No. 4197.

FEBRUARY 6, 1904.

A LectureON

THE PHYSIOLOGICAL ACTION AND ANTI-DOTES OF SNAKE VENOMS WITH APRACTICAL METHOD OF TREAT-

MENT OF SNAKE BITES.1Delivered in the Physiological Laboratory of the University

of London on June 9th, 1903,

BY LEONARD ROGERS, M.D., M.R.C.P. LOND.,CAPTAIN, INDIAN MEDICAL SERVICE.

DURING the last few months the physiological actions of anumber of snake poisons, representing every class of thesepoisonous reptiles, have been investigated by me in this

laboratory in continuation of previous work in India, themain results of which I propose to bring before you to-day,illustrating the different points as far as possible by myown experience but referring to previous work whereveradvisable.

In some of the earlier investigations on snake venoms novery essential differences were detected in the action of thevarious classes, but the large amount of work which hasbeen carried out in recent years has shown that they may bebroadly divided into two classes : first, the colubrines-ofwhich the cobra is the best worked out-acting mainly byparalysing the respiratory centre in the medulla and themotor end plates of the phrenic nerves, more especiallycombined with a much less important action on the blood ;and, secondly, the viperine class, which have hitherto been 1

thought to act mainly on the blood, producing intravascular

TABLE I.-GIVING A SUMMARY OF THE ACTIONS OF THE DIFFERENT CLASSES OF SNAKE VENOMS.

clotting as in Russell’s viper of India, or loss of coagulabilityand haemorrhages as in the rattlesnake of America. Ishall hope to show you presently that a still more importantand constant action of the viperine class is the production ofa paralysis of the central vaso-motor centre in the medulla,just as the colubrine class paralyse the respiratory functionsof this part of the nervous system, a factor which has beenhitherto largely overlooked except for a reference to it byWeir Mitchell and Reichart in their classical work on therattlesnake. It will simplify matters if I first direct yourattention to a table in which I have summarised the actionsof each of the four classes of snake poisons, illustratingthem by examples of species which I have myselfinvestigated (Table 1.).You will see from the table that the venoms having the

colubrine action characterise the sea snakes (which I have

1 A grant in aid of the research work on which this lecture ismainly based was received from the Royal Society, by whom theoriginal full papers have been published. Some work done since thedelivery of the lecture has been added.No 4107

carefully investigated curing the lat two years), the

hamadryad or king cobra, and the two kinds ot krait.The viperine poisons include the viperidse, represented bythe daboia. Russellii of India and the African puff adder;and the crotalidea or pit vipers (which differ from the formerin having a depression in the scales beneath the eye thefunction of which is not known) which are represented by therattlesnakes of America and the trimensurus, or tree viperof India. A study of the venoms of these species will serveto illustrate all the important points of this extensive subject,a brief summary of which is all that I can attempt to-day.With regard to the chemical nature I will only mention thatthe venoms all contain actively poisonous albumoses (thepeptones of the older literature) and that the viperine onesare coagulated and rendered inert at a lower temperaturethan are the colubrine ones. You see in the table a verymarked difference between the colubrine and the viperinepoisons, especially in their actions on the nervous system.Nevertheless, the difference is not absolute ; there are con-necting links between the two classes and I shall show youpresently that the venom of the bungarus fafCiatus, or

banded krait, is of mixed colubrine and viperine action, aswas found to be the case by C. J. Martin in the Australiancolubrine snake the psendechis porphyacus. Further,according to Weir Mitchell and Reichart and to Flexner,some of the pit vipers of the Western Hemisphere containvarying proportions of the colubrine element acting byparalysing the vaso-motor and respiratory centre, so thatin certain species mixtures in varying proportions of the twoactive nerve poisons are present. Again, the relatively slightaction of some at least of the colubrine poisons in reducingthe coagulability of the blood and in lowering the bloodpressure may well be minor degrees of the much more

marked similar effects brought about by the viperine poisons.There is, then, a gradation by means of connecting linksbetween the main colubrine and viperine divisions-a pointthe great interest of which will become clearer after I havedescribed the actions of the different venoms.

ACTION OF COLUBRINE VENOMS ON THE NERVOUS SYSTEM.

The best known of the colubrine venoms is that of thecobra, the physiological action of which was first carefullystudied by Brunton and Fayrer some 30 years ago. Theyshowed that its primary action was a paralysis of therespiratory centre and of the motor end plates, especially ofthe phrenic nerves ; they also as certained the important factthat by means of artificial respiration the circulation couldbe kept going for many hours after natural breathing hadfinally stopped as a result of the poison. Their researcheswere confirmed by Ragotzi and by Vincent Richards andWall in India, although attempts by an Indian commission,including Vincent Richards, failed to obtain completerecovery in animals by artificial respiration. More recentlyCalmette’s serum has been made by injecting horses withincreasing doses of a mixture of venoms, mainly consistingof cobra poison, for many months and it has an undoubtedspecific action against cobra venom. It has thereforebecome a matter of practical importance to ascertain

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whether the physiological action of other colubrine venoms(including that of the hydrophidas which are morphologicallycolubrines adapted to an aquatic existence) is the same asthat of the cobra and if so whether Calmette’s serum is alsoeffective against them and in what doses, especially in viewof the fact that O. J. Martin has found that it had only avery slight and practically unimportant. antidotal action

against the Australian colubrine snakes.

HYDROPHIDae OR SEA SNAKES.

