HEALTH DEPARTMENT, CRIMINAL COURT BUILDING, NEW YORK CITY. A Study of Tetanus and its Treatment. BY ALEXANDER LAMBERT, M.D., VISITING PHYSICIAN TO BELLEVUE HOSPITAL; ASSISTANT BACTERIOLOGIST TO THE NEW YORK HEALTH DEPARTMENT. FROM THE NEW YORK MEDICAL JOURNAL, June 5, 1897. • A STUDY OF TETANUS AND ITS TREATMENT BY ALEXANDER LAMBERT, M. D. VISITING PHYSICIAN TO BELLEVUE HOSPITAL J ASSISTANT BACTERIOLOGIST TO THE NEW YORK HEALTH DEPARTMENT. REPRINTED FROM THE NEW YORK MEDICAL JOURNAL JUNE 5, 1897 NEW YORK D. APPLETON AND COMPANY 1897 Copyright, 1897, By D. APPLETON AND COMPANY. A STUDY OF TETANUS AND ITS TREATMENT/ Statistics.-Since the advent of antiseptic surgery tetanus has become less common than before, and is now usually considered a rare disease. That it is, however, of more frequent occurrence in New York city than is gen- erally supposed is shown by the following table of deaths from tetanus, taken from the records of the Bureau of Vital Statistics for New York city. Record of the Deaths from Tetanus in New York City from 1868-96. TETANUS NEONATORUM. IDIOPATHIC TETANUS. Male. Fe- male. Total. Aver- age. Male. Fe- male. Total. Aver- age. 1868- 77 278 193 471 47'1 52 24 76 7-6 1878-'87 305 202 507 50'7 16 9 25 2-5 1888-'96 219 144 363 403 31 21 52 5-7 The foregoing statistics of tetanus neonatorum may be considered as accurately representing the death-rate from that form of tetanus; while the statistics of idiopathic tetanus show a less number of deaths than actually oc- curred from traumatic tetanus. This is because in all cases of traumatism in which death occurred from tetanus the record of death was placed under the accident which caused the trauma. These figures, therefore, represent only the number of deaths from the so-called idiopathic * Read before the Society of Alumni of Bellevue Hospital, April, 1897. LAMBERT: TETANUS AND ITS TREATMENT. 4 and rheumatic tetanus-that is, those cases in which the lesion giving rise to the infection was either overlooked or had healed and could not he found. The death-rate in tetanus neonatorum is usually estimated as from ninety to ninety-five per cent. (1); therefore, the number of cases from this disease in children in the last twenty-nine years has amounted to about fourteen hundred and fifty, or fifty a year. Counting the traumatic cases, it seems a safe estimate to say that in this city there have aver- aged about sixty cases of tetanus a year for the past twen- ty-nine years. The Tetanus Bacillus.-The tetanus bacillus is now accepted as being the cause of all the various so-called forms of tetanus, such as puerperal tetanus, tetanus neonatorum, idiopathic, rheumatic, and traumatic tet- anus. To produce the disease there must always be some wound in which the bacillus finds lodgment. The ba- cillus itself is a slender, round-ended rod, usually occur- ring singly, but in cultures often growing in long threads. In its resistant stage it contains a round spore at one end. It will not grow at temperatures below 14° C., but grows at ordinary temperatures of 20 to 22° C., and best at body temperature of 37° C. It will not grow in the presence of oxygen, but is a strict anaerobe. Its growth in the animal organism is comparatively scanty, and is usually in association with other germs. It remains at the seat of infection, and does not spread through the body. The disease is a true toxaemia. The spores are very resistant to external influences. Henri jean (2), by means of a splinter of wood which had once caused tetanus, was able after eleven years to again cause the disease by in- oculating an animal with the same splinter. The Occurrence of Tetanus Bacilli in Nature.- Since Nicolaier, in 1884, discovered and identified the tetanus bacillus as the cause of tetanus, the bacilli have been found not only to be exceedingly common inhabit- ants of the soil, but when present even being as abun- dant at the depth of six or seven feet as in the superficial layers (3). They have also been found in many different substances and places-in hay dust (4), in horse and cow LAMBERT: TETANUS AND ITS TREATMENT. 5 manure (5), in the mortar of old masonry (6), in the dust from horses' hair (7), in the dust in rooms of houses, barracks, and hospitals (8), in the air (9), in spider webs (10), in the water of the Dead Sea (11). Ledantec (12) has proved that the arrow poison of certain savages in the New Hebrides is made by smearing the arrowhead with dirt from crab holes in the swamps, and thus infecting the head with the spores of malignant oedema and tetanus. It is well known that certain localities in the vicinity of New York are notorious for the number of cases of tetanus which develop from slight wounds-for example, some parts of Long Island and New Jersey. The writer has obtained tetanus bacilli from the dirt from various parts of Long Island and New Jersey as well as from the dirt of New York streets. Dr. Williams, of the New York Health Department, has twice obtained them from air in this city. Factors favoring Tetanus Infection.-Considering the wide distribution of the germs, why does not tetanus occur more frequently? The work of Vaillard, Vincent (13), and Rouget (14), corroborated in the main by Klipstein (15), throws some light on the subject. These authors found that pure cultures of tetanus, after the germs had sporulated and the toxines had been destroyed by heat, could be injected into animals without producing tetanus. Even one or two millions of spores, if deprived of the toxines, proved harmless to guinea-pigs, and from fifteen to thirty cubic centimetres of broth cultures were harmless to rabbits. But if a culture of a non-pathogenic organism, such as the Bacillus prodigiosus, was injected simultaneously with the spores, or if there was an effusion of blood at the point of injection, or if there was a previous bruising of the tissues, the animals surely died of tet- anus. Even irritating foreign bodies were introduced simul- taneously with the spores deprived of their toxine and tetanus did not develop. But if the wounds containing the foreign bodies became infected with extraneous germs, tetanus developed and the animals died; or if the spores 6 LAMBERT: TETANUS AND ITS TREATMENT. were protected by filter paper, or even by such a soft sub- stance as agar jelly, the animals invariably died. Because, as was assumed, the phagocytes were prevented from at- tacking them, they thus had time to germinate, and the bacilli formed from them were able to produce their tox- ines. The pus from several cases of human tetanus was injected into animals, and both the tetanus bacillus and each separate species of germs were cultivated out in pure cultures. A pure culture of each germ was mixed with the non-toxic spores and injected into animals. The majority of the animals did not have tetanus; only certain species of germs favored the development of the spores and produced tetanus. In some cases the species was found to be a bacillus, in others a coccus; in one case none of the bacilli or cocci alone favored the develop- ment of the tetanus spores, but it was necessary to inject a mixture of one of the bacilli and one of the cocci with the