuscular Injection of Quinine" (Scientific Memoirs by Officers of the Departments of the Sanitary and Medical Government of India, No. 43), only serves to complicate matters by drawing attention to the possibility of quinine when given hypodermically, beino- the means in some cases of activating latent he is tetaiuis infections, a possibility which
proper?
evidently
not
449
TETANUS AND QUININE.
1911.]
to
accept. Major Smith points
prepared
out for the In his article benefit of medical practitioners in malarious about quinine countries : (a) his own ideas mouth his method of the ; (b) when given by and ; (c) he then giving quinine hypodermically offers a few criticisms on tetanus and quinine. As the statements made by Major Smith under the first two headings are somewhat at variance with the opinions held by the vast majority of medical men practising in malarious climates, and also opposed to experimental facts in regard to the absorption and action of quinine, it. is a few of his statements in necessary to deal with detail, after which it will be necessary to say words about his remarks on tetanus a few
|/fime
that quinine can be taken with advantage the reaction of the stomach is acid, namely, after a meal, and best after tho largest meal of the day. Only when so taken is quinine in the form of pills of any use at all. If the usual doses of quinine given often in disregard of this fact cure oases of malaria, or are efficient as a prophylactic, probably one-tenth of such doses given at the economical moment would suffice. By no means does all the quinine taken get into the system?the proportion absorbed requires investigation ; but in my opinion one per cent, would be above the mark, especially in cases of active malaria, whero I find I get more certain results by the hypodermic injection of half a grain of quinine on two consecutive days than by the administration by the mouth of, say 30?40 grains a day." Briefly, the quotation I have given amounts to this ; quinine when given by the mouth is only absorbed from the stomach ; the best time to give quinine is after a meal, and preferably after The largest meal of the day, when it is necessary, only to give one-tenth the amount, one would give at other times ; the amount of quinine absorbed when given by the stomach is less than one per cent, of what is given ; and lastly, hypodermic injections of half a grain of quinine on two consecutive days give better results than 30?40 grains a day given by the mouth. On reading this, some might be led to think i that the of the absorption of quinine I when stomach had been settled the given by for all time, but unfortunately the conclusions arrived at by Major Smith are not the conclusions arrived at by those who have studied the subject, I and carried out experiments in order to arrive at the truth. Conclusions based on scientific facts are more likely to point in the direction of the truth than those based on opinions, probabi-
is, when
question
lities,
or
When
injected
guess work. quinine is
the into the
given by
hypodermically,
or
stomach, muscles,
or
its indication that the
appearance in the urine is an drug has been absorbed, and an early appearance in the urine means that it has been absorbed quickly. This is a fact which can be used to determine the rapidity of absorption of quinine only and quinine. when given by any of the usual channels. The It will be as well to follow the three subtotal amount eliminated in the urine after a dose headings of the article referred to, viz., quinine administered by the mouth while fasting, amounts tetanus on an average to about 40 per cent, by the"mouth ; quinine hypodermically; according to the results obtained by and quinine. six independent observers quoted by MacGilchrist in his Scientific 1.?Quinink by thr Mouth. Memoir No. 41, page 14 ; so that 40 per cent, Under this heading Major Smith after mention- must have been absorbed from somewhere, ing that the salts of quinine usually given require irrespective of what happened to the remainder. acid to dissolve them, and that they can There is a wide difference between 40 per cent, a free be absorbed when in solution, makes the and less than one per cent, suggested by Major only following statements, "such absorptions can only Smith. The total amount absorbed would be representtake place through the walls of the stomach. As soon as the solution passes into the intestine ed by the amount eliminated in the urine plus the the drug is precipitated, and no further use can amount which had undergone cleavage in the be made of it. It at once follows that the only body ; but there is no means at present of
THE INDIAN
450
MEDICAL GAZETTE.
estimating this latter amount, except, perhaps indirectly by a process of reasoning based on a minimum lethal dose for animals. There is, however, the fact to fall back upon that very little
is in the fceces, so absorption when given by the mouth is under normal conditions fairly
passed
complete.
In an endeavour to throw some light on the debated points regarding the absorption of quinine, Major MacGilchrist, i.m.s , has lately carried out a series of experiments, and published the result of his work in a Scientific Memoir.* In regard to the absorption of quinine from the stomach it would be as well to hear what Major MacGilchrist has to say on the subject, when it will be seen that his conclusions and the conclusions of others quoted by him differ widely from those of Major Smith. " In fact recent investigators are in harmony regarding the retardation of quinine absorption when administered with or soon after a meal. According to Mariani, the maximum elimination of quinine given while food is in the stomach takes plaoe between the 6th and 12th hours after administration ; but, given when no food is in the stomach, between the 3rd and 6th hours. As food does not, under normal circumstances, remain in the stomach more than five hours, it follows that most of the quinine given with food is absorbed from the small intestine. Subjective symptoms moreover, just like the maximal elimination of quinine in the urine, are at their height between the 3rd and 6th hours when quinine is given while fasting, and between the 6th and 12th hours when given with a meal. That some absorption may take place from the stomach cannot be denied for the following reasons, but such absorption is probably very insignificant." The reasons referred to will be found given in detail in Major MacGilchrist's Scientific Memoir, No. 41, pages 16, 17 and 18. After discussing the subject from the point of view of a number of continental authorities, and given the results of a series of feeding experiments with quinine carried out on guinea-pigs : (1). After fasting 24 hours ; and (2) immediately after food, he arrives at the following conclusions :? " There is, therefore, reason to believe that, under ordinary circumstances, most of the quinine administeied by the mouth is absorbed from the small intestine ; a small amount possibly from the stomach, especially if administered while fasting and in the form of a salt easily soluble in water, and also a relatively small amount from the large intestine. As already mentioned, the absorption of quinine is normally very complete, the feces after very little being passed with medium doses." It will be seen from the foregoing that Major Smith's statements on the oral administration of ?
* MacGilchrist. Quinine and its salts. Their solubility and absorbability : Scientific Memoirs by the Officers of the Medical and Sanitary Departments of the Government of India, No. 41.
[Dec.,
1911.
quinine are directly opposed to the conclusions arrived at by MacGilchrist, and the eminent authorities quoted by him in his Scientific Memoir, conclusions be it noted which are the outcome of carefully carried out experiments by experienced workers. In the face of such evidence it is difficult to understand why Major Smith has chosen the time after the largest meal of the day as the "economical moment" to give quinine. It would also be interesting to know what are the facts upon which an opinion is based that one-tenth of the usual doses of quinine when given at the " " would have the same effect economical moment as full doses given at other times. A saving of quinine is the only possible economy that could result from such treatment, and this would certainly be a false economy as far as the patient is concerned. Possibly also the question of economy comes in when a hypodermic injection of half a grain of quinine on two consecutive days is recommended in preference to 30 or 40 grains a day given by the mouth. A proper value is allotted to this method of treatment under the next heading. 2.~
Quinine
Hypodkrmically.
This is a method of treatment which Major Smith has practised for some years, and he relates his experience of having treated since 1899, all, except dispensary outpatients, suffering from acute malarial fever, by the hypodermic injection of quinine. During the greater part of that time he used quinine hydrobromate, but latterly he has used quinine bihydrochloride. In addition to describing his method of sterilising the syringe, skin of the patient, etc., he gives in detail his method of sterilising the quinine used, which is as follows :? " If a solution of quinine is being used, that is boiled ; if the tabloids, a tea-spoon is sterilised. A tabloid is then placed in the sterilised spoon, 10 to 15 minims of water are poured over it, the whole is boiled over a spirit lamp and the tabloid broken up with the point of a needle. The solution is then drawn up into the syringe and this is placed in carbolic solution until it is quite cool and then injected, the needle being at the same time gradually withdrawn, so that the fluid is distributed along its tract and does not tear up room for itself in one spot. The solution on cooling becomes opaque, but this does not interfere with its efficiency." In the majority of cases of malaria he finds that two injections at that interval of 24 hours are sufficient to bring the temperature to normal, or in cases of other diseases to eliminate malaria. At each injection he never gives more than 2 grains of quinine in not more than 20 minims of He states that the use of larger doses is water. to be deprecated, as the smaller amount produces the full pharmacological action of the drug. Before attaching any value to the statement
SIR DAVID SEMPLE'S REPLY.
Dec., 1911.J
quoted let quinine.
us
see
what
effect
boiling
has
in a tea-spoon held over a spirit lamp Smith's method of sterilising quinine) for a longer period th:in one minute produces changes in the salt which diminish its lethal effect for small animals such as rabbits and
quinine
on
It is a well-known fact that boiling produces deleterious changes in some salts of quinine in a few minutes. According to Fluckiger (quoted by MacGiilchrist) quinine preparations when exposed to heat and sun light lose water of crystallization and become decomposed, a yellowish brown product being formed which he names " quineretin." In some cases boiling produces this change in a few minutes. Major Smith does not state for what length of time he boiled his quinine preparations in a tea-spoon held over a spirit lamp, but he does state definitely that the solutions he treated in this way became opaque on cooling, and he also adds that this does not interfere with the efficacy of the quinine. With a view to testing this point I carried out the experiments detailed in Tables I and II. It will be seen from these experiments that a certain lethal dose of quinine bihydrochloride for a guinea-pig when given hypodermically is no longer a lethal dose when treated according to Major Smith's method : and that a certain lethal dose for a rabbit when given intravenously becomes non-lethal when treated by the same In these experiments there was no method. haziness after boiling for one minute; slight haziness after two minutes ; and marked haziness after three minutes' boiling. When boiled for minutes the than three solutions became longer somewhat opaque on cooling, so Major Smith in order to obtain opacity must have boiled the solutions for longer than three minutes. these experiments It is very evident from that boiling a solution of bihydrochloride of
(Major
guinea-pigs. Now the object of boiliug a quinine solution before injection is to sterilise it, or in other words to destroy any bacteria or spores, especially tetanus spores, which some imagine might be present in compressed quinine tabloids. The destruction of tetanus spores would, I take it, be the main object of those who resort to boiling as a
on
guinea-pigs
micalhj, o
a
?