Enhydrina Bengalensis.-This is the commonest and mostdeadly of the sea snakes which swarm round the coasts ofIndia and not infrequently cause loss of life among fisher-men. I have collected venom from four out of the six generamet with in Indian seas and found them all to produce deathwith typical colubrine symptoms, so that the enhydrina willserve to illustrate the action of the whole class. The sym-ptoms of poisoning by comparatively small doses are as

follows. After a long latent period, which in the case ofvery small doses may last several hours, the animal beginsto show signs of sleepiness, closing the eyes now and thenand nodding its head. After a while it sits down and beginsto show signs of commencing muscular weakness, for whenaroused movements are only carried out with difficulty. Itwill now be found that the animal is breathing both morequickly and deeply than normal, but before long the numberof respirations becomes decreased in frequency while stilllaboured in character. The paralysis increases until theanimal cannot stand or raise its head, the respirations becomeslower and slower, finally violent respiratory convulsions setin, the animal rolls over on its side, and the breathing finallyceases, the heart continuing to beat for a few minutes longer.After death the blood is found to be dark, but it clots veryfirmly when placed in a test tube and after a time exudes anearly clear serum. Stimulation of the phrenic nerves withthe secondary coil of faradic current produces no contractionof the diaphragm, but the muscle responds to direct stimu-lation. A typical curara effect is thus present and I findthat the nerve trunks are not affected, as the direct applica-tion of strong solutions of the venom does not alter thenegative variation of the current of injury. The sciatic andother nerves may or may not show this complete motor endplate paralysis, it being most marked after large doses of thevenom.

The symptoms which I have just described are preciselysimilar to those produced by cobra venom, of which

respiratory paralysis is the characteristic effect. For theircloser study I have taken simultaneous tracings of the

respirations by means of a Sandstom’s recorder and of thecarotid blood pressure by a Gad’s manometer and will nowshow you some slides illustrating the results. The sequenceof events you will see is the same in each, the time in whichthey appear ’varying inversely with the dose administered.The first change noted is a steady slowing down of the

respiration, the amplitude of which is also decreased until

breathing ceases, by which time the blood pressure hasbegun to rise above the normal as a result of commencingasphyxia, only to fall rapidly soon after respiration hasfinally ceased. This asphyxial rise of pressure is mostevident after small doses in which respiratory convulsionsare marked. In every case the respiration failed before thecirculation and motor end plate paralysis was found postmortem affecting the phrenic nerves and after the largerdoses also the sciatics, &c. In order to study the timerelationship between the paralysis of the respiratory centreand of the phrenics an experiment was performed in whichthis nerve was exposed in the neck, and the minimal faradiccurrent, which would produce a contraction of the diaphragmwhen applied to the nerve, was noted. It was found that

Ialmost complete failure of respiration occurred before thephrenics showed any weakening, so that the primary actionof the poison is clearly on the respiratory centre in themedulla. Next I tried the effect of artificial respiration in-maintaining the circulation after cessation of naturalbreathing. The process was begun when the respirations hadalmost ceased at the commencement of the usual terminalasphyxial rise of pressure. The result was that the rise wascounteracted and the circulation was steadily maintained as10ng as the inflation of the lurgs was carried on only to riseonce more on leaving it off. This sequence of events occurredrepeatedly and even when respiratory convulsions were

allowed to begin renewed artificial respiration both loweredthe excessive blood pressure and stopped the convulsions.Here once more we find similar results to those obtained byBrunton and Fayrer with cobra venom.

There are a few other points of interest concerning thesea-snake venoms which I made out while in India. Thequantity of venom obtained from them was very small, theaverage amount got from an enhydrina four or five feetin length being 0’ 010 gramme only, but it makes up for thisby its great toxicity, which in the case of birds I foundto be ten times as great weight for weight as that of cobravenom, being by far the most potent snake venom I know of.On comparing its action on fish (which these sea snakes liveon) with that of cobra venom I found that while 50 times asmuch cobra venom per kilogramme was required to kill fishas was necessary to kill birds, in the case of the enhydrinapoison only ten times as much was necessary, while the venomof some other sea snakes killed fish in only very slightly largerdoses than they killed birds-a remarkable adaptation of thepoison of the sea snakes to the needs of their environment.Again, some harmless snakes withstood 100 times the fataldose for a fish and 1000 times that for a bird. Further, Ifound that the enhydrina poison resembled tetanus toxin inthat small quantities of it may be fixed and rendered inertby being mixed for some time at blood heat with fresh brainmatter of a highly susceptible animal, so that the greatdifferences I have just mentioned in the susceptibility ofdifferent classes of animals to the venom may possibly bedue to varying affinities of their nervous systems for thepoisons.

INDIAN POISONOUS COLUBRINES.

Hamadryad or king cobra.-This is the largest and mostdeadly snake in India, if not in the world, but is fortunatelyrare. In a few experiments made by Fayrer many years agoit was not observed to differ in its effects from cobra venom,but I am not aware that its physiological action has hithertobeen closely examined. I will show you some tracingsillustrating its action on the respiration and circulation.In the first experiment five milligrammes per kilogrammeadministered intravenously paralysed the respiration inone and a half minutes, while the blood pressure beganto fail half a minute later. In the second, with one-

fifth of the former dose, you see that there occurred atemporary increase in the number and amplitude of the

respirations, followed by the usual steady failure andcessation after ten minutes. In both cases the phrenics werecompletely paralysed after death, but stimulation at regularintervals in the first experiment showed that their paralysishad not commenced until after failure of the respiratorycentre. In the third tracing you see the effect of artificialrespiration, showing that the circulation could be kept upfor a long time after respiration had finally ceased bythis means, just as in cobra and enhydrina poisoning.Hamadryad venom, then, also resembles in its action cobravenom.

Bungarus CaerUle1bS or common krait.-This is a small, verywidely distributed poisonous snake of the colubrine class.Thanks to the kindness of Dr. V. W. Shaw in giving me asmall quantity of its venom I have been able to get a tracingof its action on the respiration and circulation and to dosome other experiments with it. The tracing presents the

I characters typical of a colubrine poison. The respirationceased in four and a half minutes, while the blood pressureshows the usual late asphyxial rise and the heart continues tobeat for some minutes longer. After death the end plates ofthe phrenics were weakened but not completely paralysed,this venom having apparently less action on them than thatproduced by the other colubrine poisons. In other experi-ments on small animals the symptoms were typically those ofcolubrine poisoning.