spores before tetanus could be produced. From these experiments it seems that a mixed infection is necessary to the development of tetanus when the infection is produced by spores. As a matter of fact, in human tetanus the infection may be considered as probably universally produced by the germs in their spore state. If in any given case, the tissue being healthy, the ordinary saprophytic germs are killed by proper disinfection, a mixed infection does not take place, and tetanus will not develop. Or, if the germs happening to be present, even if not killed by disinfection, do not favor the development of the spores, either by interfering with the integrity of the tissues or in some other way, tetanus will not develop. If, however, the tissues infected be badly bruised or lacerated, the spores may develop, as in the experiment on animals with pre- viously bruised tissues. This conception of the impor- tance of concurrent infection is still further supported by experimental data. It has long been noticed that direct infection from animal to animal with pus from wounds causing tetanus could not be carried beyond the third or fourth generation. The third or fourth animal would not become tetanic or would acquire only local and pass- LAMBERT: TETANUS AND ITS TREATMENT. 7 ing tetanus. Vaillard and Rouget (16) infected animals with earth known to contain tetanus spores, and counted the number of colonies developing in a given amount of the pus in each successive animal. In the animal infected with earth some thousands or hundreds of colonies were obtained, in the next animal scarcely a hundred colonies, and the pus from the third animal failed to produce tetanus. For example: Guinea-pig 1, inoculated with earth, died of tetanus in five days; pus gave 32,570 colonies. Guinea-pig 2, inoculated with pus from No. 1, died in thirty-six hours; pus gave 120 colonies. Guinea-pig 3, inoculated with pus from No. 2, died in forty hours; pus gave 7 colonies. Guinea-pig 4, inoculated with pus from No. 3, did not have tetanus. The writer, as well as many other workers, has sev- eral times repeated these experiments with similar results. The micro-organisms which enhance the infective capa- city of the tetanus bacilli, being usually saprophytic, can not be indefinitely transmitted from one animal to an- other, but soon die out, leaving the tetanus germs without favoring assistance, and these are thus unable to prolifer- ate and produce their death-dealing toxines. Thus, in spite of the wide distribution of the tetanus germs, they seem to require some favoring condition of the wound or some favoring concurrent infection to enable them to grow in the animal organism. Localization of Tetanus Bacilli in the Body.-Another factor in the case is that the tetanus bacillus does not belong to the septicaemia class of organisms which spread through the body and by their growth and enor- mous increase produce their effects, but, on the contrary, remains localized at the original point of infection. While there are a few cases on record in which the bacilli have been found in the tissues of the animal body other than at the point of infection, it does not militate against the fact that in the vast majority of cases the tetanus bacillus remains localized. This will be seen later to have an im- portant bearing on the treatment of the disease. Niko- LAMBERT: TETANUS AND ITS TREATMENT. 8 lai er (17), in many experiments, found, tetanus bacilli only twice in the spinal cord and once in the sciatic nerve. Bosenbach (18) found only occasional individual bacilli in two rabbits. Tizzoni and Cattani (19) also obtained positive results in their search for the bacilli. Monastyrski (20) in one out of four cases in human beings found the bacilli. Vaillard and Vincent (21), using a whole brain of a guinea-pig, once obtained a culture of the bacilli. Schnitzler (22) found them in the lymphatic glands in the groin of a patient who died from tetanus following an extensive gangrene from frostbite of the leg and foot. Dor (23) found the bacilli in an effusion of blood in the gray matter of the brain in a patient who died from tetanus from a compound fracture of the skull, and in the cerebro-spinal fluid from this patient. While this case is usually classed as one in which the tetanus bacilli were found away from the point of infection, it cer- tainly would be more conclusive if the primary infection had not probably occurred within the skull. Biidinger's (24) experiments with the lymph nodes of tetanic animals, also cited as proving the presence of bacilli in the nodes distant from the seat of infection, do not sufficiently prove what the author alleges for them. The writer endeavored in two cases of human tetanus to repeat the findings of Schnitzler, but without success. The cultures remained sterile, and the animal experiments absolutely negative. Nature of the Tetanus Poison.-What is the nature of this poison, and what is the mechanism of its action on the organism? Richardson (25) in 1859 expressed his belief that the production of tetanus in traumatic cases was due to the fact that the wound in the process of healing secretes a special albuminous product which has the property of a ferment. This substance absorbed into the body excites new chemical changes, and as a product of these there is developed an alkaline or alkaloid substance having properties analogous to strychnine. Of course it was un- known to this observer that this " ferment " was of mi- crobic origin, but after many years of research this the- LAMBERT: TETANUS AND ITS TREATMENT. 9 ory has again been brought forward by several observers as the true solution of the character and action of the tetanus poison. These views are strenuously defended by Courmont and Doyon (26) and Uschinsky (27), this last observer having succeeded in obtaining albuminous sub- stances from tetanus cultures grown in non-albuminous media, and considered the substances obtained to be the tetanus poison, more or less pure, and classifies it as a ferment, but the isolation of the pure poison was unsuc- cessful. As the result of their earlier experiments,. Kund, Faber (28), Vaillard and Vincent (29), Tizzoni and Cattani (30), all believed that the tetanus poison was a ferment or enzyme. Fermi and Pernossi (31), in a long series of experiments, seem to have proved conclusively that the poison is not a ferment, and can not be classed with the enzymes. Brieger (32) has worked on another theory, and at first thought the poison a ptomaine, as he succeeded in separating four ptomaines from impure cul- tures of tetanus; these he named tetanin, tetano-toxine, spasmo-toxine, and the fourth was an unnamed base. But these substances did not on injection give the typical clinical picture of tetanus, though they caused the death of the animals by convulsions, etc. Brieger and Frankel (33) shortly after this obtained from pure cultures of tetanus a substance which they called the toxalbumin of tetanus, which, on injection into animals, induced the symptoms of tetanic infection. Recently Brieger and Cohn (34) and Boer (35) have succeeded in isolating the tetanus toxine in seemingly a nearly pure state, and