THE CAUSE OF DEATH FROM CHLOROFORM. BY. H. C. WOOD, M.D., PROFESSOR OF MATERIA MEDICA AND THERAPEUTICS IN THE UNIVERSITY • OF PENNSYLVANIA, H. A. HARE, M.D., DEMONSTRATOR OF THERAPEUTICS FROM THE MEDICAL NEWS, February 22, 1890. [Reprinted from The Medical News, February 22, 1890.] THE CAUSE OF DEATH FROM CHLOROFORM. By H. C. WOOD, M.D., PROFESSOR OF MATERIA MEDICA AND THERAPEUTICS IN THE UNIVERSITY OF PENNSYLVANIA, AND H. A. HARE, M.D., DEMONSTRATOR OF THERAPEUTICS. In the Indian Medical Gazette for February, 1889, it is stated that a Commission composed of Dr. Hehir, Mr. Kelly, and Mr. Chamarette, assisted by the students at the Hyderabad Medical School, have made a series of experiments upon 128 full-grown pariah dogs, to ascertain the method in which chlo- roform causes death. It is further affirmed that the investigators varied the doses and the method of administering the chloroform in every way, and tested the value of artificial respiration by reviving the dogs over and over again, after breathing had stopped, and while the heart was still beating, and that they found that no matter in what way the nsesthetic was given the heart became dangerously affected only when the breathing had ceased. We have not had the opportunity of seeing the original report of this Commission, but learn from current medical journals that under the auspices of 2 WOOD, HARE, the Nizam of Hyderabad, Dr. Lauder Brunton, of London, has gone to investigate the matter. It is also stated in the Lancet that cablegrams have been received from Dr. Brunton affirming that the expe- riments of the Commission have been verified and their conclusions justified, and that as many as 450 animals have been used in the study of the question. The surprising statements which have been made in the Indian journals and in the London Lancet, with the practical deductions which apparently follow upon them, seem to us of so great import as to demand the putting upon record of our own experience. We believe that physiologists in general hold the opinion that when chloroform is given to the lower animals in a very dilute form, and gradually pushed, it causes by its action upon the nerve centres a paralytic relaxation of the muscles and at last death by paralysis of the respiratory centres ; but that when it is administered freely in concentrated vapor by inhalation, or when it is injected in sufficient amount into the jugular vein, it kills by a paralytic arrest of the heart, the viscus stopping suddenly in its beat, and being found after death relaxed and incapable of reacting to stimuli. It has generally been believed that the danger from cardiac arrest by chloroform increases in direct ratio with the ra- pidity of administration ; but that in animals, as well as in man, cardiac arrest sometimes occurs almost at once on the inhalation of the anaesthetic in small amount; or, in other words, that compara- tively small amounts of chloroform have at times caused death by syncope, through direct action CAUSE OF DEATH FROM CHLOROFORM. 3 upon the heart. This vve believe has been the teaching of all the instructors, both clinical and physiological, in the Medical Department of the University of Pennsylvania, and we desire to reit- erate, as the result of our past experiences, that chloroform does, in the ordinary American dog, sometimes kill by paralyzing the heart, such paral- ysis accompanying or preceding, according to our past experiments, the arrest of the respiration. It has been the custom of one of the authors of this paper, in his lectures before the University class, to demonstrate by means of the respiratory tambour, the mercurial manometer, and the kymo- graphion, a continuation of respiratory movements after cardiac arrest through chloroform. Further than this, we have at various times in the Laboratory of Experimental Therapeutics, at the University, taken tracings proving the same facts. Moreover, on experimenting with other drugs in the laboratory, the point at issue has been deter- mined, because we almost invariably kill the dog which has escaped the drug being studied, with chloroform, whilst its artery is still attached to the kymographion, and the needle is still registering the play of the blood. We have sometimes given the drug intravenously, but in many cases we have administered it by inhalation of the concentrated vapor, and we have often noticed that death has been produced by primary cardiac arrest. When chloroform is injected into the jugular vein it is carried first in its concentrated form to the right side of the heart, and when it is absorbed 4 WOOD, HARE, through the lungs it is carried directly to the left side of the heart. In either method of administra- tion the anaesthetic reaches the heart in a concen- trated form before it is scattered in the circulation and gets to the respiratory centres. This may have connection with the frequent early occurrence of cardiac arrest during chloroformization in the human subject, but we desire especially to emphasize the point, that in either method of administration