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The
Practical Medicine Series
Comprising Eight Volumes on the Year's Progress in Medicine and Surgery
Under the General Editorial Charge of
CHARLES L. MIX, A. M., M. D.
Professor of Physical Diagnosis in the Northwestern University Medical School
Volume VI
Pharmacology and Therapeutics
EDITED BY
BERNARD FANTUS, M.S., M.D.\
Associate Professor of Therapeutics, Rush Medical College, Chicaso
Preventive Medicine
EDITED BY
WM. A. EVANS. M.S., M.D., LL.D., D.P.H.
Professor of Sanitary Science, Northwestern University Medical School
SERIES 1919
CHICAGO
THE YEAR BOOK PUBUSHERS
304 South Dearborn Street
COPYRIGHT 1920 BY
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TABLE OF CONTENTS.
PHARMACOLOGY AND THERAPEUTICS.
Introduction 7- 8
General Considerations 9-23
Etiotropic Therapy 23- 75
Chlorine Preparations 23- 34
Iodine Preparations 34- 37
Silver Preparations 37- 41
Copper 41-43
Dyes 44
Volatile Oils 43-44
Arsphenamin 44- 62
Mercury 62-63
Quinine 64-69
Ipecac and Emetine 69- 73
Alleged Specifics 73- 75
Restorative Therapy 76-146
Acids 76
Adsorbents 76-81
Alkalies 81- 85
Astringents 85- 86
Alteratives 86
Restorative Organotherapy 87-90
Blood Transfusion 90-113
Hematinics 114
Hemostatics 115-119
Oxygen 120-122
Immunization 122-136
Pyretotherapy 136-146
Functional Therapy 146-178
General Pharmacodynamics 146-150
Alcohol 150-153
Local Anesthetics and Analgesics 153-157
3
4 TABLE OF CONTENTS.
Antipyretics 157-158
Benzyl Benzoate 158-160
Digitalis 160-162
Diuretics 162
Epinephrine 162-170
Hypophysis 170-174
Miscellaneous 174-178
Toxicology 178-203
Acetylsalicylic Acid 178-179
Alkalies 179-180
Arsenic 180-181
Barium 181
Barbital 181-183
Camphor 183-184
Chloroform 184-185
Fungi 185-199
Heroine 199-200
Morphinism 200-203
Non-Pharmacal Therapeutics 203-230
Diet .203-207
Sugar 207
Vitamines 207-214
Electrotherapy 214-215
Mechanotherapy 216-217
Psychotherapy 217-222
Radium 222-227
Roentgen Rays 227-231
PREVENTIVE MEDICINE.
Medical Sociology and Economics 235-265
Genetics 265-270
Public Health Administration 270-282
Child Welfare 282-285
Personal Hygiene 285-291
Prevalence of Preventable Diseases in the Army and
Among Civilian Population 291-304
Infectious Diseases 304-359
Influenza 304-323
Epidemic Encephalitis 323-324
Pneumonia 325-327
TABLE OF CONTENTS. 5
Infantile Paralysis 327-330
Measles 330-331
Diphtheria 331-333
Smallpox 334-336
Tuberculosis 336-341
Trench Fever 341-342
Spirochetosis Icterohemorrhagica 342
Typhoid and Paratyphoid Fevers 342-346
Malaria 346-351
Yellow Fever 351-352
Scabies 353-354
Venereal Diseases 354-357
Miscellaneous Diseases 357-360
Industrial Hygiene 360-369
INTRODUCTION.
''The war is over, but its effects are not/' This is true of its baneful as well as of its beneficial effects. We are now reaping the harvest of a tremendous volume of experience in certain phases of medicine and surgery that civilian practice could never have furnished. Among these is blood-transfusion, which not being medical and yet not strictly surgical either (especially in its simpli- fied forms) is a topic likely to fall into unmerited neglect, unless its discussion is taken up by the Department of General Therapeutics. Likewise, enormous experience with tetanus antitoxin, quinine in malaria, with the treat- ment of venereal disease, with antiseptics and disin- fectants is reflected in the current reports on these topics.
Among the most notable advances of the year may be mentioned the demonstration that histamine is probably the active principle of hypophysis, and that benzyl ben- zoate is likely to be a useful antispasmodic. Our knowl- edge of the vitamines is becoming more definite in our understanding and management of certain nutritional disorders, and is likely to lead to as profound a revolu- tion as has been wrought by our knowledge of the hormones.
The ''Practical Medicine Series" seems to be a good medium for the introduction of useful new terms. Hence, the word "bacteriostatic'' has been introduced instead of the ambiguous term "antiseptic" in its limited sense. That " Pyretotherapy " has practical value can no longer be doubted. Almroth B. Wright — he who introduced the concept of "opsonins" into medical literature — finds it necessary to coin a number of new terms, "phylaxis," "kataphylaxis," " epiphylaxis, " " ecphylactic, " for the discussion of the practical problems of immunology ; and, while one may at first feel repelled by this array of new words, the ideas they express so briefly are of such prae-
7
8 INTRODUCTION.
tical importance that it would be well to give these terms currency. . It may be noted parenthetically that, with the introduction of these terms, A. E. Wright, the high-priest of vaccine therapy, admits and emphasizes its limitations.
The fact that, before the next publication of this volume of the *^ Practical Medicine Series/' the U. S. Pharmacopoeial Convention will meet in Washington. D. C. (May, 1920), and the importance of obtaining the greatest possible cooperation at this occasion from the rank and file of medical practitioners, make it appear desirable to call attention to the necessity of formulating the results of experience in such a manner that they exert due influence. By devoting some time to this topic in medical society meetings and by forwarding sugges- tions to delegates to the Convention, every physician, no matter where he be located, may do his bit in improving our national standard on medicines.
Bernard Fantus.
PHARMACOLOGY A^D THERAPEUTICS.
GENERAL CONSIDERATIONS.
New Names for Syntheties. It was pointed out in this volume last year^ that the Federal Trade Commis- sion adopted the names arsphenamin and neo-arsphen- amin for the drugs first introduced under the proprie- tary names of ''salvarsan'' and ' ' neosalvarsan, " re- spectively; the terms barbital and barbital sodium for the substances first introduced as *' veronal" and ''veronal sodium/' and the word procain as the name for the compound first marketed as ''novocain."
The Journal of tlie American Medical Association^ calls attention to the fact that the Chemical Founda- tion, Inc., which has purchased some 4,500 German- owned patents, many of them for synthetic drugs, pro- poses to continue the policy of the Federal Trade Com- mission by requiring that those who receive licenses for the use of patents for synthetic drugs must use a com- mon designation for each drug selected by the founda- tion. ^^CinchopJien^^ has been selected as the designa- tion for the substance introduced as "atophan," de- scribed in the U. S. Pharmacopeia under '^phenyl- cinchoninic acid."
The Council on Pharmacy and Chemistry of the American Medical Association has recognized the con- tracted term "cinchophen" as a name for this drug; and it is well for physicians to adopt this simplifica- tion.
Report of the Drug Market for 1918. H. B. French^
(1) Practical Medicine Series, Vol. VI, 1918, pp. 12-14.
(2) Aug. 9, 1919.
(3) Jour. Amer. Pharm. Ass'n., August, 1919.
9
10 PHARMACOLOGY AND THERAPEUTICS.
finds that American crude drugs are advancing in price, owing largely to the lack of labor and to the high cost of labor. There are, of course, some notable excep- tions. Opium was kept in storage in Asia Minor for several years and a very large stock has been accumu- lated. As soon as possible, holders rushed as much of their product as they could ship to the El Dorado of America, so that they might realize something to meet their present necessities; consequently, there has been a very important reduction in the price of opium, al- though the manufacturers of the derivatives of opium have steadfastly maintained the prices of those products. Glycerine has fallen to about one-third of its highest price. Castor oil is another article that has shown a decisive decline. French ventures the general predic- tion that during the balance of 1919 the tendency of chemicals will be to lower prices and of crude drugs to remain as at present or to advance.
Some of the comparative prices given in the report might be of interest. It is to be noted that these prices are for large quantities.
Name of drug— 1914. 1919.
Spanish ergot $0.75 $3.25
Digitalis leaves 08 .30
Henbane leaves 08 .65
Colcliiciim root 11 1.75
Ipecac root 1.45 2.75
Colchicnm seed 20 2.50
Strophanthus seed, Kombe 40 1.70
Egg albumin 40 2.25
Tannic acid 50 1.40
Acetanilide 22 .37
Acetphenetidin 80 2.40
Alcohol 2.48 4.65
Antipyrine 22 15.00
Cocaine hydrochloride 2.60 9.50
Codeine sulphate 5.50 9.00
Glycerine (1918 60c) 17^ .22
Magnesium carbonate, powdered 04% .14%
Menthol 2.95 6.50
Calomel 60 1.59
Morphine sulphate 4.95 11.00
Potassium permanganate 10 .60
Quinine sulphate 26 .80
Russian white paraffin oil, medicinal . .45 1.00
PHARMACOLOGY AND THERAPEUTICS. H
Socotrine aloes 22 1.00
Asafetlda, gnm 25 4.50
Camphor 44% 1.50
Oil coriander seed 7.00 60.00
Oil of mustard, artificial 1.25 10.75
Oil of peppermint 2.75 10.00
Oil of rose 10.00 22.00
Oil of santal wood 4.65 11.25
[With most other drags quoted the price has prac- tically doubled, which is another illustration of the H. C. of L.— Ed.]
Therapeutic Progress, as Shown by Figures. Fig- ures from the Central Hospital Pharmacy to show fluctuation in the consumption of principal medicaments during the past ten years as compared with the previ- ous decennium are presented by M. L. Grimbert.*
Certain old remedies present but slight variation. In fact, some of them have not changed at all in twenty years. Such are rhubarb, senna, sodium sulphate, mag- nesium sulphate, sodium bicarbonate, subnitrate of bis- muth, sodium salicylate, sodium nitrate, Kermes mineral and white oxide of antimony.
A remarkable exception to the constancy in the use of ancient remedies is opium, the consumption of which, while practically constant for forty years, has greatly decreased during the last ten years. There has like- wise been an enormous decrease in the consumption of alcoholic medication with the exception of Todd's mix- ture (brandy, egg, sugar and cinnamon water) , the use of which has remained constant. Another ancient remedy that for a while seemed almost to disappear from use is cantharides.
Other products, the use of which has diminished, are cacodylate of sodium, arrhenal, petrolatum, lard and starch. Likewise showing decrease are iodide of potas- sium, bromide of potassium, chlorate of potassium, citric acid, glycerine, liver of sulphur, mercurial ointment, diachylon plaster, cod-liver oil, cinchona wine and extract.
On the increase is the use of sodium benzoate, calcium phosphate, syrup of iodotannin, tincture of iodine, wool fat, and mustard.
(4) Bull, de 'I'acad. de mSd., Sept. 9, 1919,
12 PHARMACOLOGY AND THERAPEUTICS.
Calomel, calcium, glycerophosphates, methyl salicyl- ate, and bismuth subgallate have shown marked fluctua- tions. Among the alkaloids, morphine and quinine have been stationary for twenty years, the latter even for forty years. The use of caffeine has decreased; while, on the other hand, the use of theobromine has increased. There has also been a slight increase in the consumption of codeine.
Chloroform has been stationary and ether shows a marked increase.
The consumption of pyramidon has remained con- stant, that of antipyrine is going down, that of aspirin on the contrary continues to increase.
A rapid decrease in the use of most of the antiseptics has continued during the last ten years. This includes corrosive sublimate, boric acid, potassium permanganate, biniodide of mercury, phenol, salol, and iodoform. The intestinal antiseptics, betanaphthol and benzonaphthol, have remained stationary after having had a great fall in consumption during the previous decade. Hydrogen peroxide has shown fluctuations, but at present it is diminishing in favor. Formaldehyde, on the other hand, has shown an enormous increase in consumption. Among the new remedies, the consumption of hexamethylena- mine, barbital, coUargol and protargol has increased. On the other hand, the use of sulphonal and trional has diminished. While arsphenamin has practically held its own, there has been a great increase in the consumption of novarsphenamin.
[It Avould be an excellent thing if druggists of large hospitals in this country were to give us similar reports of their experience. — Ed.]
Medication in Children. H. B. Sheflfield*^ gives the results of his experience and rules of his practice, from which the following are selected:
Digestants occupy but an infinitesimal space in pedi- atric practice.
The simple bitters fully deserve their striking cog- nomen, since they are surely very bitter and simple, insignificant, in therapeutic action.
(I») Med. Record, June 22, 1918.
PHARMACOLOGY AND THERAPEUTICS. 13
In pertussis, quinine bisulphate may be given in doses of from 0.06 to 0.12 gm. every two to four hours.
Iron is always useful for children and especially in- fants fed exclusively on milk, which is poor in iron, and the solution of peptomanganate of iron will be found to act exceedingly well in all simple anemias of infancy.
The syrup of the iodide of iron is an ideal hematinic tonic in children, more especially in secondary anemias following or complicating acute infectious diseases, rachitis and divers forms of glandular enlargement. In the so-called scrofulous affections, it often acts almost specifically, more particularly if combined with cod-liver oil.
Liquid preparations of iron with destructive effect upon the teeth should be avoided. Whenever possible, powdered iron with a little sugar or in tablet form should be given instead. [Sweet tablets of reduced iron or of ferrous carbonate constitute veritable candy medication. —Ed.]
Cod-liver oil, contrary to all expectations, is taken by young children with considerable delight.
In anorexia of children, dilute hydrochloric acid com- bined with essence of pepsin and small doses of nux vomica often works wonders.
The dilute nitromuriatic acid, in doses of from 2 to 5 drops, well diluted, is indicated as a preventive of the so-called bilious attacks, characterized by recurrent vomiting, headache, and catarrhal jaundice.
The syrup of hydriodic acid is an invaluable remedy in all chronic bronchial affections of children, more par- ticularly in unresolved pneumonia and asthma.
Arsenic is practically useless in the so-called rheumatic or infectious variety of chorea, which calls for absolute rest in bed and salicylates. In the neurotic type of chorea. Fowler's solution may be pushed to its full physiologic effect, provided the urine is carefully watched for a possible renal irritation.
Mercury, the specific in syphilis, may be administered to children by inunction of 0.30 to 0.60 gm. of a 50 per cent, mercurial ointment rubbed in thoroughly once a day, and from 0.004 to 0.005 gm. of protoiodide of mer-
14 PHARMACOLOGY AND THERAPEUTICS.
cury three times daily. In the beginning of the treat- ment, it may be necessary to administer a few drops of paregoric daily to allay intestinal irritation. In new- born infants with congenital syphilis, we may, at first, order 0.006 gm. of calomel every three hours and follow it up with the aforementioned remedies a few weeks later.
Water internally and externally is the best antipyretic in children. Warm tub baths tranquilize the nervous sys- tem, equalize the circulation, produce diaphoresis, and reduce the temperature without shock or depression. In highly nervous children antipyretic drugs, such as acetphenetidin, antipyrin, etc., are also indicated ; and, if given in moderate doses at long intervals, are perfectly harmless. They may be made fairly palatable in syrup of acacia and orange-flower water.
[An acetphenetidin chocolate tablet may be made as pleasant as chocolate candy. — Ed.]
A moderate dose of antipyretic will often promptly control an attack of convulsions in children, at any rate long enough for the cause to be determined and ap- propriate remedies employed for its permanent removal.
Small repeated doses of antipyretics, more particularly pyramidon, will frequently subdue grotesque choreic movements when the usual treatment utterly fails.
Salicylates are tolerated by children in larger quanti- ties than by adults; and, if administered with a little caffeine sodium benzoate or strophanthus, are perfectly free from depressing after-effects. On many occasions, Sheffield says, he has had the opportunity to convince himself as well as others of the distinct abortive powers of sodium or ammonium salicylate in acute poliomyelitis. It is more efficient, he states, than immune serum.
The salicylates are valuable in all acute infectious dis- eases; and, whenever in doubt as to what medicine to prescribe, the physician will almost invariably strike it right by selecting this remedy. It also has the good qual- ity of being palatable.
The safe dose of paregoric for children is one drop for every year of the child *s age, and one-tenth of this quan- tity when the tincture of opium is prescribed. In gastro- intestinal affections in which an opiate is indicated
PHARMACOLOGY AND THERAPEUTICS. 15
preference should be given to Dover ^s powder (1/10 grain for every year of the child's age), because of the beneficial effect of the ipecac it contains; and whenever vomiting precludes its administration, an opium supposi- tory will be found to act admirably. When very prompt action is desired, as for example, in cholera infantum with profuse vomiting and purging, we may advantage- ously resort to a hypodermic injection of morphine (0.001 gm.), and atropine (0.0001 gm.). Morphine and atro- pine hypodermically are occasionally indicated also in uremic convulsions of children. Lumbar puncture should be used in conjunction with them.
Whenever a hypnotic is indicated, codeine added to bromide will act far better than the newer coal-tar products.
Belladonna will be found useful in ordinary catarrhs of the respiratory tract with profuse mucous discharge and in rhinitis of infants when the nasal discharge in- terferes with nursing. In combination with codeine, in the form of suppositories, belladonna is of particular value in irritable bladder, strangury, and tenesmus. There is no better antispasmodic and anodyne in dysuria accompanying cystitis than hyoscyamine sulphate. The dose is 0.00008 gm. for every year of the child's age, dis- solved in syrup of althaea and water.
The author believes that strychnine and strophanthus are indicated in almost all infectious diseases of chil- dren ; and should be administered early rather than late ; 0.0002 gm. of strychnine and 1 minim of tincture of strophantus will ordinarily serve the purpose admirably. In urgent cases, we are often called upon to add caffeine sodium benzoate, and even epinephrine. It is always a good plan to provide the nurse with an ample supply of quick stimulants for a possible emergency during the crisis.
Regarding sterile camphorated oil as a stimulant, more especially in pneumonia, Sheffield has never been con- vinced of its utility and has often felt that the sorely tried patient ought to be spared the pain and discom- fort almost invariably associated with its hypodermic administration. He fears that recently the needle has
16 PHARMACOLOGY AND THERAPEUTICS.
been grossly abused, be it in subcutaneous injections of drugs or in that of an unlimited number of inert vac- cins and serums ; though, of course, he firmly believes in the life-saving properties of antidiphtheria and anti- meningococcus serums.
Digitalis, while the indispensable remedy in chronic cases with ''ruptured compensation" is more or less harmful in acute heart disease, with compensation intact, in which an ice-bag to the precordium and small doses of codeine with or without sodium salicylate are in- dicated.
Aconite, the standby of the homeopath, is a dangerous drug in the hands of the inexperienced. However, in homeopathic doses and well diluted, it probably can do no harm.
Whenever the production of emesis is very urgent, a hypodermic injection of from 0.004 to 0.005 gm. of apo- morphine will prove most satisfactory. It is to be re- gretted that emetics are dropping into disuse, for many a case of acute indigestion in children could promptly be arrested by swift emesis. Moderate doses of ipecac are invaluable in whooping cough with prolonged suffocating paroxysms, thus by emesis imitating Nature in aborting the attack.
In cases of persistent coughing arising from naso- pharyngeal or laryngeal inflammation, the physician should be inclined to allay the source of irritation by local measures and administer sedatives to relieve the cough. With this object in view excellent results are usually obtained from daily instillation of from 2 to 5 per cent, of argyrol or silvol in the nose and the in- ternal administration of creosote carbonate and codeine, well mixed with glycerine, mucilage, and water. On the other hand, when dealing with an harassing cough in acute bronchitis or pneumonia in which the expectora- tion is very adhesive and cohesive, scanty in amount, and hard to raise, a stimulating expectorant, with or without wine of ipecac or the compound syrup of squills will, in the majority of instances, prove beneficial to the patient by assisting Nature to rid the lungs of effete material and save the patient's energy for the terrible
PHARMACOLOGY AND THERAPEUTICS. 17
battle ahead of him. in chronic bronchitis and unre- solved pneumonia, satisfactory results are frequently ob- tained from ammonium iodide, 0.03-0.06 gm. for every year of the child's age, every 3 or 4 hours, or the syrup of hydriodic acid or syrup of the iodide of iron. The iodides are useful also in the exhausting cough accom- panying non-compensated heart disease, and may ad- vantageously be combined with digitalis and an occa- sional dose of some morphine derivative.
Diuretics are practically useless, nay, often harmful, in acute nephritis while the urinary tubules are ob- structed by the inflammatory changes. In such cases, it is much better to produce active diaphoresis by means of packs and hot baths and intestinal flushing. On the other hand, in subacute and chronic nephritis, diuretics must be resorted to whenever the excretion of urine is dimin- ished and a tendency toward dropsy becomes manifest. In such cases, the solution of iron and ammonium acetate seems to act exceedingly well. If, however, the dropsy is extensive and of cardiac origin it is always necessary to fall back on digitalis and strophanthus with or without diuretin or theocin sodium. Another indication for free diuresis is pleurisy with effusion, and this medication should be coupled with abstention from fluids in the diet.
There is no particular reason for giving calomel in divided doses and bothering a child unnecessarily. Any baby can stand a grain of calomel, Sheffield says, with- out much ado. Effervescent citrate of magnesia is contra-indicated when there is a tendency to vomit, the milk of magnesia being by far preferable.
In treating chronic constipation of children, efforts in the direction of regulation of the diet and induction of regular habits will only too often fail and the physician is frequently called upon to advise a suitable laxative. Sheffield believes that malt extract with olive oil or cas- cara will answer the purpose in the majority of cases. The value of mineral oil in chronic constipation is greatly exaggerated, at least so far as its efficiency in children is conctrned.
Sheffield prefers bismuth subcarbonate to the sub- nitrate and advises giving the patient from 0.60 to 1.30
18 PHARMACOLOGY AND THERAPEUTICS.
gm. after each evacuation. In this manner, it is possible to control the dosage in accordance with the severity of the diarrhea.
In chronic enteric affections, benefit will be derived from daily intestinal irrigations with from 0.25 to 0.5 per cent, of nitrate of silver — in addition t^ an appro- priate diet. Bicarbonate of soda is, of course, the specific in diarrhea due to acidosis or fat indigestion, and should be administered in large doses by mouth as well as by rectum.
Last in line but foremost in importance, when all food or medication is promptly ejected, is settling the stom- ach. In the majority of instances this is readily accom- plished by one large dose of sodium bicarbonate, from 2 to 4 gm. in water, and followed by smaller quantities of bicarbonate of soda and subcarbonate of bismuth with or without calomel.
In recurrent vomiting, lavage is indispensable and in some cases it may even be necessary to resort to a hypo- dermic injection of morphine. Of course, in all cases of severe vomiting careful attention must be given to the etiology, more particularly involvement of the appendix or brain.
In administering medicines to children, it is often help- ful to divide the full dose in several small doses, if need be, giving it drop by drop until the whole teaspoonful has been taken. In this manner even a most irritable stomach will often retain the medication, whereas it would otherwise reject it.