show that the purer the poison the more it lacks the reactions characteristic of the albu- minous bodies. Blumenthal's (36) researches seem to confirm the non-albuminous nature of the poison. What the true composition and constitution of the tetanus poison are, thus remain as yet unknown, but the vigor of its action stands out with terrible distinctness. Brieger and Cohn found that their purified poison was surely fatal to a fifteen-gramme mouse in a dose of 0.00000005 gramme. Reckoning according to the body weight for a man of seventy kilogrammes or a hundred 10 LAMBERT: TETANUS AND ITS TREATMENT. and seventy-five pounds, it would require but 0.00023 gramme, or 0.23 milligramme, to prove fatal. Comparing it with the snake poisons, Calmette (37) has found that the dried cobra venom requires 0.25 milligramme to kill a rabbit of four-kilogramme weight, and according to body weight it would require 4.375 milligrammes to kill a man of seventy kilogrammes, or a hundred and seventy-five pounds. As the fatal dose of atropine for an adult is a hundred and thirty milligrammes, of strychnine from thirty to a hundred milligrammes, and of anhydrous prussic acid fifty-four (38) milligrammes, the appalling strength of the tetanus poison can readily be appreciated. Without doubt, this poison is the most deadly yet dis- covered. The Action of the Tetanus Poison in the Body.-Al- though the exact mechanism of the action of the tetanus poison on the animal organism is still a subject of con- troversy, especially concerning some matters of detail, the main points of its action may be considered as fairly proved. After the poison is once formed or injected in the body its absorption is rapid, as the following experi- ment shows, lloux and Vaillard (39) injected a fatal dose of toxine into the middle part of the tail in several rats; after varying lengths of time the tails were cut off at the base. All animals in which this operation was delayed for forty minutes or more died with the same rapidity as the controls. The blood usually contains the poison, as has again and again been proved. Nissen (40) first proved that the blood of a tetanic patient was capable of inducing tetanus in animals when injected subcutaneously. Kitasato (41) also found the serous exudates of the pleural and peri- cardial cavities, as well as the blood, of tetanic animals would cause tetanus when transferred to other animals. Kallmeyer (42), Bruschettini (43), and others have ob- tained similar results. The blood, after absorption, soon carries the poison over the whole body, the rapidity of the development of the symptoms depending on the amount and virulence of the poison. In experimental tetanus, and in about one third of the cases in human LAMBERT: TETANUS AND ITS TREATMENT. 11 beings, the first symptoms appear in the muscles adjacent to the point of inoculation or infection. In mild cases, or when a dose too small to be fatal has been received, the tetanic spasm may remain confined to these same mus- cles. But this peculiar localization of the earliest symp- toms can not be explained by the diffusion of the poison through the body by means of the blood, because after absorption the poison must be evenly diffused wherever the blood circulates. Brunner (44) brought forward the theory that the nerve fibres themselves were the diiect carriers of some of the poison from the point of entrance, and that the cells in the cord from which the nerves originated were thus the first to receive the poison, and, receiving it in more concentrated doses, first succumbed to its destructive action. Bruschettini's (45) experiments support this view. He found that the part of the spinal cord adjacent to the point of inoculation, either above or below, was always toxic, while other parts were non- toxic. Key and Retzius (46) injected solutions of Rich- ardson's blue in the subdural space with low pressure, and found that the color made its way into the nerve trunk, often through the ganglia, and far out into the nerve branches. When injected into the ganglia or into the nerves the injection mass permeated the perineurium in all directions, and into the endoneurium, and isolated the individual fibres from each other. Injections into the cord showed a spreading of the fluid in all directions, up and down, and transversely. Hence, a fluid can easily go from the periphery to the centre. It is probable that such is the action of the tetanus poison. After the poi- son reached the central nervous system we had no clew, until lately, as to its further action. There was no appreciable characteristic pathological lesion which could be discovered macroscopically or microscopically. Beck (47), however, has described a peculiar degeneration in the motor cells of the cord in animals killed by tetanus. This degeneration does not seem to attack the entire cells, but only a peripheral part, and seems to be confined chiefly to the body of the cell, usually leaving the nucleus intact. Only very late do the nucleus and the nucleolus 12 LAMBERT: TETANUS AND ITS TREATMENT. take part in the changes. The changes consist in a swell- ing of the cell and a homogeneous or finely granular degeneration with a swelling, and finally coarse lumping together of the chromatin. This is especially evident at the tiny eminence from which the axis cylinder arises and in the axis cylinder itself. Beck considers this as proving that the poison travels along the axis cylinder, and that, as the nucleus is the last portion affected, the change is not a necrosis, but only a modification of cell function. Nissl (48) and Sailer (49) have also found undoubted changes in the ganglion cells in animals, and Nerlich (50) has found, in a case of human " head tetanus," a vacuole formation and progressing degeneration in the cells of the nuclei of the motor portion of the trigeminus, and in the nuclei of the facial and hypoglossal nerves. The experiments of Gumprecht and Brunner prove that the lesion is undoubtedly confined to the central nervous system, the muscles and motor nerves of the inoculated portion of the body having nothing to do with the origin of the tonic spasm nor of the convulsions. The sensory nerves may convey irritant stimuli to the cord, and in this way cause convulsions, but are not otherwise directly the cause of the convulsions. After section of the sensory nerves the convulsions occur in the completely anaes- thetic limb. Goldscheider (51) also believes that the action of the tetanus poison is on the central nerve cells, in conse- quence of which they assume an increased and ever-in- creasing excitability, the change taking place gradually, but going on continuously as long as there is absorption of poison from the wound. He maintains that the poison is conveyed to the nerve centres by the nerve trunks, and that it there acts on the ganglion cells gradually, covering a larger and larger area and increasing their excitability. But he believes, in addition, that there is a diffusion of the poison by means of the blood and lymph, to which the general spasms are to be attributed. It seems, therefore, without doubt that the tetanus poison causes an increased reflex excitability of the motor gan- LAMBERT: TETANUS AND ITS TREATMENT. 