which should be preferred. A comparison of the two procedures is as preposterous as it would be to discuss whether it is better to extract a foreign body from the œsophagus, or perform œsophagotomy or gastrotomy. In cases in which the milder operation is sufficient, certainly the severer and more fatal operation should never be performed. The object of the operative procedure being to relieve dyspnoea, that operation should. be selected which can do it most effectively and most safely-by safely we mean ultimate as well as immediate safety. It will be conceded without argument that even in the hands of the most skilful surgeon tracheotomy is by far a more serious operation than intubation; but to enumerate all of the advantages of the latter operation is hardly necessary when it is remembered that the percentages of recovery from intubation, taking all the cases, are vastly better than those from tracheotomy. Many parents who will subject their disease having extended below the level of the tube, the latter no longer is effective. It is hardly within the province of this paper to discuss the method of the performance of these two operations. A few important points in management of intubation cases cannot be too often repeated. 1. I have found the best tubes those most recently manufactured, with the bulbous ends. 2. In inserting the tube the gag should be placed well back between the last molar teeth. 3. The tube should be thoroughly sterilized before being inserted by dipping in boiling water. I think that frequently the extension of the disease below the level of the tube is due to the use of a dirty tube. 4. Liquids should be fed the patients in small quantities, the patient lying on the back, on the lap of the nurse, with the head thrown back, thus bringing the back of the pharynx on a lower level than the larynx. 5. If the baby be a nursing baby it should be fed in child suffering from croup to intubation would refuse tracheotomy; superior surgical skill is not requisite to its performance. There is little or no danger from the operation, if we exclude the possibility of pushing down false membrane in front of the tube, which occurs rather rarely. The after-treatment is simple, and does not absolutely require trained nurses for its proper fulfilment. There is no wound to heal after the tube is removed. The objection to intubation is the difficulty in feeding patients with a tube in the larynx; even small quantities of liquids when swallowed pass into the trachea instead of the oesophagus, and gives rise to a pneumonia, due to the lodgement of liquids in the smaller bronchi and air-vesicles. And yet taking all the advantages and disadvantages into consideration, I think we may formulate the rule that in cases in which the dyspnoea can be relieved by intubation, this operation should be performed. If subsequently the tube no longer relieves the dyspnoea, then a larger tube may be tried, or tracheotomy may be performed. I should then limit the performance of tracheotomy to those cases of membranous croup in which the tube does not relieve the dyspnoea primarily, or secondarily, when the I that way even when intubated. I have been accustomed, in older children, where in spite of all efforts neither food nor drink can be swallowed, to remove the tube every second day, sometimes even every day after the second day, feed the patient, and then replace the tube; this, however, is very rarely necessary. generally order ice for the thirst instead of water; icecream, condensed milk mixed with ordinary milk in equal parts, thick broth, the yolk of eggs, these are the chief articles of diet while the tube is in situ. Before extracting the tube the blades of the extractor should be examined to see that they are firm. I have seen one of them break off just as the extractor had been placed in the mouth. The patient should be kept warm steam while the tube is under a tent filled with in the larynx. A word as to emetics. I do not ever think it necessary to administer emetics, except at the beginning of the disease, and then chiefly as a means of differential diagnosis between true and false croup. The latter cases are cured by a sharp emetic, and little other treatment, while true croup is temporarily relieved, but soon the membrane reforms, the swelling returns, and the patient is as bad as ever. To relieve dyspnoea in true diphtheritic laryngitis, emesis can be but a temporary expedient. The emetic I prefer in all of these cases is the yellow subsulphate of mercury. Constitutional Treatment.