Bungarus fasciatus or the banded krait.-This snake ismuch larger than the common krait, yet it has been con-sidered by Fayrer, Wall, and others to be less deadly than itssmaller relative. Wall has also described a chronic form ofpoisoning by it, in which respect its effects differ from thoseof other colubrine snakes. I have performed a number ofexperiments with it which bring out these points more

distinctly. In the first place weight for weight it is a verymuch weaker venom than the other colubrine poisons, for Ifound its lethal dose to be seven milligrammes per kilo-gramme in pigeons, or 14 times as weak as cobra venom. 28times as weak as the common krait, and no less than140 times as weak as the venom of the enhydrina(see Table III.). When small doses are injected into

pigeons typical colubrine symptoms are produced, butwith larger doses intravascular clotting may be foundmore especially in the portal system, just as I shall showyou presently is typical of most of the viperine poisons.This venom, then, contains both the colubrine and the,I .

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viperine elements. I shall return to this point in speaking Iof the antidotes to the colubrine poisons and will now show

Iyou tracings illustrating its action and exhibiting what Iregard as points of exceptional interest. The first three

experiments were carried out on rabbits the blood pressureof which is always rather low. In each of them the firsteffect of the poison was to cause a marked fall in blood

pressure which was to a considerable extent recovered fromafter a short time. Then a steady failure both in frequencyand amplitude of the respirations occurred (preceded in thecase of the smallest dose of five milligrammes per kilo-gramme by a temporary increased rate). With the failure of

respiration the usual asphyxial rise of blood pressure to abovethe original height took place and the heart continued tobeat for several minutes after the cessation of the breathing.So far the effects were typically colubrine, but in one ofthese animals a small clot was found post mortem inthe portal vein such b. as is commonly produced bya viperine poison, but never by a purely colubrine one.In the other two cases, however, there was no clottingto account for the temporary fall of blood pressure.The next tracing from a cat injected with ten milli-

grammes per kilogramme intravenously shows a still moremarked primary fall of blood pressure accompanied by animmediate cessation of respiration, both of a very temporarynature, and this was followed by the usual steady respira-tory failure of colubrine poisoning. In this case as soon as

breathing finally ceased artificial respiration was started, butit had only a momentary effect in keeping up the circulationinstead of a prolonged one, as in all purely colubrine arrests.In each instance the phrenics were found to be completelyparalysed after death, and in one case of a dose of 20milligrammes per kilogramme the sciatics were also similarlyaffected. The primary temporary fall of blood pressure andthe failure of artificial respiration to avert the final circu-latory failure after cessation of breathing are, then, peculiarto the poison of the banded krait among Indian colabrinesnakes, while I shall show presently that these are charac-teristic features of viperine poisons, so they are doubtlessdue to the viperine element already pointed out. In order totest this further a lethal dose of venom was heated to 900 C.for half a minute, an application of heat which has a muchgreater effect on the viperine than on the colubrine element.The result was a much less marked primary fall of bloodpressure and a much greater effect of artificial respirationin maintaining the circulation than in the last experiment;doubtless due to the elimination of most of the viperineaction, thus confirming the presence of this element in theunheated natural poison.

ACTION OF COLUBRINE VENOMS ON THE BLOOD.

Haemolytio action.-The very marked action of cobravenom in dissolving the red corpuscles of the blood haslong been known and has been more especially studied byD. D. Cunningham and by Kanthack and Stephens, the firstnamed having considered that it played an important part inthe lethal action of this venom. I have examined thisaction of all the colubrine poisons in Table I. by addingsmall measured quantities of blood to varying strengths of thevenoms dissolved in isotonic salt solutions and counting thenumber of red corpuscles at various times after, as well as incontrols, and by noting the degree of haemolysis. Table II.gives the strengths required to produce complete, or verynearly complete, haemolysis in 24 hours.

TABLE II.-Homolytic Action of Colubrine Venoms.

It is evident from these figures that the cobra venomhas an exceptionally powerful haemolytio action comparedwith the other colubrine venoms. The common krait comesnext to it, while that of the others is very slight indeed,especially in the case of the enhydrina venom, which

relatively to its lethal power has only one-thousandth partof the haemolytic action of cobra venom. Yet even in the

case of the cobra, if the red corpuscles be counted beforethe administration of a lethal dose and again immediatelyafter death, the decrease in their number is very far short ofwhat would be required to produce a lethal effect, while inthe case of the enhydrina I have not been able to detect anyreduction in the number of the red corpuscles as a result ofa minimal lethal dose. it is clear, then, that the hamolyticaction of the colubrine venoms as a class is of very slightimportance compared with their action on the nervous

system and that it is quite a negligible quantity in producingdeath, except perhaps in the case of cobra venom in verylarge doses.Action on the coagulability of the blood.-Cobra venom

when added in solution to blood prevents its clotting, as wasshown by D. D. Cunningham. I have found that this actionis possessed also in a lesser degree by enhydrina venom, forwhile a 1 in 200 solution of cobra venom permanently pre-vented the clotting of the blood, the same strength ofenhydrina venom only prolonged the clotting time by a fewminutes. This action in both cases is too slight to influencethe mass of circulating blood of an animal in ordinary dmes,but it will be sufficient to render it fluid locally at the seatof injection of the venom and so may materially increasethe rapidity with which it will be absorbed through the openmouths of the small vessels severed by the fang, and in thisway it probably plays an important part in producing theextremely rapid action of relatively very large doses ofcolubrine venoms.

ANTIDOTES TO COLUBRINE VENOMS.

The relative value of Calmette’s serum against digerentIndian colubrine venoms.-We have learned that the phy-siological action of the venoms of the hydropbidse andpoisonous Indian colubrine snakes is identical with theexception of the added viperine element in the case of thebanded krait. We now have to see if Calmette’s serum hasthe same specific action against the others as it has againstthe cobra. To test this I have carried out a series of ex-periments with each of the colubrine venoms by mixingvarying quantities of the same serum with an equal amountof the venoms (about ten times a lethal dose being em-ployed) and injecting the mixtures after half an hour atroom temperature (18° to 20° C.). The amount of serumrequired to neutralise a given quantity of serum in vitro wasthus obtained and the results are shown in Table III. In

TABLE IlL-Showing the Relative Value of Calmette’s Serumagainst the Colubrine Venoms.