13 glion cells of the cord and medulla, and is thus analogous in action to strychnine. This theory of the action of the tetanus poison seems to the writer far more probable than the theory of Courmont and Doyon (52). According to these observers the so-called toxine elaborated by the tetanus bacillus is not the true poison, but is a ferment, which forms the poison in the body at the expense of the organism, and is found in the blood, sometimes in the urine, and in especial abundance in tetanized muscles. After this poison is formed it can be extracted from the muscles by boiling, and when injected into other animals causes immediate tetanic symptoms without any period of incubation. The contractures are the results of an irrita- tion of the peripheral sensory nerves, and not due to any direct action on the medullary nerve centres. The char- acteristic incubation period is the time necessary for the fermentation to take place, and after the minimal fatal dose has been given any larger dose will not shorten the incubation period. The results of Brieger, Cohn and Boer, and Fermi and Pernossi seem to prove that the poison is not albu- minous and is not a ferment. Uschinski and Brunner (53), repeating the experiments of obtaining an imme- diately tetanizing substance from the muscles, have failed to confirm Courmont and Doyon's results. The incuba- tion period can be as well explained by the dilution of the poison in the blood. From the experiments of Kita- sato, and from his own experiments, the writer is con- vinced that the amount of toxine injected influences the duration of the incubation period. Gumprecht and Brunner have shown that the tetanic spasm and convul- sions occur after section of the sensory nerve, and are not dependent on it for a causation of the spasm or con- vulsions. The injection of blood from tetanic animals causes tetanus in other animals, but always with the char- acteristic incubation period. These are the reasons, briefly stated, why Courmont and Doyon's theory does not seem tenable. All experiments fail to show why in the majority of cases in human beings, and in some of the higher animals, 14 LAMBERT: TETANUS AND ITS TREATMENT. as the horse and ass, trismus and spasm of the pharynx are the first symptoms, regardless of the point in the body at which the infection has taken place. We must here suppose an elective action of the poison in some animals for the motor cells in the medulla, or, as the poison is slowly formed and acts slowly, an accumulation is necessary, and the muscles in which the inhibitory mechanism is least developed will be the first attacked (54). When the poison is circulating in the body, do the excretory organs endeavor to discharge it? There is no doubt that this takes place in man and animals, as both the urine (55) and saliva (56) have been found to pro- duce symptoms of tetanus when injected into animals. Treatment of Tetanus.-The successful treatment of any infectious disease depends largely on our thorough knowledge of its mode of infection, and the mechanism of its action in the body after the infection has taken place. It is for this reason that in this paper the patho- logical physiology of tetanus has been dealt with in so much detail, for the best treatment of the disease is based upon the logical deductions drawn from our knowledge gained by scientific research. From the foregoing it is readily seen that the indi- cations for treatment in tetanus are both local and gen- eral. Local Treatment.-First, what are the local indica- tions and how are they best fulfilled? As has been shown, the infection as it occurs in practice can be considered in the majority of cases as an infection with tetanus spores. These spores require favoring circumstances to develop. If we remove these favoring elements we render the germs harmless. Thus, in regions where tetanus is prevalent, thorough cleansing of all wounds, however in- significant, becomes of more than the usual importance. Tetanus may and often does arise from wounds so insig- nificant that they are healed and forgotten before even the first symptoms of tetanus develop. For this reason there still remain ideas of idiopathic and rheumatic tetanus. But these forms of tetanus are LAMBERT: TETANUS AND ITS TREATMENT. 15 nothing more than cases of true traumatic tetanus, in which the point of infection can not be found or is over- looked from its supposed insignificance. A case re- ported by Sahli (57) well illustrates this point. In a boy suffering from tetanus the only lesions found were some insignificant scabs on the knee and one on the dorsum of the foot. This last was pulled off, and showed underneath healthy granulations nearly healed and no pus. This scab was put in culture and under the skin of a mouse which died of typical tetanus. The cultures showed no tetanus bacilli. The scab, therefore, was sim- ply a source from which fresh toxine might be absorbed. The blood of the child at this time was non-toxic. Not only, therefore, should we carefully attend to slight fresh wounds, but the most strict and careful search should be made in cases in which tetanus has developed for all lesions of the skin, and all scabs should be pulled off and the surface beneath thoroughly treated by the cau- tery or by some disinfectant. Disinfection.-Our ordinary disinfectants or antisep- tics must here be considered from a different standpoint than is the case in ordinary surgery. Such disinfectants must be used as are not only antiseptic, but also antitoxic- that is, not only destructive to the micro-organisms them- selves, but also destructive to their toxic products-for, as we have already seen, the toxines in the tetanic wound are almost as great a source of danger as the tetanus ba- cilli themselves. Against our ordinary antiseptics tetanus spores are quite resistant, as five-per-cent, carbolic acid requires fif- teen hours' contact to destroy them, and solutions of bichloride of mercury (1 to 1,000) require three hours (58). If, however, a half per cent, of hydrochloric acid is added to either of the above-mentioned solutions the ac- tion is greatly accelerated. Five-per-cent, carbolic and a half-per-cent, hydrochloric acid kills them in two hours, and 1 to 1,000 bichloride and a half-per-cent, hydrochloric acid kills them in thirty minutes. If the solution contains 1 to 1,000 bichloride with five-per-cent, carbolic and a half-per-cent, hydrochloric acid the spores are killed in 16 LAMBERT: TETANUS AND ITS TREATMENT. ten minutes (59). Silver-nitrate solutions destroy the spores in one minute in one-per-cent, solution, and in five minutes in l-to-1,000 solution (60). Bichloride alone, still further, does not fulfill the requirements in a tetanus wound, as it is absolutely inactive against the tetanus poison (61). The most active antitoxic agents we have are the iodine preparations-e. g., iodine trichloride, Gram's solution, and Lugol's solution. These, besides be- ing antiseptic, destroy the toxine already formed; iodine trichloride, in a half-per-cent. (61) solution, destroying it in less than an hour, and it is with Gram's