In conclusion, the author gives the following general rules to facilitate the selection and administration of drugs to children:
*'l. Never prescribe any medicine unless you are con- vinced of its necessity; if only a placebo is required, prescribe a palatable adjuvant.
*^2. Never prescribe a medicinal preparation requir- ing a large quantity, when a small one of the same or an equally as useful drug will do the work just as efficiently.
**3. Never prescribe a painful therapeutic procedure or a nauseous mixture when the patient will do equally
PHARMACOLOGY AND THERAPEUTICS. 19
as well — and surely much better — without the unneces- sary pain and annoyance. ' '
[11* every observant physician of large experience would publish once or twice in his lite a number of aphorisms of practice, what a fund of valuable informa- tion would accumulate. — Ed. J
THEKArEUTiC TECHNIQUE.
Disinfection of Needles and Syringes by Means of Liquid Petrolatum. K. Waterhouse'' advises the em- ployment of liquid petrolatum for disinfection of needles and syringes, used m the following manner :
The upper part of a test tube three-quarters full of liquid petrolatum is heated, moving the test tube up and down in the flame, until currents appear (indicating a temperature of about 150° C.) or rather longer. The heated fluid is then drawn at once into the syringe until it comes into contact with the whole of its interior, and then ejected. The method is simple, rapid, reliable, and devoid of deleterious effect upon the needles. It is par- ticularly valuable for giving intramuscular injections of suspensions of medicament in oil as, for instance, mer- curial cream.
Transduodenal Lavage. This method was first de- scribed in 1912, by M. E. Jutte,^ who reports a number of cases of suffering from post-operative vomiting, due to ileus, as well as a case of vomiting due to postpartum eclampsia, and a case of obstinate hiccough following an operation, all of which were relieved by insertion of a duodenal tube just beyond the pylorus and allowing slightly hypertonic salt solution to run through the tube into the bowels in sufficient quantity to produce a thor- ough flushing. The author considers it reasonable to attribute the prompt relief produced by this procedure in these various conditions to the stopping of the reverse peristalsis and the re-establishment of normal peristalsis, the reverse peristalsis having been brought about by the operation or parturition. Jutte also believes that the toxemia of pregnancy offers a promising field for the employment of transduodenal lavage.
(6) Brit Med. Jour., Aug^. 2, 1919.
(7) Jour. Amer. Med. Ass'n., March 29, 1919.
20 PHARMACOLOGY AND THERAPEUTICS.
[Duodenal intubation offers an opportunity for ad- ministration of medicaments against the action of which the stomach must be protected; as, for example, in the case of ipecac. — Ed.]
Subarachnoid Irrig-ation and Medication. Lewis H. Weed and Paul Wegeforth^ found that irrigations of the spinal and cerebral subarachnoid spaces are well tolerated by cats if the irrigating fluid is composed of sodium chloride, potassium chloride, and calcium chloride in proper proportions (modified Ringer's solu- tion, made up as follows: NaCl, 0.9 per cent.; CaCLj, 0.024 per cent.; KCl, 0.042 per cent.). If, however, the irrigation be done with isotonic solutions of sodium chloride alone, various toxic effects become apparent. Many of these animals die during or innnediately after the irrigation; if this immediate toxicity is survived, convulsve seizures and acute mania are almost invari- able. Recovery from such attacks is frequent.
Single irrigation with modified Ringer's solution of infected meningeal spaces has prolonged the life of the animals, as compared with controls. The period of sur- vival in many cases has been doubled as a result of this washing-out of the infected meninges. Multiple irriga- tions have not been attempted.
The authors tested the toxicity of various antiseptics and found that most of the chemical bodies employed possessed definite toxicity so that unless given in suit- able dilution and amount, death of the animal would ensue. With chloramine and flavine, in addition to the initial toxicity, a secondary cause of death in from five to ten days was brought about through direct injury to the central nervous system. With the injection of small amounts of a suitable dilution the animals remain ap- parently normal but all have shown at autopsy pathologic changes in the meninges.
The lesion consists of a more or less complete oblitera- tion of the meningeal (subdural and subarachnoid) spaces with serofibrinous exudate; in the more severe cases the nervous system becomes involved in a process of destruction by direct continuity from the meninges.
(8) Jour. Pharm. and Exp. Therap., July, 1919.
PHARMACOLOGY AND THERAPEUTICS. 21
The blocking-off of the subarachnoid space was complete in only one case, as demonstrated by the subsequent in- jection of ink. It was not, however, sufficient for the localization of the infection. The subarachnoid injection of lysol and of potassium permanganate in the presence of an otherwise fatal meningeal infection, did not pro- long the life of the animal.
[This opens up a new prospect in the treatment of meningitis — namely, irrigation ; and ought to lead to the discontinuance of the certainly useless and often harmful attempts at antiseptic medication of the subarachnoid space. — Ed.]
Intravenous Injection of Substances Insoluble in Water. Paul Chevallier^ arrived at the conclusion that, if one desires the foreign substance to get into the most intimate possible relation with the tissues, one should introduce it in a form insoluble in the blood stream (but capable of transformation in the organism). Such substance will remain much longer in the system than one that is soluble. If, on the other hand, a stormy action is wanted, soluble substances should be injected. If, for instance, a soluble salt of iron be in- jected, it is promptly eliminated from the body. If, on the other hand, the iron be injected in insoluble form, it accumulates in the system and becomes gradually as- similated. Injections of calomel have shown a remark- able activity.
Chevallier introduced as much as 10 c.c. of a suspen- sion of talcum powder, as concentrated as possible, into the ear vein of rabbits without more than transient dis- turbance. Not only is the intravenous injection of col- loidal metal harmless — in this case we have to deal with a very minute quantity of solid as compared with the amount of water — but even quite concentrated suspen- sions of such substances as ferric hydrate, silica, hydro- carbonate of cobalt, and oxide of nickel have been in- jected without the production of embolism. The elimina- tion of such solids introduced into the blood is extremely slow. Most of it accumulates in fixed connective ele- ments and in macrophages which multiply in order that
(») Presse m§d., June 20, 1918,
22 PHARMACOLOGY AND THERAPEUTICS.
they may take them in. Thus, one can, for example, color a guinea-pig completely blue by means of trypan- blue of Ehrlich. Talcum accumulates in the vascular spaces of the muscles of the extremities, producing verit- able calcareous lines.
Influence of Various Solvents on the Cutaneous Irri- tation by Mustard Oil. Torald Sollman^ applied 1 per cent, solutions of mustard oil in various solvents to the inner surface of the forearm by saturating a small pledget of cotton with the solution, and fixing this to the arm by a few turns of bandage. This was left in place for five minutes.
Very striking and constant differences were observed in the degree of hyperemia, according to which the ir- ritant efficiency of the 1 per cent, solutions or suspen- sions of mustard-oil in the various solvents is as follows :
1. Olive oil. Practically no hyperemia.
2. Turpentine. Practically no hyperemia.
3. Ether. Very little hyperemia.
4. Absolute alcohol. Very little hyperemia.
5. 95 per cent, alcohol. Distinct hyperemia.
6. 50 per cent, alcohol. Marked and lasting hyperemia.
7. Mucilage of acacia. Most intense and persistent
hyperemia.
8. Simple syrup. Most intense and persistent hyper-
emia.
In interpreting the results, the author says: ** Emol- lient and demulcent action play no essential part ; for the viscid olive oil (1)* and the mobile turpentine (2) pre- vent the irritation about equally; while the mobile 50 per cent, alcohol (6) and the viscid mucilage (7) favor it almost equally.
''Concentration of the mustard-oil by the evaporation of the solvent plays a very subordinate part, as seen by the comparison of the olive oil (1) and ether (3) ; and of the 50 per cent, alcohol (6), and the mucilage (7). How- ever, it may explain the slight differences between the volatile ether (3) and the absolute alcohol (4), on the
(1) Jour. Pharm. and Exp. Therap., April, 1918. • The numbers /correspond to the position of the drug- in the series.
PHARMACOLOGY AND THERAPEUTICS. 23
one hand, and the non-volatile olive oil (1) and the tur- pentine (2), on the other hand.
''The true explanation of the difference is evidently the affinity of the vehicle for the mustard oil. The greatest irritation occurs in the watery mixtures in which the mustard oil is merely suspended (6, 7 and 8).
*'In the alcoholic solutions (4, 5 and 6) the irritant eflSciency increases directly with the percentage of water.
''This relation of the irritant efficiency to the solution partition-co-efficient is strictly analogous to the effects of solvents on the penetration of phenol into the skin. In both cases, the irritant distributes itself between the solvent and the skin in proportion to its solubility in these two media. '*
ETIOTROPIC THERAPY.
Bactericidal and Bacteriostatic Substances. The at- tempt to make the word "antiseptic'' mean "a sub- stance capable of inhibiting the growth of microorgan- isms in doses inoffensive to the issues," seems to have failed. One finds this word used so loosely in general literature, that one might well despair that it can ever be confined to the connotation proposed for it.
Hence, it seems desirable to use the word "bacterio- static''— a term proposed by Basil Gildersleeve — for the word antiseptic, in its limited sense. For, while etymologically the latter term might just as well be used in a general sense as a substance antagonistic to microorganisms even to the degree of killing them — - and probably ought to be — the derivation of the word "bacteriostatic" makes it plain that mere inhibition of development is meant.
CHLORINE PREPARATIONS.
An Automatic Distributor for Neutral Solution of Chlorinated Soda (Dakin's Solution). The following apparatus, which is easily made in any hospital labora-
24
PHARMACOLOGY AND THERAPEUTICS.
tory, is described by L. J. Strong. ^ The essential device consists of **a large size test tube, D, of about 100 c.c. capacity, fitted with a three hole rnblDer stopper. This
test tube serves as a reservoir to collect the solution from the drop tube. Through one hole of the stopper a piece of glass tubing, placed so that it extends the entire length of the test tube, controls the pressure in the test tube when emptying and filling'' (Fig. 1).
^'U Tube 1 is connected with the outflow from the drop tube by a rubber tube, C. U Tube 2 is connected with U Tube E, which has one long arm and one short arm. This rubber tubing .should be long enough for U Tube E to be elevated or low- ered a distance equal to the length of the test tube. Raising U Tube E increases the quan- tity of fluid discharged into the vv^ound. For example, to de- liver 80 ml. every two hours, the drip is set at 10 drops a minute. U Tube E is set three-quarters up the test tube.
''The long arm of U Tube E connects with regularly used Dakin's tubes that are planted in the infected wound.
''As fluid runs from the can through the drop tube, it is con- veyed by Tube C into the test tube, which stops it from flowing into the wound until is reaches the level of U Tube E. When it reaches this level a siphon is formed, and the quantity of fluid in the test tube is expelled at one time into the wound.''
(2) Jour. AniPi'. Med. Ass'n., Nov. 9, 1918.
Fiff. 1. tributor solution soda.
Automatic dis-
for neutral
of chlorinated
PHARMACOLOGY AND THERAPEUTICS.
25
Max Bornstein^ describes another apparatus blown entirely of glass and fused into a compact piece to serve the same purpose as the one just described (Fig. 2). ^^Two bells (A and B) annealed one to the other are con- nected by a siphon tube (C). A drip point is annealed into the upper end of the upper chamber. Both chambers have air vents.''
^'The apparatus works as follows: Solution from an irrigating bottle or bag is allowed to pass a pinch-cock at a fixed rate. It accumulates in the upper chamber until it reaches the highest point of the siphon, when it sud- denly is emptied by the siphon into the lower chamber. Here, by virtue of its height and its weight, it forces its way through the holes in the Carrel tube and flushes the wound. The flushing is periodic and eliminates the inconstant human element which is so often the cause of failure in the Dakin-Carrel technique."
Relative Irritant Properties of the Chlorine Group of Antiseptics. In ster- ; ilizing infected wounds with hypo- chlorite solution one of the most im- portant problems has been that of avoiding excessive irritation. Dakin ^^,,,,,,^ ^.^xxv^v. found that sodium hypochlorite solution i^ ^^f^^er^ and could be used clinically if its concen- v|iiwer cham tration was not greater than 0.5 per cent, and if the excess alkalinity of the solution had been reduced until there was no longer color with powdered phenolphthalein.
In view of the many modifications of Dakin 's original solution, that have been proposed, Glenn E. CuUen and Herbert D. Taylor^ considered it desirable
(3) Jour. Amer. Med. Ass'n., June 15, 1918.
Fig-. 2. Glass automatic si- phon, for de- 1 i V e r i n g- a definite amount of fluid to the wound at a definite period
fbers; C, siphon [tube; D, tube Heading- to so- flution tank; E, : tube leading to .Carrel tube; F, ;drip point.
26
PHARMACOLOGY AND THERAPEUTICS.
to gain some idea of their relative irritant properties. The authors emphasize the fact that Dakin's hypochlor- ite solution adjusted to the end point of powdered phenolphthalein is not a neutral solution as it has often been described, but is a solution with an alkalinity of about 1,000 times that of water (pH— 10.2). Moreover, there is a lower limit of alkalinity, at about 100 times
U
A XH,0 10
wm/////m/H7rrmm J
100 XHj^O
10 XH^O
8
Powdered phenolphthalein
luruiuiuinuiuimniinrni
lExccjasive ''alkalinib^
Alcoholic solution aP
^Suitablefor clinical use
Alcoholic solution of phenol ph tha.1 el 1^
23
>Unstable
Neutrality
Figr. 3. Approximate alkalinity of a 0.5 per cent, sodium hypochlorite solution at end-points to phenolphthalein and o-cresolphthalein. Also the relation between alkalinity of solutions and their availability for clinical use. Alkalinity is expressed in terms of hydrogen ion concentration (pH) and compared with that of water.
that of water (pH about 9), below which this solution becomes too unstable for clinical use. Powdered phenolphthalein alone is not a sufficient criterion of the reaction, but is the test for the upper limit of alkalinity. The end-points of alcoholic phenolphthalein (pH of 8.5
(4) Jour. Exper. Med., December, 1918.
PHARMACOLOGY AND THERAPEUTICS. 27
to 8.8) or o-cresolphthalein (pH of 9.2 to 9.4) can be used as tests for the lower limit of alkalinity. It is desirable, therefore, to adjust the solution to these upper and lower limits. The relation between these limits is expressed graphically in Figure 3.
The authors used the ears of rabbits, immersing them in solutions for a fixed time daily for consecutive days. They found that 0.5 per cent, sodium hypochlorite solu- tions have minimum irritant effects over a range of al- kalinity of from about 100 to 1,000 times that of water (pH about 9 to 10), to which solutions may be adjusted by use of the end-points of powdered phenolphthalein, of alcoholic solutions of either o-cresolphthalein or phenolphthalein.
Solutions that have an alkalinity less than that indi- cated by the end-point of alcoholic phenolphthalein solu- tions (pH of 8.5 to 8.8) or greater than that indicated by the end-point to powdered phenolphthalein (pH of 10.2) are intensely irritating.
Two per cent. chloramine-T solution has no irritant action.
Five per cent. dichloramine-T in chlorcosane and chlorcosane alone irritate rabbit ears to a slight degree only.
[It must be borne in mind that these conclusions are only correct as applied to the skin, and that they have a bearing on the relative irritant properties of these solutions ; but that to the mucous and serous membranes such fluids may be highly irritant, as is shown by the next communication. — Ed.]
Antiseptic Irrigution Harmful in Empyema. W. T. Dodge^ arrives at the opposite conclusion from that of J. G. Sherrill,® who reported favorably on this treatment, on the basis of further observation of the very cases reported on by Sherrill.
Fifty-three patients had been treated, with twenty- three deaths; simple thoracotomy had been performed forty -nine times, and rib resection four times. All were treated with open drainage and the instillation of sur-
fs) Jour. Amer. Med. Ass'n., June 21, 1919. (6) Surg-., Gynec. and Obstet., April, 1919.
28 PHARMACOLOGY AND THERAPEUTICS.
gical solution of chlorinated soda (Dakin's solution). These patients were ill for a long time, and eventually the use of Dakin's solution was discontinued, and in- stillations of 2 per cent, formaldehyde solution in glyc- erine (containing approximately 0.07 per cent, of abso- lute formaldehyde) were substituted. Immediate im- provement took place, the septic condition disappeared, the patients put on flesh, and it was confidently expected that they would speedily recover.
When Sherrill was transferred from the hospital, all the patients who had been under his care had apparently recovered. Fifteen of these patients recovered under the use of Dakin's solution and were discharged. Fifteen remained under treatment after the change was made to formaldehyde-glycerine solution. The wounds closed in four patients who were returned to duty and not heard from again at this hospital. In five of the remain- ing eleven, the wounds also closed and these patients were discharged, but in a few weeks were re-admitted with re-opened sinuses leading into the pleural cavity. During August, these eleven patients were subjected to costatectomy, after a study of their chests in the Roent- gen-ray laboratory. This was done by passing a small catheter through the sinus and introducing a solution of potassium iodide. This procedure outlined the cavity as viewed through the fluoroscope. In each case large quantities of partically organized lymph and pus were found in the pleural cavity. Two patients are still in the hospital after more than a year, and each presents a small sinus through the thoracic wall. Each has had several operations for the purpose of collapsing the chest wall, and at present is convalescing and will soon be ready for discharge.
For the next series, it was decided that the early treatment, aspiration and instillation of formaldehyde- glycerine solution, be given a fair trial. The use of the aspirator soon convinced Dodge that this was not an entirely harmless procedure. Also the instillation of formaldehyde-glycerine solution was found to be with- out beneficial effects. He then limited the use of the aspirator to diagnostic purposes, and, after the fluid
PHARMACOLOGY AND THERAPEUTICS. 29
became purulent, opened the chest by resection of one rib and introduced two large drainage tubes.
In no case were instillations into the pleural cavity permitted during the first ten days. Cases presenting profuse and offensive discharge were then treated with instillations. Dakin's solution was used in five cases; formaldehyde-glycerine solution in five cases, and simple flushing with 50 per cent, solution of glucose in a con- siderable number.
Eventually, the use of all irrigating solutions except that of physiologic sodium-chloride solution was aban- doned, because the ten patients treated with Dakin'^ solution and the formaldehyde-glycerine solution were found, after several months, to have partially collapsed lungs and cavities of considerable size. They were sub- jected to secondary operations, and in each case a very thick layer of organized lymph was found holding the lung in a state of partial collapse. Ribs were removed and numerous incisions were made across the confining layer of lymph; four of the patients are now con- valescing and the others are ambulatory and in good physical condition.
Similar experience is reflected from a private letter received from Major F. C. Warnshuis, who received from another service eleven active empyemas, and flve cases healed. In going over the histories he found that the eleven empyema patients had been treated with Dakin's solution, while the five healed empyemas had not.
Dodge further treated three cases according to Capt. A. E. Mozingo's ^'closed method." This consists of introducing a small rubber tube into the pleural cavity through a cannula or by puncture through the chest wall with a pair of forceps, evacuating fluid by suction with bulb syringe introducing Dakin's solution, withdrawing it again by means of a bulb and repeating this procedure at intervals of two hours for several days, after which formaldehyde-glycerine solution is instilled through the tube after the irrigation with surgical solution of chlori- nated soda. In the interval, the tube is closed by a shut-off and no air at any time is permitted to enter the pleura. In all three cases, the wound closed spon-
30- PHARMACOLOGY AND THERAPEUTICS.
taneously. The Eoentgen-ray laboratory reports, how- ever, were not reassuring, as each examination revealed gradually increasing amounts of fluid in the pleura, and no evidence was found that the collapsed lungs were expanding to fill the space. One month after the closure of the openings in the thoracic wall, the fluoroscope dis- closed fluid in each case up to the level of the third rib. The aspirator revealed the presence of pus, which in one cause resulted in a culture of hemolytic streptococci. In two cases, culture was negative. Rib resection was performed in these three cases, and very large cavities were discovered. The same firm-appearing layer of or- ganized lymph confined the lungs in compression, as had been found in all the other cases treated by in- stillation of irritating antiseptics. Dakin's solution, as well as formaldehyde-glycerine solution, causes the de- velopment of large cavities due to irritation of the serous membrane and the formation of thick and resisting lymph deposits, assisting in blocking off the system from the infecting organism, but in so doing effectually bind- ing down the collapsed lung. It is greatly to be re- gretted that this is so, because it is the most agreeable method of treatment to use in the early stages.
The conclusions arrived at by Dodge are that the presence of fluid in the pleura is at first protective to the diseased lung, and it should not be removed at an early period, unless it is replaced, in part, by some other fluid.
If the patients survive the pneumonic process and the fluid becomes purulent, it should be drained through a large tube introduced after a rib resection under a local anesthetic, and under no circumstances should this pro- cedure be adopted before the twelfth day of the disease and as early as that only under exceptional circum- stances.
Drainage having been established at the most depend- ent point in the cavity, irrigations with, or instillations of, irritating chemical solutions should be abstained from. If the drainage is adequate they will not be re- quired. If not adequate, flushing with physiologic
PHARMACOLOGY AND THERAPEUTICS. 31
sodium-chloride solution will be all that will be neces- sary.
Dichloramine-T the Best Dressing for Wounds. Da- vid T. Huston^ reports that dichloramine-T has given better results than any other germicide so far used. It combines simplicity, cleanliness, and speed in dressing. The solution used is a 5 per cent. dichloramine-T in chlorcosane, except in burns, when a 2 per cent, solu- tion was used, 5 per cent, causing too much distress in such cases.
His specifications for successful use are as follows: ''The instruments required are a pair of dressing for- ceps, scissors, glass eye-dropper, a long pipette, made to fit a Luer syringe, swab sticks, paraffined mosquito netting, and gauze.
''Rubber gloves should be worn and forceps used to handle all dressings.
"The edges of the wound and surrounding tissue are first swabbed off with the dichloramine-T solution; the wound itself, if possible, is then swabbed with the solu- tion, care being taken to get in all the crevices. This is followed by completely bathing the wound with the solu- tion by dropping from an eye-dropper; or, if there bi a sinus, by instilling the dichloramine-T with a dropper or, if the sinus be too narrow, by means of a pipettt attached to a Luer syringe.
"The paraffined gauze is then put directly over th( granulating surface, covered with gauze of several thick nesses, and held in place with a bandage or adhesive plaster.
' ' In deep wounds it has been found that the paraffined gauze should be folded so as to make a gutter or wedge, the gauze drainage inlaid in this, and the gauze dress- ing applied. In every case in which drainage is usee paraffined gauze is put directly over the drainage whether it be gauze or rubber tubing. This prevents the drain from adhering to the dressing."
Rubber tissue was found to block up the wound and instead of draining was really plugging. Rubber tubing is advocated only where the quantity of pus is great,
(7) Therap. Gazette. February, 1919.
32 PHARMACOLOGY AND THERAPEUTICS.
and the wound large. In most instances it was found that the tube was blocked up and that pus was escaping around the sides of the tube.