Lamb. t D. D. Cunningham.

column 1 is given the minimal lethal dose of each of thevenoms per kilogramme weight, which, you see, varies so

greatly that the differences can be explained only on thehypothesis that they contain widely different proportions ofthe active respiratory paralysing poison. If this is so, thenan equal weight of enhydrina poison will contain ten timesas much of the active toxin as does cobra venom, and theamount of serum required to neutralise ten milligrammes ofthe former must be divided by ten before we can compare theaction of the serum against equal quantities of the active

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principles of the two venoms. In this way the figures havebeen obtained showing the cubic centimetres of serum

required to neutralise toxin equivalent to ten milligrammesof cobra venom. Two different varieties of cobra venom havebeen tested, the first being the common one, from whichmost of the antivenin is prepared; and you see that theantivenin acts better against this than against the rarervariety. Not far behind comes the closely relatfdhamadryad,then the enhydrina (a sea snake), while its action againstthe krait is more feeble. In all of these some of the animalswere saved by the serum from at least ten lethal doses ofthe venoms, but, on the other hand, no recovery took placefrom the venom of the banded krait, for, although th3colubrine symptoms were neutralised by the larger dosesof serum used, the animals died three or four days after-wards with symptoms of slow viperine poisoning-probablythe chronic form described by Wall-thus confirming theconclusion I had previously come to that this venom is amixture of the colubrine and viperine elements.The fact that Calmette’s serum has a definite specific

action against all the above purely colubrine poisons,including one of the sea snakes, is an interesting and

important one, but we have further to consider the doseswhich must be used. In column 4 of Table III. is enteredthe amount of serum required to neutralise one lethaldose of each venom for a man of 50 kilogrammes weight,about the average of natives of India, and you will see thatthe amounts are very large except in the case of the commoncobra. Further, we must know how many lethal doses thedifferent snakes eject at a single bite on an average, as wellas the limits within which they vary, but even here the dataavailable are incomplete and even contradictory. Thus,D. D. Cunningham, working in Calcutta, a home of thecobra, gives the average amount for this snake at 0-254gramme, while Lamb quotes Calmette as placing the amountat from 0’ 030 to 0 045 gramme, or about one-sixth to one-eighth of Cunningham’s figure. In the case of theenhydrina I obtained an average of O’ 010 gramme, or

about four lethal doses for a man, judging from its effectson birds and rabbits. In column 7 the amounts of serumrequired to neutralise in vitro the average amount ejected bydifferent snakes is entered, the doubtful ones being placed inbrackets, and it will be seen that the amounts are very large,while if injected after the venom they would be still larger.It is clear, then, that the serum must be made much strongerif it is to be relied on to save patients who have receivedfull doses of any of these venoms. If sufficient is given toneutralise all but a little less than one lethal dose the patientwould be saved, so that theoretically the dose of serum canbe reduced by an amount equivalent to a little under onefatal dose, but in practice it could not be cut so fine, whileit is advisable to prevent all symptoms by fully neutralisingthe whole of the venom received.

In view of the conclusion just arrived at I think thatwherever possible such serum as is available should beinjected intravenously so as to obtain the fullest and mostrapid action possible. In colubrine poisoning its use shouldnever be neglected as we cannot know the dose injected bythe snake and whether the serum available may not sufficeto reduce it below a fatal dose, especially if combined witha method of destroying much of the venom locally, which Ishall describe to you presently. I think also that it may be

possible to obtain a more generally powerful antitoxin byusing in its preparation a mixture of the different purelycolubrine venoms. Artificial respiration may also be of greatvalue in keeping the patient alive while medical aid or anti-venine is being sent for ; one case is on record where life

appears to have been saved by this method of treatment.

VIPERINE POISONS.I have already mentioned that hitherto the main action of

the viperine poisons has been considered to be their effectson the blood but that my observations of the last fewmonths have led me to the conclusion that the blood changesare altogether secondary in importance to the failure ofcirculation by paralysis of the vaso-motor centre. It willthen be most convenient in the case of these venoms first toconsider their effects on the blood and to see if they aresufficiently constant and extensive to account for the

symptoms and lethal effects observed and subsequently todeal with their action on the nervous system and with theirantidotes.

ACTION ON THE BLOOD.On the coagulability.-The first point I have to draw your

attention to is the marked difference between the action onthe blood of the daboia Russellii, a true viper, and of therattlesnake, a pit viper, the two vipers which have beenhitherto most carefully investigated. In the case of thedaboia it was suggested by C. J. Martin and shown by Lamb.that, in small animals at any rate, the most marked action isthe production of intravascular clotting, causing rapid deathwith violent convulsions. On the other hand, Weir Mitchelland Reichart found that a total loss of clotting power of theblood accompanied by haemorrhages was the essential feature-of rattlesnake poisoning ; they considered that it also had a.marked action in paralysing respiration. Flexner, who hasrecently made a careful study of the blood changes causedby the rattlesnake, lays stress on the absence of intra-vascular clotting. This apparently opposite action is,however, largely a difference of degree, for when thrombosisis produced by daboia venom the remaining unclotted bloodhas usually entirely lost its coagulability, as in rattlesnakepoisoning. D. D. Cunningham showed that if repeated smalldoses of daboia venom, each insufficient in itself to cause-death by thrombosis, are injected subcutaneously, then no.intravascular clotting takes place, but on the contrary the-negative phase of reduced coagulability is produced as inrattlesnake poisoning. I have fully confirmed this importantobservation and have found further that rapid death fromcirculatory failure without any intravascular clotting can be-readily and constantly produced by first giving small doses.either subcutaneously or intravenously, and after a timelarger doses by either method of administration. The.

significance of these observations lies in the fact that in the-case of such large animals as man intravascular clotting hasnot been found to occur, but only a loss of clotting andhaemorrhages.That the difference between the action of daboia and

rattlesnake venom on the blood is one of degree rather than;of kind is confirmed by some results which I have obtainedin the cases of the African puff adder (for the venom ofwhich I am indebted to Dr. J. W. W. Stephens) and of anIndian representative of the rattlesnake-namely, thetrimensurus anamallensis (for which I am indebted to Dr. W..Dowson), the physiological action of which has not, so far asI am aware, been previously investigated. The puff addervenom, whether administered subcutaneously or intra-

venously, may cause intravascular clotting like the daboia;,but it is more easily prevented by a single small preliminarydose than in the case of daboia poison, and in that case

complete loss of coagulability alone results. Again, in thecase of the trimensurus venom I have obtained still moreremarkable results, for in small doses intravenously loss ofcoagulability without any thrombosis was produced, as inthe rattlesnake, while larger doses caused immediate intra-vascular clotting of a rapidly fatal nature, as in daboiapoisoning. These differences evidently depend solely on therapidity with which the poison enters the blood, andprecisely parallel results are obtained when Wooldridge’s" tissue fibrinogens " are injected intravenously. It is clear,then, that there is no essential difference in kind in theaction of viperine poisons as a class on the coagulability ofthe blood, but only a difference in the amount of the

thrombosis-producing element in the different venoms,the daboia containing the largest proportion and pro-ducing the most marked clotting, and the rattlesnake theleast, while the puff adder and trimensurus are intermediategradations between the two extremes.

