Roux's Anti-Diphtheric Serum; the New Prophylactic and Curative Treatment-Historical

Notes and Modus Operandi.

[Prepared for THE MEDICAL WORLD.]

inoculated into this last one without any effect whatever. They experimented on animals for diphtheria and tetanus, but without direct prac. tical results as to human beings or hospital treatment. The possibility, however, of sero

CANADA. I.

Prof. Landouzy, of Paris, while recently lecturing, uttered the following very timely and appropriate sentence: "This century shall have long ceased to be denominated as Napoleon's century, when it will yet be known to history as Pasteur's." The true genesis, in fact, of all present ideas on preventive vaccination and serotherapy by the different anti-toxines, must necessarily be traced back to Pasteur's immor tal discoveries. In every corner of the scientific world, in every sphere of human knowledge, Dr. Roux's treatment, and its gratifying results and successes, is the almost all-absorbing topic. Political newspapers have discussed the subject down to its minute details, and are constantly publishing marvellous statistics in its behalf. Pictorial reviews have also made the public quite familiar with the laboratory technique,

etc.

The fertile idea which is nowadays simply revolutionizing medicine really originated in France. The protagonists of the method of which Dr. Roux is the gifted continuator, were Richet and Héricourt, who many years ago predicted the success of serotherapy, in tuberculosis particularly, and experimented very satisfactorily in 1891-92. Their example was soon followed by German scientists, who completed and generalized this same idea until it became itself the generator of Koch's system (tuberculin), which too much haste and insufficiency of preparation have rendered inadequate to its purpose.

After some peregrinations abroad, serotherapy is settling anew in Paris. Already French experimentalists claim that anti tuberculous vaccination will soon come complete out of the laboratories.

Roux's treatment, to sum it up briefly, consists in injecting hypodermically into the patient the serum of an animal, the blood of which has acquired immunity; this serum, in turn, either as a prophylactic or curative agent, will produce immunity in the patient. Two followers of Dr. Koch, Messrs. Behring and Kitasato, were the first to prove that the blood of an animal, rendered refractory to an infectious disease by progressive doses of toxine (or microbe culture) had effectually the power of giving immunity: that is, if the serum from that blood be afterwards injected into another animal, the disease may be

(who, by the way, had previously, in 1888, '89 and '90, at the Pasteur Institute, and conjointly with Mr. Yersin, proved that the Klebs-Loeffler bacillus acts upon the organism not so much by its presence as by the toxines which it secretes, and that all symptomatic manifestations, from fever down to paralysis, are the result of this toxic action) set himself again to work (1891), and after many months of arduous investigations he was at last able to experiment at the Hospital des Enfants malades (Paris), (from February to July, 1894), where 75 per cent of the children suffering from diphtheria were saved as a first result. He then attended the Buda-Pesth (Hungary) congress (last summer), where he made his report. Since that moment the civilized world has turned its gaze upon and investigated the new discovery.

About the same time Dr. Aronson was carrying on quite as successfully the same experiments in a Berlin hospital.

II.

At the Pasteur Institute the following mode of preparation is adhered to: The bacillus is cultivated in tubes of prepared blood serum (mixed with the necessary nutrient, beef broth, and inoculated with the swab), placed into an incubator through a damp draught; of cubic centimeter (1 minims) of this culture is injected hypodermically into a guinea-pig, which then dies from diphtheria in forty-eight hours. The same culture is afterwards injected by gradually increasing doses into a sound horse until this noble beast can bear, without reaction, as much as 800 c.c. (263 oz ). The horse is bled, the serum extracted from its blood, and this serum is injected into a guinea-pig in the dose of go of this last named animal's weight. Twelve hours later the same guinea pig may receive as much as c c. (8 minims) of toxine without any effect whatsoever; it has henceforth acquired immunity against diphtheria, at least for a certain number of years. Moreover, if diphtheria be inoculated into a guinea pig, and, waiting till the exudates have developed on the mucous membrane, a dose of serum of 5000 the animal's weight be then injected into it, the disease will at once retrograde, and the false membranes fall out before two days have elapsed.