.?
o' ^
O
Smith finds that, in the majority of of malaria, two injections of not more than 2 (Trains of boiled quinine given at an interval of?24 hours are sufficient to bring the temperature to normal, or, in the case of other disease, to eliminate malaria. This is certainly a comfortintf discovery for those who live in malarious countries, for it means that now we have malaria, and tetanus after quinine robbed of their terrors Major Smith's tea-spoon-sterilisation method
Major
cases
by
3 4
Weight of guinea-pig.
Salt of quinine used.
390 grms.
Bihydrochloride
4
370 grms.
Ditto
3
420 grms.
Ditto
with unboiled
Fluid in which dissolved and bulk given.
Amount
given.
430 grms.
grains
also given
Length of time boiled.
3
grains
3 grains
Ditto
1?
minutes
!
Normal saline solution, 4 c.c.
I
Normal saline 2 minutes solution, 3 c.c.
grains
given hgpodev-
hypodermieally.
Whether opaque
Results.
cooling.
on
Water, 3
c.c.
Water, li
,
3
Traces
of hazi-
Died after 8 hours.
ness.
minutes
Haziness.
Had twitching of muscles after one hour, but j this soon disappeared. Survived.
|
Marked haziness, Survived,
c.c.
3
minutes
Ditto
c.c.
3 minutes
Ditto
no
symptoms.
no
symptoms.
j Survived,
I Survived, no symptoms.
Ditto
3
grains
Water, 1?
425 grms.
4
grains
Normal saline solution, 4 c.c.
Not boiled
Clear.
f?
Ditto
420 grms.
Ditto
3
grains
Water, 30 min.
Not boiled
Clear.
'l7 I
Died after 1^ hour.
380 grms.
Ditto
2^ grains
Normal saline solution, 2$ c.c.
Not boiled
Clear.
Died after 2? hours.
"o | O
quinine
when boiled and
380 grms.
5
= o
efects of quinine
to demonstrate the
compared
I.
&,
1
*
as
safeguard.
According to Theobald Smith,* the spores of some strains of tetanus resist boiling for as long from 40 to 70 minutes. Are we then to as boil for over one hour in order to be 011 the safe side ; or are we to adopt Major Smith's method and boil until we get a solution which on cooling becomes opaque, and which is then no longer quinine, and might still contain living tetanus' spores, if they were ever in the tabloids to begin with, a point which has never yet been demonstrated ?
Table
Experiments
451
,
o
^pcrimonts
seen"frotu"tho
results of the control It will be i.rkodlv diminishes its lethal effects for guinea-pigs when given ?
Journal
of
that boiling
a
solution of
I Died after
quinine
hypodermically.
1908. the American Medical Association, March 20th,
until it become,
one
hour.
hazy
on
cooling
452
THE INDIAN MEDICAL GAZETTE.
[Dec,
1911.
Table II.
Experiments
on
rabbits to demonstrate the
effects of quinine given intravenously.
B
O
Weight
o
?"
rabbit.
Salt of quinine used.
1460 grms.
Bihydrocliloride
1230 eras,
Ditto
1400 grms.
of
f6
O
I
o
I
O L7
Fluid in which boiled and bulk
boiled,
then allowed to cool and
Length of time boiled.
Whether opaque
N or m a 1 saline 0-75 c.c.
1 minute...
Clear
Ditto
Ditto
2 minutes.
Slight
Ditto
Ditto
Ditto
1470 grms.
Ditto
Ditto
Distilled water 075 c.c.
1330 gvms.
Ditto
Ditto
Ditto
146") grms.
Ditto
Ditto
Ditto
Not boiled
1520 grms.
Ditto
Ditto
Ditto
Not boiled
o
m
Amount
when
given.
i grain
given.
cooling.
on
Died within 1 minute.
haziness
Marked haziness
Ditto 3 minutes.
of respiration for 2 minutes after the ex periment, but no other symptoms. Remained well.
Difficulty
Survived,
no
symptoms.
Ditto.
Ditto
Giddiness for half a minute after the experiment. No other symptoms. Remained well.
Ditto
Ditto
Results.
Died within 1 minute.
Ditto.
The amount of quinine used for these experiments is the least amount which (when not boiled) invariably kills a 1,500 gramme rabbit when given intravenously. It will be seen from the results of the experiments recorded in this table that boiling a solution of quinine until it became hazy on cooling markedly diminishes its lethal effects for rabbits when given intravenously.
of
giving two small hypodermically. Personally I do not injection of 2 grains
doses
of boiled
quinine
think that a hypodermic of quinine in a solution which had been boiled until it became opaque would be likely to give rise to tetanus ; and I gravely doubt whether such a dose given to an adult would ever cure a case of malaria, and it certainly could not produce the full pharmacological effects of the drug. Owing to the facts that quinine has a destructive action on the tissues at the seat of injection, and that none of the salts of quinine stand sterilisation well, one would think that these drawbacks would be enough to condemn this method of administration, but in addition we have also the fact that the salt unless given in a fairly dilute form may be precipitated to the extent of over 60 per cent, at the seat of injection. I have known of several cases at post-mortem examinations where masses of quinine were dug out from the sites where injections had been given to the patient before death. MacGilchrist as the results of his own experiments on guinea-pigs, and the work of others, sums up the position of subcutaneous or intramuscular injections of quinine in the following words : " As regards guinea-pigs, the lethality (and therefore absorbability) of quinine by the several modes of administration is in the following order, beginning with the most lethal mode of administration ; (1) subcutaneous injection in extreme dilution (1 in 150); (2) oral administration during fasting ; (3) oral administration with or immediately after food; and (4) subcutaneous
in the strengths generally used for hypodermic injection (L in 2, and 1 in 8). The oral administration of quinine also affords more prompt therapeutic action of the alkaloid than
injection
does the subcutaneous, the subcutaneous injection of quinine in extreme dilution (1 in 150j being excluded for clinical reasons. Further, suboutaneous injections are followed by various complications and mutilations. Intramuscular injections are attended by the same draw-backs as subcutaneous proper ; and although ulceration rarely occurs, they are more liable than the latter to be followed by thrombosis and paralysis. The harmony between the results of various observations on man and those of my experiments on guinea-pigs justify the inference of general applicability that subcutaneous and intramuscular quinine injections in solutions of the usual strength (1 in 1 to 1 in 10 j are inferior to quinine bj the month in rapidity of action and thoroughness of absorption, and that they are liable to be attended by grave complications, mutilations and dangers. Quinine and its salts are, moreover, fundamentally unsuited for hypodermic use. This mode of quinine administration should therefore be abandoned. The results of my own experiments on rabbits and guinea-pigs with hypodermic and intramuscular injections of quinine harmonise with the conclusions which I have quoted. 3.?Tictanus
and
Quininh.
At the outset of his criticisms under this heading Major Smith tenders the following advice? " In view of the usefulness of quinine adminis-
Dec, 1911.]
TETANUS AND QUININE.
tered hypodermically, it behoves every practitioner in India to carefully weigh all that Sir David Semple says in his Scientific Memoir (on " The Relation of Tetanus to the Hypodermic or Intramuscular injection of Quinine ") published by the Government of India. An improvement in the introductory wording of this advice would " be, In view of the risks incurred when quinine is administered hypodermically it behoves every " practitioner in India carefully to weigh, etc. ; but even apart from my suggested improvement 1 am very pleased to recommend the advice which Major Smith has tendered to every practitioner in India. I would also recommend every practitioner in India carefully to weigh all that Major Smith says in his article "Quinine without Tetanus," published in the Indian Medical Gazette for September 1911, and especially to reflect on what he says under the first two sub-headings of his article. While on the subject of advice I would also recommend those who may take the trouble to read my Scientific Memoir to be more careful than Major Smith has been to grasp the meaning of my experiments with "washed tetanus spores" and quinine, a task which I think most readers will find to be comparatively easy. I should not expect anyone who had carefully studied my Memoir to reproach me with not finding tetanus spores in guinea-pigs (which had received no quinine) in any other part of their " washed tetanus tissues, except at the site where been had ; injected yet spores" Major Smith remarks : " It is not claimed that they can be recovered from any other part of the body, nor that when a man becomes infected with dormant tetanus spores which produce no symptoms, that he harbours the spores in anything like the same numbers as are injected into the guinea-pig." " " Washed tetanus spores injected into guineano hypodermic which receive injections of pigs quinine are never found anywhere else in the tissues except at the site of injection, naturally, therefore, 1 do not claim that they can "be recovered from any other part of the body. Of course the intestinal tract of man and animals may harbour tetanus infection under natural conditions, but this is a different question. I would like to know how Major Smith would attempt to find out when a man becomes infected with dormant tetanus spores which produce no symptoms, and how he would proceed to draw a comparison between the number of spores in such an infected man and the number injected There are some questions into a guinea-pig. which require a lot of ingenuity to solve, and these two conundrums might be included amongst them. If animals can be proved experimentally to harbour tetanus spores in their tissues for months, surely it is reasonable to infer that human beings may also harbour tetanus spores for months, yet Major Smith considers this an astounding statement. It was not, however, considered an astounding statement when first made
453
Vincent of the Pasteur Institute, Paris, in explained the origin of "spontaneous" tetanus as due to latent tetanus spore infections being stirred into activity by a heatstroke, a chill, hypodermic injections of quinine, or other depressing influences. In the 10 cases of tetanus following the hypodermic injections of quinine brought to my notice, Major Smith objects to my not publishing all details of these cases. Surely he must have known that the cases were not under my care, and that it is not usual to publish other people's I am, however, in a position to state that, cases. with the exception of one case, no aseptic precautions were omitted in carrying out the injections ; and even in this case the quinine was to some extent to blame, although the water in which it was dissolved contained tetanus spores. It will be asked what evidence is there for attaching any blame to the quinine in this particular case, seeing that the water was infected with tetanus to begin with. A sample of the distilled water used to dissolve the quinine given hypodermically to this patient was sent to me for examination, when in addition to other tests 1 carried out the following experiments on guineapigs, and the results of these experiments will serve to clear up the question under discussion.