-U6emor,rkagic <MMM.&mdash;The next most important action ofthe viperine poisons on the blood is the production ofpetechial haemorrhages, more especially in the mesentery andother parts of the peritoneum, the peri- and endo-cardium,especially of the left ventricle, more rarely in the pleura, andalways at the seat of injection into the tissues. Here, again,different degrees of the effect are produced by the variousvenoms which I have investigated. They are far the mostmarked in the case of the rattlesnake, while they are almostabsent in fairly rapid poisoning by the daboia even wherethere is no intravascular clotting. After intravenous injectionof a fatal dose of rattlesnake venom I have seen markedhaemorrhages at the end of 15 minutes, while when watchingthe circulation in the mesentery the passage of red corpusclesinto the tissues outside the vessels can be seen within a fewminutes following the very marked vaso-dilatation of the

portal system. The pericardium may also contain a blood-stained effusion within an hour of the injection of the

) poison. Flexner has recently attributed this phenomenon, to a dissolution of the endothelial cells lining the

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vessels. On the other band, in acute daboia poisoningwith death from circulatory failure without any intra-vascular clotting such bastnorrhages are usually entirelyabsent, although I have occasionally seen slight petechisein the endocardium of the left ventricle similar tothose occurring in rattlesnake poisoning. Here, again, Ihave found intermediate degrees in other vipers, for the puffadder venom, although this is a pure viper like the daboia,produces very marked petechial haemorrhages only second indegree to those of the rattlesnake, while the trimensurus,although a pit viper, causes less marked haemorrhages thanthe rattlesnake or the puff adder but greater in degree thanthose of the daboia, so that here again we have a regulargradation running through the viperine venoms, only thelesser degrees are not peculiar to the true vipers or the moresevere ones to the pit vipers.

Haemolytic action.-In all four of the vipers dealt with afairly marked hasmolytic action was met with, for if theincoagulable blood obtained after death be allowed to standin a test-tube for a day the corpuscles will sink and theserum remaining above will be found to be blood-stained.Lamb has studied this action and concludes that it is moremarked in the body than in vitro, but in any case it is muchless than that produced by cobra venom and it is certainlyof very slight importance as a factor in the causation ofdeath by these venoms, especially in the more rapidly fatal- cases.

Will the blood changes accountfor the fatal symptoms?-Inow come to the question whether these blood changes willsatisfactorily account for the lethal effects of the viperinevenoms. In the case of small animals bitten by a daboia orpuff adder death is certainly commonly produced by intra-vascular clotting, but this is not so in the case of rattlesnakepoisoning, or in man when affected by either class of viper.In such cases the further question arises: Will the secondaryloss of coagulability of the blood accompanied by hmmor-rhages fully account for death ? That mere loss of clottingpower will not be fatal unless it produces uncontrollablehaemorrhages is clear from what we know of haemophiliacs.Further, cases have been recorded by Weir Mitchell andothers in which animals injected with rattlesnake venomshowed complete loss of clotting power for several days,accompanied by marked haemorrhages, yet made a completerecovery, so that even persistent loss of coagulability is notnecessarily fatal in these cases. More conclusive still is thefact that with all the four viperine venoms mentioned I wasable repeatedly to produce death without any thrombosis andwithout anything more than a few petechial haemorrhages,which could not have materially affected the vitality of theanimals. Lastly, in one experiment with trimensurus venomthe usual well-marked circulatory failure occurred, but afteran hour very evident signs of recovery showed themselvesand persisted. The animal was killed and the blood wasfound to be completely incoagulable and petechial hasmor-rhages were present, so that recovery, for a time at any rate,was taking place in spite of the persistence of the bloodchanges produced by the venom. In the fairly rapid deathswithout thrombosis, then, it is clear that there is some

important factor present other than the blood changes, andour question must be answered in the negative and somemore potent cause of death sought for. This we shall find inthe circulatory changes already referred to.

ACTION ON THE CIRCULATION.

This has been studied by taking similar tracings to thoseI have already shown you in the case of the colubrinepoisons. First, single lethal doses of daboia venom wereinjected intravenously and subcutaneously and the expectedintravascular clotting followed a few seconds after the directinjection into the blood stream and some minutes after thesubcutaneous injection of a much larger dose of the venom,the tracings showing a primary circulatory, quickly suc-ceeded by a secondary respiratory, failure or just the reverseof what occurs in colubrine poisoning.On reducing the dose a very different and unexpected result

was obtained, for when 01 milligramme per kilogramme(one. tenth of what produced immediate thrombosis) wasgiven intravenously a primary steady fall of pressure occurredeight minutes after the injection, followed quickly by asecondary cessation of respiration and respiratory convulsionssuch as commonly appear just before death. But instead ofthe heart quickly ceasirg to beat the blood pressure roseagain rapidly, well-marked Traube-Hering curves appeared,and slow breathing recommenced. A few minutes later the

blood pressure suddenly declined once more, although theslow but well-marked pulse indicated that the heart was stillbeating strongly. On the recurrence of respiratory convul-sions the pressure once more rose and Traube-Hering curvesreappeared, this sequence of events being repeated no lessthan five times before the final fatal circulatory failureoccurred. Post mortem there was absolutely no intravascularclotting found anywhere, nor were there any haemorrhages,although the blood was quite incoagulable. Here, then, wehave a primary cinculatory failure of peculiar characterproduced by a very small intravenous dose of daboia vencmwithout any intravascular clotting. At first I thoughtthe peculiar curve I have just described might beexplained by capillary clotting in the pulmonary cir-culation, the obstruction caused by which was over-

