No. 3807.

AUGUST 15, 1896.

A LectureON

THE TREATMENT OF ANIMALS POISONEDWITH SNAKE VENOM BY THEINJECTION OF ANTI-VENOMOUS

SERUM.Delivered in the Laboratories of the Conjoint Board of the

Royal Colleges of Physicians (London) and Surgeons(England) on July 27th, 1896,

BY A. CALMETTE, M.D.,OF THE INSTITUT PASTEUR, LILLE.

GENTLEMEN,-T’he importance of the treatment of snake-bite, though comparatively slight in this country, assumesmuch greater proportions in connexion with the Indian,Burman, Australian, and African colonies, as in India alonethere is an annual death-rate from snake-bite of between

twenty and thirty thousand people, whilst the financial lossthrough the death of cattle due to the same cause is veryconsiderable. For this reason it is obvious that any treat-ment of snake-bite which offers reasonable promise of

diminishing this mortality should be seriously considered bythose who are responsible for the health administration ofdistricts in which snakes are found. For some time past I

have devoted considerable attention to the production of ananti-venomous serum, and after many experiments I suc-ceeded some time ago in placing in the hands of medical menin India and Australia a serum the value of which hasnow been proved in a small number of cases in which thesnake which has bitten the patient has been identified andcaptured. Many of my observations have been confirmed, somein this country by Professor Fraser and others by observersin British colonies, but the importance of the serum methodof treatment has even now not been fully realised. I have

to-day, however, the opportunity of giving you the resultsof experiments that have been performed under Dr. Wood-head’s licence, but under my direct personal supervision, sothat they may be relied upon as affording direct proof of thevalue of my method. Those animals that have been success-fully treated you may examine for yourselves; others thathave been poisoned with the snake venom, but have notreceived the serum, have succumbed ; these latter serve ascontrol experiments with which to compare the resultsobtained when the serum has been given.These experiments are easily carried out and are abso-

lutely painless; in rabbits, as in the human subject,the first symptom indicating the action of snake poisonis slight somnolence, which, becoming more and more

marked, is gradually succeeded by a condition of uncon-

sciousness associated with, first, muscular contractionand then with loss of motor power, which commencing inthe hind limbs passes forwards until the respiratory centresare affected, the cardiac centre being the last attacked ;when the animal dies the heart is found in a condition ofdiastole. The venom may be injected in two ways-intra-venously, when a comparatively small dose acts with greatrapidity; and subcutaneously, when the dose also acts power-fully but more slowly. A lethal dose of cobra poisoninjected subcutaneously is about 1 milligramme of driedsubstance, which proves lethal in about twelve hours. Twicethis quantity injected into the veins kills a rabbit of about1500 grammes in sixteen minutes. Five times as muchintroduced subcutaneously proves fatal in about three and ahalf hours. I may, however, give you the results of experi-ments devised to bring out the exact action of the anti-venomous serum, which experiments have been followed bythose who are working in these laboratories.

Protective injections.-At nine o’clock this morning fourrabbits weighing between 1450 and 1770 grammes wereinjected intravenously in the lateral aural vein, each with3 c.c. of the anti-venomous serum. This afternoon theserabbits have been injected intravenously with 2 milligrammesof dissolved dried venom sufficient to kill the animal in six-teen or seventeen minutes. None of these animals show anysymptom of sleepiness, and it_is evident that the venom will

have little if any effect upon them. At the time that theseanimals were injected with the two lethal doses two controlrabbits weighing 1340 and 1275 grammes respectively weresimilarly injected intravenously with 2 milligrammes of thevenom; these both succumbed with the symptoms above-mentioned, one in about sixteen minutes and the other inseventeen minutes. We have here then ample evidence of thegreat protective power that the serum exerts when injectedinto the body before the venom is introduced. In a secondseries of experiments carried out to demonstrate the curativeproperties of this serum six rabbits were similarly treatedwith 5 milligrammes of venom injected under the skin. Halfan hour afterwards two of these animals received 3 c.c. ofthe serum intravenously; neither of them showed anysymptoms of poisoning and remained perfectly well. Twoothers of these poisoned animals one hour after thevenom had been introduced were similarly injected intra-venously with 3 c.c. of the serum ; they also remainedwell. Two of the other rabbits should have been left for oneand a half hours, but the dose of poison was so large thatone of the animals succumbed at the end of an hourand twenty minutes ; the other animal was immediately in-jected with the same dose of serum as above, with the result.that it is now well although the dose of venom was so largeand had been allowed to act for so long a time, longenough, indeed, to kill the other animal injected at the sametime. This is a very striking proof of the efficacy of theserum.