1

50000

of

Dr. Roux's serum can be kept for a very long period of time without altering. At the Pasteur

Institute it is protected from light, put up in sterilized flasks filled to the neck, with nothing but a small piece of camphor added to the liquid. It may be, according to Dr. Roux's own statement, dessicated, in vacuo, and thus easily transported to distant places. Its preventive qualities (in the dry state) are recovered by dissolving it anew in eight or ten times its weight of pure water. This last solution will give a small, transient, local tumefaction under the syringe, which is not the case with natural liquid antitoxine. After January next a special distributing sale of dessicated serum will be made at the Pasteur Institute. This will undoubtedly be of great benefit to country and foreign physicians. When the institute or its branches shall have produced a sufficient amount to meet the enormous demand, wholesale druggists will probably devise some convenient form (whether liquid or dessicated) of supplying it to family physicians.

During the French war against Dahomey last year, it was found possible to forward to the troops in Western Africa some dessicated powder of anti tetanic serum, which was utilized and appreciated in the treatment of the wounded.

Actually, Roux's anti toxine is quite an expensive luxury to the ordinary doctor. Tubes of serum cost as much as twenty dollars apiece. Of course, this is solely due to the scarcity of the article. It takes four months for preparation-one for culture, and two to three months for granting immunity to horses, and it has so far been manufactured in Paris and Berlin exclusively. I see with pleasure that the Washington government is getting interested in the subject, and will probably have the product prepared in the United States. Dr. Paul Gibier, the enterprising and highly gifted director of the New York Pasteur Institute, is also heard from, and the matter could, no doubt, not be placed in better hands on this side of the Atlantic.

In our Province of Quebec a syndicate is being formed in Montreal to endow the city with a municipal laboratory for the production of anti-toxine, and the city council will be asked to vote $2,000 in favor of the scheme. In Europe (Germany, Sweden, France), the question is being officially studied from a sanitary standpoint, and many a town has voted sums of money in order that children may be gratuitously treated. The blood-serum is being supplied without charge by the Pasteur Institute to the Paris physicians, and the French government has already voted 100,000 francs ($20,000) to cover the expenses.

III.

How is the injection to be practised? First,

let us describe the syringe itself. It is represented by four different parts:

1. A glass and metal pipe, the glass being separated from the metal by two small rubber pads.

2. A rubber piston.

3. An adjutage or rubber tube, fitted to the end of the pipe, and about the diameter of an ordinary large-sized drain, and 10 centimetres (4 inches) in length.

4. A needle, 4 to 5 centimetres (13 to 2 inches) long.

In order to inject hypodermically (after the syringe has been filled with the necessary dose of anti-toxine), hold it firmly between the three last fingers and palm of the right hand, and grasp the needle at its base, i. e., at its joint with the rubber tube, between the unoccupied thumb and forefinger. With your left hand you then draw out a pinch of skin (generally on the hypochondrium), and push in the needle at the base of it, being careful not to thrust too far in, so that the subcutaneous cellular tissue only may be immediately reached by the injected liquid. At this moment, when the needle is well in, change your hold upon the syringe from the right to the left hand, and use your right hand to press down gently on the piston, meanwhile giving it a slight rotatory motion.

Before the injection, the skin (at the point where the needle is to be thrust in) should, of course, have been washed thoroughly with an antiseptic solution (bichloride, 1 to 1000). When the injection has been made, cover the spot with absorbing cotton. This will form, by mixing with some of the serum which is ejected back, a sort of collodion, and the small orifice thus remains completely closed up.

Edema of the surrounding tissues is generally produced during the operation, but will totally disappear in some fifteen to thirty minutes afterwards. In no case has there been any general reaction.

IV.