come for a time by the pumping action of the respiratoryconvulsions. To test this hypothesis I transfused both salinesolutions and the fluid blood always found after viperinepoisoning through the pulmonary, portal, and systemiccirculations from given heights in a series of cases of bothdaboia and rattlesnake poisoning without any naked-eyeintravascular clotting and found that both fluids alwayspassed through readily from a head of only from 30 to 40millimetres, so that it was evident that there was nocapillary obstruction due to clotting or other cauize. Itherefore proceeded to carry out a long series of experimentswith the four varieties of viperine poisons already mentionedin order to ascertain the real nature of the lethal circulatoryfailure without clotting which was the one important factorwhich I found to be common to the action of all of them.

In the first place I established the fact that by first givingsmall doses of daboia venom, either intravenously or sub-cutaneously, to produce the negative phase of reduced or lostcoagulability, followed by a further larger dose by eithermode of injection, the primary circulatory failure withoutany intravascular clotting could always be induced, while itwas still easier to get it with the puff adder venom. In thecase of the rattlesnake it was always caused by a singlelethal intravenous dose and also sometimes with trimensurusvenom. This circulatory effect is, indeed, the only importantsymptom which is common to all four of these venoms ;neither the thrombosis nor the haemorrhages are produced byall of them and the heamolytic action is of slight lethalimportance. Secondly, on testing the effect of these venomson the heart directly they were found to have no power toslow or to stop its action even in stronger solutions thanthose which produced circulatory failure when injectedintravenously, so that the action of the venoms could not beexplained by any direct action on the heart itself.The remarkable Traube-Hering curves, already mentioned,

pointed to an action on the vaso-motor centre, so this pointwas next investigated in the following ways. Completevaso-dilatation was produced in a dog by cutting acrossthe spinal cord in the cervical region and the circulationwas maintained by means of artificial respiration. On nowinjecting first a small and a few minutes later a largedose of daboia venom no sudden primary circulatory failurewas produced, such as occurs in like circumstances inwhich vaso-dilatation has not previously been produced, whilethe continuation for some minutes of the pulse showed thatthe heart also was not paralysed. Again, wben a verymarked and persistent fall of blood pressure, without anythrombosis, has been produced by a viperine venom,then section of the spinal cord in the cervical regioncaused no further persistent fall of pressure, showingthat complete vaso-dilatation had already been producedby the venom. This was confirmed by the fact that oncethe Traube-Hering curves (of vaso-motor origin due to thestruggles of the affected centre to maintain the bloodpressure) had disappeared and a persistent very low pressurehad been produced by the venoms, then stimulation of thecentral end of the sciatic nerve with a strong faradiccurrent failed to cause any rise of blood pressure, provingthat the vaso motor centre had been completely paralysed bythe venom. Once more the circulation in the mesentery oromentum was watched under the microscope and the portalvessels were seen to dilate very markedly coincidently withthe primary fall in blood pressure. The rise of blood

pressure on the occurrence of respiratory convulsions canalso be readily explained by the mechanical aid afforded tothe circulation by the contraction of the diaphragm andother muscles emptying the dilated portal and systemicvessels and driving the blood on to the empty heaJt andpossibly assisted by stimulation of the failing vaso-motor

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centre by the venous blood produced by the previous cessa-tion of respiration Lastly, I have been able to demonstratethe dilatation of the portal circulation coincidently with thefall in the general blood pressure by means of simultaneoustracings of the carotid pressure and of the variations in thevolume of a loop of small intestine (the ends of which hadbeen ligatured) placed in an oncometer connected with arecording apparatus. If the fall of general blood pressurewas of cardiac origin the lever of the oncometer should fallsimultaneously with the decrease of the carotid pressure,owing to less blood passing to the intestinal vessels as well asto the carotid artery, but you see from the tracings that withthe fall in the carotid pressure the oncometer lever rises

rapidly showing a very marked dilatation of the portal vesselsand that this rise is already well marked by the time thecarotid pressure begins to show itself. The only exceptionsto this were when intravascular clotting occurred in the

portal circulation, when both levers fell rapidly together.These experiments furnish final proof that the primary cir-culatory failure is due to vaso-dilatation, while I have alreadygiven you some evidence that this paralysis is of central

origin. It is conceivable, however, that it might be partlydue to a local action on the blood-vessels, especially in viewof the undoubted action of some of these venoms in dis-solving the lining cells of the small vessels and so causinghaemorrhages. In order to test this Dr. T. G. Brodie verykindly tried the effect of cobra and daboia venoms on theperipheral vessels cut off from the central nervous system,using his perfusion apparatus, and we found that both cobravenom in large doses and daboia venom in very small onescaused marked local vaso-constriction. It is clear, then, thatthe vaso-dilatation is purely of central origin, occurring inspite of a contrary local action on the blood-vessels.We arrive, then, at the conclusion that the essential lethal

factor of all the viperine venoms tried is the production ofa paralysis of the central vaso-motor centre producing aprimary circulatory failure, followed by a secondary respira-tory failure, due to deficient supply of blood to the medulla.

I should also mention that none of the viperine venomsever produce any paralysis of the motor end plates of thephrenics or other nerves.

ANTIDOTES TO VIPERINE POISONS.

Calmette’s anti-venine.-Calmette’s serum has no efficiencyagainst the viperine venoms, apparently because he heats fora short time the mixtures of venoms which he uses in its

preparation and thus destroys, or very greatly weakens, thesmall proportion of viperine poison in the mixture. A fewobservations which I have made support the conclusion thatthe antivenine is useless against the vipers ; its failure againstthe mixed venom of the banded krait already referred topoints to the same conclusion.