by
11)04, who
1.?Two guinea-pigs hypodermic injection of 2
each of a of the distilled water used to dissolve the quinine for the patient referred to. Both animals remained well.
Experiment
(riven
a
Sample
were
c.c.
Experiment 2.?Two guinea-pigs were each given a hypodermic injection of half a grain of quinine dissolved in 2 c.c. of a sample of the Both these guinea-pigs developed same water. tetanus.
Experiment 3.?Two guinea-pigs were given a hypodermic injection of 1/10 grain morphia. In one case the morphia was given in 2 c.c. and the other in 1 c.c. of the sample of water referred to. Both animals remained well. Experiment 4.?Two guinea-pigs criven
same
were
each
hypodermic injection of 1 grain of the sample of quinine used for experiment No. 2, a
but dissolved in normal saline solution. AVith the exception of sloughing at the seat of injection both animals remained well. This experiment exonerates the quinine used for experiment No. 2 from any suspicion of containing tetanus spores.
Experiment 5.?A growth of tetanus was obtained from the sample of water used for experiments 1, 2 and 3. In my opinion the results of these experiments are very strong evidence that quinine was the no-ent which made a tetanus infection possible
in this case, and that a morphia injection made up with the same water and given to a patient would in all probability not have been" followed by
'
:
It requires something more than the introduction of tetanus spores into the living tissues to produce tetanus, and evidently quinine can readily supply the accessory conditions required for the spores to germinate. In this connection 1 might also refer to the experiments recorded in Tables X and XI of my Scientific Memoir No. 43, pages 42 to 45, from which it will be seen that washed tetanus spores when mixed with quinine or lactic acid, and given
tetanus.
hypodermically
to
guinea-pigs produce
tetanus ;
but when the spores are mixed with a nonirritating solution of morphia, or normal saline solution, the animals remain well. These experiments taken in conjunction with the experiments carried out with the tetanus-infected water recorded above, demonstrate clearly the favouring influence of the hypodermic injection of quinine in the production of tetanus when a tetanus-spore infected fluid is used, as compared with morphia given under similar circumstances ; and they al.-o afford a reasonable explanation as to the rarity of tetanus following hypodermic injections other than quinine. Major Smith states that he gives at least 50 injections of quinine for one of morphia, and on this account he doubts the correctness of the statement that morphia injections are more frequently given than quinine injections. There are exceptions to most rules, so 1 take it thnt Major Smith's practice of giving small doses of boiled quinine hypodermically to all his cases of malaria is an exception to the general rule. We all know that hypodermic injections of morphia are given probably thousands of times for once thai quinine is given, but can any one mention 10 cases of tetanus following morphia injections ? In the literature on the subject I can find onl}' one case mentioned, there may be others ; but, as Major Smith remarks, the injuries for which the morphia is often given would be a reasonable source of infection, and would exonerate the
morphia.
|i>EC'>
THE INDIAN MEDICAL GAZETTE.
454
The remainder of Major Smith's remarks show that he has failed to grasp the meaning of the experiments given in my Memoir, and as an example of"this I may quote his concluding remarks: The only conclusion that can be drawn from the Memoir is that if tetanus spores are injected, there is a slightly less chance of a tragedy if quinine is withheld, but nothing has been shown to justify us in running the risk of withholding the hypodermic injection of quinine in every case where it is indicated, provided it is given antiseptically." When he refers to tetanus spores. I presume " he means " washed tetanus spores and in this case demonstrate clearly that my experiments there is no chance of a tragedy when quinine is withheld, but a very considerable chance of a tragedy when quinine is given, and that tetanus will follow for certain when the spores are mixed with quinine, but not necessarily when they are mixed with a morphia solution or normal saline.
1911-
Evidently Major Smith puts a very liberal interpretation 011 not withholding hypodermic injections of quinine in every case where they are indicated, for he tells us that he has treated ail his cases of malaria (except dispensary outpatients) since 1881) by this method ; and he also remarks, "In addition during the last five years, in order
to prevent a possible recurrence of malignant malaria, or any fresh infection, 1 have given a hypodermic injection to every patient
who has been ansesthetised, just before he comes round, and on two consecutive days to all inpatients suffering from acute diseases, such as pneumonia, typhoid fever, small-pox, etc." I should withhold a
certainly not recommend any one to hypodermic injection of quinine from
where it was indicated ; but 011 the I should be very sorry to recommend this method of giving quinine as a routine in all cases. I should confine myself measure to the exceptional cases in which quinine by this method is indicated, and these I should safeguard b}r a dose of tetanus antitoxin, especially in those localities of tropical countries where tetanus frequently occurs. It is evident from Major Smith's account that very small doses of a solution of quinine boiled until it became opaque 011 cooling did not do bis patients an}' harm, and it did not give them tetanus but would such treatment cure or prevent malaria ? A small dose of quinine after being treated in such a way that it was 110 longer quinine, and then given hypodermically, would not be likely to have any influence in bringing about a tetanus infection, and it would certainly have very little influence in curing or preventing malaria. case
any
other,
4.?This Reviewer
of
Tetanus
and
Quinine
Reviewed. A review of my Scientific Memoir No. 4^, On the Relation of Tetanus to the Hypodermic " or Intramuscular Injection of Quinine appeared in the Indian Medical Gazette for September 191 J. On reading over what the reviewer said I came across some remarks which 1 propose to deal with not only for the information of the readers of the Indian Medical Gazette, but possibly also for the benefit of the reviewer. I shall quote from the points requiring attention and deal with them in the following order :? "
"
Whatever lethal effect quinine may have spores a point which has never yet been settled?it certainly can have little effect until dissolved." These remarks were made when the reviewer came across a passage in my Memoir where I stated that quinine being a protoplasmic poison is not likely to harbour living tetanus spores before being dissolved. When making this statement I was thinking of compressed tabloids of the kind generally used for hypodermic injections, and not loose powdered
(a)
on
tetanus
quinine.
i>KC
,
QUININE
1911.]
AND TETANUS.
In order to test the point whether tetanus could survive in the interior of a compressed tabloid of quinine bihydrochloride, I carried out the following experiments as a preliminary to further test-experiments which I hope to carry out at an early date :? spores
1. A five-grain tabloid of quinine bihydrochloride was taken and a hole drilled into the " washed tetanus centre. A measured amount of dried at a temperafter being thoroughly spores" ature of 37" Centigrade was then placed in the of the tabloid, and powdered quinine centre prepared from a similar tabloid pressed down tightly on to the spores, and the drilled hole carefully filled up in this way. The tabloid was then placed in a sterile tube, and allowed to remain in a dark cupboard at room temperature for a week, after which it was dissolved in a bulk of 5 c.c. of normal saline solution, and four guineapigs were each injected with 1 c.c. None of these animals developed tetanus. 2. Control experiment.?A similar amount of "washed tetanus spores" prepared from the same culture, and at the same time as those used for the interior of the tabloid, were placed in a sterile test tube, and slowly evaporated to dryness The tube was then at a temperature of 37?G. placed in a cupboard at room temperature for a week, when a 5-grain tabloid of quinine bihydrochloride was dissolved in it in a bulk of 5 c.c-. of normal valine solution, and 4 guinea-pigs each injected with 1 c.c. All 4 animals contracted tetanus on the second day, and died on the third
day. with the washed tetanus spores" used for experiments 1 and 2, remained well, which proved that the spores had been completely freed from toxin. 3.
same
A control
amount of
guinea-pig injected
a
sample
of the
"
It is reasonable to infer from these few experiments that tetanus spores probably do not survive for long inside a compressed quinine tabloid ; but before finally settling the point further experiments are indicated. I may also mention that after numerous attempts 1 have never yet succeeded in obtaining a growth of any kind from compressed quinine tabloids when precautions were taken to avoid contaminations from the outside of the tabloids (b). The reviewer " merely tested the complains that I have antitoxin of under the most prophylactic power favourable conditions tor its effective action,'" and that " there is no experimental proof given of the duration of passive immunity ; or that one injection of serum would render several daily injections of quinine safe : and even granting that immunity may la?t so long, there is always the possibility?almost certainty?of malarial relapses and reinfection, with the consequent danger of anaphylactic phenomena, both in their acute fatal and commoner subacute forms." These remarks savour of extreme caution, and a tendency to err on the right side.