-I do not think that anyone will question that by far the most frequent cause of death from diphtheria, except when it is located in the larynx, is the pathogenic action of the toxin. formed under the influence of the Loeffler bacillus. This toxin is absorbed into the general circulation, and gives rise to the familiar manifestations of toxic diphtheria, such as fever, swelling of the lymphatics, disturbance of the heart's action, manifested by rapid and feeble pulse, and sometimes heart failure, inflammation of the kidneys, lungs, brain and its meninges, the formation of abscesses in different portions of the body, and in the later stages of the disease, paralysis due to toxæmia and inflammations of the peripheral and central nervous system. All of these are chiefly the result, in a general way, of the absorption of the toxic material into the blood. Even The Method of Intubating. where the inflammatory lesions are due to the direct extension of the diphtheritic process, as in diphtheritic bronchitis, and pneumonia, inflammation of the middle ear and mastoid sinus, the absorption of toxins into the blood adds greatly to the danger. The constitutional treatment of diphtheria, then, is by far the most important of any that we have considered. Such constitutional remedies at present in use in this disease are either symptomatic, empirical, or rational. The symptomatic remedies are those whose use is intended to counteract the evil symptoms of the action of the toxin. Thus digitalis, strychnine, caffeine, etc., are intended to obviate and remove the signs of weak heart's action; empirical remedies are such as have been found to exert a favorable influence upon the constitutional manifestations of diphtheria, by experience, without a really adequate explanation of their action being known. In this group I would class the most important remedies that we have against the action of the diphtheritic toxin, bichloride of mercury and tincture. of the chloride of iron, although some might class both of these among the so-called rational remedies for diphtheria. Finally, we have the most recent remedy for diphtheria toxin, the so-called antitoxin treat ment, which, if all that has been claimed for it turns out to be true, will, as is always the case with rational remedies, replace the empirical absolutely. In considering the symptomatic remedies for the constitutional symptoms produced by diphtheria toxin, one of the most important symptoms which comes up for treatment is the fever. This varies in amount, but not in proportion to the gravity of the disease. Very septic cases of diphtheria may have little or no fever, while mild cases sometimes "run" high temperatures. At the beginning of the disease the fever is probably due to the local inflammation of the tonsils and not to the absorption of toxins. This fever will subside within the first twenty-four hours, so that a patient with a high temperature at the outset may be bright and smiling on the following morning, while the throat is found to be full of membrane. The treatment of the fever of diphtheria should never be by antipyretics. These drugs weaken the activity of the heart. Hydrotherapy only should be used. This includes cold compresses about the neck for their local action, sponging with a mixture of five parts cold water and one part alcohol, and Ziemssen's baths. о The temperature does not require any treatment if it be below 102 F., and cold sponging in a warm room, followed by gentle rubbing with a dry towel is to be preferred to baths. The frequency of the sponging or baths will depend upon the temperature, and should be suspended entirely when the temperature has fallen to 101° F. In this connection it is well to remember that a small amount of fever has a sustaining rather than a weakening effect upon the pulse. The sustaining of the weak heart of diphtheria is the most important symptomatic indication in the treatment of this disease. It should be enforced in every case before the appearance of the signs of a failing heart. In diphtheria as little work should be placed upon the heart as possible. Such patients should not sit up, but maintain a recumbent position. The patient should be kept lying in bed, as long as membrane is present, however slight the symptoms may be. Severe cases should be kept in bed for weeks after the membrane has disappeared. All local applications made to the throat should be so made with the least possible physical disturbances, and, when possible, with the patient in the recumbent position. In an excessively excitable patient I frequently prefer to suspend for a time the local treatment of the disease rather than exhaust the patient. Indeed, the frequency of local applications, such as irrigation, should depend partly upon the severity of the local disease, and partly upon the strength and resistance of the patient to the local treatment. Stimulants and diet should be such as will best maintain the strength of the heart. Thus I give whiskey, brandy, and other alcoholics, together with a fluid diet, milk, beef-broth and beef-juice, eggs, etc., avoiding all forms of diet and stimulation which cause vomiting. In severely sick children, where the patient refuses food and stimulants, rectal feeding must be employed; I have no experience in feeding such patients with the stomach-tube; the objection to this is the struggling of the patient when the tube is passed, although some cases, I have no doubt, will do better fed in this way than by the rectum. As much of the alcoholic and fluid diet as possible should be given at frequent intervals and in small quantities at a time. Of the alcoholic stimulants, whiskey is to be preferred, diluted with milk or water. Of stimulant drugs strychnine should be given at the very beginning, in order that its maximum physiological effect may be attained about the time when the heart begins to flag. It is best to give considerable doses, frequently repeated; to a child two years of age of a grain