Although the anti-venomous serum does not act directlyupon the toxin, but only through the cells, it begins to exertits influence immediately it is introduced into the body.This fact is well brought out by the following experiments.Three c.c. of the serum were injected into the lateral vein ofthe left ear of a rabbit weighing 1280 grammes ; fifteenminutes later this animal received into the lateral vein ofthe right ear 2 milligrammes of the venom, sufficient to killit in less than twenty minutes had it not received the serum.The animal has remained perfectly well and still shows noevidence of poisoning by snake venom. A more strikingexperiment still is one of which I give a description. Arabbit having received intravenously 2 milligrammes ofvenom, two minutes later is injected with 5 c.c. of the anti-venomous serum in the vein of the opposite ear. The animalhas remained perfectly well.l Such an experiment showsthat the venom does not destroy the cellular elements at

once, and that even when the poison has already found its.

way to the circulation these cells may be rendered insensibleto the action of the poison by means of the action of theserum.

[Dr. Calmette then gave extracts from his paper which hebrought forward at Carlisle, and concluded by asking Dr.Woodhead to read the following :]

Gentlemen, the experiments that have been described toyou concerning the efficacy of the "anti-venomous serum,"the results of which you have before you, prove that the saidserum really constitutes a specific remedy against venomoussnake bites. The use of this serum must necessarily becomegeneralised at no distant date in all countries wherevenomous snakes are found, in order that both men anddomestic animals may be protected. Is it not advisable,therefore, for the British or Colonial Governments which aredeeply interested in this matter to take rigorous measuresto prevent the sale in England and in its coloniesof serums for which no absolute guarantee of efficacy and

, purity is given ’I I have the honour to propose that you willadopt the following propositions and bring them in some waybefore the Government at as early a date as possible:-

1. That there be instituted in London and in each Britishi colony where there are found venomous snakes a sanitaryi committee to be entrusted with the duty of testing the

efficacy of anti-venomous serums offered for sale or sent out, to be delivered gratuitously by druggists and others.

2. That no bottle shall be sold or distributed unlessbearing the mark of such control.

3. That this control be effected according to the sole,simple, and rapid method which alone presents every

.

guarantee of accuracy.4. The method proposed is the following : A standard

solution of venom will be placed at the clisposal of theappointed experts. The toxic unit of this solution will bebased on the quantity of venom necessary to kill a rabbit of

1 All these animals were still alive and in excellent health eight dayslater.

G

450

two kilogrammes in twenty minutes by intravenous inocula- ]tion in the marginal vein of the ear, the above quantity 1

corresponding on an average to two milligrammes of cobra ! ivenom (weighed dry) and to four milligrammes of rattlesnake ivenom. An anti-venomous serum to be sufficiently active fortherapeutic use must be a preservative in a minimum dose oftwo cubic centimetres on intravenous injection into a rabbitof two kilogrammes against an intravenous injection of thetoxic unit of venom. The preventive inoculation must bemade fifteen minutes only before the inoculation of thevenom. The testing of the serum is thus effected in lessthan one half-hour.

5. That stations provided with serum and all the necessaryapparatus for its application be established in the principalcentres of agriculture and in the mining and forest districts ofthe colonies infested with venomous snakes, such as Australia,Burmah, and India, so that every person bitten may be ableto come at once and receive treatment.

[Dr. Calmette spoke in French, and at the close of thelecture, which was listened to with great interest by a largenumber of experts, including Professor Michael Foster, Pro-fessor Ray Lankester, Dr. Lauder Brunton, Dr. P. Carmody(Trinidad), Dr. Liveing, Dr. Rose Bradford, Dr. Washbourn,Mr. Arthur Stradling, Dr. F. W. Mott, Dr. Buckmaster, Dr.Slater, Dr. Starling, Mr. H. E. Durham, and Dr. Macfadyen,the members of the Laboratories Committee and many of thosecarrying on investigation in the laboratories, Dr. Pye-Smithproposed a vote of thanks to Dr. Calmette for the very lucidand convincing manner in which he had handled the subject.He was sure all those present wished Dr. Calmette success inhis efforts to treat a condition so important to us, especiallyas it affects our colonial brethren. This vote was adoptedmost cordially.]

A CASE OF ANEURYSM BY ANASTOMOSISINVOLVING THE VESSELS OF THE

HARD PALATE.1BY A. MARMADUKE SHEILD, M.B.CAMB.,

F.R.C.S. ENG.,ASSISTANT SURGEON TO, AND LECTURER ON PRACTICAL SURGERY

AT, ST. GEORGE’S HOSPITAL.

ON the afternoon of Jan. 18th I was requested byDr. Norton of Queen Anne’s-mansions to see immediately apatient whose condition was stated to be serious on accountof persistent bleeding of an arterial character into the

mouth. He was a retired officer aged fifty-seven years, and hadsuffered from "liver affections," but never from malaria. In