Nearly always gauze, soaked in dichloramine-T solu- tion and loosely packed in the wound, gave the best results. The sprayer originally advocated was found to be of little use, the quantity of solution it sprayed being negative and the time consumed making it more of a hindrance than a help. The solution dropped from a pipette is more efficacious.
In a few cases there seemed to be an idiosyncrasy. Dermatitis was controlled with sodium bicarbonate, given internally. That the sodium bicarbonate really did control this condition was demonstrated by the fact that when it was discontinued the dermatitis would promptly begin, and when again started would dis- appear.
All manner of infected or pus-producing wounds were treated with most satisfactory results.
Daily dressings were found all that was necessary, and the soaking of the dressing between times seemed unnecessary.
Dichloramine-T Dressing for Bums. Torald Soll- mann^ reports an experimental search for an ideal dress- ing for bums, one that would have all the advantages of a petrolatum dressing without furnishing, as this does, protection to the bacteria as well as to the tissues, causing superficial infection to flourish, and the healing to be delayed. Dichloramine-T was chosen as the best antiseptic for this purpose, but it was found that com- mercial petrolatums are highly destructive for dichlora- mine-T ; so much so, that the efficiency is at once prac- tically completely destroyed. On the other hand, a ''paraffin ointment, 3:7" prepared by mixing 30 parts of melted surgical paraffin wax with 70 parts of liquid petrolatum (Stanolind brands) caused considerable deterioration on mixing, but a practical efficiency was maintained for a week. Such dressing might therefore be advocated, or a 2 per cent, solution in chlorcosane overlaid with paraffin ointment 3:7.
(8) Jour. Amer. Med. Ass'n., April 5, 1919.
PHARMACOLOGY AND THERAPEUTICS. 33
Sollmann also points out that liquid petrolatum can be used in emergencies as a vehicle for dichloramine-T, although it is inferior to chlorcosane.
The Germicidal Power of Antiseptic Oils and of Sub- stances Dissolved in Oil. This subject was studied by Philip D. MeMaster^ by means of agar slants inoculated with B. typhosus and incubated for 24 hours. The oily solutions were then poured over these so as entirely to cover the agar and the tubes allowed to stand 24 hours in the incubator at 37.5^ C. The oily solutions were then poured off and the tubes twice washed out carefully with sterile salt solution. A transplant was then made to a tube containing 8 c.c. standard broth and readings made after 24 and 48 hours' incubation.
Solutions of phenol, made in paraffin oil and in water were tested simultaneously, with the following result : In paraffin oil, phenol kills at 0.4%; not at 0.3% In water, phenol kills at 1.0%; not at 0.9%
Control tubes in which paraffin oil alone was used, gave growth in all instances. The following data given by McMaster are of interest:
Lethal May Does Co.-
point kill not kill efficient
Substance tested. % % %
Phenol in paraffin oil 0.4 0.3 0.2 1.00
Iodine in paraffin oil 0.4 0.3 0.2 1.00
Phenol in cotton seed oil 2,5 2.0 1.0 0.16
Paracresol in paraffin oil 0.25 0.2 0.1 1.55
Guaiacol in paraffin oil 0.9 ... 0.8 0.44
Dichloramine-T in 10% chorinated eucalyptol in chlorinated para- ffin on 0.05 ... 0.03 8.00
Dichloramine-T in plain paraffin oil. 0.4 ... 0.2 1.00
Experiments with menthol, camphor and turpentine resin showed that these did not kill in the highest con- centrations that could be obtained.
A comparison of the time required for disinfection w^as made for dichloramine-T, and phenol. In six hours the dichloramine had exerted its full action w^hile the
(9) Jour. Infect. Dis., April, 1919.
34 PHARMACOLOGY AND THERAPEUTICS.
phenol required over twelve hours. Hence, the co- efficiency of dichloramine-T would be even higher than 8.
[The real disinfecting value of dichloramine-T dis- solved in chlorinated liquid petrolatum is greater yet than indicated by above figures, as its toxicity to the host is very much less than that of phenol.
The generalization that oil-soluble disinfectants lose much in disinfectant power on solution in oil, while true for other oils, as is shown by the low value of phenol in cotton seed oil, does not obtain for solutions in liquid petrolatum. Thus, phenol-petrolatum solution is more than twice as active than aqueous solution of phenol, as shown above. This demonstrates the danger of careless generalization, on the strength of which, for instance, phenolated petrolatum was condemned as worthless. — Ed.]
IODINE PREPARATIONS.
Iodine Tinctures, Water Soluble. The tincture of iodine U. S. P. is compared by T. Sollmann^ with two widely advertised proprietary preparations — Burnham's Soluble Iodine and Sharpe and Dohme's Surgodine.
The actual results indicated that Burnham's prepara- tion was the more irritant, and the U. S. P. tincture (re- duced to the same iodine percentage) was the less irri- tant; but the differences were so small that they could easily be accidental.
The potassium iodide of the official tincture has a re- straining effect on the coagulation of protein. This would tend to make it less irritant than the other preparations. The more even spreading and the more rapid coagulation of protein render the simple alcoholic solution of iodine (the tincture of the old U. S. P.) prob- ably the best for disinfection of the skin; while the de- layed protein precipitation by the U. S. P. tincture would probably render this somewhat superior for the disin- fection of open wounds. The secret and non-secret '* water-soluble tinctures'' do not appear to have any material advantages.
(1) Jour. Amer. Med. Ass'n., Sept. 20, 1919.
PHARMACOLOGY AND THERAPEUTICS. 35
The Disinfectant Value of Iodized Xylol. Louis Bory^ reports a series of clinical observations on the value of iodine dissolved in xylol in dermatologic and venereal practice. Xylol which is dimethyl benzine is an energetic fat solvent, extremely diffusible, and a power- ful antiseptic. He recommends the following formula :
Iodine 1.0 gm.
Xylol 15.0 to 20.0 ml.
Petrolatum to make 100 gm.
Dissolve the iodine in the xylol and add it drop by drop to the petrolatum while triturating in a glass mortar.
This forms a most efficient application against pubic lice, one treatment being generally sufficient. It should replace the offensive and occasionally dangerous mer- curial inunction.
All mild infections of the skin are rapidly cured by two or three applications of this product. It is a most efficient remedy in cutaneous trichophytosis (herpes circinata, inguinal epidermophytosis, sycosis). In sycosis, whether due to mould or microbe, it is the effica- cious complement of epilation, but must not be applied at the beginning of the treatment, when the surface is purulent and highly inflamed. Bory always uses it after three, four or more days of treatment with com- presses of Dakin's solution. After three or four days' treatment with iodized xylol, it is often well to change for a day or two to compresses with Dakin's solution, bismuth creme, or a salicylate paste, strong or feeble.
He uses this remedy daily in impetigo, echthyma, folliculitis and even in subacute (but not in acute) eczema.
He advocates it as a primary dressing for war wounds, substituting liquid petrolatum for the soft form, and using it to saturate the wound and the compress covering it.
In venereal prophylaxis, he considers xylol combina- tions superior to the older calomel ointment, which he has found at times disappointing.
He gives the following formulas.
(2) Presse m6d., Feb. 10, 1919.
36 PHARMACOLOGY AND THERAPEUTICS.
Iodized Xylol Pencil.
Iodine 3 gm.
Xylol 15 gm.
Wax 32 gm.
Olive oil, washed with alcohol 50 ml.
Perfume, as desired.
Calomel Xylol Pencil.
Calomel 38 gm.
Xylol 12 gm.
Wax 16 gm.
Olive oil, washed with alcohol 20 gm.
Perfume, as desired.
Either of these is to be applied before coitus and after thoroughly soaping the part and drying it. A second inunction should follow immediately afterward.
For the female he advocates the following ointment :
Calomel 40 gm.
Xylol > 20 gm.
Petrolatum 20 gm.
Hydrous wool fat 20 gm.
He also finds xylol an excellent solvent vehicle for iodoform, which dissolves in it to the extent of 10 per cent.
He recommends the following formula for chancroid and buboes after incision:
Iodoform 1 gm.
Xylol 10 gm.
Petrolatum 40 gm.
To be used freshly made.
Intravenous Use of Iodine. D. M. Baillie^ used tinc- ture of iodine intravenously in doocs of from 20 to 30 minims (22 m. = 0.03 gm. of iodine), diluted with 9 c.c. of an 0.85 per cent, solution of salt in freshly distilled water and given in the same fashion as a neoarsphenamin injection — once daily for several days in ten bad cases with definite signs of influenza bronchopneumonia. Of these, nine patients recovered and one died. The drug was tolerated very well, and there were no untoward
(3) Lancet, March 15, 1918.
PHARMACOLOGY AND THERAPEUTICS. 37
symptoms except that two patients had a rigor about an hour after the first injection and another case de- veloped a typical iodine rash.
The therapeutic effect of the iodine was generally shown within 20 hours by a marked fall in the pulse- rate and temperature (the latter resembling a crisis) and a marked change for the better on the part of the patient. The presence of albuminuria was no contra- indication as to the use of the iodine ; dense albuminuria in one case cleared up tw^o days after the first dose.
While it is highly improbable that the iodine given thus into the blood-stream has any direct bactericidal action, it is feasible to think that it may have an in- hibitory effect on the reproduction of the organisms, at any rate in the blood-stream.
[This is doubtful. It might have an expectorant value, for which oral administration of iodide would probably be just as efficient. — Ed.]
The Use of Iodine in Influenza. Iodine is considered a remarkable, almost specific, remedy in influenza by L. Boudreau.* He administers tincture of iodine in doses of 10 drops constantly and at least every hour, without intolerance, as might be expected from theoretic con- siderations. The medicine is taken in any kind of fluid vehicle. He advises against small or ^^prudent^' doses; and rather recommends proceeding vigorously as, if an intolerance should perchance manifest itself, it will be after the disease has been conquered.
He even advocates iodine as a prophylactic against the contagion of influenza and says, regarding it, that one should not only take it but take enough.
SILVER PREPARATIONS.
Classification of Organic and Colloidal Silver Com- pounds. Torald Sollmann^ attempts to classify the large number of silver protein compounds now on the market and finds that coUargol, argyrol and protargol
(4) Jour, de m§d. de Bordeaux, November, 1918,
(5) Jour. Amer. Pharm. Ass*n., Augrust, 1918.
38 PHARMACOLOGY AND THERAPEUTICS.
represent quite distinct types, under which, most of the other compounds may be arranged.
To these needs be added a group containing free silver ions. These precipitate ordinary proteins and are there- fore highly irritant to the tissues. Compounds contain- ing their silver in non-ionized or *^ masked*' or *^ col- loidal'' form do not precipitate and, therefore, largely avoid the irritation. This is the main object in the therapeutic use of these silver compounds. AH but two of the preparations tested contain all of their silver in non-ionized form; and these two (albargin and Roche silver nucleinate) contain only a small, but not negligible, amount of ionized silver, presumably as a contamination.
According to total silver content, the three typical compounds, collargol (78 per cent.), argyrol (20 to 25 per cent.) and protargol (8.3 per cent.) are distinctive; most of the other compounds approach one or the other of these types.
Irritation. This is perhaps the most important cri- terion for a clinical classification. It is easily judged by placing a few drops of the 1 :10 watery solutions in the nostrils, and in case of doubt also in the conjunctival sac. The differences are sufficiently striking to permit arrangement into three groups, as in the accompanying table (Table I).
Table I — Irritatioi^.
No Irritation. Slight 'but Distinct, Marked Irritation,
Argyrol Protargol
Argonin (5%) Heyden Silv. Prot.
Silvol Cargentos Albargin
Sophol Silv. Nucl. Roche
Squibb Sil. Prot Silv. Prot. Roche (very slight)
Novargan Hegonon (very slight)
Collargol
Collargol Old (5%).. Solargentum
Albumin Precipitation: This is, in a sense, an index of astringency. It is an objective confirmation of the dis- tinct though slight astringent action of all the members of the protargol type (protargol, Roche and Heyden sil-
PHARMACOLOGY AND THERAPEUTICS. 39
ver proteinate, and hegonon) ; and of the marked astrin* gent action of those containing free silver ions (albargin, Roche silver nucleinate).
The author concludes with making the following classification :
The Collar gol Group: Comprising coUargol and car- gentos.
The Argyrol Group: Argyrol, Squibb 's silver pro- teinate, sophol, silvol, solargentum.
The Protargol Group: Protargol, Roche's silver pro^ teinate, Heyden silver proteinate and hegonon.
The Free Silver Group: Albargin and Roche's silver nucleinate.
The Pale Group: Novargan and argonin.
Incidentally he calls attention to the fact that, the specific gravity of 25 per cent, solutions of some of these compounds being high, some ophthalmologists use the protein-silver compounds, especially the argyrol type, for their specific gravity rather than for their antiseptic effect, the idea being that the heavier silver solutions would displace the secretions, pus and bacteria by gravity. Some such mechanical action would doubtless occur, if the patient were placed in the proper position ; but, if this has any value, it would be obtained equally well and much more cheaply, by a 25 per cent, solution of acacia.
Use of Argyrol in the Eye. H. D. Bruns^ finds argyrol a useful agent when employed as follows: A strength of 2 or 2.5 per cent, possesses the valuable properties of the drug and reduces to a minimum all unpleasant or harmful effects. Such a solution is un- irritating, seems to be most diffusible — and great dif- fusibility is one of the valuable properties of argyrol — while its specific gravity is sufficient to float out of the cul-de-sac every particle of pus or mucus. The colora- tion it imparts to such otherwise invisible particles makes argyrol a very useful adjuvant in thoroughly cleansing the eye when alternated with a borax wash or a neutral solution. Solutions of from 25 to 50 per cent, in strength are, by their thickness, made less diffusible ;
(6) New Orleans Med. and Surgr. Jour., April, 1919.
40 PHARMACOLOGY AND THERAPEUTICS.
they seem to form with the secretions uncomfortable clots, and they are irritating; so irritating that after a few instillations it is hard or even impossible to per- suade the patient to continue their use.
The intervals at which the solution is instilled must be short if we are to achieve the results for which we hope. Instillations should be made every hour; in the severest affections every fifteen minutes, and in the mild- est at least every two or three hours.
The use of argyrol must never be long continued. Probably two weeks is the utmost length of time it can be used with benefit. After that, even the weaker solu- tions begin to irritate the conjunctiva. We must not forget that argyrol is no astringent. By undue per- sistence in its use w^e can produce one of the very mis- chiefs— irritation of the conjunctiva — that we are seek- ing to subdue.
Only fresh solutions made from fresh material can be used, even in the weaker solutions, without producing redness, smarting and watering of the eyes.
Thus employed, argyrol is useful in cleansing the conjunctival sac, especially before operations, in cases of beginning epiphora without obvious cause; in the treatment of simple corneal ulcers, erosions, excoria- tions; in mild cases of conjunctivitis, alternated with a borax-wash. Bruns also uses it in cases of Koch-Weeks bacillus conjunctivitis — in 10 or 15 per cent, solution alternated every hour or two with a solution of zinc sulphate of 0.03 to 0.06 gm. to 30.0 ml., depending on the severity of the case.
In cases of ophthalmia neonatorum, Bruns finds a 10 to 15 per cent, solution an efficient remedy, when in- stilled day and night, with the patient recumbent and the lower lid gently drawn down with the finger on the cheek. The argyrol solution is instilled into the un- affected eye half as often as into the diseased one — every other time. As argyrol is without astringent action, after all swelling and pus have disappeared for a day or two, he generally begins the application of weak silver nitrate solution to the everted lids, continuing until the conjunctiva has become normal.
PHARMACOLOGY AND THERAPEUTICS. 41
The author has records of fifty-nine cases of gonor- rheal ophthalmia, with satisfactory results.
He believes that most striking proof of the value of the treatment to be the fact that, although no attempt was made to protect the healthy fellow-eye, save by drop- ping into it the argyrol solution, no unaffected eye ever became infected during the course of treatment. There have been but two cases of staining of the cornea by arg3^rol. In both the area was minute.
COPPER.
The Therapeutic Uses of Copper Sulphate. De
Herain^ finds copper sulphate a most valuable skin remedy, most especially in infectious dermatoses. De- pending on w^hether they are irritable or non-irritable, it is necessary to vary the formula, using the strong salve for such conditions as favus, tricophytosis, papil- loma, seborrheic eczema, ecthyma, furuncle anthrax, in- fected wounds and ulcers, chancroids and buboes. In these affections he employs the following formula:
Copper sulphate 20 gni.
Dissolved and incorporated with wool fat.
Zinc oxide 150 gm.
Wool fat 100 gm.
Petrolatum, enough to make 1000 gm.
If this seems too strong, the amount of copper sul- phate is reduced one-half.
A salve containing only 0.2 per cent, of copper sul- phate, but otherwise of the same composition, the author advises in more irritable dermatosis, such as eczema, im- petigo, sycosis, acne rosacea, burns, non-infectious ulcers and in herpes zoster.
He also employs copper sulphate in powder form on chancres, incised buboes, and sores, using a powder of the following composition :
Copper sulphate 20 gm.
Dissolve and incorporata with: Talcum 1 kg.
(7) Presse m6d., Oct. 31, 1918.
42 PHARMACOLOGY AND THERAPEUTICS.
A powder containing only one-tenth of this amount of copper sulphate he recommen(Js in excessive sweat- ing, burns, superficial sores, eczema and cuts.
He also uses intravenous injections of copper sulphate in infectious conditions in which he considers the local application insufficient. Thus, he believes that he has been able frequently to abort buboes by intravenous injections. Furunculosis, he states, is rapidly and cer- tainly arrested by a series of intravenous injections; likewise is anthrax immediately improved by this treat- ment. For these injections he uses ampoules containing 5 ml. of a soluton of 0.5 per cent, in distilled water. Stronger solution is not advisable because of danger of thrombosis. De Herain injects 5 ml., and often as much as 10 ml., of such solution (corresponding to 0.05 gm. of copper sulphate). In serious cases he repeats the injection tAvice a day for eight, ten, fifteen or even more days.
In eczema daily baths are employed with a solution of 0.10 gm. per liter and the application of the mild salve and powder alternately during the intervals. Baths and powder are most active in moist eczem.a. In rebellious conditions a lotion as strong as 0.25 gm. per liter is employed. He recommends similar treatment in juvenile acne.
A solution of 0.10 gm. per liter has been used with great success in ocular infections.
In intestinal infections. De Herain employs cachets or pills (0.05 gm.) of copper, giving from three to six a day. The cachets have the following composition:
Copper sulphate 0.03 gm.
Prepared chalk 0.25 gm.
To be taken during the meal, using two or three cachets daily.
He finds that the gelatine coated pills are often bet- ter borne by the stomach than the cachets, which some- times produce vomiting. This treatment has, according to this author, a marked antiseptic, even bactericidal power, similar to that of benzonaphthol or lactic acid bacillus.
PHARMACOLOGY AND THERAPEU'X'ICS. 43
He has obtained good results in amebic dysentery by the combined use of cachets or pills, enemas of 300 ml. of a solution of 0.25 gm. per liter, and intravenous in- jections.
VOLATILE OILS.
Santal Oil and Potassium Permanganate Treatment of Gonorrhea. A routine course of treatment for ordi- nary, early and uncomplicated cases of gonorrhea in otherwise healthy men, as employed at Camp Logan is described by J. B. Clark.^ The treatment is, of course, interrupted in event of complications or of intolerance.
During First Two Weeks: In bed from four to eight days, then ''up" if inflammation has subsided. Bland diet. Two-glass test each morning with first urination. Smear on Monday and Thursday mornings, before uri- nation. Sandalwood oil, 5 minims three times a day, after eating and increase 5 minims daily until 15 minims three times a day, after eating; then decrease 5 minims daily. Irrigation twice daily (at 5 feet, patient stand- ing) with potassium permanganate 1 :8,000 at 105 to 115 F. The irrigation not to be ''through,'' i. e., into the bladder, until the patient can relax without the sligJitest discomfort. Hand injections to be used while infection remains anterior.
During Second Two Weeks: Bland diet continued. Patient should be up all day, and doing from two to four hours of light work. Two-glass test and smear as before. Do not repeat sandalwood oil course if improvement is marked as it should be. Irrigation twice daily, as before, with potassium permanganate solution, 1 :6,000 at 6 feet, or injections if infection is still anterior.
During TJiird Two Weeks: Diet bland, but increased. Patient should be having from three to six hours daily of light work. Two-glass test and smear as before. If any discharge or cloudiness of urine is present, potas- sium permanganate, 1:4,000, irrigation.
When free from symptoms (no discharge and clear urine) for two weeks without treatment, and doing from
(8) Jour. Amer. Med. Ass'n., April 26. 1919,
44 PHARMACOLOGY AND THERAPEUTICS.
three to six hour's work daily, the patient in most cases may be considered fit for duty and infection-free.
DYES.
Flavine in the Treatment of Acute Septic Stomatitis.
The use of flavin in comminuted compound fractures of the jaws as well as in acute stomatitis is reported favor- ably by H. W. Turner.^
In the latter condition, the following method of pre- liminary treatment has yielded excellent and rapid re- sults. The mouth is syringed out with flavine 1 :1000, special attention being paid to all pockets. Then gauze soaked with flavine solution is lightly packed into the angle of the cheek and all round the gums, and is retained in the mouth for from 20 to 30 minutes. This procedure is repeated thrice daily.
Not merely is the application painless, but it leads quickly to relief of pain and to subsidence of the acute inflammatory condition. Further, in several cases in which the mouth was so foul that one could readily de- tect the bad odor at a distance of several yards, 24 hours after commencing treatment with flavine, the breath has become quite free from smell.
ARSPHENAMIN.
Cause of Early Death from Arsphenamin. D. E.
Jackson and M. I. Smith^ undertook an investigation upon animals to determine the cause of early death from arsphenamin. They arrived at the following con- clusions :
The slow injection of therapeutic quantities of arsphe- namin in very dilute, alkaline solution (monosodium salt) produces no striking results in anesthetized dogs. As the rate of injection and the concentration of the drug are increased, toxic symptoms soon begin to mani-
(1) Lancet, Aug. 2, 1919.
(2) Jour. Pharm. and Exp. Therap., November, 1918.
PHARMACOLOGY AND THERAPEUTICS. 45
fest themselves. The earliest of these symptoms con- sist in a dilatation of the heart, perhaps mainly of the right side at first, a progressively increasing pulmonary blood-pressure, and a slow, gradual, but not severe, fall of the systemic pressure.
The cause of this rise in pulmonary arterial tension the authors believe to be due partly to the alkalinity of the solutions of arsphenamin used, and partly to the specific action of the drug itself. While the authors have not so far been able to prove that the formation of emboli in the pulmonary arterioles and capil- laries may not be in part responsible for the increased pulmonary arterial tension, still they believe that no such action as this occurs. With large toxic doses the right heart may have to contract against a pulmonary pressure increased by 100 per cent, above the normal, while at the same time the left ventricle may be con- tracting against a systemic pressure reduced by 25 to 50 per cent, below the normal. These peculiar conditions may tend to establish a state of increased irritability and instability in the heart, and in rare instances delirium cordis may result. Drugs of the epinephrine type might tend to increase the instability of the heart under these conditions.