I will now give statistics. "Nothing like figures" to convince and convert the skeptical. On February 1st, 1894, Dr. Roux took the entire and exclusive direction of the department of diphtheria in the Hospital des Enfants malades (Paris). Nothing was changed as to the ordinary treatment except that each child, upon its admission to the diphtheritic ward, received an injection of 20 cubic centimeters (320 minims, or oz.) of serum; twenty-four hours later, if the bacteriological examination should prove the angina to be truly diphthericic, another injection of 20 c.c. or 10 c.c. (160 minims, or oz) would then be given, and in the majority

of cases this suffices to effect a cure. From the first day after treatment fever diminishes, the pulse improves, and the general state is remarkably improved; the membranes have usually all fallen out before the third day. The mortality rate of diphtheritic children at the abovenamed hospital was thus reduced last winter to 12 per cent. for simple anginas. In croup, especially operated cases (by tracheotomy), the death rate after serotherapy was naturally higher (39 per cent.), and in croup with associations of microbes (staphylococci and streptococci), it went up to 63 per cent., but fortunately these last cases are most uncommonly met with. To condense briefly : Out of three hundred children actually suffering from diphtheria of every kind and gravity, and treated by Roux's serum in the Hospital des En'ants mala des, the mortality was reduced from 50 per cent. (previous death rate) to 26 per cent.; and pray notice this result to have been obtained only on actually diphtheritic patients. What now can be expected from the preventive treatment, or serum vaccination, which will save 100 per cent. of those who submit to it, if administered in time? The prophylactic effect of anti toxine has been first proved in Paris and Berlin, where, up to this date, out of two hundred and fifty-six children inoculated against the disease, two only suffered from a very mild attack of diphtheria: and nothing goes to effectually prove that these two children were not already in the incubation period when treated. When we think that an average of TWO HUNDRED THOUSAND people die yearly from diphtheria, and that if governments would agree to supply municipalities, etc., with serum, at least one hundred and ninety thousand lives could be saved during the same period, we cannot but feel deeply moved, and, above all, grateful to the modest savant whose philanthropy has so practically fortified us in the battle against death. The dose of Roux's serum has just been given above: 20 c.c. as a preventiveone such dose confers immunity; if the patient has already diphtheria, the dose may be repeated or doubled the next day. This is ordinarily sufficient. Behring's anti-toxine is adminis tered at the average dose of 10 cc.; Aronson's at the dose of 1 to 7 c.c. (16 to 112 min) for immunization, and 2 to 8 or more for therapeutic purposes. In laryngeal and complicated cases full or repeated doses are necessary. In all cases where the remedy is given after beginning of attack, the injections are best made, if possible, in from twenty four to thirtysix hours from the outset. Dr. Roux advises physicians not to disregard, however, the local antiseptic treatment, which helps to destroy the toxine secreting bacilli. He deprecates the use

of cauterizing medicaments, of bichloride and carbolic acid, and prefers to everything, as a local auxiliary, gargles or sprays of boric acid, or swabbing the throat and nose with salicylated (5 per cent.) glycerine. Milk diet he strongly advocates.

In Berlin, with the new method, from March to July, 1894, Dr. Aronson reduced the deathrate of diphtheria from 60 per cent. to 14 per cent., and during that time tracheotomy was but twice performed. In fact, this sad operation will soon be dispensed with altogether-that horrid picture, impressed on the mind of parents, of a child struggling against asphyxia, would be forever done away with. Feuillet's masterly book, "La Morte," will be consulted fifty years hence for a classical description of that obsolete curiosity-"tracheotomy." In cases complicated with measles, scarlatina, erysipelas, bronchopneumonia, where the diptheritic laryngitis (croup) sets in from the very outset, and without angina (where serotherapy has not, consequently, been administered), intubation would be quite sufficient while the membranes are dissolving under the anti-toxine treatment. At the other Paris hospitals, where no experiments have been made on diphtheritic patients, the average mortality from diphtheria alone is 60 per cent. (at the Trousseau Hospital, particularly, 316 died out of 525 children attacked with the disease). In Norfolk, England, an epidemic broke out in September last; children were dying at the rate of 33 per cent.; some anti-toxine was imported, and up to October 8th all the inoculated children had perfectly recovered.

The latest report comes from Dr. A. Campbell White, of the Willard Parker Hospital, New York City. This physician, in a communication to the New York Academy of Medicine, on November 8th last, concludes from the experiments he has personally conducted that: "In addition to conferring immunity from diphtheria for a certain length of time, anti-toxine is a specific for this disease, and is capable of averting death from absorption of its toxins. The mortality from laryngeal cases (croup), formerly of 50 per cent., was lowered, under serotherapy, to 28.5 per cent., and from 40 per cent. to 6 per cent. in simple anginas of children. under five years.