Vaso-constricting drugs.-The discovery of the main lethalaction common to all the viperine venoms dealt withnaturally led me to try how far the primary circulatoryfailure due to vaso-motor paralysis can be counteracted bysuch drugs as have a powerful effect in contracting theperipheral vessels, the most important of which is suprarenalextract. I found that 0 - 1 to 0’5 cubic centimetre of a 1 in1000 solution of adrenal chloride (Parke, Davis, and Co.)immediately sent up the blood pressure in cats poisoned byviperine venoms, but that if the vaso-motor centre was

already c?mpletely paralysed (stimulation of the central endof the sciatic nerve no longer causing any rise in pressure),then the effect of the adrenal extract only lasted a fewminutes. On the ether hand, if there were still well-markedTraube-Hering curves present the effect was much more

lasting and powerful. Nicotine, which was suggested to meby Sir Lauder Brunton, in doses of one milligramme for acat, also had a similar effect in restoring the blood pressureand at the same time it powerfully stimulated the flaggingrespiratory centre, being superior to adrenal in this respect.Further, some increase of the blood pressure of considerableduration was obtained by means of pressure applied to theabdomen by a binder acting by partly emptying the portalvessels and bandaging the limbs might also assist in asimilar way. As, moreover, the venoms of the vipers aremuch weaker weight for weight than the colubrine venoms(daboia being about ten times as weak as cobra venom) it isprobable that the vipers do not often eject much more thanone lethal dose for a man. Hence a larger proportion ofborderland cases of viperine poisons may be expected to bemet with than in the case of colabrine bites and the methodsof maintaining the circulation just described may very

possibly prove to be of value in saving the lives of somecases which not so treated might prove fatal, so that in theabsence of any specific antidote to viperine poisons the abovesuggestions appear to be well worthy of consideration.

A SIMPLE AND PRACTICAL METHOD OF DESTROYING SNAKEVENOM IN THE BITTEN PART.

Lastly, I come to a practical method of treating any kindof snake poisoning which promises to be of great value inall cases seen early and which might be carried out by anyintelligent person if a medical man was not at hand. I haveshown you that Calmette’s serum is not strong enough toprove efficient against full doses of colubrine venoms, whileit is very seldom at hand when wanted and tends to lose itspower in a hot climate. It is also useless for viper bites,while the methods I have described of counteracting thephysiological effects on the circulation of the latter wouldnot be likely to succeed when very full doses have beeninjected. If, however, most of the poison could be destroyedlocally at the seat of its injection before much of it hadgained access to the circulation, then the above methodsmight prove efficient in dealing with the comparatively smallamount of venom already in the system. Many attemptshave been made to find some substance which would destroythe poison at the seat of injection, the best known of which ispermanganate of potassium, which Wynter Blyth first showedwill rapidly destroy the power of cobra venom when mixedwith it in vitro. But experiments by Brunton and Fayrerand others, in which strong solutions of this substance wereinjected at the seat of insertion of the poison, did not provesuccessful in averting the death of the animals. They have,however, recently suggested a more radical plan of using thesalt-namely, first to place a ligature round the limb abovethe seat of inoculation of the venom and then to make asmall incision through the place of injection and to rub inpure crystals of the permanganate moistened with a littlefluid, with a view to neutralise as much as possible of thevenom before it has had time to be absorbed into the circula-tion. At their request I have carried out a preliminary seriesof experiments to test this method of using the salt withvery promising results.

. -......

In the first place I set to work to find out if the per-manganate will destroy other venoms than that of the cobraby mixing from 10 to 20 lethal doses with a fraction of acubic centimetre of a 10 per cent solution of permanganateof potassium, enhydrina, bungarus fasciatus, rattlesnake,African puff adder, and daboia venoms beivg tried. Themixtures were injected into animals after from five to tenminutes, with the result that none of them showed any sym-ptoms of poisoning except one which had received a verylarge dose of bungarus fasciatus venom mixed with less thanits own weight of the permanganate and in this case theanimal lived longer than a control with less than one thirdof the dose, so that most of the venom had been destroyedlocally in this instance. It is clear, then, that the salt willdestroy in vitro nearly its own weight of every class of snakevenom. Next, rabbits and cats were chloroformed andinjected with several times a fatal dose of cobra or daboiavenom, a ligature was applied after half a minute, five, or10 minutes, and the treatment described was carried out, theligature being released immediately after its completion. Inthe case of the rabbits only very marked prolongation of life,as compared with the controls with the same doses, wasobtained, owing to these animals being found to be muchmore susceptible to the venoms than cats, so that the dosesinjected into the rabbits were many times a lethal quantity.In the case of the cats much more favourable results wereobtained, only two out of 12 animals treated having died, onebeing the first case treated with cobra venom, while theother had received five times a fatal dose of daboia venom (amuch larger dose than this snake could inject in the caseof an adult man) and the ligature was not applied until afterfive minutes. On the other hand, recovery took place after10 lethal doses of cobra venom treated after half a minute,from five lethal doses after five minutes, and from threelethal doses after ten minutes ; while with daboiavenom animals were saved from five lethal dosesafter half a minute and from three lethal doses afterfive and ten minutes respectively. I also found thateven 30 seconds after the injection of the venoms therewas a local extravasation of blood-stained serum presentwhich clearly indicated the position of the poison and thesalt was rubbed in directly over this until the tissues werequite blackened. The amount of tissue thus destroyed was

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quite superficial, while the salt has antiseptic properties. I

hope to have an opportunity of carrying out further experi-ments on my return to India very shortly with fresh venomsand to wait longer before ligaturing the limb so as toascertain the exact limits of the value of this method. The

rapid local effusion which I have just mentioned makes methink that after the first few seconds this pouring out oflymph will very materially retard the rapidity of the absorp-tion of the venoms so that it is possible that even half anhour or more from the time of the bite a considerable pro-portion of the venom may still be unabsorbed at the site ofits injection and so may still be destroyed by the treatmentsuggested, and it is obvious that if this can be done at anytime before a fatal dose has entered the circulation life willbe saved and in any case the chances of success with theother methods of treatment will be greatly enhanced. Thatthe absorption of a subcutaneous injection of snake venomsis very slowly completed is shown by the fact that one milli-gramme per kilogramme of cobra venom in a cat will kill ina few minutes when injected intravenously, yet the samedose takes from 24 to 48 hours to cause death when injectedsubcutaneously. When a very large dose, such as 50times a lethal amount, is injected subcutaneously into adog’s tail and this member is cut ofE inside the seatof injection within a few seconds the animal will stilldie, as shown by Fayrer years ago. The reason is thatone fatal dose may be absorbed out of such a largequantity within a few seconds. In the case of man, how-ever, such a relatively large dose can never be received, sothat there is much longer time for action, how long canonly be determined by further experiments on animals.Nevertheless, I think that the results I have given you aresufficient to warrant the use of this method in practice,especially as it is efficient against all kinds of snake venoms.At the suggestion of Sir Lauder Brunton an instrument hasbeen made consisting of a lancet covered with a sheath, ina small space at the base of which permanganate crystalsare kept, the whole being but one and a half inches in