or with Lugol's solution that the French experimenters weakened their toxine in their first immunity experiments. Kresol, in one-per-cent. (61) solution, is also markedly destructive to the toxine, destroying it within an hour; (61) carbolic acid, one-and-a-half-per-cent. solution, is equally anti- toxic, while formalin, one-to-two-per-cent. solutions, ex- erts a decidedly destructive action in twenty-four hours' contact, as shown by the writer's experiments. Iodo- form, chromic acid up to two per cent., and pyrogallol have no effect on the poison, while lysol (62) and potas- sium manganate, ten-per-cent, solution, require twenty- four to forty-eight hours to be effective. A tetanus wound should not, therefore, be casually cleaned with bichloride or carbolic alone, but should be treated with a stronger mixture, to kill whatever germs are present; but above all should the treatment further consist in a thorough application of the iodine solutions. In sloughing wounds these solutions should be deeply injected in the neigh- borhood around the wound. When the iodine solutions are not immediately available, and perhaps the hydro- chloric acid, carbolic, or bichloride solutions are at hand, rather than rely too much on the hydrochloric acid, which, though antitoxic in a half-per-cent, solution, would be quickly neutralized in the alkaline tissues, it would be advisable to use caustic soda or potash (63) in solutions of 0.3 per cent, or 0.4 per cent., as they are as active as the 0.5 per cent, hydrochloric acid, and would not be subject to the same disadvantage, and would thus act more effect- ively. LAMBERT: TETANUS AND ITS TREATMENT. 17 Amputation.-The question of amputation, when the wounds are on the fingers or toes, or when the tetanus follows serious contusions of the limbs, is a question to be carefully weighed and acted upon promptly. It is better for a patient to live minus a finger, toe, or limb than to risk in an acute attack of tetanus the absorption of more poison from a wound whose lacerated and dirty condition prevents a thorough cleansing. In severe wounds of the head and body this question, of course, does not arise, and disinfectants must be relied on to pre- vent further absorption. General Treatment.-In the general treatment of tetanus we have, as in all cases of poisoning, three indi- cations to follow: 1. The speedy elimination of the poison. 2. The administration of physiological anti- dotes to counteract the action of the poison on the body cells. 3. Chemical antidotes which change the poi- son by destroying it or by rendering it inert, and thus prevent, retard, or arrest its action. Means to further the Elimination of the Tetanus Poi- son.-To fulfill the first indication we have but to assist the action of the kidneys and endeavor, by their in- creased action, to eliminate the poison circulating in the blood. Probably the best means for this purpose is an excessive addition of fluids in the body. There is usually no trouble in persuading tetanic patients, if they can swallow, to drink an abundance of milk or water, as their thirst is usually excessive. Sahli (64) reports that in one of his cases he used with advantage subcutaneous and intravenous injections of salt solution. The intra- venous injections seem preferable, as the subcutaneous irritation of the sensory nerves would distinctly tend to increase the convulsive seizures. Diuretin may be rec- ommended to aid the diuresis, as it increases both watery and solid constituents of the urine. Whether the toxines are eliminated by the sweat is unknown; therefore it is hard to say whether an increase in the usual excessive sweating of tetanus would be an advantage. On the grounds that as the urine and sweat vary in inverse ratio to each other, and we are sure of elimination by the kid- 18 LAMBERT: TETANUS AND ITS TREATMENT. neys, it does not seem that it would be of advantage to increase the already excessive sweating. The toxine is also eliminated by the saliva, but whether this be dis- charged or swallowed can be disregarded so far as reab- sorption is concerned, for in both herbivora and carniv- ora the living intestinal mucous membrane quickly de- stroys the tetanus toxines (65). Physiological Antidotes.-Secondly, in choosing our physiological antidotes we must look for those that will counteract the damage already done by the tetanus poi- son. We are dealing with an enormously increased re- flex excitability of the central nervous system, especially of the motor cells of the cord and medulla. Now, if we are able to hold in check the dreaded tetanic spasms and convulsive seizures of the glottis and respiratory muscles until the organism can recuperate, or if we can prevent the complete exhaustion by the incessant spasms of the cells governing the respiratory and circulatory functions, we may hope for success in our treatment. Fortunately, we possess several excellent remedies which can control this reflex excitability. The best remedy of all is chloral, while the use of morphine, bromides, physostigmine, and antimony is often indispensable. All narcotics act more or less to diminish the reflex excitability, but chloral is the most reliable and effective. Bromides exert their action more on the cortical centres, and are thus less powerful in a disease like tetanus when the cerebrum is not involved. Physostigmine has been highly praised by many writers for its action in tetanus, seeming especially to control the convulsions. Its action is on the gray matter of the cord, acting first on the posterior horns and then on the ante- rior. It may in this way diminish the ability of the sen- sory nerve fibres to conduct external stimuli to the already overexcited motor centres, and thus diminish the reflex convulsions. Later, its paralyzing effect on the anterior horns would in itself prevent the spasms. Antimony was suggested to the writer as a remedy in tetanus by Dr. W. R. Bross, of New York city, who used it in Costa Rica in five cases of acute tetanus with short incubation periods, LAMBERT: TETANUS AND ITS TREATMENT. 19 and succeeded in saving all five patients. He recom- mends that it be given in an eighth to a sixth of a grain doses with an equal amount of morphine every two hours. When given in this way it does not cause vomiting, and certainly seems to control the spasms, as was evident in a case of tetanus recently under the writer's care. Ac- cording to Nothnagel and Rossbach (66), antimony causes complete disappearance of reflex activity, which on physio- logical grounds places it among the desirable remedies. Morphine has an especially advantageous action of its own. Only in large doses is it usually considered to dimin- ish the reflex excitability of warm-blooded animals; still it causes a cessation of the pain and produces sleep. As the tonic spasm in tetanus relaxes during sleep, morphine indirectly secures the end in view. Sleep in itself to the exhausted patient is a necessity, so that morphine fulfills two indispensable indications. The bromides are also useful in this connection, as they tend to diminish the overwrought condition of the brain and aid in producing sleep. The anaesthetics