Let
us see
455 in wbicli direction the truth is to be it is to be arrived at by means of
found, and liow experiments.
rfhe anaphylactic phenomena referred to may be dismissed in a few words, for it is well known that serum can be injected into animals once a week for months without anaphylactic phenomena ever appearing, and it is generally believed that it is much more difficult to render man supersensitive to the effects of serum than it is in the case of animals, liesides it requires an interval of about 12 days or longer to elapse after an animal such as a guinea-pig receives a sensitisit becomes supersensitive before dose of serum ing to a second dose. AVe can also fall back from the experience gained from the numerous instances in which antidiphtheritic serum is given to children at various intervals without any accidents happening, and certain other seiuins, such as anti-tubercle serum, and anti-rheumatic serum which are constantly being used at intervals of days and weeks without any ill-effects. Practically speaking it is a negligible quantity as far as man is concerned, and need not interfere with serum prophylaxis. Possibly my reviewer was of what is generally referred to as thinking " serum sickness," accompanied by pains in the and and urticarial rashes, appearing about joints the iOth day in 8 or 10 per cent, of cases after dose of serum ; but even this need not a single give any cause for anxiety when it does appear. It is only necessary to mention to patients that " serum sickness," so there is such a thing as that they may not be alarmed should it appear. As regards the duration of passive immunity after a dose of serum, it is common knowledge and accepted as a fact that it may last from a fortnight to six weeks or longer. Taking the shortest period, viz., a fortnight, this would give ample time to give a patient as many hypodermic injections of quinine as it would be good for him to receive. The question of the efficacy of antitetanic serum was settled by Roux and Vaillard years ago. These observers showed that " antitetanic serum does not cure tetanus after it has set in, but that it infallibly prevents it." It is also well known that there is no antitoxin more active than antitetanic serum. The experiments recorded in Table III serve to demonstrate the prophylactic power of tetanus antitoxin under much more unfavourable conditions than are ever likely to be met with in actual practice. They also demonstrate clearly that the period of protection even under the very adverse conditions tested lasted for a fortnight at least. " (c). The reviewer complains that the chapter of on effects animals is the small quinine showing he and that a to think pretends disappointing," dilution of quinine of the strength of 1 grain in " a curious mixture of two 1 c.c. of saline is and measures." He also of weights systems " mentions that there is a difficulty in arriving at dose due to the author not a minimum lethal its technical sense." in the term accepting ?
?
?
i
i
?
THE INDIAJS
456
MEKICAL GAZETTE.
TABLE III..
efficacy Experiments guinea-pigs of antitetanic serum in warding of tetanus infections ichen quinine is given hypodermically. Date of
Date of No. of
experiment.
Date of
hypodermic injection of hypodermic of
injection
antitetanic serum.
Cct. 11th, 3 e.c.
|
q???ne-
Oct. 13th, 1 grain. Oct. loth, 1 grain. Oct. ISth, 1 grain. Oct. 21st, 1
grain.
hypodermic
injection of a
virulent
Result.
tetanus
culture.
Oct. 13th, A c.c.
Oct. '_'5th, 1 grain.
Oct. 25th,
Oct. lltli, 3 c.c
Oct. 24th, 1 grain. Oct. 26tli, 1 grain. Oct. 27th, 1 grain.
Oct. 25th,
3
Ditto
Ditto
Ditto
4 Control of tetanus culture used.
Nil.
Nil.
i \
Remained free from tetanus.
Ditto.
c.c.
Oct. 13th, A c.c.
Ditto.
Developed
tetanus on the 2nd day, and died on the 4th day.
These experiments prove that tetanus antitoxin confers a
(Expt. 1).
When the reviewer made these statements he opening paragraphs of Chapter 111, page 13, in my Memoir, where it is stated, "In these experiments no attempt was made lo follow up the excretion of quinine from the systems, or to enter minutely into its physiological effects. The principal objects were : must have overlooked the
effects
arrive at a dose, which, without provwould produce well marked visible
;
To arrive at some conclusion as to what the local effects of quinine are when given hypo-
(2)
dermically.
(3) To prove whether the local and general effects of quinine when given hypodermically have any influence in favouring tetanus infections. (4) To obtain information as to whether animals can withstand larger doses by the stomach than hypodermically. of
(5) To gain some information on quinine when given intravenously.
the stomach ; (b) for rabbits, when given hypodermically, 6 grains per kilogramme of weight ; and when given by the stomach the amount is at least double the hypodermic lethal dose. A minimum lethal dose for a guinea-pig or rabbit of a certain weight is not necessarily a lethal dose for other guinea-pigs or rabbits of the The smallest dose which will never same weight. fail to kill any guinea-pig or any rabbit of a certain weight may be more than a minimum lethal dose for some of these animals. The smallest dose that may kill, and the smallest dose which will never fail to kill are two different " the curious mixture of two systems " referred to, viz., " 1 of weights and measures " grain to 1 c.c. I can assure the reviewer that it is a most convenient mixture for any one administering quinine either to man or animals by means of a syringe, on account of the fact that English preparations of quinine are sold in grains, and the best syringes and the most convenient measures are graduated on the c.c. scale. Any other combination of weights and measures would have no advantages over grains per c.c. (d). An important point referred to by the reviewer is the following :?" In the intravenous experiments where the majority of animals died within oi\e minute from asphyxia, the quinine was in far too great a concentration (1 grain to 1 c.c.), and would undoubtedly form a dense precipitate I inside the blood vessel at the site of injection ; and the mode and rapidity of death suggests embolism." The lethal effect of quinine when given intravenously to rabbits depends on the amount given at a single dose, and not on the dilution in which it is given. The question of the precipitate referred to above does not come in when intravenous experiments are carried out, although a precipitate can be easily demonstrated when a concentrated solution of quinine is added to A careful study of the serum in a test tube. results of the experiments recorded in Table IV should convince any one that whatever else the cause of death may have been due to in experiments I, 2 and 3, it could not have been due to a precipitate inside the blood vessel at the site of injection, as the dilution of quinine used, namely, 1 in 150 ; 1 in 160 ; 1 in 200 do not give rise to any precipitate when added to serum in vitro. A rabbit of a certain weight which receives intravenously the least amount of quinine which invariably kills, dies just as quickly and with the same symptoms irrespective of whether the quinine is given in a dilution of 1 in 200, or in the proporlion of 1 grain to 1 c.c. It is the amount of quinine given at a single dose which is the lethal factor and not the dilution in which it is given.
As
passive immunity on guinea pigs for 14 days at least against the injection of a dose of tetanus culture lethal for nonprotected animals, and that the immunity is not upset when several injections of quinine are given in the meantime
(1) To ing fatal,
is, (a) for guinea-pigs, when given hypodermically, 1 grain per 150 grammes of weight ; and that an increase of from A to ? of this amount will invariably kill when given bv
things.
c.c.
the effects
It will be seen from this that a determination of the minimum lethal dose for small animals was not by an) means the primary object of my experiments, but nevertheless it is clearly proved and definitely stated that when quinine bihydrochloride is used, the smallest dose that will
1911.
fail to kill
never
prove the
to
on
[Dec.,
regards
Dec.,
RADIO-ACTIVITY OF THERMAL SPRINGS IN BOMBAY.
1911.J
Table
Experiments
on
rabbits
solutions, No. of
ex-
periment.
4
Control
as
compared
Salt of quinine used.
Weight of rabbit.
1520 grms.
demonstrate the
to
i
Bihydrochloride
grain
effects of quinine
when
...
Normal saline solution.
given intravenously given intravenously.
Dilution used and bulk given intra-
Fluid in which dissolved.
given.
i
IV.
zvith strong solutions also
Amount
457
in very weal-
1'ESCLTs.
venously.
Died within one minute.
1 in 150 (6 6 c.c.)
1500 grms.
Ditto
Ditto
Ditto
1 in 160 (
7 c.c.)
Ditto
1500 grms.
Ditto
Ditto
Ditto
1 in 200 (
9 c.c.)
Ditto
1470 grms.
Ditto
Ditto
Ditto
1 in 17 (0-75 c.c.)
1560 grms.
Ditto
Ditto
Ditto
Ditto
Ditto
Ditto
Control G Control
1450 grms.
9
c.c. Normal solution.
saline
7 Control
1490 grms.
10 c.c. Normal solution.
saline
No symptoms, remained
well.
No symptoms, remained well.
The amount of quinine used for experiments 1. 2, 3, 4 and 5 (f grain) is the least amount which invariably kills a 1500 gramme rabbit when given intravenously. It will be seen from these experiments that it is just as rapidly fatal when given in dilutions of 1 in 150; 1 in 160 ; and 1 in 200 as in a dilution of 1 in 17 (1 grain to 1 c.c.). It will also be seen from experiments 6 and 7 that the bulk of the fluid in which the quinine was given had no influence on the fatal effect.
(
riflinal ^rlitlps. A NOTE
ON
TETANUS,"
"QUININE WITHOUT AND SOME REMARKS
ON TETANUS AND By
SIR DAVID
QUININE.
SEMPLE, m.d.,
lt-col.,
Director, Central Research Institute, Kasauli.