The reactions of the internal organs when arsphenamdn is injected are variable, and the reasons therefor are obscure. Apparently both central and peripheral in- fluences are concerned. As a rule, the authors have found oncometric tracings of the spleen and intestinal loop to show a dilatation, while the kidney usually con- tracts, sometimes in a most vigorous fashion. The toxicity of arsphenamin is not increased by the breath- ing of high concentrations of carbon dioxide, nor by the injection of calcium hydrate, calcium lactate, or of monosodium phosphate.
Jackson and Smith suggest that in those cases in which severe, acute, toxic symptoms suddenly mani- fest themselves, either during or shortly after the in- travenous injection of arsphenamin, tyr amine is more likely to be of benefit to the patient than is any other drug with which they are acquainted.
46 PHARMACOLOGY AND THERAPEUTICS.
The Cause of Nitritoid Crises After Arsphenamin Injections. Louis Berman^ makes a contribution to the cause of that type of clinical picture occurring dur- ing or immediately after an intravenous arsphenamin injection, the chief symptoms of which are redness of the face, dyspnea, a feeling of anguish and distress, cough and precordial pain. Wechselmann theorized that it was caused by water contaminated by dead bacteria, moulds or dissolved protein used in dissolving the arsphenamin.
After more comprehensive study, Iwaschenzow in 1912 concluded that the symptoms were definitely not caused by protein or organic substances in the water used, but depended on a sensitized condition of the patient. Mil- lian (1912) gave to the complex of symptoms under discussion the name of nitritoid crises, because of their similarity to those of amyl nitrite poisoning and ob- tained with epinephrine treatment good prophylactic and therapeutic results.
Of the theories to explain the nitritoid crises two stand out most preminently: one is the sensitization of the patient to arsphenamin, in the anaphylactic sense; sec- ond is the acidity and concentration of the solution and its physicochemical effect on the blood.
A number of observers have shown that the severity of the reaction varied directly with the acidity. Thus, in Meissner^s experiments on animals, it was found that if the arsphenamin was alkaline 400 mg. per kilogram could be given with impunity. On the other hand, 5 mg. per kilogram of a 0.5 per cent, acid solution caused dyspnea and often death. Necropsy showed all the organs normal except the lungs, which showed a throm-- bosis of the blood-vessels and an inflammatory exudate in the parenchyma. He also obtained a precipitate in vitro with acid arsphenamin and serum, and thought the thrombosis due to precipitates in the pulmonary capil- laries. MacKee proved that the weight of the precip- itate in vitro varied directly as the acidity and concen- tration.
Auer demonstrated that the toxicity was inversely
(8) Archiv. Int. Med., August, 1918.
PHARMACOLOGY AND THERAPEUTICS. 47
proportional to the acidity and concentration. This law must be considered in any explanation of the nitritoid crisis.
The problem that remained was: why, after the use of thoroughly alkalinized arsphenamin, did a few pa- tients still continue to react? In them, it occurred gen- erally after one injection had previously been given, and, having once happened, could be predicted to recur. The problem of the mechanism of these reactions the writer set himself to solve. He found that when properly alka- linized arsphenamin was brought into contact with serums from the non-reacting, it produced no, or a little, opalescent precipitate. Those from the reacting, how- ever, caused a heavy whitish yellow precipitate. Thus, by testing previously the serum and the solution, one could say whether or not a reaction would follow the injection. In those in whom a precipitate was produced, a prophylactic dose of epinephrine seemed to prevent the onset of the nitritoid crisis. After its appearance, also, the same drug hypodermically shortened the duration of the alarming symptoms.
Blood from two patients showed an increased protein content. Hence, the author puts forward the hypothesis that the increased protein content of the blood in cer- tain syphilitics may favor precipitation in vivo, even of properly alkalinized arsphenamin.
[Should this work be generally conJ5rmed, a prelimin- ary test of the patient's serum with the arsphenamin solution to be employed, to discover tendency to pre- cipitate formation, would constitute an important part of the technique of arsphenamin treatment. — Ed.]
Reactions PoUowing the Administration of Arsphe- namin. An analysis of reactions in a series of twenty- five thousand injections is presented by William H. Guy.^
Just what constitutes a correct technique varies widely in the opinion of equally eminent authorities; but cer- tain essential principles have been established as the result of clinical observation and animal experimenta-
(4) Jour. Amer. Med. Ass'n., Sept. 20, 1919.
48 PHARMACOLOGY AND THERAPEUTICS.
tion, and these were observed in the administrations. Thus, most clinicians report fewer reactions when using dilute solutions. Just what dilution is best is an open question, but most agree that reactions are more frequent when using a concentration greater than 0.1 gm. to 15 ml. Since oxidation products of arsphenamin are quite toxic, it is wise to inspect each ampoule for possible air leaks, and to use the solution as soon after it is pre- pared as possible. Incomplete neutralization of arsphe- namin has probabl}^ accounted for more avoidable reac- tions than any other one factor. The author states that acid solutions of arsphenamin are from 50 to 60 per cent, more toxic than the alkaline. To prevent undis- solved particles from entering the circulation, the solu- tion should always be filtered before it is used. As dif- ferent brands of arsphenamin vary considerably in toxicity, it is of interest to note that of the 25,000 injec- tions, al30ut 15,000 were of the arsenobenzol brand and about 10,000 were of the salvarsan brand. The arseno- benzol brand seems to have made the better record of the two preparations. But with the best technique and with a drug that is comparatively non-toxic, reactions will be encountered that have their origin in the patient himself. Guy's experience is in support of the theory (Hermans) that some reactions are due at least in part to the destruction of enormous numbers of spirochetes, liberating the protein of their bodies into the blood- stream with the production of reaction of anaphylactic type. Patients with elevated temperatures or with demonstrable pathology of almost any kind do not tolerate arsphenamin well.
The following technique was used:
''The usual preparation of the patient is ordered.
''A general physical examination precedes the begin- ning of treatment, and a urinalysis is made before the injection of either arsphenamin or mercury as a routine measure.
''Instruments, glassware, etc., are sterilized by boil- ing.
"Ampoules are floated in alcohol to detect those not intact.
PHARMACOLOGY AND THERAPEUTICS. 49
'* Ampoules are opened and the drug dissolved in sterile distilled water, hot water being used only with the arsenobenzol brand.
''The solution is neutralized with 15 per cent, sodiuni hydroxide to complete precipitation and clearing, after which a few drops in excess are added.
' ' The solution is filtered and then diluted by running sterile distilled water through the filter until each 0.1 gm. of the drug is contained in 20 c.c. of fluid, the tem- perature of the solution being approximately that of the blood-stream. Finally the solution is tested with litmus for alkalinity.
''The solution is then placed in graduated glass cylin- ders hung about 3 feet above the level of the table, and supplied with tubing leading to a needle connection.
' ' With the patient reclining, the bend of the elbows is cleansed with alcohol or painted with iodine, a small piece of gauze being placed just below the site selected for the injection. An assistant grasps the patient's arm just above the elbow, the patient closing his fist to dis- tend the veins.
' ' The check valve on the tubing is released, the opera- tor pinching off the flow of the solution with the thumb and index finger of the left hand. The needle is held in the right hand, being introduced first through the skin and then into the vein.
' ' On obtaining a flow of blood on the gauze, the assist- ant releases the arm, the patient opens his fist, and connection is made with the solution. Dosage is esti- mated at the rate of 0.1 gm. to each 30 pounds of body weight, and the requisite amount of the standard solu- tion allowed to flow into the vein. The tubing is then disconnected from the needle, which is withdrawn after allowing a few drops of blood to wash it out, and a gauze compression is made over the site of the injection until all bleeding has stopped.
"Following the injection, patients rest in the ward for an hour and a half, after which they are returned to their organizations, excepting those patients with infec- tious lesions who are kept in the hospital until all lesions have healed. ' '
50 PHARMACOLOGY AND THERAPEUTICS.
Among reactions due to technical errors, may be counted vomiting in those with insufficient preparation. Of 150 patients who were injected, without preparation in special instances, as in early primary lesions, eight vomited within an hour after receiving a full thera- peutic dose of the drug. The others in the series of primary lesions (dark field positive), numbering 350 all told, were given the usual preparation the night be- fore and four of them were nauseated and emptied their stomachs.
Cold solutions are counted for three successive reac- tions with a moderate chill. On one occasion, the still being out of order, Guy used tap water, and five of forty men injected complained of shortness of breath, were flushed, and after a period varying from fifteen minutes to an hour, vomited and complained of intestinal cramps. Three cases of rather severe thrombophlebitis were seen that may have been due to local implantation of infec- tion; or, more likely, to an infiltration of the drug be- tween the coats of the vessel. The inflammatory process was an ascending one beginning at the site of injection and extending up the arm. These patients complained of pain and tenderness along the course of the swollen, inflamed and thrombosed vein, accompanied by an ag- gravated aching pain located rather vaguely at the shoulder. Cold applications and splinting gave the most relief in these cases.
On one occasion, when a new lot of salvarsan (Metz) was used, thirty-five severe reactions developed in thirty- five patients injected. On investigation it was proved conclusively that the cause of these reactions lay in faulty technique rather than in the drug itself. The one source of trouble seems to have been in the water; that used was some of the first from a new still, and had stood in the new tank for about four hours before being used. Just why this water gave such a serious lot of reactions the author is not prepared to state, unless they were due to bacterial or chemical contamination, the result of standing in the new metal tank.
Vasomotor reactions with flushing of the face, dysp- nea, cough, and precordial pain were seen in but 120
PHARMACOLOGY AND THERAPEUTICS. 51
isolated instances, and in nearly all of these, with re- course to epinephrine and a few minutes' wait, the injec- tion was finished without further trouble.
A generalized urticarial eruption developed in two cases. In one of these, a mild generalized dermatitis developed after eight weekly injections, persisted for three weeks, and then the patient made an uneventful recovery. In the other patient, a generalized pruritus developed an hour after the administration of a single therapeutic dose, and persisted for ten hours. A chill, followed by fever and vomiting and diarrhea, was noted in twenty isolated instances.
Of particular interest is a group of about forty cases in which reactions developed that could be shown to be due to an aggravation of a non-syphilitic pathologic condition. For instance, several men who had a few bronchial rales at the preliminary examination, devel- oped a moderate chill, cough, and a rather severe aggra- vation of their mild bronchitis. More patients with evi- dent mild chronic interstitial nephritis tolerated the drug well. Contrary to what was expected, no unfavorable results were noted in five proved cases of pulmonary tuberculosis. In another case of the same kind, arsphe- namin could not be given, because with each injection there was an exacerbation of the pulmonary symptoms. Men with elevated temperatures, except those due to the syphilitic infection itself, did not tolerate the drug well. In two cases with early reactions, a drug idiosyncrasy seemed to exist. About three hours after receiving arsphenamin, patients developed a chill, vomited, and w^ere quite prostrated. Heart action became weak and irregular. Symptoms persisted from forty-eight to seventy-two hours, even with comparatively small doses of the drug. Epinephrine did not seem to be of any use. Finally, a mild dermatitis appeared on the forearms. Of delayed reactions the author has seen six examples. The third or fourth day after injection, they developed a train of symptoms differing but little from those seen earlier.
Of Herxheimer reactions, Guy has seen only a few. It is his opinion that Herxheimer reactions are the results
52 PHARMACOLOGY AND THERAPEUTICS.
of the stimulating activity of non-sterilizing doses of arsphenamin and that they may be avoided by full thera- peutic dosage.
There have been two fatalities that might be ascribed in any way to antisyphilitic treatment in this series. In one case, after two 0.4 gm. injections four days apart, the patient developed an acute dilatation of the stomach, death occurring on the ninth day. The other case was that of a soldier much overweight, but otherwise, so far as it was possible to determine, quite normal. He re- ceived two injections of 0.06 each of mercuric salicylate. On the third day following his last injection of arsphe- namin, he was given 0.06 gm. grain of mercury, and the next morning was found unconscious in bed. A catheterized specimen of urine showing almost a solid coagulum of albumin, was laden with blood and granu- lar casts. The man died the same day, and at necropsy an acute diffuse hemorrhagic nephritis was found. This points to the necessity of routine examination of urine before each injection of either arsphenamin or mercur5\
Atropine and Induced Anti-Anaphylaxis as a Pro- tection against Acute Arsphenamin Reactions. J. H. Stokes^ suggests these two measures for the control of acute reactions due to the administration of arsphenamin, in addition to those heretofore accepted, such as special care in the preparation of the patient (catharsis and empty stomach), caution in the alkalinization of arsphe- namin solutions, and to the use of the epinephrine solu- tion (suggested by Milan) in from 5 to 10 minim doses as a means of controlling the reaction after it develops and also as a prophylactic. His objection to epinephrine is that this drug administers a shock of no mean in- tensity by its powerful effect on the vascular system, so that patients have for the moment seemed in as much risk of serious damage from the treatment as from the original arsphenamin reaction.
Stokes supports the belief of Danysz and of Berman that the nitritoid crisis is a form of anaphylactic shock due to formation of a precipitate in the blood-stream when acid of imperfectly alkalinized arsphenamin is em-
(5) Jour. Amer. Med. Ass'n., Jan. 25, 1919.
PHARMACOLOGY AND THERAPEUTICS. 53
ployed. Berman differs from Danysz, in believing that this precipitation involves the proteins of the serum, while the latter believes it is the arsphenamin base that is precipitated.
[Berman 's theory is discussed on pages 46-47. — Ed.] The proposal of Schamberg and his collaborators that there is a factor in the preparation of arsphenamin, an impurity of as yet unknown constitution, present in the drug, is not at all incompatible with an allergic explana- tion of the reaction. It is conceivable that it is not the arsphenamin base alone which precipitates, but the precipitation of serum proteins may be accomplished with especial ease even in comparatively normal persons by a substance present as an impurity in the drug. No other satisfactory explanation can be found for the ex- treme frequency of reaction to certain brands of the drug, and its extreme rarity under identical technical conditions in others. Thus in the author's own service, in which the operators and the technique of operation remain unchanged for months and even years at a time, there can be no other satisfactory explanation for the fact that during 5,000 injections in which German preparations were used there were considerable periods when scarcely a day passed without a nitritoid crisis, while in 7,000 subsequent injections in which arseno- benzol-Policlinic and novarsenobenzol-Billon have been employed, the nitritoid crisis has become so rare that he has been all but compelled to abandon the work neces- sary to confirm the results presented in this paper. There can be little doubt in the minds of large users of ars- phenamin that there is a factor of toxicity and a ten- dency to the production of anaphylactic response in cer- tain preparations v/hich can not be explained in abso- lutely general terms, and this is probably the presence of specific impurities.
The author has resorted a number of times to the in- duction of anti-anaphylaxis as a protection against acute arsphenamin reaction, notably in the treatment of pa- tients with tuberculosis, who show an idiosyncrasy in about 50 per cent, of the cases. Small preliminary in-
54 PHARMACOLOGY AND THERAPEUTICS.
jections ''vaccinate" the susceptible patient, so to speak, against the larger doses.
Thus a patient who received 0.05 gm. of neo-arsphe- namin in 0.5 ml. of water, intravenously, one hour pre- viously, tolerated 0.55 gm. of neo-arsphenamin intra- venously in concentrated solution with the complete in- hibition of all reaction usual for this patient.
If a nitritoid crisis sets in and the injection is stopped, it can sometimes be resumed again in ten minutes with- out further ill effect.
The nitritoid crisis can apparently be inhibited by a previous injection of atropine (0.0012 gm.) which further suggests that the reaction is a form of anaphy- lactic shock. Less than this dose failed to protect the patient.
Preparation of Solutions of Arsphenamin for Intra- venous Use. Herman Goodman^ states that the prep- aration of arsphenamin or its equivalent begins with the cleansing of the glassware. The necessary cylinders, gravity tubes, and funnels are washed twice with soap solution, using a long-handled brush. They are then rinsed in running tap water, and again in distilled water. After drying, the glassware is baked in a ster- ilizer at 160° C. for thirty minutes. Wet sterilization is less desirable. Distilled water should be used to boil the glassware, otherwise a film of deposited salts and dirt is evident. Rubber tubing, if new, should be boiled several times with at least three changes of water to remove the powder both within and without. Tubing once used should be rinsed thoroughly before boiling.
The water used for arsphenamin solutions is freshly distilled and not more than six hours old. Although the modern stills deliver sterile water, all water should be boiled for seven minutes.
The sodium hydroxide is a 15 per cent, solution pre- pared with freshly distilled water.
The arsphenamin ampoules are taken from their wrap- pers and put into a dish of alcohol. No tube that does not float is used. The tubes are dried with sterile gauze, as is the alcohol-sterilized file, before the tubes are opened,
(6) New York Med. Jour., June 15, 1918.
PHARMACOLOGY AND THERAPEUTICS.
55
When using salvarsan, neosalvarsan, diarsenol, neodiar- senol, or novarsenobenzol (Billon), the ampoule is readily- opened by scratching the neck with the file and smartly- tapping the far end. This method is not desirable with ampoules of arsenobenzol of Schamberg because the
s^ ii;s:g*t!gg'*g'^'^.S55;s:sH:sg:s^jgs;^s5§^ )
Fig". 4. Apparatus for the intravenous injection of arseno- benzol by the gravity method. Note site of filing" is below the constricted neck of the ampoule.
powder of this arsenobenzol has great cohesiveness and comes from the narrow neck with comparative difficulty. ''Open Schamberg 's tubes down on the body of the am- poule (Fig. 4), and the powder drops out easily. If it falls to the bottom of the cylinder as one mass, it is wise
56 PHARMACOLOGY AND THERAPEUTICS.
to shake the cylinder from side to side and break up the lump."
Water is now added to the powder, using approx- imately 5 mils, to the decigram. For ease in bringing on solution of Philadelphia arsenobenzol, this water should be bubbling, boiling hot. Shaking for a minute is all that is necessary to bring about solutions of all products except Schamberg's. His arsenobenzol requires vigorous shaking for at least five minutes. One should always re- lease the stopper from the cylinder for a moment after shaking to permit the heated air and liberated gas to get out, otherwise they are likely to force the stopper out and literally shoot some of the solution along.
Sodium h3^droxide solution is now added to solutions of salvarsan, diarsenol, or arsenobenzol ; and the gradual drop by drop method is delayed until the neutral point is almost reached. Shake after each addition of alkali and determine this by the speed with which the precipi- tate is formed. The slower the alkali is added, the more precipitate is formed. On further addition of the hy- droxide solution, the precipitate dissolves. The cylin- ders should be shaken slowly and a slight pause made be- fore further alkali is added as this feature is noted. Often the drop of sodium hydroxide that was thought necessary is discarded after this precaution. The final neutral solution is absolutely clear. If the first solu- tion is not complete and alkali is added, there will always be undissolved particles in the cylinder even when the neutral point has been reached.
Ordinarily use for injection 20 ml. of fluids to the decigram. At one time, this second dilution was done with saline, but now sterile water is used without ill effect.
For the injection proper, take a single gravity tub© of 250 ml., nozzle tip at the bottom, and rubber tubing about five feet long. A window of glass tubing may be inserted. At the end of the rubber tubing is a male connection which fits the slip-on hilt of the Fordyce needles. The entire apparatus is suspended with its outlet tip about two feet above the level of the vein into which the needle is to be introduced. Water is
PHARMACOLOGY AND THERAPEUTICS. 57
first run through the gravity tube to displace all the air, and create a complete water system from a visible level in it to the end of the tubing. A pinch cock clamp on the rubber tubing holds well enough, and does less dam- age to the rubber than does an artery clamp. The solu- tions are always filtered through wet gauze from the mix- ing cylinder to the gravity tube. If dry gauze is used, it is very possible for a few loose ravelings from its under surface to be washed into the filtrate. The solution should not vary very much either above or below blood heat. It is not necessary to use a thermometer, judging the warmth of the cylinder with the hand suffices.
Skill in getting into veins with needles comes only with practice. The uninitiated should first take a num- ber of bloods for Wassermanns before attempting these injections. This training will avoid some painful ex- periences.
No patient receives an injection whose bowels have not been emptied by a cathartic taken the night before. Omitting the meal previous to the time of injection is also of value, and in many cases it is wise to caution the patient against eating within several hours after.
It is best in all cases, except in primary lues, where the abortive cure is attempted, to precede the intraven- ous injections of arsphenamin by one or two intramus- cular injections of mercury. This procedure reduces the possibility of the Herxheimer reaction, which is the intensification of the response of the body to the presence of the SpirocTiaeta pallida. Skin and mucous membrane lesions appear brighter, and the pains and aches of specific origin become more marked.
Patients with lesions of the central nervous system and with specific disease of the vascular system do best on small, oft repeated doses than the small number of doses of 5 decigrams, for instance. Patients with one kidney, or with impaired renal organs, may be given doses not greater than 3 decigrams with safety.
Concentrated Solution in Administration of Arsphe- namin. Approximately 2,000 injections by the syringe and in concentrated solutions have been given by A,
58 PHARMACOLOGY AND THERAPEUTICS.
Nelken/ The routine practice is to dissolve 0.6 gm. of the drug in 20 ml. of freshly distilled water. The aver- age dose given to an adult man of normal weight is 0.5 gm. and to a woman 0.4 gm. In fresh infections, especially before the onset of a positive Wassermann test, Nelken commonly gives 0.6 gm. to a man and 0.5 to a woman, repeating this dose weekly for three doses, and then given at least two more injections at longer in- tervals, with mercury and iodides in some form between and following the later injections.
Hundreds of times he has injected 0.6 gm. arsphe- namin in 20 ml. of water in from twenty to thirty sec- onds without the slightest unpleasant results, either im- mediate or delayed. The slo\vness of the injection, on which so much stress is laid, may be of importance when a large quantity of fluid is being introduced, but when the quantity is as small as 20 ml., rapidity of injection is not significant. The so-called ''nitritoid crises" are un- usual when the syringe method is employed. Since using this method, the author has seen less of other complica- tions. He has had no fatalities, only one case of severe nephritis, the patient being noAv entirely well, one case of jaundice and four cases of toxic dermatitis preceded by hyperpyrexia.
Nelken uses arsphenamin put out by the Dermatolog- ical Laboratory of the Philadelphia Polyclinic.
The author concludes that success in the administra- tion of arsphenamin depends chiefly on the following points: First, the selection of a reliable preparation; second, the use of freshly distilled, boiled water, both for dissolving the arsphenamin and for the sodium hydroxide solution ; third, care in selecting the patient and adjusting dosage and frequency of repetition.
Apparatus for Administering Arsphenamin at Tem- perature of Blood. S. R. Thompson^ believes that *' chills and fever" following intravenous injections of arsphenamin are due to injecting the solution below the normal temperature of the blood. He discovered that
(7) Jour. Amer. Med. Ass'n., June 7, 1919.
(8) Ibid., Nov. 16, 1918.