every two or three hours if necessary. Should symptoms of heart-failure occur, hypodermatic injections of strychnine, nitro-glycerine, and caffeine, in the shape of the double salicylate of soda and caffeine, are indicated. Counter-irritation to the heart is also indicated. Digitalis does not act well, in my experience, in the heart-failure of diphtheria. There has always been in this disease the desire, on the part of our profession, to discover a specific remedy that is common to all frequently fatal diseases; such specific remedies have generally been advocated upon an empirical basis. The empirical drugs in treating diphtheria, with which I have had experience, are the tincture of the chloride of iron, and the bichloride of mercury. I do not think that the use of either of these is really empirical in the treatment of diphtheria. The tincture of the chloride of iron in large doses, fifteen to sixty drops every hour or two, undiluted and only mixed with a little glycerine, certainly has some local effect upon the throat as it is swallowed. The recommendation by Loeffler of the perchloride of iron solution as a local specific against diphtheria, of which I have already spoken, would indicate its local value; when swallowed, if absorbed by the stomach, it would appear to act as a blood stimulant, supporting the heart through a wasting disease. This remedy in large doses, and only in such doses has it any possible effect, is very popular, having the sanction of the highest authority. I must protest against the administration of this drug in small doses, at long intervals, unless the physician intends it to act simply as a placebo. While I consider the iron treatment as given above adequate in milder cases of diphtheria, I do not rely upon it exclusively in severer cases, but have much more confidence in the use of large and frequently repeated doses of corrosive sublimate. This treatment of diphtheria and diphtheritic croup was first introduced into this city by Dr. A. Jacobi, and unless the antitoxin treatment should prove all that is claimed for it abroad, I have considered it by far the most valuable remedial agent given to us in diphtheria. Its good effects are as remarkable in the treatment of diphtheritic croup as in the treatment of general diphtheria. In this respect it differs widely from the iron treatment; I consider the latter absolutely valueless in cases of uncomplicated membranous croup, with no septic manifestations, while the mercurial treatment is to the medical treatment of true croup what intubation is to the operative treatment of the same disease. Fully half the cases of membranous croup, if properly treated sufficiently early by corrosive sublimate, will not require intubation of the larynx, and those that have been intubated do far better if they have been under the influence of the mercurial sublimate solution before the intubation, even if this has not succeeded in relieving them without the operation. I have already stated that the most valuable local remedial agent in croup is calomel fumigation, and I am convinced that this is of value only through the absorption of the mercury by the mucous membrane of the bronchi and through the air-vesicles. In other words, calomel with mercury. fumigation only hastens the saturation of the blood As to why the internal administration of the bichloride of mercury is of such value in diphtheria I cannot say. Mercury certainly is excreted by the mucous membrane of the respiratory tract. It increases the secretion of the mucous follicles as it does that of saliva, and probably in this way accelerates the loosening and separation of the false membrane. Upon pharyngeal diphtheria it can possibly exert a slight local effect, of an antiseptic character, as the hourly or half-hourly dose is swallowed. As to whether it exerts it exerts a destructive action upon the diphtheria toxins in the blood is very doubtful. Nevertheless clinically this is by far the most powerful curative medicinal agent in the treatment of diphtheria. It should be given in comparatively large doses frequently repeated. I give to a baby a year old grain every half-hour or hour, and this can be continued for several days if necessary. Salivation in these little patients is very rare. The occurrence of mercurial diarrhoea is the chief indication for the suspension of the remedy. It is rarely or never vomited. It should be given alone, dissolved in distilled water; never given in a mixture with iron, never mixed with an organic drug or sirup. If albumin be present in the urine when the treatment is begun, its increase should signify a diminution of the drug; if no albumin is present in the urine, its appearance means a suspension or diminution of the remedy. The iron treatment is also contra-indicated if the albumin in the urine of the patient is increasing. We now come to the consideration of the most remarkable method of treatment that has ever been proposed for true diphtheria, and the only one to which the term rational can be applied, namely, the serum therapy as applied to this disease, that is to say, the antitoxin treatment of diphtheria. By the methods hitherto advocated, diphtheria has been treated with considerable success; indeed, with rather more success