In the Indian Medical Gazette for September 1911, an article by Major F. "A. Smith, j.m.s., Quinine without appeared under the heading author the which in rightly emphasises Tetanus," the question of administration of quinine as being of fundamental importance to medical practitioners in malarious countries. is to the effect that Major Smith's experience much ignorance and many fallacies exist as to the method of administering quinine; and he is also of opinion that a recent publication by " On the Relation of Tetanus to the me Hypodermic or Intramuscular Injection of Quinine" (Scientific Memoirs by Officers of the Departments of the Sanitary and Medical Government of India, No. 43), only serves to complicate matters by drawing attention to the possibility of quinine when given hypodermically, beino- the means in some cases of activating latent he is tetaiuis infections, a possibility which
proper?
evidently
not
449
TETANUS AND QUININE.
1911.]
to
accept. Major Smith points
prepared
out for the In his article benefit of medical practitioners in malarious about quinine countries : (a) his own ideas mouth his method of the ; (b) when given by and ; (c) he then giving quinine hypodermically offers a few criticisms on tetanus and quinine. As the statements made by Major Smith under the first two headings are somewhat at variance with the opinions held by the vast majority of medical men practising in malarious climates, and also opposed to experimental facts in regard to the absorption and action of quinine, it. is a few of his statements in necessary to deal with detail, after which it will be necessary to say words about his remarks on tetanus a few
|/fime
that quinine can be taken with advantage the reaction of the stomach is acid, namely, after a meal, and best after tho largest meal of the day. Only when so taken is quinine in the form of pills of any use at all. If the usual doses of quinine given often in disregard of this fact cure oases of malaria, or are efficient as a prophylactic, probably one-tenth of such doses given at the economical moment would suffice. By no means does all the quinine taken get into the system?the proportion absorbed requires investigation ; but in my opinion one per cent, would be above the mark, especially in cases of active malaria, whero I find I get more certain results by the hypodermic injection of half a grain of quinine on two consecutive days than by the administration by the mouth of, say 30?40 grains a day." Briefly, the quotation I have given amounts to this ; quinine when given by the mouth is only absorbed from the stomach ; the best time to give quinine is after a meal, and preferably after The largest meal of the day, when it is necessary, only to give one-tenth the amount, one would give at other times ; the amount of quinine absorbed when given by the stomach is less than one per cent, of what is given ; and lastly, hypodermic injections of half a grain of quinine on two consecutive days give better results than 30?40 grains a day given by the mouth. On reading this, some might be led to think i that the of the absorption of quinine I when stomach had been settled the given by for all time, but unfortunately the conclusions arrived at by Major Smith are not the conclusions arrived at by those who have studied the subject, I and carried out experiments in order to arrive at the truth. Conclusions based on scientific facts are more likely to point in the direction of the truth than those based on opinions, probabi-
is, when
question
lities,
or
When
injected
guess work. quinine is
the into the
given by
hypodermically,
or
stomach, muscles,
or
its indication that the
appearance in the urine is an drug has been absorbed, and an early appearance in the urine means that it has been absorbed quickly. This is a fact which can be used to determine the rapidity of absorption of quinine only and quinine. when given by any of the usual channels. The It will be as well to follow the three subtotal amount eliminated in the urine after a dose headings of the article referred to, viz., quinine administered by the mouth while fasting, amounts tetanus on an average to about 40 per cent, by the"mouth ; quinine hypodermically; according to the results obtained by and quinine. six independent observers quoted by MacGilchrist in his Scientific 1.?Quinink by thr Mouth. Memoir No. 41, page 14 ; so that 40 per cent, Under this heading Major Smith after mention- must have been absorbed from somewhere, ing that the salts of quinine usually given require irrespective of what happened to the remainder. acid to dissolve them, and that they can There is a wide difference between 40 per cent, a free be absorbed when in solution, makes the and less than one per cent, suggested by Major only following statements, "such absorptions can only Smith. The total amount absorbed would be representtake place through the walls of the stomach. As soon as the solution passes into the intestine ed by the amount eliminated in the urine plus the the drug is precipitated, and no further use can amount which had undergone cleavage in the be made of it. It at once follows that the only body ; but there is no means at present of
THE INDIAN
450
MEDICAL GAZETTE.
estimating this latter amount, except, perhaps indirectly by a process of reasoning based on a minimum lethal dose for animals. There is, however, the fact to fall back upon that very little
is in the fceces, so absorption when given by the mouth is under normal conditions fairly
passed
complete.
In an endeavour to throw some light on the debated points regarding the absorption of quinine, Major MacGilchrist, i.m.s , has lately carried out a series of experiments, and published the result of his work in a Scientific Memoir.* In regard to the absorption of quinine from the stomach it would be as well to hear what Major MacGilchrist has to say on the subject, when it will be seen that his conclusions and the conclusions of others quoted by him differ widely from those of Major Smith. " In fact recent investigators are in harmony regarding the retardation of quinine absorption when administered with or soon after a meal. According to Mariani, the maximum elimination of quinine given while food is in the stomach takes plaoe between the 6th and 12th hours after administration ; but, given when no food is in the stomach, between the 3rd and 6th hours. As food does not, under normal circumstances, remain in the stomach more than five hours, it follows that most of the quinine given with food is absorbed from the small intestine. Subjective symptoms moreover, just like the maximal elimination of quinine in the urine, are at their height between the 3rd and 6th hours when quinine is given while fasting, and between the 6th and 12th hours when given with a meal. That some absorption may take place from the stomach cannot be denied for the following reasons, but such absorption is probably very insignificant." The reasons referred to will be found given in detail in Major MacGilchrist's Scientific Memoir, No. 41, pages 16, 17 and 18. After discussing the subject from the point of view of a number of continental authorities, and given the results of a series of feeding experiments with quinine carried out on guinea-pigs : (1). After fasting 24 hours ; and (2) immediately after food, he arrives at the following conclusions :? " There is, therefore, reason to believe that, under ordinary circumstances, most of the quinine administeied by the mouth is absorbed from the small intestine ; a small amount possibly from the stomach, especially if administered while fasting and in the form of a salt easily soluble in water, and also a relatively small amount from the large intestine. As already mentioned, the absorption of quinine is normally very complete, the feces after very little being passed with medium doses." It will be seen from the foregoing that Major Smith's statements on the oral administration of ?
* MacGilchrist. Quinine and its salts. Their solubility and absorbability : Scientific Memoirs by the Officers of the Medical and Sanitary Departments of the Government of India, No. 41.
[Dec.,
1911.
quinine are directly opposed to the conclusions arrived at by MacGilchrist, and the eminent authorities quoted by him in his Scientific Memoir, conclusions be it noted which are the outcome of carefully carried out experiments by experienced workers. In the face of such evidence it is difficult to understand why Major Smith has chosen the time after the largest meal of the day as the "economical moment" to give quinine. It would also be interesting to know what are the facts upon which an opinion is based that one-tenth of the usual doses of quinine when given at the " " would have the same effect economical moment as full doses given at other times. A saving of quinine is the only possible economy that could result from such treatment, and this would certainly be a false economy as far as the patient is concerned. Possibly also the question of economy comes in when a hypodermic injection of half a grain of quinine on two consecutive days is recommended in preference to 30 or 40 grains a day given by the mouth. A proper value is allotted to this method of treatment under the next heading. 2.~
Quinine
Hypodkrmically.
This is a method of treatment which Major Smith has practised for some years, and he relates his experience of having treated since 1899, all, except dispensary outpatients, suffering from acute malarial fever, by the hypodermic injection of quinine. During the greater part of that time he used quinine hydrobromate, but latterly he has used quinine bihydrochloride. In addition to describing his method of sterilising the syringe, skin of the patient, etc., he gives in detail his method of sterilising the quinine used, which is as follows :? " If a solution of quinine is being used, that is boiled ; if the tabloids, a tea-spoon is sterilised. A tabloid is then placed in the sterilised spoon, 10 to 15 minims of water are poured over it, the whole is boiled over a spirit lamp and the tabloid broken up with the point of a needle. The solution is then drawn up into the syringe and this is placed in carbolic solution until it is quite cool and then injected, the needle being at the same time gradually withdrawn, so that the fluid is distributed along its tract and does not tear up room for itself in one spot. The solution on cooling becomes opaque, but this does not interfere with its efficiency." In the majority of cases of malaria he finds that two injections at that interval of 24 hours are sufficient to bring the temperature to normal, or in cases of other diseases to eliminate malaria. At each injection he never gives more than 2 grains of quinine in not more than 20 minims of He states that the use of larger doses is water. to be deprecated, as the smaller amount produces the full pharmacological action of the drug. Before attaching any value to the statement
SIR DAVID SEMPLE'S REPLY.