PHARMACOLOGY AND THERAPEUTICS.
59
the patients receiving the injection at the temperature of blood had no reaction or chill.
The apparatus he uses consists of a glass container practically closed with a wooden cover to prevent the en- trance of cold air. In the center is a regular arsphenamin graduate. In the air chamber around this there are three 10-watt incandescent lights and a thermometer. The
Pigr. 5.
Apparatus for administering arsphenamin at temperature of blood.
temperature is regulated by the number of lights used, Before the injection is begun, the solution in the rub- ber tube can be brought to the proper temperature by allowing it to run back into the graduate (Fig. 5). A Portable Arsphenamin Outfit. This apparatus is described by L. W. Harrison.^ It is a portable outfit contained in two boxes. Figure 6 shows a ^'606'' and saline funnel, such as is used in military hospitals, sus-
(9) Brit. Med. Jour.. Nov. 9, 191S.
60
PHARMACOLOGY AND THERAPEUTICS.
pended on a frame carried on a telescopic stand, which is screwed into the hinged end of the box. The funnels are set up at home, with the straining gauze in position at the top of each and the rubber tubing attached. The stand is collapsed and the whole turned into the box,
fn
Fig-. 6. A portable arsphenamin outfit.
which is closed and sterilized in a steamer. At the bed- side, the box is opened, and its hinged end carrying the apparatus is turned down and fixed in position by two sliding bars in the bottom of the box. The telescopic stand is then extended to its full length, and the ap- paratus is ready. The other box contains three Soxhlet bottles of 250 ml. capacity, fitted with Eyre's special rub- ber caps, which are designed to permit of sterilization without the necessity of opening and closing the bottles ^— one of the bottles is graduated and is used for mixing
PHARMACOLOGY AND THERAPEUTICS. 61
purposes, the other two are for saline; two spare fun- nels; a cylinder with foot, fitted with a graduated pipette, and containing caustic soda solution; an iodine pencil, as devised by Major C. F. White, for steriliza- tion of the puncture site ; and two needles in alcohol.
In the remainder of the space are packed ampoules of arsphenamin, a small dressing, and a tourniquet. The Soxhlet bottles, funnels, and cylinders are sterilized in a steamer and thanks to special caps on the Soxhlet bot- tles, these can be carried quite safely in the box provided. The arsphenamin is mixed in the graduated bottle, which should contain about 50 mils, sterile distilled water, the cap being removed, the powder poured into the water, and the cap replaced for shaking. The soda is then added to alkalize, and the necessary amount of saline to bring to the required dilution, leaving enough saline for the saline funnel.
Routine Dosage of Arsphenamin and Mercury. James B. Clark^ gives the following routine course of treat- ment for ordinary fresh cases of syphilis in otherwise healthy men as practiced at Camp Logan;
Each patient is carefully scrutinized for signs of stomatitis or general malaise, his weight is taken, and his urine tested before each injection, as the treatment is to be interrupted in the event dermatitis, jaundice, or other signs of intolerance supervene.
The scheme of arsphenamin dosage is based on 150- pound men: 1 decigram to about 30 pounds of body weight.
Mercuric salicylate 33 per cent. Arsphenamin. in olive oil.
( Intravenously ) ( Intramuscularly ) Gm. Gm.
First day 0.3 0.06
Sixth day 0.4 ^ 0.06
Eleventh day 0.4 0.06
Eighteenth day 0.6 0.06
Twenty-fifth day 0.6 0.06
Thirty-second day 0.6 0.06
Thirty-ninth day 0.06
Forty-sixth day 0.09
Fifty-third day 0.09
(1) Jour. Amer. Med. Ass'n., AprU 26, 1919.
62 PHARMACOLOGY AND THERAPEUTICS.
This is followed by one month's rest, then a Wasser- mann test is taken; if positive, the entire course is re- peated; if negative, the mercury alone is repeated.
At the end of the second course, a rest of two months is allowed ; then a Wassermann taken, and a third course given in accordance with the rule for the second course.
During the second year, if the "Wassermann reaction is positive, the course is repeated as above. If negative, two mercury courses are given with four months between.
MERCURY.
Benzoate of Mercury Solution for Injection. M. E.
Leger^ considers benzoate of mercury one of the useful mercurial compounds. This salt, which is nearly insolu- ble in water, can be brought into solution by the addition of certain neutral salts, among them sodium chloride. Aqueous solutions of benzoate of mercury by means of sodium chloride have been advocated and used by several authors. It is necessary to note that if these injections are made with an insufficient quantity of sodium chloride they are painful, perhaps because they contain bichloride of mercury which coagulates albumin. It has been shown that if one adds an excess of sodium chloride to bichloride of mercury such solution becomes perfectly painless on injection. Leger recommends a solution of the following composition :
gm. or c.c.
Mercuric bichloride 0.60
Sodium chloride 2.25
Sodium benzonate 0.70
DistiUed water, to make 100.00
In this solution, the irritant action of bichloride of mercury disappears under the influence of sodium chloride. In such a solution, a certain amount of hydro- chloric acid is liberated. To remove this, the sodium benzoate is added, which causes the liberation of an equivalent amount of benzoic acid which [being much less ionized — Ed.] is less harmful than hydrochloride acid. Chemically, this solution is identical with the older
(2) Bull, de I'acad. de m^d., April 15, 1919.
PHARMACOLOGY AND THERAPEUTICS. 63
formula, in which benzoate of mercury is dissolved in sodium chloride solution ; but the method of preparation given above is preferable.
Mercurophen — Sodium Oxy - Mercury - Ortho - Nitre Phenolate. This compound, elaborated by J. F. Scham- berg, John A. Kolmer and George W. Raiziss^ during a systematic investigation on the chemotherapy of mer- curial compounds, was subjected to laboratory and clin- ical studies, on a large scale; and it was found that it possesses the following advantages over other mercurial compounds: While equal or superior in germicidal activity to mercuric chloride and other mercurial com- pounds containing more mercury, it is generally more rapid in its germicidal activity. Mercurophen appears to possess a special destructive affinity for cocci and spore-forming bacilli. It has proved superior to mer- curic chloride in the disinfection of urine, feces, sputum, pus, catheters, instruments, rubbers gloves and the skin. Mercurophen maintains a higher degree of germicidal activity in blood serum than mercuric chloride. It does not precipitate protein in as high concentration as 1 :100 ; nor does it irritate the skin or tarnish surgical instru- ments. Mercurophen is somewhat more trypanocidal than mercuric chloride and is capable of temporarily raising the bactericidal action of the blood after intravenous ad- ministration. In terms of mercury, mercurophen is less toxic for animals than other soluble mercurial compounds and this constitutes a fact of much importance in the chemotherapy of compounds of this class.
Mercurophen is remarkably free from irritant effects, and it may be used in contact with the skin and mucous membranes in dilutions as high as 1:1,000 without ap- parent harm.
It is a brick red powder, freely soluble in hot water. Solutions may be prepared as concentrated as 1:100. The solutions are deep amber in color, which is distinc- tive in dilutions as high as 1 :10,000 or more. The powder and its silutions are odorless; solutions of 1:1,000 have a slightly bitter metallic taste; while higher dilutions, as 1 :5,000 and 1 :10,000, are practically tasteless.
(3) Jour. Infec. Dis., June, 1919.
54 PHARMACOLOGY AND THERAPEUTICS.
QUININE.
A Comparative Study of Various Methods of Quinine Administration Undertaken by the British War Office.
This investigation, an abstract of 2,460 cases, is reported by Sir Ronald Ross,^ who was able to do this by reason of the fact that early in 1917 the "War Office had ordered the concentration of malaria cases in England at a num- ber of special centers, partly that these patients might receive treatment by specially qualified medical officers, and partly in order to enable a comparison to be made between various lines of treatment. The majority were cases of benign tertian.
The following summary is presented :
Prom the results of treating 1,040 old cases of malaria with anti-relapse quinine prophylaxis, it would appear that comparatively small doses, amounting to about 4.0 gm. a week, distributed in various ways, reduce relapses to about 10 per cent, of the cases monthly, and also diminish the severity of the relapses when they do occur. But 0.30 gm. daily seems less effective, and 1 gm. daily is no more effective than 0.60 gm. daily and less well borne by the patients.
Sterilizing treatments, given in 1,420 cases, illustrate the difficulty of sterilizing cases entirely, but also seem to show that success in this tends to vary directly with the magnitude of the daily dosage. No permanent bad effects with large dosage have been reported.
The author can not say that he has been able to note any marked superiority in any one of the three modes of administration of quinine — oral, intramuscular or intra- venous— as regards either the speedy reduction of the fever and the parasites (in relapses) or as regards com- plete sterilization of cases. The method of using oral and intramuscular administration together is valuable when large doses are employed, which is, after all, probably somewhat more successful than any of the other forms tried. With the present information, the following treat- ment seems to be the best for resolving infections :
Quinine bihydrochloride by intramuscular injection, 1
(3) Indian Med. Gaz., July, 1918.
PHARMACOLOGY AND THERAPEUTICS. 65
gm., simultaneously in each deltoid, with 0.60 gm. orally, of hydrochloride thrice daily, totalling 4.0 gm. daily, for twelve days — patient remaining in bed for this period.
Old cases generally do so well under anti-relapse treat- ment that it is a question whether efforts to establish early and absolute cure in them by the sterlization meth- ods tried are always very much worth while, especially as numerous patients under anti-relapse treatment seem to recover by themselves, either completely or sufficiently to be able to return to light or full duty.
The Principles of Quinine Prophylaxis. Sir L. Rog- ers* ascribes the reported failures of quinine prophylaxis to inadequacy of the methods used in the particular cases. Much of the confusion and disappointment regarding quinine prophylaxis appears to be due to the principles on which it should be based being neglected or ignored. A most important point which is often overlooked is that in places with a very high endemic index, such as 80 to 100 per cent., the population is already so almost universally infected with malaria that prophylaxis is out of the question, and the comparatively small and in- frequent doses given for that purpose can not possibly be expected to cure the infected persons to whom it is administered; or to prevent the inevitable recurrences of the disease in insufficiently treated malarial infec- tions. What is wanted in such cases is to give three weeks' treatment with full curative doses of quinine once a quarter.
The second principle is that to be effective prophylac- tically, quinine should be given at least the full period which each form of parasite takes to develop before the end of the incubation period.
The accompanying table gives the data for the various types :
The Incubation Periods of Malarial Fevers.
Variety. Max.
Quartan 18
Benign Tertian 21
Malignant Tertian 14
|
Days between |
|
|
doses of |
|
|
Min. |
Mean, quinine. |
|
11 |
14 11 |
|
6 |
11 8 |
|
2 |
6 2 |
(4) Indian Med. Gaz., July, 1918.
66 PHARMACOLOGY AND THERAPEUTICS.
When malignant tertian malaria is very prevalent, as a double infection is commonly present, the quinine should be given on two consecutive days to catch each brood at the stage when they are most susceptible to the drug.
The third important and most essential factor in ob- taining success is to give an adequate dose of quinine, which will kill all the young, recently inoculated para- sites and not allow some to escape and produce the dis^ ease.
The two main methods in use are Koch^s plan of giv- ing a full dose of quinine on two consecutive days of each week, and the plan of giving 0.30 gm. daily.
1. Koch's method of giving 0.60 to 1.00 gm. on two consecutive days each week was once very popular and it has scored successes as well as failures. The principles laid down will suffice to show that it is especially likely to fail in highly malarious districts, where the malig- nant tertian variety predominates. Koch's method leaves a five-day interval between the prophylactic doses, which is too long in the case of the predominat- ing malignant tertian infection. This method should be abandoned as being unreliable and contrary to the correct principles of quinine prophylaxis.
2. The plan of giving 0.30 gm. doses of quinin daily has been largely adopted during recent years, with some- what contradictory results. The data obtained are clearly much more favorable to the system of small daily doses than to biweekly larger ones, the failures having been chiefly in intensely malarious parts of Africa and the Malay States, where curative rather than prophylactic doses are indicated. Nevertheless, several failures have been reported, and the question arises whether 0.30 gm. is not too small a dose to be relied on.
A sufficient dose, which it seems advisable to deter- mine, is not less than 0.60 gm., to eliminate the danger of some of the parasites surviving and becoming re- sistant to quinine, which is said to be a danger if only 0.30 gm. doses are used.
The intervals without quinine between the doses should not exceed four days, except when malignant
PHARMACOLOGY AND THERAPEUTICS. 67
tertian malaria is present in an epidemic form, when the intervals without quinine should be reduced to two days, and the dose increased to 1 gm.
Administration of Quinine in Malaria. It is the opin- ion of C. C. Bass*^ that the most effectual and practical method of disinfecting malaria infected persons is to give them 0.60 gm. of quinine sulphate every night be- fore retiring for a period of eight weeks. The author quotes the following doses for children to obtain the same result 0.60 gm. gives in adults :
Under one year 0.03 gm.
One year 0.06 gm.
Two years 0.12 gm.
Three and four years 0.18 gm.
Five to seven years 0.24 gm.
Eight to ten years 0.36 gm.
Eleven to fourteen years 0.48 gm.
Fifteen years and over 0.60 gm.
The quinine is best administered to adults in the form of tablets [capsules might be preferred, and perforat- ing the capsule with a pin prick just before swallowing might be of advantage. — Ed.] To children, the dose is best administered in a teaspoonful of the aromatic syrup of yerba santa (Syrwpus enodictyi aromaticus).
The full eight weeks' treatment should be prescribed at one time, and the patient impressed with the neces- sity of taking the full treatment without missing a dose ; otherwise a relapse is likely to occur.
During acute attacks of malaria, 0.60 gm. doses should be given three times a day for a period of three or four days, which always relieves the acute symptoms, and then the eight weeks' treatment undertaken to eliminate the infection.
Bass believes that this treatment will disinfect more than 90 per cent, of cases. To disinfect 100 per cent, would take more than three months' treatment. In case of relapse, the full treatment must be repeated and continued longer than eight weeks. No credit can be allowed for previous treatment.
(5) Jour. Amer. Med. Ass'n., April 26, 1919.
68 PHARMACOLOGY AND THERAPEUTICS.
Administration of quinine by month is the only method to be considered in the treatment of malaria, except in rare incidences of pernicious malaria, when one or more doses, given intravenously, may save life. The dose for this purpose should never exceed 0.60 gm. The dihydro- chloride of quinine is a good salt for this purpose. Ad- ministration by mouth should be started just as soon as practicable in such cases. Bass advises those who con- template injecting quinine hypodermically by deep in- jection to take a few doses themselves, which he thinks would soon quiet their enthusiasm for the method. For oral administration quinine sulphate is as effective as any other salt. The greater solubility of some other salts is of no advantage in the treatment of malaria, but on the contrary may be a disadvantage.
The use of 0.60 gm. of quinine sulphate by mouth for the sterilization of the blood of malaria carriers is also advised by J. C. Geiger, W. C. Purdy and R. T. Tar- bett^ w^ho believe that a thirty days' period of treat- ment is sufficient for a season.
[It will be noted that all these authorities agree on 0.60 gm. as the best dosage for quinine. — Ed.]
Colloidal Quinine in Treatment of Malaria. F. Roux^ reports favorable results with the intravenous injection of colloidal quinine (base) in doses of 2.5 to 5 mg. in- old cases of malaria with enlargement of the liver and spleen which had resisted other quinine medication. He usually gives an injection daily or every second day; and he has never had to administer more than four doses. The injection is generally followed by a reaction of vary- ing symptomatology, such as chill, fever, vomiting, head- ache and profound sleep. He has never observed serious results. Roux believes that this method of administra- tion of quinine is superior to any of the classical meth- ods, especially in the presence of hemoglobinuria.
Quinine as Pneumococcide Mouth Wash. S. Solis Cohen and Edward SteinfiekP have tested a number of quinine solutions in different flavoring vehicles with the
(6) Jour. Amer. Med. Ass'n., March 22, 1919.
(7) Presse med., June 27, 1918.
(8) Jour. Amer. Pharm. Ass'n., May, 1919.
PHARMACOLOGY AND THERAPEUTICS. 69
purpose of determining palatability and germicidal activity against pncumococci.
These solutions have all been found capable of destroy- ing pneumococci of Types I and II in vitro. Those con- taining acacia have been less efficacious than others. On the other hand, neither glycerine, syrup nor honey seems to interfere materially with the action of the germicide.
A solution contciining quinine and urea hydrochloride and phenol, each in a dilution of 1 :200, made up with 20 per cent, of glycerine and flavored with oil of pepper- mint, is fairly palatable. This was tested against Type III pneumococci also and found effective. It exhibits, likewise, penetrative ability in sputum.
The following formula is therefore recommended:
Quinine and urea hydrochloride 0.5
Phenol 0.5
Glycerine 20.0
Oil of peppermint 2 drops
Water, to make 100.0
The solution mentioned may readily be associated with the compound guaiac gargle, which has been found so effective against tonsillitis and other throat infections, and which of itself shows considerable germicidal ac- tivity against pneumococci. To do this one simply sub- stitutes compound gargle of guaiac (N. F.) for the water of the formula.
Infusion of coca may be substituted for water in all the formulas with advantage as to palatability; but, owing to the tannin it contains, it precipitates some of the quinine. This may perhaps lessen slightly the germicidal activity, but even insoluble quinine tannate in small proportions will inhibit the growth of pneu- mococci in test-tube cultures.
IPECAC AND EMETINE.
Comparative Value of Ipecac and Its Alkaloids in Treatment of Intestinal Endamebiasis. Sidney K. Si- mon® considers ipecac superior to its alkaloids. While
(9) Jour. Amer, Med. Ass'n., Dec. 21, 1918.
70 PHARMACOLOGY AND THERAPEUTICS.
no question can be raised of the prompt amebicidal action of the emetine on the free living or vegetative organisms, more extended opportunity for observation has made it increasingly clear that, in the matter of the destruction of the endamebic cysts, the alkaloidal ther- apy in many instances meets with marked failures, thereby opening the way for repeated recurrences of the infection.
A close analogy exists, in fact, between the Endameba Mstolytica and the malarial hematozoa in the matter of their behavior to specific medication. Both organisms, in common with protozoa in general, exhibit two separate and distinct phases in their life cycle, including a free living or vegetative stage of existence which permits of free locomotion enabling the cell to obtain its nutriment, and a second state in which the vital activities of the cell are found in abeyance within the enclosure of a cyst wall (the so-called gamete). It is only in the latter state that infection is conveyed from host to host, since the vegetative organism is prone to succumb or to under- go encystment when removed from its original environ- ment. The pathologic conditions arising in the human organism are, however, the sole result of the vital mani- festations of the free living protozoon. In its encysted state the organism lies dormant, incapable of tissue harm, but offering marked resistance to external influence. Protozoa once having become encysted have acquired thereby an increased resistance to their specific drug, in sharp contrast to the ease with which the organism in its vegetative state may be reached and destroyed in the same dosage. In fact, relatively small amounts of the specific drug, instead of killing the organism outright, will often induce the obverse effect of driving it into en- cystment. While the immediate clinical symptoms are promptly relieved by such a process, the difficulties surrounding the complete eradication of the infection are largely increased. Just as relatively small amounts of quinine tend to encourage the formation of gametes, so, in endamebic disease, unless appreciably large doses of ipecac or of its alkaloids are employed, the free liv-
PHARMACOLOGY AND THERAPEUTICS. 71
ing organism seeks protection against the toxic action of the drug by enclosing itself within a cyst wall.
While the crude ipecac, in amounts as high as 5 gm. in daily doses repeated over a period of ten days, has been found singularly devoid of toxic effects, experi- ence has shown that the alkaloids, in an equivalent dosage, possess no such immunity. They must be charged with the not infrequent occurrence of a peri- pheral neuritis, an intractable form of watery diarrhea, gastric hyperemia and irritability, cardiac arrhythmia and, in addition, various types of skin reaction at the site of injection of the drug.
Cephaelin has greater emetic properties and is far more irritating to the skin when given hypodermically than is emetine. Its destructive effects on the vegetative endameba is probably equally as great as that of emetin. However, the same failure in the matter of the destruc- tion of the cysts was noted.
In connection with emetine mercuric iodide and emetine bismuthous iodide, it was hoped that their emetic effect might be reduced to a minimum. However, according to most observers, this hope has scarcely been realized. Walters and Koch^ have carried on experimental work with synthetic derivatives of cephaelin, and found that cephaelin iso-amyl ether hydroiodide was uniformly effective in destroying both the vegetative and the en- cystic endameba in the intestinal tract of cats. When, however, this substance was tried on three human sub- jects, its action on the free living endameba proved to be equal in value to that of the simple alkaloids, but no definite effect could be noted in its action on the cysts.
In view of the evident inadequacy of the alkaloidal therapy, Simon thinks that a return to the use of the original crude ipecac root should be most seriously con- sidered by the profession at the present time. Failure to observe the smaller details of the plan has been the cause of much of the former prejudice surrounding the administration of the crude ipecac. ''First of all, it is essential that the patient be put to bed for the full course of the treatment, extending ordinarily over a
(1) Jour. Pharm. and Exp. Therap., 1917. 10, 73.
72 PHARMACOLOGY AND THERAPEUTICS.
period of ten days, and also that the dietary be re- stricted in the beginning to articles of food which leave no residue in the intestinal tract, such as broths, whey, albumin water and the various nutrient alcoholic prepa- rations. To this list, milk is to be added only after the fifth or sixth day of treatment. A dose of castor oil should be administered on the morning of the first day of treatment and in the evening, around 9 o'clock, from ten to fifteen salol-coated pills should be taken, each containing 0.30 gm. of the powdered ipecac. The patient is advised to swallow these slowly with the help of mod- erate amounts of water. No nourishment is allowed for two hours preceding and likewise for six hours follow- ing the administration of the pills. Each succeeding night the same plan is to be repeated, the number of pills varying on each occasion from ten to fifteen. It may be found necessary, especially in the presence of any depressing effect, to discontinue the use of the pills for a one-night period. Each day the attending nurse keeps a record of the number of pills which might have passed undissolved in the stool, with the view of deter- mining the total amount of ipecac retained at any stage of the treatment. ' '
The complete dosage includes the retention of at least 100 pills, equivalent to 500 grains of the powdered ipecac. This is accomplished usually within a period of ten days and only under rare conditions must it be made to extend over two weeks. Should nausea and vomiting arise as troublesome features, an extra enteric coating should be added to the pills. Under average con- ditions, a coatinn;- of one-tenth inch of salol is ample. Should large numbers of the pills pass through the intes- tinal tract in an undissolved state, making from one or two punctures into the outer layers of the pill surface, with a small sized surgical needle, will be helpful. When ipecac is not tolerated in pill form, the duodenal intuba- tion method might be used, employing for the purpose daily installations of 2 gm. of the powdered ipecac sus- pended in water. "With the use of the ipecac mass orally, in daily amounts as high as 5 gm. and yielding approx- imately 0.09 gm. of total alkaloids, a concentration of
PHARMACOLOGY AND THERAPEUTICS. 73
the effective properties of the drug is attained in the infected colon, without any possible danger of toxemia. It is the author's firm conviction, based on clinical ob- servations extending now over several years, that the treatment of intestinal endamebiasis by means of the crude ipecac offers a most promising outlook for com- plete and permanent cure, not attainable with the use of the alkaloids alone, whether administered orally or hypodermically.