than they have had in Germany or France, judging from statistics recently published. And yet diphtheria has been a frightful scourge to very young children, killing larger numbers of them than perhaps any other acute infectious disease. With the view of eradicating this scourge bacteriologists and clinicians turned their attention to discovering some method by which human beings could be rendered immune to attacks of true diphtheria, and in a general way to attacks of other acute infectious diseases. While methods were discovered by which animals, sensitive to diphtheria, could be rendered immune to the action of the Loeffler bacillus and its toxin, it was found that similar principles could be applied, in the treatment of diphtheria which had already developed in animals, with success. As early as 1868 an Italian had vaccinated patients suffering from diphtheria with diphtheritic virus, and under this method of treatment lost but one case out of fifteen treated. Bagola, of Sienna, using a like method of treatment, had similar results in twenty-nine cases. One can readily see the objections, however, to a method of treatment, or of procuring immunity which would necessitate the inoculation of human beings with active poison like diphtheria virus, or the injection of cultures of diphtheria bacilli into the blood of human beings with the object of rendering such persons immune; the reaction to the poison might be sufficiently great to cause a fatal diphtheria. Brieger and Fraenkel succeeded in rendering guinea-pigs immune against virulent cultures of the diphtheria bacillus by injecting bouillon cultures, three weeks old, of Loeffler bacilli; they sterilized these cultures by exposure for an hour to a temperature of 60° to 70° C. They injected from 10 to 20 c.c. subcutaneously. the end of two weeks immunity was complete. It was found that all animals that are susceptible to diphtheria can be rendered immune to the disease by injecting into their bodies pure cultures of Loeffler in bouillon of gradually increasing virulence, beginning with the weakest cultures, such as will produce only the slightest reaction, and terminating when the most virulent cultures can be injected without producing any reaction either locally or generally. Such animals retain their immunity against diphtheria for a considerable period of time, varying in different animals, but not in any case permanently. Behring should have the credit of first having discovered the fact that the blood-serum of animals that have been thus rendered immune to diphtheria contains some substance which neutralizes the toxic agent contained in virulent cultures of Loeffler bacilli; the blood Proper Method of Feeding Intubated Patient. serum of such animals produced this wonderful effect when it was added to the filtered virulent cultures outside of the body, as well as when the cultures were injected into the living animal together with, immediately preceded or followed by, an injection of the blood-serum of the immune animal. Indeed he found that when the toxin is injected into a susceptible animal several hours before the injection of the blood-serum of an immunized animal, the diphtheria toxin is still neutralized and the animal recovers. This protection and curative influence of the serum of animals rendered immune to diphtheria was observed not only against the toxin but against injections of the pure cultures of the bacillus. Upon the application of these discoveries to the human body depends the serum therapy of diphtheria in human beings, and from what we have said it will be seen that the following points are of importance in this connection: 1. How is the toxin, which is required for rendering animals immune, made and used? 2. How are animals rendered immune? 3. How is the blood-serum of immune animals containing the antitoxin to produce its effects? 4. How is it to be applied, as to dose, frequency of application, etc., in the therapy and prevention of diphtheria? 5. What are the therapeutic benefits of the antitoxin treatment as compared with other forms of treatment of diphtheria? 1. The toxin for immunizing animals to diphtheria poison, that is, inducing in them, as it were, the diphtheria habit, is best made by cultivating extemely virulent bacilli in a current of moist air.1 Alkaline bouillor containing two per cent. of peptone is placed in flatbottomed vessels, supplied with a lateral tube for the admission of air above the level of the fluid. These solutions are sterilized and inoculated with very poisonous Loeffler bacilli, and heated in an oven to 37° C. When the culture has begun, a stream of air is admitted. After three or four weeks the culture is rich in toxins, and can be used for purposes of immunization of animals. These cultures are filtered through a porcelain filter. The clear fluid remaining is kept in the dark, in bottles well corked, at ordinary temperatures. 0.10 c.c. of this toxin, thus kept, will kill a guinea-pig weighing 300 gm. in forty-eight to sixty hours. 