V.

What is the future of the new method in diphtheria and of serotherapy as a whole? The first question may be readily answered after perusal of the preceding lines.

As to serotherapy itself, we think a great future lies before it, and that it will gradually

dethrone all other methods at present known to medicine. The physician of the twentieth century will be, above all, a serotherapist. His first care and occupation shall be to prevent disease; and we all feel how comparatively limited our knowledge is in this connection, but the impulse is now given, and the world will follow. Both antisepsis and serotherapy are a consequence of Pasteur's discoveries. Surgery has undoubtedly risen to a great importance in this fin de siècle, but if medicine progresses perhaps more slowly, it must nevertheless be admitted that it is now making wonderful strides in the right direction. So we may hope for the future. Perhaps typhoid fever will soon be treated by serotherapy, as Eberth's bacillus acts also by the toxines which it secretes. Then will come the turn of tuberculosis, syphilis, scarlatina, measles, pneumonia, cholera. Drs. Haffkine and Simpson have been widely experimenting against this last-named disease in India this year, but the results published are not yet quite satisfactory). The same may be said of Tizzoni's anti-tetanic

serum.

Apart from the natural serums, or anti-toxines, if I may thus designate them, some European scientists are actually at work experimenting, very successfully, with "artificial" se

rums.

I will conclude with a descriptlon of these and their principal applications. Modern surgeons are every day realizing more accurately the danger of blood-transfusion (which is employed, for instance, in the treatment of the wounded, after hemorrhage, etc.). It is being It is being now demonstrated that the blood corpuscles injected from one subject into another act precisely as foreign bodies towards each other, destroy mutually, and in so doing are liable to form in the vessels magmas or residuums, which are a source of danger (thrombus, embolism). But there fortunately exists another method, easily applicable, and which now prevails in many European hospitals. I mean the injection of artificial serum. This system is destined to take the place of blood transfusion. It seems demonstrated that by injecting into the subcutaneous cellular tissue of an exsanguious subject, from one to two ounces of artificial serum, and repeating, in the same proportion, these injections every half hour, the individual may be brought back to life. Is not this new and interesting application of therapeutic physiology to surgery quite singular? It goes to prove once more the old saying, that no man can be qualified as a good surgeon if he be not at the same time a consummate physician. Artificial serotherapy has also been recently applied, and with constant success, to the cure of cutaneous affections

(eczema, psoriasis, etc., and even lupus). According to Dr. Monnet, of Paris, the different cutaneous efflorescences, i. e., the external manifestations of a general constitutional state, are simply caused by fermentation of the blood, or, more exactly, by the presence in the blood itself of fermented elements. On the skin appears what will grow on old cheese-scabs and spots. From this principle, Dr. Monnet concludes that the most appropriate treatment in dermatology should be to stimulate blood exchanges, re-constitution and new supply of corpuscle material. He has therefore invented his artificial serum, which, by its elements of composition, its antiseptic properties, and the arterial tension it determines, will cause a very noticeable organic superactivity. The corpuscles are thus more rapidly oxidized, more actively moved, and, along with the n, the viciated principles which they conceal and carry about in the organism. There are, at the present time, two notable formulas of artificial serums extensively used in France and throughout the world-Dr. Chéron's and Dr. Monnett's. Dr. Robins' new glycerophosphates are also being used with immense advantage, by the hypodermic method, in the treatment of neurasthenia.

58 St. Ursule St., Quebec, Canada.

University of Pa. Notes. [Reported especially for THE MEDICAL WORLD.]

Dr. Wood speaks enthusiastically of cocaine as a tonic in doses of one-sixth to one quarter grain. [How about the danger of the cocaine habit?-ED.]

A pinch of salicylic acid added to a fourounce vial of urine will prevent decomposition for many days, and in no way impairs the reactions or alters the sediments. This is valuable in hot weather, or at any time when urine has to be transported a distance, or its examination for any reason has to be postponed for some time.-Prof Tyson.