ALLEGED SPECIFICS. Inft^uenza Remedies.
Cinchona Bark in Treatment of Influenza. Raphael Du Bois^ reports excellent results from the administra- tion of finely powdered yellow chinchona bark, given in doses of three or four heaping teaspoonfuls daily. One spoonful is given every three or four hours in a cup of strong black coffee, hot and sweetened. It is, of course, important that the drink be stirred while being taken, so that the powder be completely ingested. He states that he has often seen a cure in from twenty- four to forty-eight hours. Improvement in the general condition is usually evident after the first dose.
Creosote in Prophylaxis and Treatment of Compli- cations of Influenza. This is recommended by L. Weil- ler^ as follows:
Every twelve hours the patient is given in an enema a glass of lukewarm milk containinof about 1 drop of creosote for each year of age for children, and from 25 to 30 drops for adults. The mixture should be well shaken and the enema retained for at least two hours. In cases of pulmonary complication, the dose should be increased by from 2 to 5 drops for children and from 4 to 8 drops for adults. The complication sub- sides rapidly. The intervals should be lengthened when the temperature becomes normal; and, two days after the cessation of pyrexia, the treatment is stopped. Al-
(2) Bull, de I'acad. de m^d., Oct. 1, 1918.
(3) Paris Letter, Jour. Amer. Med. Ass'n., Dec. 14, 1918.
74 PHARMACOLOGY AND THERAPEUTICS.
buminuria, so frequent a symptom in pnenmococcus in- fections, he does not consider a contraindication for this treatment.
Salicin in Influenza. E. B. Turner* advocates large doses of salicin in influenza, giving 1.3 gm. every hour. He obtained rapid recovery in an average of one day and a half without any complications, sequelae, or the loss of a single life, in over 2000 cases. The flrst two or three doses remove all pain and discomfort, while the temperature is materially reduced. He also believes that saturating the system with salicin does away with the infectivity of the patient. In no single case has he come across the slightest ill effects from the large dosea of the drug given.
E. W. Watson^ adds his testimony to the value of salicin given in doses of from 2 to 2.5 gm. every two or three hours, or, if the onset is at night, a heaping tea- spoonful in cold water at bed-time. He considers it a real specific, as truly so as is quinine in malaria. In some cases that have developed into so-called pneumonia, its use has seemed to turn the scale to recovery.
Reginald Pollard® has also used salicin with good re- sults in this disease.
[In view of the freak>^ nature of influenza and con- sidering the fact that all kinds of medication, including homeopathic, as well as no medication at all. have given '* excellent'/ results in this disease, we must be skeptical toward claims such as those abstracted above. — Ed.]
Magnesium.
Disinfectant and Antiseptic Action of Concentrated Solutions of Certain Magnesium Salts. This study was undertaken by Z. Northrup^ because a saturated solu- tion of Epsom salt, which has been used extensively as a substitute for talcum or face powder, by rubbing a small amount of the liquid gently all over the face until
(4) Brit. Med. Jour., Aug. 3. 1918.
(5) Amer. Medicine, November, 1918.
(6) Brit. Med. Jour., Oct. 26, 1918.
(7) Jour. Infect. Dis., February, 1919.
PHARMACOLOGY AND THERAPEUTICS. 75
dry, thus leaving a soft *^ bloom'' on the skin, has been found also to have a salutary effect on the skin, pimples drying up and disappearing.
The procedure for the phenol coefficient of MgSOi was caried out for StapJiylococcus aureus^ and also for B. typTiosits with completely negative result. Even a 50 per cent, solution, which is practically saturated, did not kill the organisms. That plasmolysis from strengths of salt above saturation plays no role, was shown by the fact that, when heavily inoculated saturated solution of magnesium sulphate was permitted to dry at incubator temperature, growth of the organisms could still be ob- tained.
On the other hand, the magnesium ion was found to have a markedly inhibitory effect on the growth of strep- tococci, as was shown by the fact, that even 5 per cent. in broth does not permit its growth. MgClg was the only magnesium salt used that had a marked inhibitory action upon the Staphylococcus pyogenes. In fact, this latter salt had the most marked inhibitory action on the growth of all organisms used in the experiment. This suggests that a substitution of MgCla for MgSO^ might be of advantage.
The author believes that further study of the specific action of concentrated solutions of MgS04 ^'^^ other magnesium salts on the infected skin or in wounds may present interesting if not valuable information. In the treatment of war wounds, MgS04 was advocated by Morison and TuUoch in 1916.
Magnesium in Cancer. Shigemitsu Itami^ treated experimental cancers in mice with intravenous injection of magnesium chloride in doses relatively eight times larger than the toxic dose for man without effect on these mouse tumours, even when two or three treat- ments were given within a few days.
Since carcinomas of the mouse are quite comparable to those of men, the assertion may be ventured that this element will prove to be useless in human cancer as well.
(8) Jour. Amer. Med. Ass'n., March 29, 1919.
76 PHARMACOLOGY AND THERAPEUTICS.
RESTORATIVE THERAPY.
ACIDS.
Large Doses of Hydrochloric Acid in Gastric Achylia.
V. Bie^ reports a case of gastric achylia with enteritis and anemia, for many years refractory to all treatment, which was successfully treated with hydrochloric acid in doses large enough to supply the proper proportion for normal digestion. As the stomach secretes a 4 or 5 per thousand solution of the acid, which corresponds to a dilution of the hydrochloric acid of the Pharma- copeia of about 1:50, the acid was given on an empty stomach, by means of the stomach tube, once a day, commencing with 1 ml. in 250 ml. of water, increasing gradually to 5 ml. and even 8 ml. in from 250 to 500 ml. water, and keeping up this dose at intervals for nearly three months. The hydrochloric acid was not given every day, only nine times in the first month and six times in the second month.
ADSORBENTS.
Animal Charcoal in Treatment of Chronic Disturb- ances of the Small Intestine and of Enterotoxicosis.
Animal charcoal in doses of from one to three heaping teaspoonfuls (5 to 10 gm.) has been administered by E. Lenz® every evening before going to bed, that is, as long as possible after the last meal, because it has been shown by experiment upon human beings that admin- istration of charcoal fifteen minutes before a test meal lessens total acidity and the hydrochloric acid value to a considerable extent. It is also reasonable to assume that digestive ferments would be adsorbed and digestive activity become impaired. Hence, the smallest amount that is likely to be useful should be employed and given as long as possible after or before meals. It should be stated, however, that as much as 20 gm. daily may well be administered and that in acute diarrheal disturb-
(8) Ug-eskrift f. Lae^er. May 15, 1919.
(9) Cor-Bl. f. schweiz. Aertze, Oct. 12, 1918.
PHARMACOLOGY AND THERAPEUTICS. ^^
ances as much as 80 to 100 gm. of animal charcoal have been administered.
The author administers the dose suspended in hot water or in a cup of chamomile, linden, or valerian tea. When satisfactory results are obtained, a dose may be administered every second or third day and is in this manner gradually discontinued. If, however, exacerba- tions set in, there is absolutely no objection to con- tinuing the use of charcoal indefinitely. The treatment has been continued for weeks and months. Indeed, it is upon this continuous use of this remedy that the author lays special emphasis. He considers this chronic ad- ministration an important therapeutic advance in the treatment of chronic putrefactive and fermentative dyspepsia and duodenal catarrh, in which conditions he has given the remedy usually in periods of 8 to 14 days with intervals of several days during which the char- coal administration is intermitted. This chronic inter- mittent administration enables the bowel to recover from local irritant action and other possible by-effects of the charcoal treatment. While so far such effects have not been demonstrated, yet it must be admitted that there is a possibility of nutritional disturbance being produced by this treatment, most especially that the charcoal might adsorb vitamines and produce an avitami- nosis. There is also a possibility that digestion might be impaired by adsorption of digestive ferments, and the author, as previously stated, has occasionally noticed diarrheal and spastic manifestations on the part of the colon which he has considered due to mechanical irrita- tion by the charcoal. This paradoxic reaction, instead of the usual constipating effect of the remedy, is dimin- ished by utilizing the finest possible powder; but there seems to be an idiosyncrasy against charcoal in some patients. We must also bear in mind the possibility of the formation of charcoal enteroliths. The possibility of anthracosis of the intestine and of the retroperitoneal lymph glands by absorption of the coal is a possibility which must also be thought of, the occurrence or non- occurrence of which future investigation will have to determine.
78 PHARMACOLOGY AND THERAPEUTICS.
The principal indication for tMs treatment is found in chronic and functional disturbances of the duodenum and in chronic intestinal catarrh, gastrogenic diarrhea, fermentative and putrefactive dyspepsia and spastic con- stipation.
On the basis of the demonstration of a prompt diminu- tion of urobilinuria in two cases of chronic cholangitis under charcoal therapy, the author considers the possi- bility of this treatment constituting prophylaxis against liver disease as not too far fetched.
Combination with saline mineral waters is especially indicated in those cases in which constipation occurs as a result of charcoal treatment, as well as when we at- tempt to antagonize enterotoxic liver disturbances, or general enterotoxicosis. The author employs, in such cases, four to six weeks' courses of an alkaline saline bitter water of which he has the patient take from 200 to 400 c.c. every morning.
Kaolin in Treatment of Asiatic Cholera. That the mortality of this disease can be reduced from the usual 45 per cent, to or near 2 or 3 per cent, by the use of kaolin or bolus alba (albuminum silicate) suspended in water, is the claim of V. Kuhne.^ The finely powdered substance is administered in an equal volume of water. Thus 250 mils of kaolin which weigh about 100 gm. are mixed with 250 mils of water by pouring the kaolin into the water and not vice versa. A small glassful of this mixture, which resembles cream, is administered every half hour or hour. It is rarely necessary to give more than six glasses, amounting to 200 gm. of kaolin during the first twelve hours. Generally, after the administra- tion of the first doses, vomiting ceases, the patient warms up, the pulse becomes less frequent and stronger, the cramps of the extremities disappear and the phenomena of dehydration become less marked. During the fol- lowing day, the patient is given several more glasses and this terminates the cure. If the cholera is treated at the first appearance of symptoms, the patient will be well, Kuhne says, in twenty-four hours and able to leave the hospital after three days. In more severe
(1) Rev. m6d. de la Suisse romande, Sept. 20, 1918.
PHARMACOLOGY AND THERAPEUTICS. 79
cases, one should count from five to six days before complete convalescence is established. Even in ap- parently hopeless cases, a patient has a good chance to recover, though it takes longer than ordinary cases. One should not be discouraged by vomiting after the first doses of medicament, but should make the patient re- peat the dose and even have recourse to a stomach tube, because the kaolin will stop vomiting. If the patient has difficulty in swallowing, the dose may be given by the spoonful. If the stomach and intestine are atonic by reason of the paralyzing action of the cholera toxin it is well to introduce the same mixture by means of enteroclysis, using as much as three liters.
This medication dispenses with all other medicinal treatment such as alcohol, cardiac tonics or other stimu- lants. The following three points are of importance:
1. During the eighteen hours which follow the first dose of bolus alba, one must not give any other drink or nourishment except water.
2. The kaolin must never be administered in any other liquid than water, which preferably should be cold.
3. One must administer this earth in most liberal doses — the more, the better — for the substance is abso- lutely non-toxic.
This treatment might be instituted in all acute diar- rheal conditions, as even in cases that are not Asiatic cholera its results are said by Kuhne to be excellent. On the other hand, this treatment is useless in diarrhea due to amebic dysentery or intestinal tuberculosis. The action ^f kaolin is partly physical, by reason of its tendency to envelop the microbial bodies which can not grow in this medium, and partly due to adsorption which renders toxic substances harmless.
The author calls attention to the fact that kaolin is also useful in treatment of wounds, burns, indigestion, abdominal pains, in meteorism, as an antidote to poison- ing and in the treatment of pin-worm infestation.
In an infant a dose of 30 gm. kaolin in from 70 to 100 mils of water would suffice. In an older child, 60 gm. in 150 mils of water is sufficient. After three hours
80 PHARMACOLOGY AND THERAPEUTICS.
it is generally well to repeat the dose. For infants, it is well to sweeten the water.
[The antidotal value of kaolin in alkaloidal poisoning is practically nil, that of fuller's earth is slight, the de- gree of action varying greatly with different specimens of this substance. It would be interesting and important to determine whether highly absorbent fuller's earth would not be superior to kaolin in the treatment of cholera. — Ed.]
Lithium Aluminum Phosphate as an Intestinal Anti- septic. Joseph B. Weighart^ thus describes this sub- stance and its effects: It is a hard, white, brittle sub- stance similar to porcelain, insoluble in water, and in acid or alkaline solution. Administered as fine powder or in tablets, it passes the stomach unchanged. But it is somewhat soluble in concentrated and diluted phos- phoric acid and in solutions of alkaline as well as of acid phosphates. Inasmuch as these are continuously present in the intestines from the ileum down to the colon, a considerable portion of the lithium aluminum phosphate administered swells up to a gelatinous mass. From analyses made, it has been determined that the principal amount of lithium contained is execreted by the urine in from thirty-six to forty-eight hours after ad- ministration. The aluminum phosphate appears in the feces in a gelatinous condition. This circumstance proves the disintegration of lithium aluminum phosphate in the lowest part of the intestines with absorption of the lithium component leaving the aluminum phosphate or some other twin salt of aluminum phosphate within the contents of the intestines. Aluminum acetate has long been known as an antiseptic by the surgeon. Calcium phosphate keeps the feces of dogs antiseptic, rendering them white and without odor.
** Aluminum phosphate, or the new twin salts formed in the lower intestines, is a very powerful antiseptic, especially in its nascent state and in collodial condition. The bacterial life in the intestines is not entirely de- stroyed by it ; but acid fermentation of the small intes- tines, as well as alkaline putrefaction in the lower colon,
(2) Western Med. Times, May, 1919.
PHARMACOLOGY AND THERAPEUTICS. 81
are controlled and kept within low physiologic limits. It may be given in diarrhea as well as in obstipation. ' '
The author has used up to 10 grams a day and in a few cases more without any toxic effect.
[Whatever effects can be obtained from this sub- stance are evidently due to colloidal adsorption and are analogous to those obtainable from fuller ^s earth or kaolin. Experiments with fuller ^s earth would not lead me to expect anything phenomenal in the direction of intestinal antiseptics from any one of these substances, unless it is used heroically and to the exclusion of all bacterial pabulum, as advocated by Kuhne in the treat- ment of cholera (pages 78-80. — Ed.]
Water Absorbing CaparCity of Dusting Powders. This property of dusting powders has been tested by Torald SoUmann^ with the following result:
Weight of Retained water held by water as
8 gm. of per cent of
Powder tested. powder, the powder.
Starch (corn) 2.39 80
KaoUn. 2.19 73
FuUer^s earth 2.09 70
Precipitated calcium carbonate 1.94 65
Talcum 1.84 61
Prepared chalk 1.59 53
The table shows that the commonly used dusting powders do not differ very materially in their capacity for holding water. However, starch, kaolin and fuller's earth are more effective in this respect than chalk or talcum.
ALKALIES.
Alkali Treatment of Influenza. Thomas C. Ely* be- lieves it to be an established fact that acidosis is a con- stant factor in all the infectious fevers, and that in the recent influenza epidemic acidosis was particularly prominent and had much to do with the extraordinary
(3) Jour. Amer. Med. Ass'n., March 29, 1919.
(4) New York Med. Jour., April 5, 1919.
82 PHARMACOLOGY AND THERAPEUTICS.
fatality. Striking clinical proof of this acidosis, he thinks, was noticed in the following ways : The peculiar acetone odor of the breath was so characteristic that some clinicians made a tentative diagnosis of influenza on this symptom alone; the symptoms of dyspnea and air hunger were severe even without other striking respiratory symptoms. The associated cyanosis is the result of the withdrawal of the alkali reserve. The therapeutic proof was most convincing. The proper administration of the three basic alkalies — sodium, potas- sium, and calcium — was immediately followed by the gradual cessation of acidosis symptoms and an extremely low mortality rate, which is in striking contrast to the high mortality in cases in which alkalies were neglected. In addition to the great number of influenza cases that were seen daily during the recent epidemic, Ely has treated twenty-six patients with pneumonia with well- marked crises, over 100 cases of lobular pneumonia, five pregnant women, and eleven instances of severe in- testinal infection. The large number of recoveries he attributes to the persistent use of early elimination and to saturation of the system with alkaline bases, avoid- ing any remedies which check secretion, such as opium or belladonna, or any heart depressant, such as aspirin, or any influenza vaccine or serum. A free water supply must be essential to carry on with advantage the laws of osmosis with these bases and to favor elimination of the products of combination with the acids. Too much alkali might produce harmful alkalosis.
The technique of treatment is as follows: Immediate elimination is instituted by profuse sweating and divided doses of calomel, one-tenth grain every half hour until a grain or more has been given. Water is given freely by mouth or by bowel throughout the attack. Sweating is preferably accomplished by drinking large bowls of boneset tea. Hot lemonade with whisky was often given. Hot mustard foot baths were always used, the patient being kept in bed covered with blankets and surrounded by hot bottles. Ely administered a teaspoonful of sodium bicarbonate to a pint of luke-warm water every four hours by enema. In routine treatment he gave, by
PHARMACOLOGY AND THERAPEUTICS. 83
mouth, sodium bicarbonate, one-half ounce, in pepper- mint water four ounces [more than will dissolve; solu- bility of sodium bicarbonate is 1 part in 11 of water. — Ed.], a teaspoonful every two hours, alternating with potassium citrate, one-half ounce in peppermint water four ounces, teaspoonful every two hours. The calcium salts he gave in the form of lime water, one-third, milk two-thirds.
''It is surprising," he says, ''how the soda in from twenty-four to forty-eight hours will relieve the early pains." In addition, he employed the common cardiac and respiratory stimulants, strychnine, caffeine, sparteine, digitalis, camphorated oil, oxygen, and aromatic spirits of ammonia. In all cases the patient was confined to bed, and the use of a bedpan was made imperative. From the first, even when no food was allowed, the patient was given orange juice and lemonade freely. The author does not believe in serum and vaccine treatment of in- fluenza. He says, "We are all familiar with numerous re-infections, and it may be questionable whether a pas- sive immunity can be induced for a disease which itself does not produce [a more efficient — Ed.] active im- munity. Can we hope to vaccinate against a disease which does not vaccinate against itself ? ' '
[My experience^ agrees well with that of the author. I can not, however, believe that the explanation of the clinical facts is as simple as he suggests. That acidosis is the chief source of danger in this infection is an un- proved assumption. It seems more rational to believe that alkali favors the establishment of immunity. The same thing might be said about the use of heat (see " Pyretotherapy, " page 132) employed by Ely and others, under the impression that it favors elimination. The amount of poison eliminated by sweating must be very small, in view of the fact that the specific gravity of sweat is but slightly above that of distilled water. That heat, on the other hand, favors the establishment of im- munity and chilling antagonizes it is an every-day ob- servation.— Ed.]
(5) Jour. Amer. Med. Ass'n., Nov. 23, 1918.
84 PHARMACOLOGY AND THERAPEUTICS.
Sodium Citrate in Treatment of Pneumonia. W. H.
Weaver^ believes that this form of treatment has not received the recognition it deserves. Sodium citrate, he claims, increases the fluidity of the blood, its alkalinity, its antitoxic power and leukocytosis. Hence, it aids the natural forces at work in the cure of the disease.
Sodium citrate is a salt of feeble alkalinity and may be given in sufficiently large doses to produce its effect without the least danger of harm, or even discomfort to the patient. Its taste is not disagreeable, nor does it disturb the gastric functions or appetite. It might be given in doses of 4.0 gm. every two hours, if that amount were considered necessary. It may be given wdth a little citric acid or lemonade in small quantities. The dose for an adult Weaver has found to be 2.5 gm. every two hours. For children, the dose should be calculated from that amount. In bronchopneumonia the dosage must be larger than in the lobar type, owing to the difference in the character of the disease.
If the cathartic action of the sodium citrate appears, it should be checked and the dose maintained, rather than reduced. Until the clearing up process is completed, the citrate must be continued at the same dosage.
If there is no improvement in from six to twelve hours, the dose may be increased. In adults, improvement does not begin until the third day, or later if the dose has been inadequate.
In an adult, from 2.5 to 4 gms. every 2 to 3 hours must be continued day and night until the lung has entirely cleared. If the citrate is discontinued before complete resolution there will be an immediate relapse.
The author reports a total of thirty-six cases, in all of which the patients recovered by lysis under the admin- istration of sodium citrate.
[Extemporaneously prepared sodium citrate, produced by giving the patient every two hours a tumblerful of lemonade with half a teaspoonful of baking soda added to it, has been a favorite treatment of many infectious diseases, including rheumatism and endocarditis, in the hands of experienced practitioners. — Ed.]
(6) New Orleans Med. and Surg-. Jour., October, 1918.
PHARMACOLOGY AND THERAPEUTICS. 85
Sterilizing" Bicarbonate Solutions. An editorial in the Interstate Medical JournaV calls attention to the fact that if the bicarbonate solution be heated in an atmosphere of carbon dioxide and cooled in the same condition, the resulting solution contains only the bicar- bonate and not the carbonate. Therefore, if the bicar- bonate solution be packed in a bottle with a spring clip stopper, such as is used for sparkling mineral waters, and charged with carbon dioxide just before closing, it may be sterilized in the autoclave at one sitting. The bottle, before opening, should be cooled, and shaken when cool. It is a wise precaution to add a few drops of phenolphthalein solution before sterilization. Should the finished solution show a pink shade it must be re- jected.
ASTRINGENTS.
Knifeless Treatment of Piles. The usual surgical operations for hemorrhoids are regarded by S. L. Katzoff^ as barbarous, unscientific and unnecessary.
He presents the following practical points:
If the inflammation has been reduced and the astrin- gent ointment is insufficient, good results may fre- quently be obtained by applications of Monsel's solution of persulphate of iron with a brush once or twice daily.
He also recommends equal parts by weight of tannin and glycerine anointed once, and in severe cases twice daily. He considers common table salt unsurpassed as a remedy for bleeding biles.
Applications of collodion to external hemorrhoids will support the pile and stimulate its contraction. It may be dropped on a few fibers of cotton, which are spread over the pile each morning after defecation. Gradually increased dilatation of the rectum will sometimes bring about the desired result, and will be helpful in almost every case.
The injection methods consist in shaving the hair around the anus, cleansing the parts thoroughly, then.
(7) November, 1918.
(8) New York Med. Jour., Dec. 21, 1918.