the heart is first reached, and that in our experience there is no essential difference in the action of chlo- roform, whether it is given by inhalation or whether it is injected into the jugular vein. As we use between us, in the laboratory of the University, many dogs 'yearly, a very large propor- tion of which are finally killed by chloroform, we may be excused for our past positive assertions that chloroform is a cardiac paralyzant and does kill dogs by a direct action upon the heart or its con- tained ganglia; especially since we have been strengthened in our opinion by the fact that Dr. Reichert, Professor of Physiology in the University, has reached results confirming our own, and has frequently demonstrated the same to the University classes. The statements that have been recently made in the Indian journals and in the London Lancet, have led us to reexamine the subject and to make a series of experiments upon it with the greatest care. We have, also, varied and extended these experiments in order to determine whether chloroform paralyzes CAUSE OF DEATH FROM CHLOROFORM. 5 the heart by a direct influence or by an indirect action through the vagus. A number of our experiments have been made by injecting the chloroform into the jugular vein; in others it has been administered by the respiratory Tracing No. i.1 tract. In all cases accurate tracings have been made by means of the kymographion and the respir- atory tambour. The theory has from time to time found advocates 1 The upper tracing represents the respirations as registered by a tambour; the second one the pulse waves, and the third the abscissa line and second marks. 6 WOOD, HARE, that the vapors of chloroform may, by irritating the larynx and adjacent parts, cause arrest of the heart through a reflex inhibition. To test the possibility of this we have made a number of experiments. When the tracheal canula is tied tightly into the trachea some distance below the larynx, it is evident that the latter organ is isolated from the general respiratory tract, and that chloroform injected into it will exert only a local influence. In all the ex- periments which we have made in the way just indi- cated, the injection has been followed by an imme- diate and very pronounced primary fall of the pressure, followed, after a very brief interval, by a rise which usually reaches decidedly above the norm. As an example of one of these experiments, we give the preceding tracing. (See page 5, Trac- ing 1.) The primary fall of arterial pressure, which has just been spoken of, can scarcely be produced ex- cept by reflex inhibition of the heart or of the vaso- motor centres, whilst the secondary rise is probably the result of a reflex vaso-motor spasm. In order to throw light upon this question, we have made experi- ments by injecting chloroform into the larynx after division of the pneumogastric nerves, the trachea being ligated so as to prevent the entrance of the anaesthetic into the lungs. (See page 192, Tracing 2.) In making practical application of the experiments just discussed, it must be noted that in no case have we succeeded in completely arresting the heart’s action by injecting chloroform into the larynx, and as the chloroform was injected in liquid form, it is CAUSE OF DEATH FROM CHLOROFORM. 7 plain that the irritation was more intense than could be produced by the mere vapors of the anaesthetic Vagi cut at first x mark; chloroform injected into larynx from x second to third x marks Tracing No. 2. however concentrated; therefore, while it must be considered that it is possible for a reflex inhibitory arrest of the heart to occur during the inhalation, 8 WOOD, HARE, No. 2a. Same continued; no break in time. No. 2b. i minute later. CAUSE OF DEATH FROM CHLOROFORM. 9 No. 2c. 30 seconds later. such an accident is extremely improbable, and we consider it practically certain that a heart so arrested would, a few seconds later escaping from the inhibi- tory control, recommence its beat. It certainly has never been proven that chloroform can cause in the human subject permanent reflex inhibitory cardiac arrest, and as our experiments upon the dog have failed to cause such arrest, we consider it very im- probable that inhibitory arrest is ever produced in man by chloroform. The second series of our experiments were made to determine the way in which large amounts of chloroform, either thrown into the jugular vein or absorbed into the pulmonic capillaries, cause death. 10 WOOD, HARE, -We have found that it is possible for the heart and respiration to be practically simultaneously paralyzed by the anaesthetic. (See Tracing No. 3.) Tracing No. 3. DOG WT- 10/2 KILOS- FULL GROWN 5CC- OF CHLOROFORM INJECTED INTO JUGULAR AT X On the other hand, the heart may be arrested during chloroformization, and the respiration con- tinue, as is shown in the accompanying tracings. (See Tracing No. 4.) We desire to call attention to the fact, that of the two tracings here inserted, one (Tracing No. 4) was made by injecting the chloroform into the jugular vein, whilst the other (Tracing No. 5) was obtained by the inhalation of chloroform. In the second experiment (inhalation) breathing continued two min- CAUSE OF DEATH FROM CHLOROFORM. 