are not to be recommended for more than short periods, and their repetition is not with- out danger. Sahli (67) rightly emphasizes two factors in dosage: one is the individual factor in each case, the other the changing and alternating the remedies, for the purpose of preventing a tolerance to the drugs. As this author points out, if from the beginning one should reckon in a given case of tetanus the dose of the narcotics to be administered for several days, one is apt to give either too much or too little, since it is quite impossible to esti- mate the sensitiveness of the patient, as it is so greatly modified by the disease itself. Even in a single day the doses may have to be modified. It is wisest to begin with doses which in a healthy individual would produce a decided effect-e. g., thirty grains of chloral hydrate, forty-five grains of bromide of sodium or potassium, and a sixth of a grain of morphine. The convulsions are the best criterion for judging whether narcotics should be in- creased or diminished. The toxic spasm is not so danger- ous as the sudden convulsive seizures, and usually begins to relax simultaneously with the cessation in frequency of 20 LAMBERT: TETANUS AND ITS TREATMENT. the convulsions, when improvement begins. As Sahli expresses it: "In the choice of the remedy the principle of alternation is the chief factor. If one always gives the same preparations, or always all the remedies in combina- tion, one will generally have the experience that the effect is soon lost by tolerance. It is in one's power to prevent this by alternating the remedies. Of course, in giving the remedies of the chloral group a careful super- vision of the pulse is necessary, while with bromides and morphine this effect is much less to be feared." Chemical Antidotes.-Thirdly, have we any true chemical antidotes which circulating in the blood are able to destroy or render inert the tetanus poison? The substances which Kitasato, and later Fermi and Pernossi, have shown to be antitoxic are, as a rule, not available for therapeutic purposes. The most effective antitoxic sub- stances, as we have seen, are carbolic acid, kresol, and the iodine solutions. While these substances are so effective outside the body, is it possible to obtain a sufficient con- centration within the body to destroy the toxine? Our experience with internal antiseptics in general infectious does not give us much hope in this direction. Too great a concentration of the antidote is necessary for us to hope for any effect on the tetanus poison. Bacelli (68), it is true, recommends subcutaneous injections of one-per-cent, solutions of carbolic acid, and several cures are reported following this plan of treatment. Though this was rec- ommended empirically at first, carbolic acid is antitoxic and it may perhaps have some action; but as a half-per- cent. carbolic acid is used to preserve the toxine in the laboratories, it is more than doubtful if sufficient concen- tration could be obtained in the blood to make it effective, and besides, its poisonous effect on the organism is cer- tainly to be feared. Antitoxine.-We have therefore to turn to anti- toxic serum, which, as we know by absolute proof, in some way renders inert the toxine circulating in the blood. Preparation of the Antitoxic Serum.-The tetanus antitoxine is prepared in the same manner as the diph- theria antitoxine, by inoculating the tetanus toxine in in- LAMBERT: TETANUS AND ITS TREATMENT. 21 creasing doses into horses. The toxine is grown in bou- illon under hydrogen, and after ten or fifteen days filtered through porcelain, and the germ-free filtrate is used for the inoculations. The horses receive half a cubic centi- metre as the initial dose of toxine, and this dose is in- creased as rapidly as the horses can stand it, until they support seven to eight hundred cubic centimetres or more at a single dose. After some months of this treatment the blood of the horse contains the antitoxine in suffi- cient amount for therapeutic use. When the animals' tem- peratures are normal and they have recovered from the dose of toxine last given, they are bled into sterile flasks and the serum collected. The serum contains the antitox- ine and is tested on white mice or guinea-pigs. The Antitoxic Serum of the New York Health Depart- ment.-The New York health department has at pres- ent two horses well immunized against tetanus, and fur- nishes serum of the strength of one to four hundred million -that is, one cubic centimetre will protect four hundred million grammes of white mice against a three-to-four-day fatal dose of tetanus toxine. Reckoning in antitoxic units, twenty cubic centimetres of serum will contain eight thousand antitoxine units, an antitoxine unit in tetanus being the amount of serum necessary to protect one mil- lion grammes of test animal. The serum is supplied in twenty-cubic-centimetre bot- tles, and should be injected in ten-to-twenty-cubic-centi- metre doses. In severe cases the patient should receive fifty cubic centimetres in the first twenty-four or thirty- six hours, and these ten-to-twenty-cubic-centimetre doses repeated once or twice each day during the following four or five days or longer, according to the course of the disease. The circular accompanying the bottles explains more fully the proper method of procedure. The Action of the Antitoxic Serum in the Body.- As has been shown by Roux (69) and Calmette (70), the antitoxic serum has no direct destructive action on the toxine itself, but through some unknown action on the body cells the serum prevents the toxine from exerting its destructive action. Behring's first idea that there was 22 LAMBERT: TETANUS AND ITS TREATMENT. a direct destructive action between the antitoxine and toxine or some neutralizing effect, such as occurs between an acid and an alkali, has been shown to be incorrect. As Buchner (71) also shows, there is no destructive ac- tion of the antitoxic serum on the toxine either out- side or within the body, the action seeming to be one which, by producing certain changes within the cells, renders the action of the toxine inert. Tizzoni (72) con- cludes that the blood serum of vaccinated animals does not act as a remedy which neutralizes in the organism a certain active principle of disease and directly counter- acts certain functional changes [as our physiological anti- dotes do], but it acts, in all probability, in curing tetanus by immunizing the parts of the body not already teta- nized, and so limits the tetanus to a local form. Comparison of Statistics.