86 PHARMACOLOGY AND THERAPEUTICS.
after having the pile in firm position, injection with a hypodermic syringe, of one or two drops of a mixture of phenol, one part, glycerine two parts in each pile, beginning with the smaller ones. He has personally em- ployed the following formula at least 200 times:
Gm. or CO. Phenol
Salicylic acid f°'^^*^'^ ^-^
Sodium biborate 4.0
Glycerine (sterilized) sufficient to make.... 30.0
One or two drops of this mixture in each pile will suffice to begin favorable results. After the injection, almost any usual ointment such as tannic acid ointment, belladonna ointment, stramonium ointment, and the like, may be smeared around the parts, and the usual reduction within the sphincter, retention and dressing may follow.
ALTERATIVES.
Iodide in Sporotrichosis. L. Ramond^ describes a case, in which, on account of gummas on the trunk and arms, the patient was given a course of mercurial treat- ment, but without effect. The indolence of the gummas, their rapid development, the absence of fistulas and the arrangement of the lesions along the lymph routes finally corrected the diagnosis to sporotrichosis which was con- firmed by cultivation of the pus. The lesions disap- peared rapidly under administration of potassium iodide, beginning with small doses and increasing to a daily dose of 4 gm. Only exceptionally is more than this required, to a maximum of 8 gm. The patient was unable to bear the iodide by the mouth and was given it by the rectum.
Iodine in Prophylaxis of Goiter. C. Roux^ suggests that an open bottle of tincture of iodine beside the bed at night might yield enough iodine to supply the deficit. Infinitesimal amounts are all that is necessary, more is harmful. Goiter must be prevented before it is dis- covered.
(9) ProgT^s m6d., April 19, 1919.
(1) Rev. m^d. de la Suisse romande, May, 1918.
PHARMACOLOGY AND THERAPEUTICS. 87
RESTORATIVE ORGANOTHERAPY.
Some Indications for Thyroid Therapy. J. L. Mas- terman-Wood^ believes that hypothyroidism in its sub- myxedemic form, is very frequently seen in general practice and that it is no respecter of age. It is more common in females, who provide the clinician with the majority of cases for observing the varying degrees of thyroid inefficiency. At puberty, at each menstrual flow, during pregnancy and lactation, the gland enlarges, which is evidence of the body's demand for further sup- plies. These constantly alternating periods of augmented functioning and comparative quiescence render the thy- roids of women peculiarly unstable. Among the exciting causes of this condition the author would give the toxemia of infection first place.
'* There is no doubt," he says, *'that in all toxemias the thyroid plays a very active and essential part, and that after severe illness in many cases it often ceases to func- tion adequately. Clinically, many instances of this may be observed in children who previous to the onset of some acute infection have been normal in every respect, but who subsequently exhibit in varying degrees signs of failure of development and other stigmata of sub- thyroidism. Likewise adults under similar conditions show evidences which point conclusively to a breaking- down of the thyroid's efficiency, which may be tem- porary or the incipient stage of chronic benign myxe- dema. The truth of this can soon be verified by the administration of thyroid extract, which, if used with care and perseverance in such cases, not only aids defer- vescence, but greatly hastens convalescence."
The stigmata of subthyroidism are as follows; (1) slight want of mental alertness; (2) sluggish bodily movement; (3) slightly sleepy appearance of the eyes; (4) sluggish bowels and fetid stools; (5) retardation of general development; (6) appearance of enlarged tonsils and adenoids; (7) relaxation of spinal and plantar liga- mentous supports, leading to lumbar lordosis and flat foot; (8) increase of weight out of all proportion to
(2) Practitioner. May, 1919.
88 PHARMACOLOGY AND THERAPEUTICS.
height; (9) nocturnal enuresis may be due to hypothy- roidism, and such cases are relieved by minute doses of thyroid; (10) the definite and rapid improvement in every respect after opotherapeutic treatment.
Masterman-Wood cites a remarkable disappearance of asthmatic attacks under thyroid medication, which leads him to call attention to the fact that the myxedemic is the pathologic prototype of the normal vagotonic indi- vidual with his ready response to cholin, and that periph- eral stimulation of the vagus produces contraction of the bronchial musculature and a constriction in the lumen of the bronchioles, leading to a great diminution in the quantity of air inhaled and an over-distension of the lung — a state of affairs which apparently occurs in true spasmodic asthma.
Inefficient thyroid activity disturbs the normal bal- ance which should exist between the sympathetic and autonomic systems. The latter is not sufficiently op- posed, and is, in consequence, very responsive to stimu- lation of its peripheral twigs. Thus even slight stimula- tion of the vagal terminals is sufficient to produce reflexly powerful contraction of the muscles of the bronchioles and a resulting attack of asthma. To complete the pic- ture, we must add the value of adrenalin. As is well known, an hypodermic or intramuscular injection of 5 to 20 minims of adrenalin hydrochloride (1-1,000) will, within the short space of five minutes, restore to the anxious sufferer his longed-for liberty to breathe. Mas- terman-Wood has never appealed to this remedy in vain, but success depends on the freshness of the solution. If exposed to air, or if kept for a long time, this prepara- tion turns a pale pink color and becomes inert. The synthetic product, under the name of ^^epinine,'' is practically identical, chemically, with adrenalin, and, in the writer's experience, is equally efficacious. It has the added advantage of being stable, and, therefore, can always be appealed to with confidence. This action of adrenalin in alleviating the acute spasm of asthma can well be explained, if the stimulating influence of the suprarenal upon the sympathetic is remembered. It is quite conceivable that this substance, after injection,
PHARMACOLOGY AND THERAPEUTICS. 89
directly excites the cervical ganglia and thus temporarily antagonizes the hitherto uncontrolled vagus.
Interesting and of possibly great practical importance are the author's ideas regarding the relations of the therapeutic effects of iodides to the thyroid. He believes that not only do iodine compounds exert a profoundly stimulating influence upon the thyroid gland, but that it is in virtue of a more or less intact thyroid that they are able to produce their beneficient effects. Iodides fail entirely to relieve the symptoms in congenital, ac- quired, or operative myxedema. They have failed, as is well known, sometimes to quell the ravages of the syphilitic virus, probably due to a parlous state of the thyroid, produced by the toxemia which has completely paralyzed its functioning power for the time being. That this is so, is borne out by the fact that in certain cases of syphilis in which iodides failed to give relief at one period, the use of the drug can be resumed later with great resulting benefit. The author quotes Eendle Short, who has found ^^ thyroid extract quite as effective as iodide of potassium in healing tertiary syphilis." This was certainly not unexpected upon theoretical grounds, and it will probably be found that where iodides fail thyroid extract may prove successful. Arteriosclerosis being one of the most outstanding and striking changes in congenital myxedema, the author considers it not un- reasonable to attribute post-syphilitic vascular changes definitely to post-syphilis sub- or dis-thyroidism.
Masterman-Wood cautions us that with elderly sub- thyroidics possessins: an enfeebled myocardium the greatest circumspection must be shown in employment of thyroid. Delirium cordis of a most alarming nature may supervene. Albuminuria is not necessarily a con- traindication to the use of thyroid, unless this symptom is associated with clinical and laboratory evidences of definite kidney disease, when the remedy should not be employed. Albumin found in the urine of submyxedema unaccompanied by the presence of tube casts or renal cells, may disappear from the urine after restoration to normal health through the agency of thyroid extract.
During the administration of thyroid extract, patients
90 PHARMACOLOGY AND THERAPEUTICS.
frequently complain of pains of a ^'rheumatic'' nature in various parts of the body. The primary * ^rheu- matism," almost invariabl}^ referred to the inter-scapu- lar region, for which the sub-myxedemic sometimes seeks relief, is often initially aggravated. In fact, on more than one occasion, this temporary exacerbation of the complaint, coupled with neuralgic pains in the legs and arms, has brought from the patient an emphatic remonstrance against the form of treatment employed. With perseverance, however, these symptoms disappear, and it is rarely necessary to prescribe anodynes.
Indeed for sufferers from so-called rheumatism, those chronic pains which the laity invariably class under this heading and which are usually localized in muscular and fibrous tissues, a very large proportion of whom have exhibited minor degrees of thyroid inefficiency small doses of thyroid extract alone, or combined in a mixture in the form of elixir with sodium iodide, work like a charm.
Of course, we must endeavor to discover in every case the cause of the thyroid's failure, otherwise, remission of the treatment will, in most cases, result in a relapse. Pyorrhea alveolaris, septic conditions of the nose, tonsils, pharynx, or vagina, or bones, are causes which must be remedied before a permanent cure can be recorded.
BLOOD TRANSFUSION.
Indications for Transfusion. Garbat^ tabulates the indications for which transfusions are undertaken as follows :
1. To replace blood In hemorrhage of all kinds:
(a) During the act of bleeding (and at the same time
also to help stop the bleeding). (6) After the bleeding has stopped and an anemia with
its sequelae remain.
2. To stimulate the blood-forming organs in blood diseases:
(a) Pernicious anemia. (&) Leukemia.
3. To alleviate or cure hemorrhagic conditions:
(a) Hemophilia.
(&) Hemorrhagic diseases of the new-born.
(c) Purpuras.
(3) Jour. Amer. Med. Ass'n., Jan. 4, 1919.
PHARMACOLOGY AND THERAPEUTICS. 91
(d) Complicating secondary hemorrhagic diseases, as jaundice, grave anemia and infections.
4. To act as a stimulant or tonic:
(a) Before operations.
(&) In debilitated conditions.
(c) In acute shock.
5. To neutralize or overcome effects of poisons:
(a) Bacterial infections. Bacteremia:
Endocarditis.
Infections with pyogenic bacteria; typhoid; etc. Toxemia only:
Diphtheria.
Peritonitis, etc. (&) Chemical:
Diabetic coma.
Acute gas poisoning.
Acute yellow atrophy of the liver, etc.
L. J. Unger^ discusses the indications for transfusion as follows:
1. Hemorrhage: It serves not only to replace loss of blood, but also to check actual bleeding.
2. Diseases of the blood: In pernicious anemia, transfusion yields results superior to any other mode of therapy. By repeated transfusions, remissions can be effected and the lives of some patients made useful for years. In certain cases, however, even this procedure is of no avail. Hemophilia is not cured by transfusion ; but for the bleeding of hemophilia, it is practically a specific. In purpura hemorrhagica, the results of trans- fusion are only fairly good. Repeated transfusions are often necessary to control the bleeding. In acute lymphatic leukemia, only a temporarily favorable effect can be secured by transfusion, even by most heroic trans- fusions. In bleeding of the new-born, transfusion is the specific. Temporizing by using less effective measures may cost the baby's life. This is especially true in cases of melena neonatorum, which are the most serious be- cause we do not know just when the hemorrhage began or how much internal hemorrhage is taking place. Just as soon as the diagonsis of bleeding from the stomach or the bowel of the new-bom child is made, transfusion should be performed.
(4) Jour. Amer. Med.. Ass'n., Sept. 13, 1919.
92 PHARMACOLOGY AND THERAPEUTICS.
3. Toxemia : Especially in the toxemia of pregnancy and in toxemias associated with acute infections, such as pneumonia and typhoid fever, transfusion ought to be employed more frequently.
4. Infections: In localized pyogenic infections, transfusion will increase the patient's vitality and aid in overcoming the infection. When the source of or- ganisms can be found and eliminated, the results are excellent, as in cases of sinus thrombosis following mas- toiditis, in which the jugular vein has been ligated. In postpartum sepsis, on the other hand, only one patient out of about twenty recovered ; the others showed merely temporary improvement.
5. Shock: Transfusion is at time valuable.
6. General Debility: Transfusion should be used preliminary to operations as a supporting measure, and thus lessen the postoperative mortality.
Hemorrhage and Blood Transfusion in the War. Bertram M. Bernheim^ points out that among the im- portant advances in medicine and surgery wrought in France during the war was the forcible demonstration of the great usefulness of blood transfusion. It was also shown that so far nothing has been found to take the place of blood, once a hemorrhage has passed beyond the limits of safety.
This war development is of real significance for, de- spite efforts to popularize blood transfusion and despite all the brilliant advances of recent years made in this line of work and the reports of innumerable lives pro- longed and saved by its use, there has always existed in the profession generally an apathy toward it — a skepti- cism not only as to its efficacy, but also as to its need.
While salt solution may relieve the condition tem- porarily, it has little sustaining power, chiefly because it rapidly passes out of the blood-vessels into the surround- ing tissues by osmosis. Blood, on the other hand, has real sustaining power because of its oxygen-carrying properties and its ability to remain intact as a circulat- ing medium. Gum solution as a substitute for blood has
(5) Jour. Amer. Med. Ass'n., July 19, 1919.
PHARMACOLOGY AND THERAPEUTICS. 93
been a disappointment. It is Bernheim's opinion that if one-half the energy and time that were spent on gum solution had been spent on efforts to get blood and secure donors, we would have more to show for our efforts
Patients who had been given gum solution faile«! to react, and in certain instances the blood-pressure not only failed to show the expected rise, out actually fell; the fluttering pulse failed to steady and the depression even had a tendency to become more alarming than it already was. When salt solution was given instead of the gum, more intensive efforts were directed toward securing blood for those most in need of help and the results were gratifying.
Even so, the number of lives thus saved, compared with the number that might have been saved, was small — and all because blood in bulk was not obtainable, and salt solution, in many cases, would not answer the pur- pose. This is particularly true in the case of com- pound comminuted fractures of the femur in which the patient came in severely shocked by loss of blood, pain, hunger, fatigue and delay in getting him back to the base. Results were too often fatal in spite of immediate operation or the most judicious use of salt infusions until operation was considered feasible. When blood was ob- tainable, it was customary to give it just as the opera- tion started, in order to tide the patient over, and those who received it invariably did better than those who did not.
In the base hospitals, a great light was shed on the value of blood transfusion in the anemia secondary to battle wounds. These were very common and most dis- tressing cases. The men would lie pale, inert, unable to eat, nervous, day by day slipping back just a little, while their wounds not only failed to heal, but became increasingly dirty, until all bodily resistance being finally overcome, septicemia ensued and death resulted. Particularly was this true of bone and joint cases. A number of these men were transfused; and in nearly every instance prompt improvement followed.
Bernheim prefers the sodium citrate method owing to
94 PHARMACOLOGY AND THERAPEUTICS.
its simplicity, its elasticity, and the fact that it could be employed under circumstances that precluded the use of any other method. The author wishes that labora- tory men would devise a method of preserving blood so that we could send for it to the drug store.
W. B. Cannon,^ in an article on secondary wound shock, admits that there is little doubt that the best method for raising the blood-pressure is transfusion of properly matched blood, as by such means not only is the pressure raised, but oxygen carriers are added to the circulation. However, if blood is not available, he insists that Bayliss' gum-salt solution, made of selected pure gum in physiologic sodium-chloride solution, or Erlanger and Gassers modification of this solution, may be employed. These colloidal solutions, if used early, can permanently raise arterial pressure. They do so by increasing the circulating volume of fluid. There is no evidence that either the subcutaneous or intravenous in- jection of physiologic sodium-chloride solution has more than temporary value, if it has any beneficial effect at all.
End Results in One Hundred and Twenty-four Blood Transfusions. Major W. G. Waugh^ of the British army gives the accompanying table of results from blood transfusions at the battle front. While he used indirect transfusion by means of paraffine-coated tubes (Vincent's method), the author considers transfusions of citrated blood best. He injected from 600 to 1,200 c.c.
The results in Class 2 indicate the usefulness of trans- fusion as a prophylactic against shock, and suggest that it should come into general use as a preliminary to severe operations.
Transfusion for pyemia has given sufficiently encour- aging results to justify, in the author's opinion, the more general use of this method. It represents an attempt to do something further than merely drain secondary ab- scesses. Patients who recovered from some slight septic lesion were employed as donors.
(6) Jour. Amer. Med. Ass'n., July 19, 1919.
(7) Brit. Med. Jour., July 12, 1919.
PHARMACOLOGY AND THERAPEUTICS.
95
|
Cases Transfused. |
|||
|
Re- |
|||
|
Clinical Condition and Operation |
cov- |
||
|
Performed. |
No. |
ery. |
Death. |
|
Class 1. |
|||
|
(a) Secondary hemorrhag-e; ligation |
|||
|
of main artery |
52 |
35 |
17=32.7% |
|
(b) Secondary hemorrhage; amputa- |
|||
|
tion of limb |
14 |
10 |
4=28.5% |
|
Class 2. |
|||
|
Sepsis or gangrene; amputation of |
|||
|
limb |
39 |
35 |
4=10.2% |
|
Class 3. |
|||
|
Pyemia |
19 |
12 |
7 — 36.8% |
|
Totals |
124 |
92 |
32=25.8% |
|
Cases not T |
ransfused. |
||
|
Re- |
|||
|
Clinical Condition and Operation |
cov- |
||
|
Performed. |
No. |
ery. |
Death. |
|
Class 1. |
|||
|
(a) Secondary hemorrhage; ligation |
|||
|
of main artery |
52 |
28 |
24—46.1% |
|
(b) Secondary hemorrhage; amputa- |
|||
|
tion of limb |
14 |
7 |
7=50.0% |
|
Class 2. |
|||
|
Sepsis or gangrene; amputation of |
|||
|
limb |
29 |
20 |
9=31.0% |
|
Class 3. |
|||
|
Pyemia |
, , |
||
|
Totals |
95 |
55 |
40=42.2% |
The Transfusion of Blood in Shock Produced by War Wounds. Out of approximately 1,600 grave untrans- portable eases, Lacoste, Lartigaut and Picque^ found only thirty-six patients in whom transfusion was indi- cated; thirty-three cases were due to hemorrhagic and three to non-hemorrhagic shock. In seven cases of this series they performed pre-operative transfusion on appa- rently moribund men who were pulseless, presented no arterial tension, and were insensible to artificial serums. Such men would have died at the beginning of the war before the eyes of the surgeon, whereas today many such patients, thanks to blood transfusion, can be put into condition to sustain an operation successfully. Immedi- ate post-operative transfusion performed in order to im- prove the general condition of the wounded to whom the shock of an unavoidable immediate operation has come in addition to traumatic shock were also seven in number. These transfusions permitted the extension of the indi- cations for surgical procedure in wounded men on whom formerly an operation could not have been attempted.
(8) Paris Letter, Jour. Amer. Med. Ass'n., Sept. 20, 1919.
96 PHARMACOLOGY AND THERAPEUTICS.
The authors find that the indications for blood trans- fusion should not be based solely on the result of the blood-cell count but rather more on the study of arterial tension.
Critical Periods in Disease Treated by Blood Trans- fusion. E. E. Lindeman^* considers it not unreason- able to conclude, in view of the complexity and im- portance of the blood — the highway for the carrying on of traffic on which animal life is dependent — that blood transplantation, in part or in toto, may favorably influ- ence the course of many diseases other than hemorrhage and anemia, in which the indications are not so apparent, and that possibilities are opened for modifying the blood of a donor to meet specific needs in a given case.
Regarding sepsis, he does not regard the fulminating, vicious types of infections, such as occur in the puer- perium, or the acute variety in which death occurs within a few days, as favorable types for this treatment, for these conditions become fatal before the treatment be- comes operative. Neither are the results obtained in malignant endocarditis with Streptococciis viridans bacteremia encouraging. One's efforts are almost in- variably defeated by the lodgment of emboli in the brain, lungs, liver, kidneys, spleen, etc., which ultimately re- sult in the death of the patient. On the other hand, in long-standing cases of sepsis, even with bacteremia, the patient will frequently arrive at the point at which he has just enough protection to prevent further advance of the infection temporarily. The organism and the host then seem to exist side by side with indifference to each other until one of two conditions will prevail: the host will either overcome the organism, or the organism will advance further so as ultimately to over- come the host. This may be regarded as a critical period in the disease of the patient, and all measures should be directed toward increasing the patient's resistance.
(9) Jour. Amer. Med. Ass'n., Sept. 20, 1919.
♦ Dr. Lindeman was accidentally drowned at Atlantic City, June 12, while bathinj^, on the very day on which he read his paper, at which occa.sion the wife of one of the patients, whom he actually resuscitated by blood transfusion, gave a rather dramatic unsolicited testimonial. — Ed.
PT.ATF. T.
Group II serum is on the left-hand part of the glass slides while Group III serum is on the right. Blood from each of the four different groups has been mixed with both II and III serums. The top slide shows the ag-g-lutination of Group I cells by both Group
II and Group III serums. The second slide shows ag-g-lutination of Group II cells by Group III serum, but not with II serum. The third slide shows ag-g-lutination of Group III cells by II serum, but not with III serum. The bottom slide shows no ag-g-lutination of Group IV cells with either Group II or Group
III serum. — -Vincent, pag-e 98.
PLATE II.
Tliiii shows the saine results as in i*late i except cover glass has been superimposed on the mixtures of known II and III and the blood of the different groups. — Vincent, page 98.
PHARMACOLOGY AND THERAPEUTICS. 97
Blood transfusion is frequently an excellent procedure in these conditions.
When a patient has arrived at a critical period in per- nicious anemia, there is no other therapeutic measure that has the power and efficacy of transfusion of unmodi- fied blood in large amounts in robbing the disease of its terrors. Remissions may be provoked. When remis- sions can not be provoked promptly, the patient bears the disease better.
Lindeman reports five cases of tropical sprue, with apparent recovery in every case. It is unlikely that the mere improvement of the anemia is responsible for the cure of the disease.
Gas poisoning may be regarded in a measure as an anemia, for the oxygen-carrying power of the blood is reduced. In six cases of gas poisoning, all the patients but one recovered.
In nephritis one may encounter a critical period in which blood transfusion may prove helpful. The func- tional activity of the kidneys improves with the improve- ment in the blood condition.
Of course, in cases of hemorrhage, blood transfusion is specific, no matter how extreme the hemorrhage, pro- vided some life is still present. To show that there is no condition so grave, in hemorrhage alone, that a patient can not be revived by blood transfusion, Linde- man cites the case of a man, who was so exsanguinated from hematemesis, that he was unconscious, with marked dyspnea and in shock. His respirations became fewer and fewer until they were mere occasional gasps. The attending physician could feel no pulse. A tourniquet was placed on the patient's arm but the veins did not distend. It was necessary then to make a small inci- sion, exposing the medium basilic vein. Not a single capillary bled at the site of incision. There was no blood in the medium basilic vein; it presented itself, when exposed, as though it were a nerve trunk, and it looked like a piece of flat white tape. By this time the patient stopped breathing, and no heart sounds were audible with the stethoscope. It requires but a few seconds to deliver blood by the syringe-cannula system,
98 PHARMACOLOGY AND THERAPEUTICS.
but even these few seconds were too precious to lose and cold saline, which was the only thing at hand, was pumped into the vessels by the assistant until blood transfusion was started. Sixty ml. of saline were intro- duced in the interim. After the patient received 200 ml. of blood, he took an inspiratory gasp, followed by a paralytic expiration. When he had received 400 ml. he was breathing more regularly; a flicker of pulse was perceptible. When he had received 600 ml., there was a decided improvement in the pulse and an increasing depth of respiration. He opened his eyes and stared, but was not conscious. When he had received 800 ml. he became startled, as though suddenly awakened out of a sound sleep, and wanted to know what all the fuss was about. The transfusion was stopped when the patient has received 1,200 ml. The pulse and respiration were then quite satisfactory. He was then fully con- scious and breathing normally. As his wife testified afterward, he is still alive today, though he required three other transfusions.