11 Tracing No. 4. DOG WEIGHT II KILOS. FULL GROWN 2/2 CC- INJECTED INTO JUGULAR VEIN AT X utes after the heart had ceased to act. (See page 12, Tracing 5.) The next series of experiments were made with small doses of chloroform. In a number of these cases the respiration ceased long before the heart’s action, as is shown in the appended tracings, in which the heart continued to beat two minutes after the cessation of respiration. (See pages 14 and 15, Tracings 6 and 7.) The final series of experiments we made to deter- mine whether chloroform arrests the heart by indi- rectly affecting the vagus or by a direct action upon it. In one experiment (Tracing No. 8, page 17) the vagi were cut before, in the other (Tracing No. 9, page 18) after the exhibition of the chloroform. It is evident that the vagal section has little or no in- 12 WOOD, HARE, Tracing No. 5. Chloroform inhaled at x. CAUSE OF DEATH FROM CHLOROFORM. 13 No. 5a. No. $&• Same tracing continued 30 seconds later. Same continued x minute later. No. sc. Same continued 30 seconds later. 14 WOOD, HARE, Tracing No. 6. CAUSE OF DEATH FROM CHLOROFORM. 15 DOG, WEIGHT 5 KILOS- GAVE CHLOROFORM BY INHALATION CONCENTRATED VAPOR- Tracing No. 7. 16 WOOD, HARE, No. 7a. Same tracing continued, no break in time. No. 7b. Same tracing continued 30 seconds later. CAUSE OF DEATH FROM CHLOROFORM. 17 No. tc. Same tracing continued i minute and 30 seconds later. Tracing No. 8. DOG,WEIGHT 20 KILOS. VAGI CUT AT X- CHLOROFORM INJECTED INTO JUGULAR AT Y. 18 WOOD, HARE, Tracing No. 9. Vagi cut at x x, but did not start heart beating again. Same tracing i minute later. CAUSE OF DEATH FROM CHLOROFORM. 19 fluence upon the cardiac action of chloroform, which, therefore, acts directly upon the heart and vaso-motor system. (See Tracings 8 and 9.) The experiments which We have given show that chloroform acts as a powerful depressant poison upon both respiration and circulation, that sometimes the influence is most felt at the heart, and death results from cardiac arrest; that in other cases the drug paralyzes primarily the respiratory centres, whilst in other instances it seems to act with equal force upon both medulla and heart. So far as practical medi- cine is concerned, it makes little difference whether the heart stops just before or just after respiration; so that those cases, in which cardiac and respiratory arrest are almost simultaneous, are, for the purposes of the clinician, the same as those in which heart- arrest precedes respiratory paralysis. Finally, the general results of our new experiments also coincide with our previous experience in the laboratory, and with what we believe to be the general belief of physiologists—that cardiac arrest is specially prone to occur when chloroform is administered rapidly and in a concentrated form. The present series of experiments which we have made with chloroform are so concordant in their results with those previously obtained by other ex- perimenters and by ourselves, that it seems to us that their results cannot be gainsaid. Therefore if a final statement should be made by Dr. Lauder Brunton and his India coadjutors that the dogs of India are killed by chloroform solely by the action upon the respiratory centre, the conclusion must be 20 WOOD, HARE, drawn that the pariah dogs of India are affected by chloroform differently from those of Europe and America. This to us seems the best explanation of the curious results obtained in India. It is possible that the climatic influence of that country may make the respiratory centres abnormally sensitive to chloroform. That the thought of the different con- stitutions of animals in different climates is not absurd, is shown by the tact that, some years ago— after one of us had stated before the Physiological Section of the International Medical Congress, at London, that if certain asserted results were ob- tained upon European dogs, said dogs must differ from those of America, and had been met with a smile of incredulity—Dr. Brown-Sequard rose and stated that he had experimented upon hundreds of dogs on both continents, and that there was a dis- tinct difference between the animals, the vascular system of the European dogs being much more de- veloped and operations upon them being, therefore, much more bloody than was the case with the Amer- ican dog. Hashish causes the East Indian to run amuck and commit crime but fails so to affect the European. Whatever explanation we may accept of the different results which have been reached, we very strongly urge the consideration that these re- sults show that the action of chloroform upon the human system is not to be estimated solely by any influence which it may have on the dogs of India. Indeed, it is possible that there may be the same difference between man in hot and cold climates as there appears to be in dogs in hot and cold climates; CAUSF. OF DEATH FROM CHLOROFORM. 