-In estimating the value of any new remedy we must have certain undeniable facts on which to base our comparisons of old and new, such as a known death-rate, and we must criticise minutely our statistics rather than simply compare the death-rate. Un- fortunately, the death-rate in tetanus has been so vari- ously stated by different authors that it is difficult to say what is the true average mortality. In acute cases it is given as being from seventy-eight to 96.6 per cent.; in chronic cases, as being from 17.8 to fifty-five per cent.; the average for all cases varying from twenty-one to 87.5 per cent. The largest number of cases collected are 1,222 (73) war cases, with a mortality of 88.6 per cent., and 280 (74) cases occurring in time of peace, with seventy-six per cent, mortality, making 1,502 cases, with 87.7 per cent, mortality. The fairest estimate seems to be eighty per cent, for acute cases, and about forty per cent, for the milder or chronic cases, and sixty per cent, mortality for all cases. In estimating the value of the antitoxine treat- ment we must consider in each case the duration of the incubation period of the disease (75), the rapidity of the onset, with the frequency and intensity of the convul- sions, and finally the promptness with which any kind of rational or radical treatment can be or has been ap- LAMBERT: TETANUS AND ITS TREATMENT. 23 plied. The prognosis in cases not treated with antitoxine is relatively favorable if the incubation period is long, ten days or more, the onset slow, and the spasms are not severe; it is bad if the incubation period is less than ten days, the onset rapid, and the spasms severe (76). The following cases of tetanus comprise published and unpublished cases treated with antitoxine. Resume of Cases Treated with Antitoxine.-We have a total of a hundred and fourteen cases with a mortality of forty-six, or 40.35 per cent. All those with an incu- bation period of eight days or less and with a rapid onset of the symptoms, or those with a longer period of incuba- tion, but with an intensely rapid onset, have been classed as acute cases. All those with incubation period of nine days or more, or those with a shorter incubation where the onset was slow, have been classed as chronic. Six cases from lack of sufficient data are not classed; five of these patients recovered, one died with a complication of pneumonia. There remain forty-seven acute cases, with twelve recoveries, thirty-five deaths, and a mortality of 74.46 per cent. Of the chronic type, sixty-one cases, fifty-one cures, and ten deaths-a mortality of 16.39 per cent. Following Kanthack's system of criticism, we must exclude all cases which have died with intercurrent dis- eases, and all cases of those who died twenty-four hours after treatment was begun, as these really prove nothing as far as a fair estimate of any treatment is concerned; but we must also exclude all mild cases of recovery which did not receive treatment till the tenth to fifteenth days of disease, as such cases usually get well under any treat- ment. We must therefore exclude sixteen deaths in the acute cases, leaving thirty-one cases, with twelve recov- eries and nineteen deaths-i. e., 61.29 per cent, mortal- ity. We must also exclude in the chronic cases thirteen cures and eight deaths, leaving forty cases, with thirty- eight recoveries and two deaths, or five per cent, mortal- ity. This is certainly an improvement on the usual death- rate, being a total mortality of only 29.57 per cent. Of course, a final judgment of any treatment must be based on a larger total than seventy-one cases. But such a num- 24 LAMBERT: TETANUS AND ITS TREATMENT. ber is sufficient to show that some new beneficial factor has been present in the new treatment which was absent in the old methods. Yandell, in 1870 (77), in speaking of the prognosis of tetanus, declared that " recoveries from traumatic tetanus have been usually in cases in which the disease occurred subsequent to nine days after the injury. When the symptoms last fourteen days recovery is the rule, apparently independent of treatment. The true test of a remedy is its influence on the history of the disease. Does it cure cases in which the disease has set in previous to nine days? Does it fail in cases whose duration exceeds fourteen days? No agent tried by these tests has yet established its claim as a true remedy for tetanus." Does antitoxine by these criteria establish a claim as a true remedy for tetanus? In acute cases, developing eight days or less after the injury, in thirty-one cases the recoveries have amounted to 38.71 per cent., deaths 61.29 per cent., as against treatment without it of twenty per cent, of recoveries and eighty per cent, of deaths. In one hundred and one cases in which the duration of the disease is given, all those which passed the fourteenth day recovered. Antitoxine, therefore, by Yandell's cri- teria, fairly establishes itself as a true remedy for tet- anus. There are some cases of tetanus of such short incuba- tion and such intense rapidity of onset that in spite of all treatment they die within from twenty-four to thirty-six hours after the first symptoms appear. These cases at present seem hopeless. Limitations of the Treatment with Antitoxic Serum.- From the nature of the antitoxic serum and its peculiar action in the body it is necessarily limited in its action. We have shown that it does not directly act on the tetanus poison and destroy it, and that it can not undo the injury already done; it can only prevent further damage. It is possible, as certain cases of Roux's (78) show, that the disease may go on to a fatal termination, even after the blood of the patient has become markedly antitoxic. This emphasizes very strongly the necessity of the early use of the antitoxine; besides, as Behring (79) has shown, LAMBERT: TETANUS AND ITS TREATMENT. 25 the amount of serum necessary to protect an animal, when introduced simultaneously with the toxine, must be increased a thousand times if we wait till the first symptoms appear, and ten or a hundred thousand times if we delay a few hours longer. The serum will render inert the toxine circulating in the blood and any more toxine which may be generated in the wound; it is there- fore necessary to inject the serum as soon as possible, and in sufficient abundance. Compared with the results of serum in diphtheria, the results in tetanus must always fall far short in their success. In diphtheria the position and character of the lesion give early warning before the body is hopelessly poisoned, but the tetanus poison has insidiously gained control and often irreparably dam- aged the organism before its symptoms show themselves. The rapidity of recovery in the cases treated with anti- toxine does not seem to depend on the amount of antitox- ine injected nor as much as one would expect on the day of injection. This seems in direct opposition to what has just been said above, but is the logical consequence of the mechanism of the action of both toxine and antitoxine. Recovery depends entirely upon the degree of damage which the toxine has done before the antitoxine has been injected. As the virulence and the amount of poison and the extent of damage already existing in any given case are always unknown, and must remain unknowable, it is but another warning, stronger than anything else can be, that we must use the antitoxine at the earliest possible moment. The general treatment of a tetanus patient, such as nourishment and absolute quiet and rest, stuffing the ears with cotton to keep out sounds, etc., has not been touched upon, as it is self-evident. Preventive Inoculations.