Dec., 1911.J
quoted let quinine.
us
see
what
effect
boiling
has
in a tea-spoon held over a spirit lamp Smith's method of sterilising quinine) for a longer period th:in one minute produces changes in the salt which diminish its lethal effect for small animals such as rabbits and
quinine
on
It is a well-known fact that boiling produces deleterious changes in some salts of quinine in a few minutes. According to Fluckiger (quoted by MacGiilchrist) quinine preparations when exposed to heat and sun light lose water of crystallization and become decomposed, a yellowish brown product being formed which he names " quineretin." In some cases boiling produces this change in a few minutes. Major Smith does not state for what length of time he boiled his quinine preparations in a tea-spoon held over a spirit lamp, but he does state definitely that the solutions he treated in this way became opaque on cooling, and he also adds that this does not interfere with the efficacy of the quinine. With a view to testing this point I carried out the experiments detailed in Tables I and II. It will be seen from these experiments that a certain lethal dose of quinine bihydrochloride for a guinea-pig when given hypodermically is no longer a lethal dose when treated according to Major Smith's method : and that a certain lethal dose for a rabbit when given intravenously becomes non-lethal when treated by the same In these experiments there was no method. haziness after boiling for one minute; slight haziness after two minutes ; and marked haziness after three minutes' boiling. When boiled for minutes the than three solutions became longer somewhat opaque on cooling, so Major Smith in order to obtain opacity must have boiled the solutions for longer than three minutes. these experiments It is very evident from that boiling a solution of bihydrochloride of
(Major
guinea-pigs. Now the object of boiliug a quinine solution before injection is to sterilise it, or in other words to destroy any bacteria or spores, especially tetanus spores, which some imagine might be present in compressed quinine tabloids. The destruction of tetanus spores would, I take it, be the main object of those who resort to boiling as a
on
guinea-pigs
micalhj, o
a
?
.?
o' ^
O
Smith finds that, in the majority of of malaria, two injections of not more than 2 (Trains of boiled quinine given at an interval of?24 hours are sufficient to bring the temperature to normal, or, in the case of other disease, to eliminate malaria. This is certainly a comfortintf discovery for those who live in malarious countries, for it means that now we have malaria, and tetanus after quinine robbed of their terrors Major Smith's tea-spoon-sterilisation method
Major
cases
by
3 4
Weight of guinea-pig.
Salt of quinine used.
390 grms.
Bihydrochloride
4
370 grms.
Ditto
3
420 grms.
Ditto
with unboiled
Fluid in which dissolved and bulk given.
Amount
given.
430 grms.
grains
also given
Length of time boiled.
3
grains
3 grains
Ditto
1?
minutes
!
Normal saline solution, 4 c.c.
I
Normal saline 2 minutes solution, 3 c.c.
grains
given hgpodev-
hypodermieally.
Whether opaque
Results.
cooling.
on
Water, 3
c.c.
Water, li
,
3
Traces
of hazi-
Died after 8 hours.
ness.
minutes
Haziness.
Had twitching of muscles after one hour, but j this soon disappeared. Survived.
|
Marked haziness, Survived,
c.c.
3
minutes
Ditto
c.c.
3 minutes
Ditto
no
symptoms.
no
symptoms.
j Survived,
I Survived, no symptoms.
Ditto
3
grains
Water, 1?
425 grms.
4
grains
Normal saline solution, 4 c.c.
Not boiled
Clear.
f?
Ditto
420 grms.
Ditto
3
grains
Water, 30 min.
Not boiled
Clear.
'l7 I
Died after 1^ hour.
380 grms.
Ditto
2^ grains
Normal saline solution, 2$ c.c.
Not boiled
Clear.
Died after 2? hours.
"o | O
quinine
when boiled and
380 grms.
5
= o
efects of quinine
to demonstrate the
compared
I.
&,
1
*
as
safeguard.
According to Theobald Smith,* the spores of some strains of tetanus resist boiling for as long from 40 to 70 minutes. Are we then to as boil for over one hour in order to be 011 the safe side ; or are we to adopt Major Smith's method and boil until we get a solution which on cooling becomes opaque, and which is then no longer quinine, and might still contain living tetanus' spores, if they were ever in the tabloids to begin with, a point which has never yet been demonstrated ?
Table
Experiments
451
,
o
^pcrimonts
seen"frotu"tho
results of the control It will be i.rkodlv diminishes its lethal effects for guinea-pigs when given ?
Journal
of
that boiling
a
solution of
I Died after
quinine
hypodermically.
1908. the American Medical Association, March 20th,
until it become,
one
hour.
hazy
on
cooling
452
THE INDIAN MEDICAL GAZETTE.
[Dec,
1911.
Table II.
Experiments
on
rabbits to demonstrate the
effects of quinine given intravenously.
B
O
Weight
o
?"
rabbit.
Salt of quinine used.
1460 grms.
Bihydrocliloride
1230 eras,
Ditto
1400 grms.
of
f6
O
I
o
I
O L7
Fluid in which boiled and bulk
boiled,
then allowed to cool and
Length of time boiled.
Whether opaque
N or m a 1 saline 0-75 c.c.
1 minute...
Clear
Ditto
Ditto
2 minutes.
Slight
Ditto
Ditto
Ditto
1470 grms.
Ditto
Ditto
Distilled water 075 c.c.
1330 gvms.
Ditto
Ditto
Ditto
146") grms.
Ditto
Ditto
Ditto
Not boiled
1520 grms.
Ditto
Ditto
Ditto
Not boiled
o
m
Amount
when
given.
i grain
given.
cooling.
on
Died within 1 minute.
haziness
Marked haziness
Ditto 3 minutes.
of respiration for 2 minutes after the ex periment, but no other symptoms. Remained well.
Difficulty
Survived,
no
symptoms.
Ditto.
Ditto
Giddiness for half a minute after the experiment. No other symptoms. Remained well.
Ditto
Ditto
Results.
Died within 1 minute.
Ditto.
The amount of quinine used for these experiments is the least amount which (when not boiled) invariably kills a 1,500 gramme rabbit when given intravenously. It will be seen from the results of the experiments recorded in this table that boiling a solution of quinine until it became hazy on cooling markedly diminishes its lethal effects for rabbits when given intravenously.
of
giving two small hypodermically. Personally I do not injection of 2 grains
doses
of boiled
quinine
think that a hypodermic of quinine in a solution which had been boiled until it became opaque would be likely to give rise to tetanus ; and I gravely doubt whether such a dose given to an adult would ever cure a case of malaria, and it certainly could not produce the full pharmacological effects of the drug. Owing to the facts that quinine has a destructive action on the tissues at the seat of injection, and that none of the salts of quinine stand sterilisation well, one would think that these drawbacks would be enough to condemn this method of administration, but in addition we have also the fact that the salt unless given in a fairly dilute form may be precipitated to the extent of over 60 per cent, at the seat of injection. I have known of several cases at post-mortem examinations where masses of quinine were dug out from the sites where injections had been given to the patient before death. MacGilchrist as the results of his own experiments on guinea-pigs, and the work of others, sums up the position of subcutaneous or intramuscular injections of quinine in the following words : " As regards guinea-pigs, the lethality (and therefore absorbability) of quinine by the several modes of administration is in the following order, beginning with the most lethal mode of administration ; (1) subcutaneous injection in extreme dilution (1 in 150); (2) oral administration during fasting ; (3) oral administration with or immediately after food; and (4) subcutaneous
in the strengths generally used for hypodermic injection (L in 2, and 1 in 8). The oral administration of quinine also affords more prompt therapeutic action of the alkaloid than
injection
does the subcutaneous, the subcutaneous injection of quinine in extreme dilution (1 in 150j being excluded for clinical reasons. Further, suboutaneous injections are followed by various complications and mutilations. Intramuscular injections are attended by the same draw-backs as subcutaneous proper ; and although ulceration rarely occurs, they are more liable than the latter to be followed by thrombosis and paralysis. The harmony between the results of various observations on man and those of my experiments on guinea-pigs justify the inference of general applicability that subcutaneous and intramuscular quinine injections in solutions of the usual strength (1 in 1 to 1 in 10 j are inferior to quinine bj the month in rapidity of action and thoroughness of absorption, and that they are liable to be attended by grave complications, mutilations and dangers. Quinine and its salts are, moreover, fundamentally unsuited for hypodermic use. This mode of quinine administration should therefore be abandoned. The results of my own experiments on rabbits and guinea-pigs with hypodermic and intramuscular injections of quinine harmonise with the conclusions which I have quoted. 3.?Tictanus
and
Quininh.
At the outset of his criticisms under this heading Major Smith tenders the following advice? " In view of the usefulness of quinine adminis-
Dec, 1911.]
TETANUS AND QUININE.