1893 he had an accidental fall" and broke his nose," andrepeatedly had suffered from severe epistaxis, referred to thecongested condition of his liver. On Jan. 15th bleedingoccurred into the mouth and he lost about half a pint ofbright blood. On the 16th the bleeding occurred again andhe lost two tablespoonfuls. On the 17th the bleeding againoccurred to a considerable amount, and he noticed that theblood issued forth in jets into the mouth. On the 18ththe same occurred. Dr. Norton saw him on the16th, and noticed an ulcer the size of a threepenny-pieceon the left side of the hard palate, about opposite thesecond molar tooth and close to the alveolus. Arterialblood was spurting in a jet from the centre of this, and thepatient was losing a quantity of blood, his mouth being filledwith clot. Dr. Norton temporarily arrested the bleeding bypressure and perchloride of iron, but it always recurred.When I saw the patient on the evening of the 18th I noticedthat he was pale and exsanguine, with a very weak pulse. Themucous membrane of the roof of the mouth was discolouredby the iron application, and a little clot could be seen onthe base of a small superficial ulcer situated opposite thesecond molar tooth on the left side close to the alveolus. Ifeared to disturb this and made a very gentle examina-tion. I soon found that a pulsatile swelling the size of afilbert occupied the tissues at the base of the alveolar

process. Its margins were not defined, but faded awayimperceptibly. The pulsations were strong, so as tolift the examining finger, and felt exactly like thoseof an aneurysm. There was one large pulsating vessel

1 A paper read before the Odontological Society of Great Britain onApril 13th, 1896.

posteriorly and this I could compress, but without alteringthe pulsation of the tumour. The teeth were quite sound,and the morbid swelling, whatever its nature, terminatedabruptly at the base of the gums. The ulcer was quitesuperficial and devoid of any induration or distinct margins;it looked like an accidental abrasion from hot food or apiece of bone. The patient was quite unable to give anexact account of the length of time the swelling hadexisted, and it seemed to me he had hardly much noticed itspresence. There was nothing to be seen on inspection ofthe nares, and there was no bulging of the palate generallyto indicate a protruding antral tumour. I directed that anurse should be employed, with instructions to press uponthe spot with a minute sponge soaked in turpentine or

with the finger should bleeding recur. On reflecting uponthe symptoms of this very unusual case I was ratherinclined to look upon it as an example of pulsating sarco-matous disease of the hard palate, yet the bone was notobviously expanded, and the pulsations were far more

forcible than I have ever seen in several examples of thisdisease in the bones of the skull and the femur, ilium andtibia. The supposition of a definite aneurysm of one of thepalatine vessels also entered my mind, but I rejected it onaccount of the rarity of such a malady and the rather diffuseoutlines of the tumour. Seeing the inevitable uncertaintyof an exact diagnosis, the great hazard of cutting into orcauterising the growth, and the desirability of definitelystopping the bleeding by some proceeding which would besure and certain, I advised that a portion of the maxillashould be removed so as to ensure complete extirpation ofthe growth. The patient, who showed great sense andcourage in his trying and dangerous position, at once

acceded to what I thought best for his relief. The operationwas performed on the morning of the 20th. Dr. Hewitt

gave the anaesthetic and Mr. Arthur Ward and Dr. Nortonassisted me. The details of the operation are of no

great consequence ; it was performed with saw and cuttingbone forceps, the lip and side of the nose being incisedand the tissues reflected. There was no unusual bleed-ing. A portion of the upper jaw was removed, comprisingthe whole alveolar margin from the second incisor toothand the hard palate as far as the middle line. The

posterior palatine artery spurted persistently and was onlyrestrained by plugging the canal with a spicule of wood. Iwould, however, draw special attention to the advantages ofthe lateral posture in all these operations, with the head wellhanging over the edge of the table. Dr. Hewitt and myselfhave drawn attention in detail to its value in a recent paper !

published in the Transactions of the Royal Medico-Chirurgical !

Society for 1896. After-oozing was checked by the appli-cation of a turpentine sponge, and a small sponge soaked in ,

the same material was left in the cavity. The after-treat-ment of the case was left entirely in the hands of Dr. Norton,and recovery was uneventful. About two hours after the

operation some more oozing came on, which was checkedby full doses of ergot and placing the feet in hot water.There was some little trouble in removing the turpentinesponge, as it clotted the blood and was firmly wedged. The-horsehair sutures were removed in a week and union of thelip was proved firm and good, the cicatrix scarcely showing.All this time the mouth had constantly been kept flushedwith benzoin and chlorinated soda mouth washes.The highly vascular nature of the tumour was apparent

after removal of the portion of bone, for it subsided and con-tracted, so that what was once a prominent pulsating masswas now only a thickened flattened area of sponge-like tissue,with a small superficial ulcer in the centre. My colleague,Dr. Rolleston, examined the tissue microscopically, and hisreport fully bears out the appearances observed during lifeof haemorrhage and free pulsation :-" A section takenthrough the growth and ulcer down to the bone showedthat underlying the granulation tissue, which was somewhatscanty, there were numerous bloodvessels. The arterieswere well formed and numerous ; one or two showed slightendarteritis obliterans ; there were a few large spaces linedwith endothelium with thin walls -probably dilated

, veins. All the blood channels seen, therefore, had properwalls, and there was no extravasation of blood into thetissues, and no pigmentation to suggest that any past

: extravasation had occurred. There was nothing to suggestL sarcoma or epithelioma. From the small amount of organi-c

sing granulation tissue, and from the absence of signs indi-; eating irritation of the adjacent mucosa, it appears probable

that the ulcer is of very recent date."