Compatibility Tests for Blood.
A Rapid Macroscopic Agglutination Test for Blood Groups. Beth Vincent^ describes a macroscopic test which is simple and rapid and sufficiently accurate for practical purposes. A brief review of some essential points will make clear the method and use of this test.
Every human being belongs to one of four blood groups. This grouping is based on the agglutinating activity of human serum and the susceptibility of red corpuscles of agglutination. The four groups formed on this basis are thus described :
Group I: Serum agglutinates no corpuscles. Cor- puscles agglutinated by serums of Groups II, III and IV.
Group II: Serum agglutinates corpuscles of Groups I and III. Corpuscles agglutinated by serums of Groups III and IV.
Group III. Serum agglutinates corpuscles of Groups
(1) Jour. Amer. Med. Ass'n., April 27, 1918.
PHARMACOLOGY AND THERAPEUTICS. 99
I and II. Corpuscles agglutinated by serums of Groups
II and IV.
Group IV. Serum agglutinates corpuscles of Groups I, II and III. Corpuscles agglutinated by no serum.
There is no agglutination between serum and cor- puscles of the same group.
The blood group to which an individual belongs can be determined by an agglutination test with his red blood corpuscles and the serums from individuals known to belong to Groups II and III.
The macroscopic test described is made by means of two citrated serums, Serum II and Serum III, obtained from the blood of two individuals belonging to Group II and Group III.
' ' To prepare the serums, 20 ml. of blood are collected from each individual under sterile conditions. When the blood has coagulated and the clot has contracted, the serum is pipetted off into two sterile flasks, and sufficient sodium citrate is added to obtain a citrated serum 1.5 per cent., and some preservative, as tricresol, 0.25 per cent. The serum is citrated to prevent the coagulation of the small amount of fresh blood mixed with the serum in making the test, which would make it difficult to determine the presence or absence of agglutination. ' '
The serums may be kept for use in sealed small glass tubes or in bottles stopped with a combination rubber cork and medicine dropper.
The two prepared serums and a clean dry glass slide are all that is needed to make the test. One or two drops of Serum II are placed on the left half of the slide, and an equal amount of Serum III on the right half of the slide. The ear or finger of the person tested is punctured, and a small drop of blood is transferred on the point of the knife blade to each of the serums in turn. The blood is stirred into the serum. The blood should be transferred before coagulation has commenced, and care should be taken to avoid mixing the two serums. Agglutination of the corpuscles is accelerated if the serum is agitated by tipping the slide from side to side. If the reaction is negative, the corpuscles make
100
PHARMACOLOGY AND THERAPEUTICS.
a "uniform suspension in the serum. If the reaction is positive, the masses of agglutinated cells usually appear in less than a minute and are readily discernible to the naked eye. With certain serums, rouleaux formation of the red corpuscles takes place and is sometimes con- fusing. Rouleaux formation usually appears more slowly than agglutination, and the rouleaux are broken up if the serum is disturbed, while agglutination is in-
SF.RUM
|
Group: |
I |
II |
III |
IV |
||
|
r |
0 |
+ |
-h |
+ |
I |
|
|
^ |
||||||
|
w |
||||||
|
^ |
H |
0 |
0 |
+ |
-(- |
II |
|
o |
||||||
|
C/3 |
||||||
|
0^ o |
III |
0 |
+ |
0 |
-h |
in |
|
u |
||||||
|
IV |
0 |
0 |
0 |
0 |
IV |
|
|
I |
II |
III |
IV |
Fig-. 7. Relation of the four blood groups.
creased by this procedure. In doubtful cases, the read- ing should be confirmed by microscope examination (Plates I and II).
Study of the photographic reproductions shows the method of reading the tests. Plate I shows the macro- scopic appearance of the known serums mixed with the blood of the different groups (the preparations have dried slightly).
It will be observed that these four different combina- tions of reactions conform to the two middle columns (between the heavy lines) in the accompanying table (Fig. 7). If a slide is superimposed on its proper
PHARMACOLOGY AND THERAPEUTICS. IQl
row in these columns, the group number of the cor- puscles at the end of the row corresponds to the blood group of the individual tested.
Except in cases in which the risk of delay is greater than the risk of hemolysis, the compatibility of the blood of donor and recipient should be determined be- fore blood transfusions are performed. Hemolysis of the red corpuscles does not take place between members of the same group. Therefore, when possible, it is pre- ferable that donor and recipient should belong to the same group. Eecent clinical experience apparently has confirmed the fact that certain definite combinations of different groups can be made without danger of hemoly- sis. Members of Group IV may be used as donors for individuals belonging to Groups I, II and III, and a Group I recipient may be transfused from individuals belonging to Groups II, III and IV. Members of Group IV, therefore, are termed universal donors, and members of Group I, universal recipients.
The selection of donors by blood groups is made as follows: A Group I recipient may be transfused from any group. Group II and III recipients may be trans- fused from the same group or Group IV. A Group IV recipient requires the same group.
Simplification of the Method of Rous and Turner. This procedure has been satisfactorily employed by linger^: **In a pipet used for counting leukocytes, one part of 10 per cent, sodium citrate and ten parts of the patient's blood are mixed. A similar specimen of the donor's blood is collected. From these specimens, by means of a third pipet, are mixed nine parts of the donor's blood to one part of the patient's, and also one part of the donor's to nine parts of the patient's. A drop of each of these mixtures is put on a slide, a drop of physiologic sodium chloride solution is added, a cover glass is applied, and examination is made under the microscope. Any clumping, not rouleaux formation, is agglutination, and this donor should not be used. Usually the clumping appears immediately, but it is wise to ob- serve the mixture for fifteen minutes."
(2) Jour. Amer. Med. Ass'n., Sept. 13, 1919.
102 PHARMACOLOGY AND THERAPEUTICS.
Technique and Methods op Transfusion.
Sodium Citrate Transfusion. Among the various methods advocated, K. F. Snyder^ favors the citrate method as the most practical routine method because :
First, it obliterates the danger of recipient to donor contamination.
Second, the preparation of the blood requires no un- usual skill in withdrawing the blood, in mixing it, or handling it.
Third, no attention need be paid to the danger of premature coagulation, after the blood is prepared, from defective preparation of paraffin surfaces or delay in injection, as the blood is not affected by the condition of the walls of its container or the transmitting system and may be kept for hours before injection.
Fourth, blood may be taken from the donor and transmitted to the bedside of the recipient at a distance.
Fifth, the danger of hemolysis is reduced to a minimum as by the technique of injection 10 ml. of the blood and interrupting the current for a few minutes to note any premonitory symptoms of this catastrophe serious re- sults may be obviated.
The potential accidents to be guarded against are:
1. Incompatibility of the bloods, to be avoided by appropriate laboratory reactions.
2. The transmission of chronic or acute disease from one patient to another, which is to be avoided by a proper history and blood examination of the donor.
3. Acute dilatation of the heart, which is to be guarded against, especially in persons suffering with myocarditis and requiring massive doses of blood, and which is easily avoided in the citrate method by pro- longing the time of infusion, but not so easily controlled in other methods where the time element is important and delay in infusion may result in premature blood coagulation and failure of the operation.
4. Air embolism, which is easily avoided by proper care.
5. Blood embolism, which is easily avoided in the
(3) 111. Med. Jour.. August. 1919.
PHARMACOLOGY AND THERAPEUTICS. 103
citrate method by proper technique and proper mild agi- tation of the blood as it comes into the citrate. It is not so easily avoided in other methods where potential coagu- bility of the blood is not altered by external means and actual coagulation, but awaits access of the air or a touch of foreign material to become inaugurated, and the life of the patient is endangered or the success of the transfusion destroyed.
The technique of the citrate method as described by Lcwisohn is as follows :
The outfit for a blood transfusion consists of two small glass jars, two large glass jars, two glass ampoules con- taining 50 c.c. of sterilized 2.5 per cent, solution of sodium citrate, one large sized cannula for taking the blood from the donor, one small sized cannula for the injection of the blood into the recipient, one glass rod and a salvarsan flask with rubber and glass taper con- nection. The arms of donor and recipient are washed with soap, water and alcohol. If the veins are visible, iodine is to be used. A tourniquet is applied to the arms, causing moderate distention of the veins. A vein in the donor is punctured with a cannula of large diameter. It is important to insert the cannula properly so that the blood runs through it rapidly in a large stream. If difficulty is encountered in the proper insertion of the canula the vein may be exposed by a small incision. The blood is collected in a large glass jar. This glass jar contains half the quantity of sodium citrate needed for the transfusion. In other words, if 500 c.c. of citrated blood are needed we pour 25 c.c. of citrate in the large glass jar and add the residual 25 c.c. after we have collected 250 c.c. of blood. The blood is gently stirred with a glass rod to insure its proper mixture with the coagulant. After the collection of the required blood volume, cannula and tourniquet are removed and the wound is sealed. The recipient's vein is then usually ex- posed by a small incision. The cannula of smaller caliber is introduced, the salvarsan flask attached to the cannula, and the citrated blood poured into the glass flask. As a rule, 50 c.c. of salt solution are run through the tubing in order to prevent air bubbles from get-
104 PHARMACOLOGY AND THERAPEUTICS.
ting into the circulation of the recipient. The technical steps for the injection are exactly the same as those for an intravenous infusion of salt solution.
The experiments which Lewisohn published in 1915 showed that a very minute dose of sodium citrate (0.2 per cent.) is sufficient to prevent coagulation of blood for two days. Furthermore, these experiments showed the absolute atoxicity of such citrated blood for the human organism, even when large amounts of blood (for instance 1,500 ml.) are required as in cases of profuse hemorrhages. The coagulation time of the recipient's blood is temporarily shortened.
Analysis of One Hundred Transfusions. A. L. Gar- bat* publishes a study of one hundred cases of trans- fusions on sixty-eight patients. He adds to the ad- vantages of the method given above, that citrated blood keeps well for days or even weeks.
Technique: The blood was usually collected into two large measuring beakers, each one holding 600 ml. or more. The blood was then filtered through several lay- ers of gauze directly into an infusion flask or arsphena- min apparatus and allowed to run into the vein of the patient. Several technical points are of importance.
Agglutination and hemolysis tests must be done as a preliminary step to all transfusions. In no instance should an incompatible blood be employed.
^^A large caliber cannula is used to get the blood from the donor so that the required quantity of blood is ob- tained in as short a time as possible.
**A large cannula is also used for the recipient with the same object in view. Naturally, there are limita- tions to this rate, depending on the particular illness or condition of the patient; for example, cardiac or pul- monary disturbances demand a slower current of blood, etc.
* * The blood should be kept at body temperature while it is outside of the body and kept outside of the body as short a time as possible. This can be assured by trans- ferring the blood from the receptacles in which it was collected into Erlenmeyer flasks or bottles, and these
(4) Jour. Amer. Med. Ass'n., Jan. 4, 1919.
PHARMACOLOGY AND THERAPEUTICS. 105
can be placed into a basin of warm water. Lewisohn has recently advised the use of vacuum bottles.
^'Although it is absolutely essential to keep stirring the blood and citrate solution so as to mix them thor- oughly and thus prevent coagulation, it is equally im- portant not to stir too vigorously in fear of the possible physical destruction to the various blood constituents.
^^The sodium citrate must be chemically pure and the water in which it is dissolved freshly distilled."
In the author's series of one hundred transfusions, 42 per cent, of the patients showed a definite reaction consisting of chilly sensations or chills, and fever; and, in the severest types, vomiting.
In the 42 per cent, there was a rise of temperature up to 103° to 105° F. in eight; there was a rise of tem- perature up to 102° to 103° F. in 19 ; there was a rise of temperature up to 101° to 102° F. in 15.
Many of these temperatures remained elevated only for a number of hours and came down rapidly by a form of crisis; in the others, the fever came down by lysis, and three or four days were required until the normal point was reached.
The chill usually comes on about one-half to three- quarters of an hour after the transfusion. If the blood flows in too slowly, as warned against above, this chill may come on during the time that the transfusion is being given, and this naturally is very disagreeable. These chills last from five minutes to a half hour. In contrast to malaria, subsequent perspiration is absent or only slight. In spite of the apparent severity, no harm- ful results either to the physical condition of the pa- tient or to the value of the transfusion could ever be directly attributed even to such a reaction. Rise of temperature usually follows the chill and will persist for several hours; normal temperature may not be reached for three of four days.
While the percentage of reactions after the sodium citrate transfusions is undoubtedly higher, and possi- bly the reactions are severer than with the other meth- ods of transfusion, they are at no time harmful in any
106 PHARMACOLOGY AND THERAPEUTICS.
way, and therefore should not influence one to select another method.
The one accident to be considered in sodium citrate mixtures of blood, aside from the accidents of trans- fusions in general, is the possibility of clotting. This is due to one of two causes : first, that the sodium citrate and blood were not thoroughly mixed; secondly, that a 0.2 per cent, mixture of sodium citrate and blood, that is, 50 ml. of a 2 per cent, solution of sodium citrate to 450 ml. of blood, was not sufficient for some donors, espe- cially for donors who had already been used for trans- fusions. Both of these errors can be overcome, the first by stirring the blood and sodium citrate constantly, thoroughly, but gently; and the second by employing a 0.25 per cent, mixture, that is, 50 ml. of a 2.5 or even 3 per cent, solution of sodium citrate to 450 ml. of blood. To be even more certain that no minute clots slip through, the blood is filtered (through several lay- ers of gauze) into the infusion apparatus.
Transfusion of Unmodified Blood. One of the dif- ferences between unmodified and citrated blood is the more frequent occurrence of reactions with the latter method. Drinker and Brittingham^ state that, after citrate transfusions, febrile reactions occur in 60 per cent, of cases and a chill in 57 per cent. In L. J. lin- ger's® series, of unmodified blood transfusions, febrile reactions have occurred in about 10 per cent, and a chill in about 3 per cent.
There is no practical method for citration of the large quantities of blood needed for transfusion which cer- tainly prevents the early changes of coagulation. These coagulative changes are associated with the platelets which become abnormal as soon as they leave the vessel.
Drinker and Brittingham have also shown that *Hhe mere addition of a dose of sodium citrate'' to red cells induces slight abnormality, as evidenced by an in- creased fragility and an increased tendency to hemolyze. This means that the corpuscles are damaged by sodium citrate, which is particularly disadvantageous, when
(5) Arch. Int. Med., February, 1919.
(6) Jour. Amer. Med. Ass'n., Sept. 13, 1919.
PHARMACOLOGY AND THERAPEUTICS. 107
transfusion is performed in hemolytic diseases. In such case, transfusion of unmodified blood should be the pro- cedure of choice. It must be admitted, however, that the technique for giving citrated blood is simple and, therefore, that in cases of hemorrhage, citrated blood may serve as a substitute.
[When it is desired to provoke febrile reaction (see ''Pyretotherapy"), then citrated blood would obviously be superior. — Ed.]
linger gives the following data regarding dosage: A donor can safely supply one quarter of his blood volume. For infants, the usual dose should be from 80 to 150 ml. For adults, from 800 to 1,000 ml. Over- transfusion from the donor's standpoint is evidenced by an increase of pulse and respiratory rates, repeated yawning or deep sighing. Changes in the rhythm of respiration may occur before a change of the pulse rate. If these symptoms appear, the transfusion should be discontinued. As regards the patient, hypertransfusion is more serious. This may lead him to complain of pre- cordial distress, headache, backache, or pain in his legs. A more important sign, however, is a short, sharp cough. If the transfusion is continued, the cough will be re- peated. The cough, when it does appear, occurs irre- spective of the rate at which the blood was transfused. One should not transfuse more than 200 ml. after the first cough. In only one case has this sign been dis- regarded. In this instance, 500 ml. were transfused after the first cough. This was the only case in Unger's series in which transfusion was complicated by hyper- transfusion; pulmonary edema developed and the patient died.
Methods of Unger and Lindeman. The following two methods of transfusion of unmodified blood are of interest: Unger's and Lindeman 's. The former requires a special apparatus, the latter does not. Unger believes that anyone seeing the two methods usedi side by side would come to prefer his.
Unger's^ method utilizes the instrument described in the accompanying illustrations (Figs. 8, 9, 10). ''The
(7) Jour. Amer. Med. Ass'n., Dec. 29, 1917.
108 PHARMACOLOGY AND THERAPEUTICS.
mechanical principle involved is the establishment of two channels by means of which a record syringe is auto- matically connected alternately with a vein of the donor and then with one of the recipient. At the same time that the record syringe is connected with the donor for the aspiration of blood, a syringe with saline solution is connected with the recipient, and vice versa (or better,
Xi.-©
Fig-. 8. Instrument for syring-e transfusion: D, recipient's cannula; R, donor's cannula; B, record syringe for aspirating and injecting blood; S, saline syringe. At any one moment, saline solution is forced through that cannula through which blood is not passing". This automatic shunting is accomplished by the stopcock.
permitted to flow by gravity method. In this way only one record syringe is required.) It is this immediate and continued flushing with salt solution of the channel through which blood is not passing that insures freedom from clotting.''
^'The technique is as follows: Alongside the instru- ment, which has been fi:xed to a table, the arms of the patient and the donor are placed. The tubes leading from the instrument are connected to the cannulas after the latter have been inserted through the skin into the recipient's and the donor's veins. A record syringe is then inserted into the instrument, and blood is aspirated. When the syringe is filled, the stopcock is turned and the blood is injected. A continuous stream of saline solution is forced in a direction opposite to the flow of blood. This procedure is continued until the desired amount is transfused. By means of a spray, a stream of ether is played on the barrel of the record syringe
PHARMACOLOGY AND THERAPEUTICS.
109
while it is being filled with and emptied of blood in or- der to prevent clotting.''
Edward Lindeman^ describes his syringe-cannula sys- tem as follows :
D -
r H
Fig-. 9. Donor's position: D, donor's outlet; B, blood out- let; BYR, blood syringe. Blood passes from donor's vein through D, and out at B into SYR. S, saline outlet; R, re- cipient's outlet. Saline solu- tion is forced from saline syringe through S, out at R, into recipient's vein. C S, central stopper (rotates through an arc of 90 degrees).
Fig. 10. Recipient's posi- tion; SYR, blood syringe; B, blood outlet; R, recipient's outlet. Blood is forced out of SYR through B, out at R, into recipient's vein. S, saline out- let; D, donor's outlet. Saline solution is forced from saline syringe through S out at D into donor's vein. C S, cen- tral stopper.
Two sets of cannulas are employed, one for the donor, the other for the recipient (Figs. 11-12).
There are three cannulas to each set (Figr. 12 — 1, 2 and 3). Each cannula telescopes within the other as shown in Figure 1.
The innermost cannula is practically a hollow needle,
(8) Jour. Amer. Med. Ass'n., June 7, 1919.
110 PHARMACOLOGY AND THERAPEUTICS.
2 6/16 inches long, 30-gauge, with one end ground to a fine point and short bevel. The hollow needle (Fig. 15 — 1) is fitted snugly into Cannula 2. Cannula 2 is 5
JL-A.
Fig-. 11. A, distal end of cannula 2; B, distal end of cannula 3.
mm. shorter than the needle and is fitted snugly into Cannula 3. Cannula 3 is 5 mm. shorter than Cannula 2. The proximal ends of Cannulas 1 and 2 are capped with stationary thumbscrew caps. The proximal end of Cannula 3 is capped with a receiver to fit any record syringe.
Fig-. 12. 1, innermost cannula, or hollow needle; 2, middle cannula; 3, outer cannula.
Cannula 3 is 2 inches long, 14 gauge, 0.064 diameter. The caliber of this cannula is the same as the tip of a record syringe.
In very small infants with very small veins only Cannulas 1 and 2 are employed. Cannula 2 being capped with the receiver to fit the tip of the syringe.
The syringes can be sterilized in 95 per cent, alcohol for a period of ten minutes and then rinsed in physi- ologic sodium chloride solution to remove the alcohol.
Operation: The patient and the donor are placed in recumbent posture in parallel position. The skin of the arms is sterilized. A small table is set between the patient and the donor. On this table are placed three basins containing sterile physiologic sodium chloride solution, at approximately room temperature, for the washing of syringes. A nurse stands behind the table and
PHARMACOLOGY AND THERAPEUTICS. m
washes the syringes by rinsing each syringe in each one of the three basins. As long as the last rinsing basin con- tains sterile normal salt solution, the other two may contain sterile tap or distilled water or salt solution. A syringe is never used a second time until washed in these basins, hence no old or residual blood is allowed to enter the patient. These syringes are washed as rapidly as they are used. The third rinsing basin should remain clear throughout the operation.
One operator manages the syringe of the donor, the other operator that of the recipient. A tourniquet is placed on the arm of the patient to distend the vein. A cannula is then inserted into the vein by a skin punc- ture only.
Insertion of Cannula: When the needle has entered the vein a drop of blood is seen to trickle from the distal end of the innermost cannula. After the first joint A has entered the vein. Cannula 1 is withdrawn about one- half inch, thus preventing the vessel wall from being punctured or injured by the needle after the vein is entered.
With the thumb now on the screw-cap of Cannula 2, the cannula is forced further until joint B has entered the vein, Cannula 3 alone now coming in contact with the vessel wall. The latter is then gently pushed into the vein to a desirable length, usually from three-quar- ters to one inch. The tourniquet is then removed.
A cannula is then inserted into the vein of the donor in a similar manner. The tourniquet is placed on the arm sufficiently tight to obstruct the venous return, but not tight enough to impede the arterial flow, and re- mains on the arm of the donor throughout the operation. Everything is now in readiness for transfusion. There is no need of haste at this stage.
The obturator in the cannula of the donor is removed and an empty syringe is promptly attached and blood IS withdrawn as rapidly as possible. When the syringe is filled, the assistant replaces it by an empty syringe, at the same time placing the filled syringe on the table. The operator places his thumb over the mouth of the cannula to prevent leakage during change in syringes.
112 PHARMACOLOGY AND THERAPEUTICS.
The operator on the recipient picks up the filled syringe, attaches it to the cannula after removing the obturator, and evacuates the contents gently but speed- ily into the vein. As soon as the contents are evacuated a full syringe is again ready for evacuation. One syringeful of blood follows another in rapid succession until the desired quantity of blood has been transfused.
Small syringes of 20 ml. capacity are found most sat- isfactory. Larger sizes are not used because it requires a longer time to fill and empty them. The time elapsing for the filling and emptying of one syringe is from six to ten seconds. It is practically impossible for any chemical or physical change to take place in that short space of time. Since the blood is transplanted in relay fashion, the entire mass of blood, regardless of the amount, is outside the body only so long as its