-By means of the antitoxine treatment, combined with other rational methods, the prognosis, even in acute cases, has been improved; but it still remains exceedingly grave, so much so that the pre- ventive inoculation of serum in all cases where dirt has been ground into serious contusions deserves a much more extensive consideration than has yet been given it. 26 LAMBERT: TETANUS AND ITS TREATMENT. In France, Dr. Bazy (80), after having four fatal cases of tetanus in one year, has made it a practice to inject ten cubic centimetres of serum into all patients who have come under his care with wounds which caused him to fear a possibility of tetanus. He has not seen a single case of tetanus since, though his practice has been in a region where the soil is notoriously contaminated with tetanus bacilli. Nocard (81), in veterinary practice, first followed this plan of treatment, and reports that of three hundred and seventy-five animals treated with immunizing doses of serum not a single animal has acquired tetanus, while in the same locality he has seen fifty-five cases of tetanus in animals not so treated. These are certainly striking re- sults, and it seems wise in a neighborhood like New York, where tetanus is not uncommon, to treat patients with immunizing doses of serum when the lacerated and dirty condition of their wounds may indicate the possibility of a tetanus infection. They will not have tetanus, and we may never know whether they otherwise might have had the disease, but we certainly shall prevent the patient from running the risk of an acute attack of tetanus, which is the main point. An attempt has been made in this paper to explain the pathological physiology of tetanus, and to build on established scientific data the rational line of treatment which promises the greatest success. There is no line of treatment which will give as brilliant results as one would wish for, but, as Roux has said, one can not choose in practice either the case or the time of intervention. We must, therefore, use that which gives us most prom- ise-local disinfection, physiological antidotes to hold the disturbed functions of the cord in check, and the anti- toxic serum to annul all further action by the toxine. By these means the recovery of the patient seems best as- sured. 1. Holt. Diseases oj Children, 1896. 2. Henrijean. Baumgarten's Jahresbericht, 1892, and Flugge. Microorganismen, 1896, and Bibliography. 3. Marchesi. Baumgarten's Jahresbericht. 1893. 4. Peyraud. Semaine medicale, 1890, p. 372. LAMBERT: TETANUS AND ITS TREATMENT. 27 5. Sormani. Centralblatt fur Bakteriologie, 1890.- Sanchez-Toledo and Veilion. Semaine medicale, 1890, p. 381. 6. Bonome. Baumgarten's Jahresbericht, 1887, p. 238. 7. Turco. Baumgarten's Jahresbericht, 1891, p. 217. 8. Turco. Ibid. 9. Schwarz. Centralblatt fur Bakteriologie, 1892, vol. ix, p. 697. 10. Turco. Loc. cit. 11. Lortet. Baumgarten's Jahresbericht, 1891, p. 219. 12. Ledantec. Annates de VInstitut Pasteur, 1890. p. 716. 13. Vaillard and Vincent. Ibid., 1891. 14. Vaillard and Rouget. Ibid., 1892. 15. Klipstein. Hygienische Rundschau, 1893, p. 1. 16. Vaillard and Rouget. Annates de VInstitut Pasteur, 1892, p. 386. 17. Cited from Gumprecht. Pfliiger's Archiv, vol. lix, pp. 105-152 and Bibliography. 18. Gumprecht. Ibid. 19. Gumprecht. Ibid. 20. Brunner. Experimentelle und klinische Studien uber Tetanus, 1894, and Bibliography. 21. Annates de VInstitut Pasteur, 1891, p. 1. 22. Schnitzler. Centralblatt fur Bakteriologie, vol. xiii, p. 679. 23. Dor. Semaine medicate, 1890, p. 184. 24. Biidinger. Wien. klin. Wochenschrift, 1893, p. 287. 25. Richardson. Medical Times and Gazette, vol. ii, 1859, p. 538. 26. Courmont and Doyon. Revue de medecine, 1894. 27. Uschinsky. Centralblatt fur Bakteriologie, vol. xiv, p. 316. 28. Kund Faber. Berlin, klin. Woch., 1890, p. 717. 29. Vaillard and Vincent. Loc. cit. 30. Tizzoni and Cattani. Centralblatt fur Bakterio- logie, vol. viii, p. 69. 31. Fermi and Pernossi. Zeitschrift fur Hygiene, vol. xvi, p. 385. 32. Brieger. Deutsche med. Woch., 1887. 33. Brieger and Frankel. Berlin, klin. Woch., 1890, p. 241. 34. Brieger and Cohn. Zeitschrift fur Hygiene, vol. 15, p. 1. 35. Brieger and Boer. Ibid., vol. xxi, p. 259. 36. Blumenthal. Zeitschrift fur klin. Med., 1896, vol. xxx, p. 538. 37. Calmette. Annates de VInstitut Pasteur, 1894, p. 276. 28 LAMBERT: TETANUS AND ITS TREATMENT. 38. Wormley. Microchemistry of Poisons, second edition. 39. Roux and Vaillard. Annates de VInstitut Pas- teur, 1893, p. 65. 40. Nissen. Deutsche med. Woch., 1891, p. 775. 41. Kitasato. Zeitschrift fur Hygiene, vol. x. 42. Kallmeyer. Deutsche med. Woch., 1892, p. 72. 43. Bruschettini. Centralblatt rilr Bakteriotogie, 1891, p. 15. 44. Brunner. Loc. cit. 45. Bruschettini. Loc. cit. 46. After Gumprecht. Loc. cit. 47. Beck. Ungar. Archiv fur Medicin, 1893, p. 344. 48. Nissl. Neurolog. Centralblatt, 1895, p. 108. 49. Sailer. Univ. Med. Mag., Philadelphia, 1896, p. 203. 50. Nerlich. Archiv fur Psychiat., vol. xxiii, p. 672. 51. Goldscheider. Deutsche med. Woch., 1895, p. 735. 52. Courmont and Doyon. Revue de medecine, 1894, p. 76. 53. Brunner. Loc. cit. 54. Allbutfs System of Medicine, 1896, vol. i. 55. Bruschettini. Deutsche med. Woch., 1892, p. 349. 56. Brunner. Loc. cit. 57. Sahli. Annates suisses de science medicate, 1895, and Bibliography. 58. Kitasato. Zeitschrift fur Hygiene, vol. vii, p. 225. 59. Tizzoni and Cattani. Centralblatt filr Bakterio- logie, vol. viii, p. 562. 60. Ibid. 61. Kitasato. Zeitschrift filr Hygiene, vol. x. 62. Fermi and Pernossi. Ibid., vol. xvi. 63. Kitasato. Zeitschrift filr Hygiene, vol. x. 64. Sahli. Loc. cit., p. 388. 65. Fermi and Pernossi. Loc. cit. 66. Nothnagel and Rossbach. Nouveaux elements de mat. med. et therapeutique. 67. Sahli. Loc. cit., p. 393. 68. Bacelli. Baumgarten's Jahresbericht, 1890, p. 205. 69. Roux. Annates de VInstitut Pasteur, 1894, p. 722. 70. Calmette. Ibid., 1895, p. 251. 71. Buchner. Berlin, klin. Woch., 1894, p. 73. 72. Tizzoni. Cited by Buchner. Ibid. 73. Schmidt's Jahresbericht, vol. cciv, p. 141.-Rot- ter. Berlin, klin. Woch., 1893. 74. Wallace. Indian Medical Record, 1891, p. 482. 75. Kanthack. Med. Chron., Manchester, 1896; N. S., vol. iii, p. 92. LAMBERT: TETANUS AND ITS TREATMENT. 29 76. Worthington. St. Bartholomew's Hospital Re- ports, 1895, p. 137. 77. Yandell. Cited by Hartley, Lancet, London, 1895, vol. ii, p. 424. 78. Roux. Annales de VInstitut Pasteur, 1893. 79. Behring. Die Blutserumtherapie, Part II, p. 21. 80. Bazy. Bull, de la Soc. de chir., 1896, vol. xii, p. 454. 81. Nocard. Bull, de VAcademic de medecine, vol. xxxiv, 1895, p. 407. THE New York Medical Journal. A WEEKLY REVIEW OF MEDICINE. EDITED BY FRANK P. FOSTER, M.D. THE PHYSICIAN who would keep abreast with the advances in medical science must read a live weekly medical journal, in which scientific facts are presented in a clear manner ; one for which the articles are written by men of learning, and by those who are good and accurate observers ; a journal that is stripped of every feature irrelevant to medical science, and gives evidence of being carefully and conscien- tiously edited; one that bears upon every page the stamp of desire to elevate the standard of the profession of medicine. 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