Dr. Griffith says babies should be offered water frequently. They are often thirsty when not at all hungry, and the use of milk at such times tends to create disorders of digestion.

Dr. Pepper calls attention to the fact that in cholera infantum with cold and cyanosed extremities, a condition of hyperpyrexia exists in the trunk, and the rectal temperature will range from 105°F. to 108°F. This is the most dangerous symptom and is to be combatted by hydrotherapy, placing the child in a 85°F. bath and cooling the water gradually. To arrest Vomiting he uses silver nitrate, gr. internally. To check purging, hypodermic in

jections of morphia grain for a child 2 years. old. He gives no food till the symptoms abate, as digestion is entirely suspended during an attack.

Dr. Griffith says that the "smile" of sleeping infants is really an expression of momentary pain due to some disturbance of digestion.

Dr. Wood says that true epilepsy is absolutely incurable. The bromide of potassium will defer and lessen the attacks, in most cases, it given early and pushed to distinctive bromism and then dropped to strong therapeutic doses and kept up continuously. Dr. Wood combine with it antipyrine. The bromides of sodium and strontium are also useful. The union of bromide of ammonium and bromide of strontium have yielded him better resuls than the single drug. To guard against skin effects he gives Fowler's solution with the bromides.

Acting on the knowledge that strontium. iodide is very well borne by the stomach, Dr. Wood began experimenting with strontium compounds and now announces that the disturbances of digestion so annoying in the administration of salicylates may be entirely overcome by the use of salicylate of strontium. He says it is the best intestinal antiseptic known. He has cured cases of rheumatism given up as incurable under the old salicylates. He sometimes pushes as far as grs. 120 in 24 hours, and the stomach is unaffected, though the system gives evidence of thorough saturation with the drug.

Dr. Balliet suggests eserine bypodermically in cases where strong and continuous purgation is desired.

Dr. McFarland says he has no faith in the reputed antiseptic properties of creolin. The doctor has grown authrax on agar agar submerged in the pure creolin, and the growth, *porulation and development of the colony was not in the least disturbed.

Dr. Cattell advises the use of ammonia to remove the odor on the hands a'ter performing a post mortem, and mentions the fact that blood makes an excellent glue for affixing labels.

Dr. Penrose says he can not conceive of a condition when it is absolutely necessary to use a uterine tent and advises their abandonment.

Dr. Wood says that more than of a grain of cocaine should never be applied at once to any mucous membrane on account of its rapid absorption and consequent danger of producing the onstitutional tonic effect of the entire amount used.

........

..gtt. i .f dram ij .f ounce j

Mist. potass citrat q. s. a. d Misce. Sig. Tablespoonful every three hours. Dr. Deaver now appears in the operating room clad in a close fitting linen cap in addition to the aseptic costume always used. The improvement is self evident. The heads of surgeons and assistants rubbing together over an open wound are liable to allow septic material (such as dandruff) to enter. This cap prevents such an accident and completes a seemingly perfect technique.

Prof. Hirst would answer 66 Perplexed," of last issue, in some such way as this:

(1.) Speak kindly to the woman, for doubtless her unnatural desire for freedom from this blessing comes from impulses that you can not

fathom.

(2.) Explain to her that life does not begin with the first wailing cry but at the moment of conception.

(3.) Show her that attempted abortion at any time after such conception is ATTEMPTED MUR

DER.

(4.) Say to her, "I will gladly oblige you, madame, but owing to the danger to yourself, I think it would be better to wait until the child is born, and then I can strangle it quietly with much greater ease and comfort to all of us."" (This will always cause the woman to see what she has asked and she will shrink in horror when the matter is presented in this light). Prof. Hirst says such a talk will bring any woman to her right mind.

They do not realize what they ask you to do until you speak to them as in No. 4.

The professor says also that many women, knowing themselves pregnant, will come and give such accurate symptoms of fibroid or some other complaint that the unwary doctor will pass a sound-only to be smilingly informed later that his services will not be required six months or so later. The professor says abortion induced by the physician (except when the life of the prospective mother is endangered by the fetus continuing longer in the uterus) is homicide and nothing else, and should be so considered by doctor and patient. The realization of the awfulness of the crime will always prevent it.