2. How are animals rendered immune? The toxin above described is too strong for a first injection; it produces a fatal diphtheria. It must therefore be diluted. Roux and Vaillard have used for this purpose iodine. Before injecting they dilute the toxin with one-quarter of its volume of Gram's solution, and after a few seconds inject it under the skin. The amount injected depends upon the size of the animal. An ordinary rabbit will stand a first injection of 0.5 c.c. of this solution of toxin and iodine. After a few days, the slight reaction having subsided, another injection is given in larger doses, and thus for a few weeks, the dose being gradually increased and the dilution with iodine diminished until the pure toxine is employed. The injection should be suspended whenever the animal shows a diminution in weight, for otherwise it may die. Some animals are more susceptible than others. Dogs thus immunized give a good serum. Sheep, goats, and cows are very apt to die during the process, and great care is required in these animals to succeed in reaching the stage of immunity. For many reasons the horse has proved to be the best animal for the purpose. The horse has the advantage of not being very susceptible to the poison; 2.5 c.c. of the strong toxin often causing very little fever and very slight local oedema. When immunized the horse furnishes a large amount of serum containing antitoxin, and the serum when injected under the human skin gives rise to no irritation and is entirely harmless. This.animal is accordingly preferred by German and French experimenters for making antitoxin for therapeutic and prophylactic purposes. Vaillard reports as to the length of time necessary to immunize a horse to diphtheria. Beginning with an injection of c.c. of the iodine toxin mixture he was able within two months and twenty days to inject 250 c.c. of the pure toxin without producing any local reaction or increase of temperature. 3. How does the blood-serum of immune animals containing antitoxin produce its effects? Aronson 2 says that his experiments prove the antitoxin contained in the blood-serum of immune animals directly destroys the toxin of diphtheria. This action occurs in the laboratory as well as in the living organism. Buchner and others, on the other hand, believe that there is no destructive action between the poison and the antitoxin. If an animal receives a proper dose of serum, it resists a subsequent injection of toxin which would kill a guinea-pig of like weight not previously treated with the serum. The same result will follow if the toxin and antitoxin be injected together, or if the toxin be injected first, followed by the antitoxin at an interval of a few hours. In all these the guinea-pig will remain healthy, provided the proper proportion of the toxin and antitoxin be maintained. The quantity of serum necessary for a cure varies with the weight of the animal, the amount of toxin to be neutralized, and the time elapsed between the injection of the curative serum and the toxin. We know very little of the real 1 Roux and Martine: Annales de l'Inst. Pasteur, November, 1894. 2 Berliner klinische Wochenschrift, 1895, No. 15, p. 356. nature of the "antitoxin" constituent of the antidiphtheritic serum. 4. As to the dose and method of application of the serum containing the antitoxin. The dose varies with the strength of the serum. Ehrlich has proposed a method for estimating this strength for any given sample of antitoxin serum. The unit of strength is of c.c. of such a serum, which so neutralizes c.c. of normal toxin that the mixture injected under the skin of a guinea-pig produces no local manifestation. The blood-serum used for therapy in human diphtheria is obtained by drawing the blood from the jugular vein. From this a perfectly clear serum is separated. To it is added a small amount of trikresol to keep it from decomposition. The immunizing power of the serum obtained from these animals is so great as to reach 100,000; that is to say, the serum will neutralize a dose of toxin that would kill the experimental animal, when it, the serum, is administered in the weight of 1 to 100,000 of the weight of the animal. Aronson has succeeded recently in manufacturing very much more powerful antitoxin serum by using for his animals toxin obtained from very old and extraordinarily virulent diphtheria cultures. Behring's normal antitoxin, Roux normal antitoxin, and Aronson's immunization solution are about of equal strength. Aronson's stronger solution is three times stronger than the immunization solution. From experiments with the serum on animals we know that the dose of antitoxin serum for therapeutic purposes necessarily varies with the weight of the individual, the virulence of the diphtheritic manifestations, and the length of time that has elapsed since the patient has been affected with the first symptoms of the disease. Behring's, Roux's, and Aronson's immunization, or weaker solution, all have the effectiveness of 50,000 to 100,000. The dose is, for theraaeutic purposes, 20 c.c. as a first injection, under the skin between the shoulder-blades or in the flank. If a bacteriological examination shows the presence of Loeffler bacilli, Roux gives 10 c.c. more in twenty-four hours. If no Loeffler are shown the case receives no more antitoxin. These two injections, made under antiseptic precautions, generally suffice, although in some cases with high temperature and rapid and feeble pulse a third injection may be given. No evil results