tered hypodermically, it behoves every practitioner in India to carefully weigh all that Sir David Semple says in his Scientific Memoir (on " The Relation of Tetanus to the Hypodermic or Intramuscular injection of Quinine ") published by the Government of India. An improvement in the introductory wording of this advice would " be, In view of the risks incurred when quinine is administered hypodermically it behoves every " practitioner in India carefully to weigh, etc. ; but even apart from my suggested improvement 1 am very pleased to recommend the advice which Major Smith has tendered to every practitioner in India. I would also recommend every practitioner in India carefully to weigh all that Major Smith says in his article "Quinine without Tetanus," published in the Indian Medical Gazette for September 1911, and especially to reflect on what he says under the first two sub-headings of his article. While on the subject of advice I would also recommend those who may take the trouble to read my Scientific Memoir to be more careful than Major Smith has been to grasp the meaning of my experiments with "washed tetanus spores" and quinine, a task which I think most readers will find to be comparatively easy. I should not expect anyone who had carefully studied my Memoir to reproach me with not finding tetanus spores in guinea-pigs (which had received no quinine) in any other part of their " washed tetanus tissues, except at the site where been had ; injected yet spores" Major Smith remarks : " It is not claimed that they can be recovered from any other part of the body, nor that when a man becomes infected with dormant tetanus spores which produce no symptoms, that he harbours the spores in anything like the same numbers as are injected into the guinea-pig." " " Washed tetanus spores injected into guineano hypodermic which receive injections of pigs quinine are never found anywhere else in the tissues except at the site of injection, naturally, therefore, 1 do not claim that they can "be recovered from any other part of the body. Of course the intestinal tract of man and animals may harbour tetanus infection under natural conditions, but this is a different question. I would like to know how Major Smith would attempt to find out when a man becomes infected with dormant tetanus spores which produce no symptoms, and how he would proceed to draw a comparison between the number of spores in such an infected man and the number injected There are some questions into a guinea-pig. which require a lot of ingenuity to solve, and these two conundrums might be included amongst them. If animals can be proved experimentally to harbour tetanus spores in their tissues for months, surely it is reasonable to infer that human beings may also harbour tetanus spores for months, yet Major Smith considers this an astounding statement. It was not, however, considered an astounding statement when first made
453
Vincent of the Pasteur Institute, Paris, in explained the origin of "spontaneous" tetanus as due to latent tetanus spore infections being stirred into activity by a heatstroke, a chill, hypodermic injections of quinine, or other depressing influences. In the 10 cases of tetanus following the hypodermic injections of quinine brought to my notice, Major Smith objects to my not publishing all details of these cases. Surely he must have known that the cases were not under my care, and that it is not usual to publish other people's I am, however, in a position to state that, cases. with the exception of one case, no aseptic precautions were omitted in carrying out the injections ; and even in this case the quinine was to some extent to blame, although the water in which it was dissolved contained tetanus spores. It will be asked what evidence is there for attaching any blame to the quinine in this particular case, seeing that the water was infected with tetanus to begin with. A sample of the distilled water used to dissolve the quinine given hypodermically to this patient was sent to me for examination, when in addition to other tests 1 carried out the following experiments on guineapigs, and the results of these experiments will serve to clear up the question under discussion.
by
11)04, who
1.?Two guinea-pigs hypodermic injection of 2
each of a of the distilled water used to dissolve the quinine for the patient referred to. Both animals remained well.
Experiment
(riven
a
Sample
were
c.c.
Experiment 2.?Two guinea-pigs were each given a hypodermic injection of half a grain of quinine dissolved in 2 c.c. of a sample of the Both these guinea-pigs developed same water. tetanus.
Experiment 3.?Two guinea-pigs were given a hypodermic injection of 1/10 grain morphia. In one case the morphia was given in 2 c.c. and the other in 1 c.c. of the sample of water referred to. Both animals remained well. Experiment 4.?Two guinea-pigs criven
same
were
each
hypodermic injection of 1 grain of the sample of quinine used for experiment No. 2, a
but dissolved in normal saline solution. AVith the exception of sloughing at the seat of injection both animals remained well. This experiment exonerates the quinine used for experiment No. 2 from any suspicion of containing tetanus spores.
Experiment 5.?A growth of tetanus was obtained from the sample of water used for experiments 1, 2 and 3. In my opinion the results of these experiments are very strong evidence that quinine was the no-ent which made a tetanus infection possible
in this case, and that a morphia injection made up with the same water and given to a patient would in all probability not have been" followed by
'
:
It requires something more than the introduction of tetanus spores into the living tissues to produce tetanus, and evidently quinine can readily supply the accessory conditions required for the spores to germinate. In this connection 1 might also refer to the experiments recorded in Tables X and XI of my Scientific Memoir No. 43, pages 42 to 45, from which it will be seen that washed tetanus spores when mixed with quinine or lactic acid, and given
tetanus.
hypodermically
to
guinea-pigs produce
tetanus ;
but when the spores are mixed with a nonirritating solution of morphia, or normal saline solution, the animals remain well. These experiments taken in conjunction with the experiments carried out with the tetanus-infected water recorded above, demonstrate clearly the favouring influence of the hypodermic injection of quinine in the production of tetanus when a tetanus-spore infected fluid is used, as compared with morphia given under similar circumstances ; and they al.-o afford a reasonable explanation as to the rarity of tetanus following hypodermic injections other than quinine. Major Smith states that he gives at least 50 injections of quinine for one of morphia, and on this account he doubts the correctness of the statement that morphia injections are more frequently given than quinine injections. There are exceptions to most rules, so 1 take it thnt Major Smith's practice of giving small doses of boiled quinine hypodermically to all his cases of malaria is an exception to the general rule. We all know that hypodermic injections of morphia are given probably thousands of times for once thai quinine is given, but can any one mention 10 cases of tetanus following morphia injections ? In the literature on the subject I can find onl}' one case mentioned, there may be others ; but, as Major Smith remarks, the injuries for which the morphia is often given would be a reasonable source of infection, and would exonerate the
morphia.
|i>EC'>
THE INDIAN MEDICAL GAZETTE.
454
The remainder of Major Smith's remarks show that he has failed to grasp the meaning of the experiments given in my Memoir, and as an example of"this I may quote his concluding remarks: The only conclusion that can be drawn from the Memoir is that if tetanus spores are injected, there is a slightly less chance of a tragedy if quinine is withheld, but nothing has been shown to justify us in running the risk of withholding the hypodermic injection of quinine in every case where it is indicated, provided it is given antiseptically." When he refers to tetanus spores. I presume " he means " washed tetanus spores and in this case demonstrate clearly that my experiments there is no chance of a tragedy when quinine is withheld, but a very considerable chance of a tragedy when quinine is given, and that tetanus will follow for certain when the spores are mixed with quinine, but not necessarily when they are mixed with a morphia solution or normal saline.
1911-
Evidently Major Smith puts a very liberal interpretation 011 not withholding hypodermic injections of quinine in every case where they are indicated, for he tells us that he has treated ail his cases of malaria (except dispensary outpatients) since 1881) by this method ; and he also remarks, "In addition during the last five years, in order
to prevent a possible recurrence of malignant malaria, or any fresh infection, 1 have given a hypodermic injection to every patient
who has been ansesthetised, just before he comes round, and on two consecutive days to all inpatients suffering from acute diseases, such as pneumonia, typhoid fever, small-pox, etc." I should withhold a
certainly not recommend any one to hypodermic injection of quinine from
where it was indicated ; but 011 the I should be very sorry to recommend this method of giving quinine as a routine in all cases. I should confine myself measure to the exceptional cases in which quinine by this method is indicated, and these I should safeguard b}r a dose of tetanus antitoxin, especially in those localities of tropical countries where tetanus frequently occurs. It is evident from Major Smith's account that very small doses of a solution of quinine boiled until it became opaque 011 cooling did not do bis patients an}' harm, and it did not give them tetanus but would such treatment cure or prevent malaria ? A small dose of quinine after being treated in such a way that it was 110 longer quinine, and then given hypodermically, would not be likely to have any influence in bringing about a tetanus infection, and it would certainly have very little influence in curing or preventing malaria. case
any
other,
4.?This Reviewer
of
Tetanus
and
Quinine
Reviewed. A review of my Scientific Memoir No. 4^, On the Relation of Tetanus to the Hypodermic " or Intramuscular Injection of Quinine appeared in the Indian Medical Gazette for September 191 J. On reading over what the reviewer said I came across some remarks which 1 propose to deal with not only for the information of the readers of the Indian Medical Gazette, but possibly also for the benefit of the reviewer. I shall quote from the points requiring attention and deal with them in the following order :? "
"
Whatever lethal effect quinine may have spores a point which has never yet been settled?it certainly can have little effect until dissolved." These remarks were made when the reviewer came across a passage in my Memoir where I stated that quinine being a protoplasmic poison is not likely to harbour living tetanus spores before being dissolved. When making this statement I was thinking of compressed tabloids of the kind generally used for hypodermic injections, and not loose powdered
(a)
on
tetanus
quinine.
i>KC
,
QUININE
1911.]
AND TETANUS.
In order to test the point whether tetanus could survive in the interior of a compressed tabloid of quinine bihydrochloride, I carried out the following experiments as a preliminary to further test-experiments which I hope to carry out at an early date :? spores
1. A five-grain tabloid of quinine bihydrochloride was taken and a hole drilled into the " washed tetanus centre. A measured amount of dried at a temperafter being thoroughly spores" ature of 37" Centigrade was then placed in the of the tabloid, and powdered quinine centre prepared from a similar tabloid pressed down tightly on to the spores, and the drilled hole carefully filled up in this way. The tabloid was then placed in a sterile tube, and allowed to remain in a dark cupboard at room temperature for a week, after which it was dissolved in a bulk of 5 c.c. of normal saline solution, and four guineapigs were each injected with 1 c.c. None of these animals developed tetanus. 2. Control experiment.?A similar amount of "washed tetanus spores" prepared from the same culture, and at the same time as those used for the interior of the tabloid, were placed in a sterile test tube, and slowly evaporated to dryness The tube was then at a temperature of 37?G. placed in a cupboard at room temperature for a week, when a 5-grain tabloid of quinine bihydrochloride was dissolved in it in a bulk of 5 c.c-. of normal valine solution, and 4 guinea-pigs each injected with 1 c.c. All 4 animals contracted tetanus on the second day, and died on the third
day. with the washed tetanus spores" used for experiments 1 and 2, remained well, which proved that the spores had been completely freed from toxin. 3.
same
A control
amount of
guinea-pig injected
a
sample
of the
"
It is reasonable to infer from these few experiments that tetanus spores probably do not survive for long inside a compressed quinine tabloid ; but before finally settling the point further experiments are indicated. I may also mention that after numerous attempts 1 have never yet succeeded in obtaining a growth of any kind from compressed quinine tabloids when precautions were taken to avoid contaminations from the outside of the tabloids (b). The reviewer " merely tested the complains that I have antitoxin of under the most prophylactic power favourable conditions tor its effective action,'" and that " there is no experimental proof given of the duration of passive immunity ; or that one injection of serum would render several daily injections of quinine safe : and even granting that immunity may la?t so long, there is always the possibility?almost certainty?of malarial relapses and reinfection, with the consequent danger of anaphylactic phenomena, both in their acute fatal and commoner subacute forms." These remarks savour of extreme caution, and a tendency to err on the right side.