length, so that it can easily be carried in a corner of thewaistcoat pocket always ready for instant use. This will

shortly be sold at a very low figure so as to bring it withinthe reach of even the poorest classes in India and elsewhere.

In conclusion, I have to express my best thanks to Dr.A. W. Waller and to Dr. T. G. Brodie and Dr. N. H. Alcockfor much very valuable advice and assistance in the courseof my researches here.

Some ObservationsON

MEDICAL EXAMINATIONS FOR LIFEASSURANCE.

Being the Presidential Address delivered before the LifeAssurance Medical Officers’ Association on

Jan. 27th, 1904,

BY SIR DYCE DUCKWORTH, M.D. EDIN., LL.D.,PRESIDENT OF THE ASSOCIATION ; PHYSICIAN TO ST.

BARTHOLOMEW’S HOSPITAL.

GENTLEMEN,-The honour which you have conferred uponme in electing me to the presidency of this society is onewhich I fully appreciate and I can do no more than tryduring my term of office to emulate the efforts of the

distinguished men who have preceded me here. It will notbe contested that during the few years of the existence ofthis association the work already accomplished in it has fullyjustified the expectations of its originators and earned creditfrom all who have taken part in it. The association is trulyrepresentative of a large body in our profession which beforeour foundation was loosely, if at all, bound togetherand devoid of any means of conference. There was

abundant experience at hand, all unrecorded and lost astime passed on, but there was no organised body of reapersto gather in the harvest of it. We are now engaged inutilising this experience for the benefit of the generalpublic as well as for ourselves. We constitute no kind oftrade union here but we bring the best traditions of ourcatholic profession to bear on all our relations with the

public and the several bodies which we repreent or act for.The results of our efforts here are, I repeat, for the generalcredit and benefit of the different life assurance associationswhich we serve, and they assuredly tend to more exact anduniform performance of our duties.

I have long been of the opinion that the habitual examina-tion of lives for assurance purposes constitutes one of themost useful and thorough methods of training for the dailywork of the clinical physician. Such work is a comtantcheck upon mere routine. Each case presents a new

problem and requires the full appreciation of the persoralfactor which is so necessary, and, alaE, not always observed,in practical medicine. It is a daily study in physiognomicaldiagnosis-a subject too little taught in our schools in thesedays. It tests and sharpens our wits in framing progno4is.Again, how great is the advantage of reviewing, as we oftenhave to do, the perfectly normal and healthy bodies of ourcandidates. We have so constantly the frail and theabnormal before us that we do well to be often in face of t,hesound and robust to recall us to the recognition of healthystandards. And here I would make this further remark,that in our daily duties as physicians we are apt, as we

gather experience, to think better of many of the frail andabnormal subjects that we encounter and to project for thema fairer forecast than is possible for the average actuary orinsurance office director to do. We follow the progress ofindividuals who present defects and manifest here or thereinadequacy of one or more organs of the body, and knowhow much can be done for them, how they may be protectedfrom their untoward tendencies, and how much recuperationis to be hoped for. But while we sometimes feel perplexityfrom this source we are bound to have regard to the businessside of the transaction which is in prcgress in each case andto look at it from the view of men of business with largeresponsibilities. This calls often for the nicest determinationand it is for us to form clear and decided opinions which wemust be prepared firmly to stand by.

It must be confessed that we are sometimes startled by theconfident opinions which are formed upon the facts disclosedin the papers which come before us, cases being placed in acategory of excellence which is in no way justified. Suchopinions emanate at times from men of good position in theprofession and not only from inexperienced examiners. Theyare largely due, as I believe, to the habit of filling up papersassiduously without due regard to the facts set down and tothe dangerous habit thus entailed of disregarding the mannerand aspect of the individual under examination. When thequestions were fewer and less searching it was formerly thepractice to pay closer attention to the examinee and thus tosee into the real inwardness of the individual. We must notbe slaves to the papers only. And here I would remark thatsome of these are over-elaborated and almost absurd,especially in the case of the American offices. Those of thebest British offices are, .1 consider, all that they need to be andany requirements beyond those laid down in them will tendto error rather than to exactitude for the reasons I have justmentioned.Some of the most profitable discussions that we have had

related to the subjects of albuminuria and glycosuria and wehave learned better how to gauge such symptoms. The formersubject, I may mention, received masterly treatment fromthe late Professor Stokvis of Amsterdam in a communicationto the Congress of Life Assurance Medical Officers held atthe Hague in 1901 and it left little or nothing to be added tothe problem. Each of the conditions just mentioned callsfor the greatest skill and experience in dealing wisely wi’hthem and we are now better than ever qualified to frameprognoses respecting them. We have discussed many otherconoitions causing anxiety to us in our duties. Amongstthese are tuberculosis and the malign influence of alcoholicintemperance. As you are aware, the latter subject comesbefore us to-night in a communication from one who is wellequipped to speak with authority upon it, and we welcomethe presence of a distinguished Parliamentary advocate oftemperance in the person of Mr. Whittaker, chairman of theUnited Kingdom T. mperance and General Provident Institu-tion, who does us the honour to unfold his views before us.For myself, I maintain the views impressed upon me as aclinical physician in respect of the employment of alcoholicliquids for both the healthy and the sick, and I am anythingbut a persona grata to those who inculcate total abstentionfor everybody. The opinions which I hold and teach arederived from full experience, without any bias in the matter,and with an equally full aversion from the degrading and