follow, either locally or generally, according to every observer who has reported his cases. Some observers have found a red rash following the injection of the antitoxin. In the cases treated at the Willard Parker Hospital, but two cases out of twenty showed a rash, of doubtful character, following the eruption. The antitoxin was used for purposes of rendering human subjects immune to diphtheria by Aronson, Roux, and others, but I have never seen it used for this purpose. It must not be forgotten that any immunity to diphtheria is only a temporary matter, for this is not a disease in which one, or at most two attacks, grant immunity. Some patients have true diphtheria several times a year. At the Willard Parker Hospital twenty cases, recently reported to a section of this Academy by the resident physician, were treated during the time of my service. The preparation used was Aronson's stronger antitoxin solution. The dose varied from 5 to 12 c.c.; the total number of injections given to all the twenty patients was thirty-an average of one and a half injections per patient-much less than Roux or the German authorities give. 5. We come finally to consider what benefits have been derived from the antitoxin treatment of diphtheria, and how do they compare with results obtained by other methods of treatment. In the year 1892 there were 4,654 cases of diphtheria reported to the Bureau of Contagious Diseases in the city of New York-1,436 died. In 1891 there were 4,874 cases reported, of which 1,361 died, a death-rate for the two years of 29 per cent. During 1892, at the Willard 1 Aronson: Internal Klein Rundschau, 1894. Parker Hospital, there were treated for diphtheria 295 cases; died during the year, 79; death-rate, about 25.4 per cent.; but in children under five years of age the death-rate was 44.55 per cent., and from five to sixteen years, 11.7 per cent. only. The number of cases reported by physicians to the Health Department is necessarily far less than the number really occurring, for the mild cases are frequently not reported, so that the diphtheria death-rate for the city is probably much lower than that given above. The death-rate above given was under the customary treatment of diphtheria. Curiously enough, the death-rate from diphtheria in the cities in Europe is very much larger than in ours. Martin and Chaillon report that in the Hospital des Enfants Malades there were treated, from 1890 to 1894, 3,971 children, of which 51.71 per cent. died-more than twice the death-rate at the Willard Parker Hospital for 1892; and probably more than twice the deathrate in the city of New York at large for 1891-92. Similar statistics are obtainable from Berlin and Vienna, hence we must conclude either that the diphtheria in these cities is far more virulent than ours, or that our present methods of treating diphtheria are twice as efficacious as those hitherto pursued on the other side of the Atlantic. Under antitoxin injections of the cases treated at the Hospital des Enfants Malades from February 1 to July 24, 1894, of 448 children, 109 died, or 24 per cent. At the same time, of 500 cases treated at the Hospital Trousseau, 316 died, or 633 per cent.-a frightful deathrate for this disease. Deducting from the 448 cases 128 that were not true diphtheria, and 20 cases that were not treated, the death-rate is 78 out of 300 cases, or twenty-six per cent. The improved death-rate, then, from antitoxin treatment at Paris, is not as low as our own death-rate under old forms of treatment. Aronson, on the other hand, reports a reduction of mortality in cases of true diphtheria treated by antitoxin to twelve to thirteen per cent., against thirty-two to thirty-seven per cent., under the old methods of treatment. Katz reports 163 cases of true diphtheria, with a death-rate of thirteen to fourteen per cent., treated by antitoxin. All observers agree that of cases coming under treatment during the first day of the disease all recover, and the further the disease has advanced before the beginning of the treatment the less hope there is from the antitoxin treatment. Of the 20 cases treated at the Willard Parker Hospital there were admitted, and treatment began In all 5 died, being twenty per cent, of the cases. In view of the fact that the most reliable observers on the other side of the Atlantic report such a vast improvement in the death-rate from true diphtheria, it is proper for us to look to the serum therapy as applied to this disease with a great deal of hope of benefit from its use in this country, but in view of the discrepancy between the results obtained by present methods of treatment in this country, as compared with results from the same treatment abroad, we must suspend judgment as to the value of antitoxin treatment in this country until we shall have proved by the treatment of thousands of cases as great a reduction in our present death-rate, relatively, as they have succeeded in obtaining in Europe. I have purposely not mentioned the complications of diphtheria in this paper, inasmuch as the subject is obviously too vast for consideration in one paper; it has been rather the aim to give a general outline of the treatment of diphtheria as followed in hospital and private practice. 245 SEVENTH STREET. |