Let
us see
455 in wbicli direction the truth is to be it is to be arrived at by means of
found, and liow experiments.
rfhe anaphylactic phenomena referred to may be dismissed in a few words, for it is well known that serum can be injected into animals once a week for months without anaphylactic phenomena ever appearing, and it is generally believed that it is much more difficult to render man supersensitive to the effects of serum than it is in the case of animals, liesides it requires an interval of about 12 days or longer to elapse after an animal such as a guinea-pig receives a sensitisit becomes supersensitive before dose of serum ing to a second dose. AVe can also fall back from the experience gained from the numerous instances in which antidiphtheritic serum is given to children at various intervals without any accidents happening, and certain other seiuins, such as anti-tubercle serum, and anti-rheumatic serum which are constantly being used at intervals of days and weeks without any ill-effects. Practically speaking it is a negligible quantity as far as man is concerned, and need not interfere with serum prophylaxis. Possibly my reviewer was of what is generally referred to as thinking " serum sickness," accompanied by pains in the and and urticarial rashes, appearing about joints the iOth day in 8 or 10 per cent, of cases after dose of serum ; but even this need not a single give any cause for anxiety when it does appear. It is only necessary to mention to patients that " serum sickness," so there is such a thing as that they may not be alarmed should it appear. As regards the duration of passive immunity after a dose of serum, it is common knowledge and accepted as a fact that it may last from a fortnight to six weeks or longer. Taking the shortest period, viz., a fortnight, this would give ample time to give a patient as many hypodermic injections of quinine as it would be good for him to receive. The question of the efficacy of antitetanic serum was settled by Roux and Vaillard years ago. These observers showed that " antitetanic serum does not cure tetanus after it has set in, but that it infallibly prevents it." It is also well known that there is no antitoxin more active than antitetanic serum. The experiments recorded in Table III serve to demonstrate the prophylactic power of tetanus antitoxin under much more unfavourable conditions than are ever likely to be met with in actual practice. They also demonstrate clearly that the period of protection even under the very adverse conditions tested lasted for a fortnight at least. " (c). The reviewer complains that the chapter of on effects animals is the small quinine showing he and that a to think pretends disappointing," dilution of quinine of the strength of 1 grain in " a curious mixture of two 1 c.c. of saline is and measures." He also of weights systems " mentions that there is a difficulty in arriving at dose due to the author not a minimum lethal its technical sense." in the term accepting ?
?
?
i
i
?
THE INDIAJS
456
MEKICAL GAZETTE.
TABLE III..
efficacy Experiments guinea-pigs of antitetanic serum in warding of tetanus infections ichen quinine is given hypodermically. Date of
Date of No. of
experiment.
Date of
hypodermic injection of hypodermic of
injection
antitetanic serum.
Cct. 11th, 3 e.c.
|
q???ne-
Oct. 13th, 1 grain. Oct. loth, 1 grain. Oct. ISth, 1 grain. Oct. 21st, 1
grain.
hypodermic
injection of a
virulent
Result.
tetanus
culture.
Oct. 13th, A c.c.
Oct. '_'5th, 1 grain.
Oct. 25th,
Oct. lltli, 3 c.c
Oct. 24th, 1 grain. Oct. 26tli, 1 grain. Oct. 27th, 1 grain.
Oct. 25th,
3
Ditto
Ditto
Ditto
4 Control of tetanus culture used.
Nil.
Nil.
i \
Remained free from tetanus.
Ditto.
c.c.
Oct. 13th, A c.c.
Ditto.
Developed
tetanus on the 2nd day, and died on the 4th day.
These experiments prove that tetanus antitoxin confers a
(Expt. 1).
When the reviewer made these statements he opening paragraphs of Chapter 111, page 13, in my Memoir, where it is stated, "In these experiments no attempt was made lo follow up the excretion of quinine from the systems, or to enter minutely into its physiological effects. The principal objects were : must have overlooked the
effects
arrive at a dose, which, without provwould produce well marked visible
;
To arrive at some conclusion as to what the local effects of quinine are when given hypo-
(2)
dermically.
(3) To prove whether the local and general effects of quinine when given hypodermically have any influence in favouring tetanus infections. (4) To obtain information as to whether animals can withstand larger doses by the stomach than hypodermically. of
(5) To gain some information on quinine when given intravenously.
the stomach ; (b) for rabbits, when given hypodermically, 6 grains per kilogramme of weight ; and when given by the stomach the amount is at least double the hypodermic lethal dose. A minimum lethal dose for a guinea-pig or rabbit of a certain weight is not necessarily a lethal dose for other guinea-pigs or rabbits of the The smallest dose which will never same weight. fail to kill any guinea-pig or any rabbit of a certain weight may be more than a minimum lethal dose for some of these animals. The smallest dose that may kill, and the smallest dose which will never fail to kill are two different " the curious mixture of two systems " referred to, viz., " 1 of weights and measures " grain to 1 c.c. I can assure the reviewer that it is a most convenient mixture for any one administering quinine either to man or animals by means of a syringe, on account of the fact that English preparations of quinine are sold in grains, and the best syringes and the most convenient measures are graduated on the c.c. scale. Any other combination of weights and measures would have no advantages over grains per c.c. (d). An important point referred to by the reviewer is the following :?" In the intravenous experiments where the majority of animals died within oi\e minute from asphyxia, the quinine was in far too great a concentration (1 grain to 1 c.c.), and would undoubtedly form a dense precipitate I inside the blood vessel at the site of injection ; and the mode and rapidity of death suggests embolism." The lethal effect of quinine when given intravenously to rabbits depends on the amount given at a single dose, and not on the dilution in which it is given. The question of the precipitate referred to above does not come in when intravenous experiments are carried out, although a precipitate can be easily demonstrated when a concentrated solution of quinine is added to A careful study of the serum in a test tube. results of the experiments recorded in Table IV should convince any one that whatever else the cause of death may have been due to in experiments I, 2 and 3, it could not have been due to a precipitate inside the blood vessel at the site of injection, as the dilution of quinine used, namely, 1 in 150 ; 1 in 160 ; 1 in 200 do not give rise to any precipitate when added to serum in vitro. A rabbit of a certain weight which receives intravenously the least amount of quinine which invariably kills, dies just as quickly and with the same symptoms irrespective of whether the quinine is given in a dilution of 1 in 200, or in the proporlion of 1 grain to 1 c.c. It is the amount of quinine given at a single dose which is the lethal factor and not the dilution in which it is given.
As
passive immunity on guinea pigs for 14 days at least against the injection of a dose of tetanus culture lethal for nonprotected animals, and that the immunity is not upset when several injections of quinine are given in the meantime
(1) To ing fatal,
is, (a) for guinea-pigs, when given hypodermically, 1 grain per 150 grammes of weight ; and that an increase of from A to ? of this amount will invariably kill when given bv
things.
c.c.
the effects
It will be seen from this that a determination of the minimum lethal dose for small animals was not by an) means the primary object of my experiments, but nevertheless it is clearly proved and definitely stated that when quinine bihydrochloride is used, the smallest dose that will
1911.
fail to kill
never
prove the
to
on
[Dec.,
regards
Dec.,
RADIO-ACTIVITY OF THERMAL SPRINGS IN BOMBAY.
1911.J
Table
Experiments
on
rabbits
solutions, No. of
ex-
periment.
4
Control
as
compared
Salt of quinine used.
Weight of rabbit.
1520 grms.
demonstrate the
to
i
Bihydrochloride
grain
effects of quinine
when
...
Normal saline solution.
given intravenously given intravenously.
Dilution used and bulk given intra-
Fluid in which dissolved.
given.
i
IV.
zvith strong solutions also
Amount
457
in very weal-
1'ESCLTs.
venously.
Died within one minute.
1 in 150 (6 6 c.c.)
1500 grms.
Ditto
Ditto
Ditto
1 in 160 (
7 c.c.)
Ditto
1500 grms.
Ditto
Ditto
Ditto
1 in 200 (
9 c.c.)
Ditto
1470 grms.
Ditto
Ditto
Ditto
1 in 17 (0-75 c.c.)
1560 grms.
Ditto
Ditto
Ditto
Ditto
Ditto
Ditto
Control G Control
1450 grms.
9
c.c. Normal solution.
saline
7 Control
1490 grms.
10 c.c. Normal solution.
saline
No symptoms, remained
well.
No symptoms, remained well.
The amount of quinine used for experiments 1. 2, 3, 4 and 5 (f grain) is the least amount which invariably kills a 1500 gramme rabbit when given intravenously. It will be seen from these experiments that it is just as rapidly fatal when given in dilutions of 1 in 150; 1 in 160 ; and 1 in 200 as in a dilution of 1 in 17 (1 grain to 1 c.c.). It will also be seen from experiments 6 and 7 that the bulk of the fluid in which the quinine was given had no influence on the fatal effect.
(