21 but we do not know of any statistics which will throw light upon such a supposition. A fact to be remembered is that though 450 pariah dogs in India have died of respiratory failure, an equal number in America have died of cardiac arrest, whilst the records of clinical medicine show that death in the human being from chloroform usually takes place either by primary arrest of the heart, or by a simul- taneous arrest of the heart and the respiration, while in etherization the respiration usually ceases distinctly before the heart’s beat. We do not pro- pose in the present paper to reiterate the statistics which may be found in the text-books and recent treatises on anaesthetics, but we do desire to say em- phatically that we believe the roll of deaths from chloroform would be very much larger if all the cases were reported, and that the present inequality between the anaesthetics, ether and chloroform, would be much more pronounced if an absolutely clear record could be obtained. One of us has seen, in a Philadelphia hospital, death produced by chloro- form through cardiac arrest. The other has personal cognizance of two cases ; but none of these instances have been reported. The surgeon who uses ether knows that he will receive no blame if a death occurs from it, and also that he has a rare case to put on record, which will give his own name a permanent place in anaesthetic literature, and consequently he naturally hastens to publish his unfortunate result; whereas the surgeon who uses chloroform knows that if death occurs from the anaesthetic, a very large proportion of the profession will condemn him 22 WOOD, HARE, either in public or secret for the use of this drug. Moreover, deaths from chloroform are only too common, so that the surgeon has nothing to gain and much to lose by publication of a chloroform death, and if possessed of the average human na- ture, holds his peace. After the present paper had been sent for publica- tion, the issue of the London Lancet ior January 18, 1890, came to hand, and we have carefully read the report of the Hyderabad Commission. The great respect and friendship which we have for some of the members of this commission—make us loath to differ from them, but the issue between us is not simply a scientific matter, which would allow of silence, but is of such immense practical importance, involving, as it does, human life, that we feel it a duty to speak. In the first place, we fear that the Commission’s statement that their object is “to test the suitability and safety of chloroform as an anaesthetic,” will mislead the minds of readers as to the proper scope of experiments upon animals in regard to thera- peutic questions. We believe that no one will ac- cuse us of attempting to diminish the importance of such experimentation, but we insist that the only proper objects of such experiments are to lead the way to clinical studies, and to explain clinical facts. A well-established clinical fact cannot be disproved by any amount of experiments upon animals. We have given elaterium to dogs until it has caused death, but it has not purged. Suppose that every dog in India had had administered to it ela- terium, without the production of purgation, would CAUSE OF DEATH FROM CHLOROFORM. 23 that prove that elaterium does not purge man ? We believe that it is proven by clinical experience that, occasionally, in man chloroform does suddenly, without warning, arrest the heart’s action. It seems to us scarcely possible that such conclusions as clin- ical reports, appear to be too definite and positive upon this point to be contradicted by experimental studies. But we believe that in verity the results of experiments with chloroform upon the lower animals are in accord with those obtained in human medicine. In any discussion with wide differences of opinion, it is a matter of importance to determine points of agreement as well as of disagreement, and the prob- ability of the correctness of the facts agreed upon is very great. We notice, therefore, with pleasure, that the Commission state (paragraph 18, p. 155): “ The theory which has hitherto been accepted is that the danger in chloroform administration con- sists in the slowing or stoppage of the heart by vagus inhibition. This is now shown to be absolutely in- correct.” This is in accordance with our own ex- perimental results and conclusions, and whilst we deprecate the extreme positiveness of assertion, we think it highly improbable that chloroform ever kills man by a reflex inhibition of the heart. In paragraph 20, p. 155, the Commission further states: “ In experiment ninety-two, repeated injections of twenty minims of chloroform were made into the jugular vein, and their effect was not to paralyze the heart, but to produce anaesthesia and a gradual fall of blood pressure, exactly as if the chloroform had 24 WOOD, HARE, been inhaled.” This statement agrees with what we have already asserted in this paper. Chloroform possesses its peculiar properties by virtue of its in- herent nature, and the method of administration does not altogether dominate the effects of the drug, so that conclusions can be predicted upon experi- ments made by injection into the jugular vein as well as upon those in which the chloroform is ad- ministered by inhalation. The agreement of the Commission with ourselves seems, therefore, to cut off any objections to our method of experimentation, especially since in every instance we have tracings obtained by inhalation as well as by injection. In any discussion it is very important that the essential point be closely adhered to, and not lost sight of in side issues. In the report of the Hyder- abad Commission there is a great deal that is novel and of much scientific interest concerning the effects of strangling, of suffocation, of vagi-irritation, etc., upon a chloroformized animal. These are in them- selves very valuable, but they are liable to obscure the one main issue—an issue which, fortunately, is tersely expressed by the Hyderabad Commission in a single line, when it says: “and, however concen- trated the chloroform may be, it never causes sudden death from stoppage of the heart.” In considering this main issue, we desire, first, to call attention to the fact that the evidence of the Commission is negative, whilst our evidence is posi- tive, and we believe it is a general law of evidence that negative testimony cannot stand against posi- tive when the latter is trustworthy. The Commission CAUSE OF DEATH FROM CHLOROFORM. 25 in substance assert: We have made a large number of experiments upon Indian animals, without ever having seen the heart arrested by chloroform before the respiration—therefore, chloroform never causes death by syncope ; or, to put it in another way, we have not seen a certain phenomenon, therefore that phenomenon never occurred. On the other hand, we state that we have seen this phenomenon repeatedly, and we offer in proof of our statement, not merely our own assertions, but tracings which have the same relation to physiology that the photograph has to the original transactions of life. Further, our resulis in conclusion are in accord with those obtained by other observers since Glover, in 1842, first pointed out that the vapor of chloro- form, when locally applied to the exposed heart, stopped its movements. The English Chloroform Commission—Gosselin, Anstie, Richardson, Ringer, and Vulpian—are among the names from whom the Hyderabad Commission appears to differ, and with whom we agree more or less closely. Much as we differ from the Hyderabad Commis- sion as to the conclusions which should be drawn from their experiments taken in conjunction with those of other investigators, we would dissent much more strongly from the language used by the Lancet itself, in its editorial of January 18th, where it says : “ The practical outcome of the research would appear to be that deaths from chloroform are not inevitable. They are, therefore, preventible, and by due care in its administration they may be with certainty avoided.” We desire most emphatically to protest against 26 CAUSE OF DEATH FROM CHLOROFORM. any such language being considered as justified by the work of the India Commission. If, with due care in administering chloroform, accidents may with certainty be avoided, they are, when they do occur, the result of ignorance or carelessness, and the coroner’s jury, in a given case, could scarcely, under the rulings of the Lancet, fail to bring an accusation of manslaughter against the surgeon. We cannot help wondering if the editor of the Lancet appreciated the force of his own words. According to the latest edition of Dr. Lawrence Turnbull’s work on Anesthesia, 375 deaths from chloroform have been recorded. If the unreported cases are borne in mind, it must be considered that at least 500 surgeons have had in their practice fatal accidents during chloroform anaesthesia; the actual number of those who have met with fatal results is probably far greater, and among these surgeons we note these names: Professors Billroth, Dumreicher, and Jaeger, of Vienna; Sir J. Y. Simpson, Sir George H. B. McLeod, Mr. J. Farrant Fry, and Mr. Francis W. Clark, of England and Scotland; Drs. Hunter McGuire, J. H. Wellford, and Dr. Chancellor, of Virginia ; Drs. W. A. Hammond, A. J. Parsons ; and Professors W. W. Dawson, Kinloch, and Mussey. Does the Lancet mean to charge that these acci- dents could have been avoided ? That these men have been practically guilty of taking life through carelessness ? THE MEDICAL NEWS. A National Weekly Medical Periodical, containing 24-28 Double- Columned Quarto Pages of Reading Matter in Each Issue. $4.00 per annum, post-paid. The year 1890 witnesses important changes in The Medical News resulting from a careful study of the needs of the profession. Its price has been reduced, and its bulk also, though in less proportion. The mass of information, on the other hand, has been increased by condensing to the limit of clearness everything admitted .to its columns. 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