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The Management of Asthma
The Management of Asthma FRANCIS M. RACKEMANN, M.D.*
THE gaps in our knowledge of asthma are still large. The first, and most important, concerns the background of the disease. How and why does asthma develop in the first place? Why do certain individuals become "allergic"? Until there is knowledge of the chemical and physiologic changes which can occur in susceptible patients, and which do not occur in normal persons, treatment of asthma, and eczema too, will be largely symptomatic and therefore unsatisfactory. THE SHORTCOMINGS IN ETIOLOGIC DIAGNOSIS
In young people the exciting cause may be simple and well defined. As soon as the patient and his family learn of the clinical sensitiveness to the cat, for example, the symptoms will clear and the patient will be well as long as further contact with the offending substance in dust-or sometimes food-is avoided. Unfortunately such simple cases are the exception. Mixed causes-allergic, infectious and psychogenic-are present together in almost every case, and unless each one of these factors is considered the results will not be satisfactory. In a number of cases with positive skin tests, the patient shows no evidence of a clinical sensitiveness until a "stress" of some kind is experienced. New colds can lower the threshold to make a slight degree of allergy become effective, and the patient will wheeze. The concept is demonstrated by the subsequent history: when the kapok pillows, for example, are found and removed, then the new cold is no longer accompanied by asthma. Physical stress-exposure to cold, undue exertion, or just plain fatigue-can result in asthma, and psychogenic stress can cause asthma, but only in those patients who have the background for asthma. Certain children appear able to produce an attack of asthma in order to escape a distasteful task, and we suspect that adults can do the same. If this is true, the mechanism presents a very interesting and important problem in itself. In another group of cases the skin tests are quite negative, and one assumes that the patient has a "bacterial allergy," but this is not easy to prove. The improved prognosis in this group (the attacks subi"ide at
* Member, Board of Consultation, Maswchusetts General Hospital; Former Lecturer in Medicine, Harvard Medical School, Boston. 1305
1306
Francis M. Rackemann
an earlier age) suggests a mechanism different from that of simple allergy-one that depends upon the nature of the offending agent. Bacteria are good antigens: they produce antibodies and immunity. They are, however, poor allergens in that positive skin tests are difficult, though not impossible, to obtain. Animal danders are both antigenic and allergenic, while extracts of pollens produce immunity rarely but positive skin tests easily: they are allergenic primarily. Skin tests are not the answer to the asthma problem or to the treatment of the particular patient. Again, and always, one must emphasize the necessity for a good history, with its orderly chronological account of the whole disease and with the dates and ages for each event or change in symptoms recorded. A good history has seven parts, and each of the seven must be covered. The Present Illness takes most of the time and most of the paper, but then comes the General Health or the System Survey, to be correlated later with a careful physical examination to find what other troubles are present besides asthma. Some of them might be connected with the cause of the asthma. The Past History and Family History come next, and the fifth is the Residence. What sort of place is it? Who else lives there? Who sleeps in the same room? Are there animals? What about the furniture and the bedding? The sixth step in taking a history is to inquire of the Occupation, since the details might be important. The patient works in a bakery, but he does not mix flour-he drives a delivery truck; or, vice versa, he is technically a truck driver, but he helps to load bags of flour in a bakery storeroom. Sources of dust in the home, including hobbies, can be important. Finally, the patient is questioned on Previous Treatment, for what has been prescribed before without success need not be repeated unless the early technique of dosage was unsatisfactory. TREATMENT OF THE ACUTE ATTACK
In considering treatment, the doctor asks himself two questions: The first is: What shall I do now-tonight-to relieve the bronchial obstruction? All too often the interest in the cause and nature of the asthma overshadows the immediate practical requirements. The nebulizer charged with a bronchodilating aerosol, like epinephrine 1 :100 or Isupre11 :200, may be a godsend. Pills containing ephedrine 25 mg., often combined with aminophylline or theophylline 100 to 150 mg., may be good, but if the patient needs "shots" of epinephrine 1 :1000, he should have them: his mother or his wife can learn easily to boil the needle and syringe and inject the dose under the skin. The dose need not produce pallor and jitters if the quantity is small, 0.20 to 0.40 cc. at the start, increasing later if no relief occurs, and the dose can be repeated in 30 minutes if necessary. But not over four or five injections should be given in 24 hours. If epinephrine is not effective, then the patient needs to have aminophylline injected intravenously. The dose of 0.25 gram comes dis-
The Management of Asthma
1307
solved in normal saline in ampules containing 10 cc. It is important to give the injection slowly, taking at least three minutes for it. Severe asthma, called status asthmaticus, must be treated in a hospital, partly because of the clean environment but more because good nursing care is so necessary. As soon as such a patient arrives in the hospital an intravenous drip of 100 cc. of 5 per cent dextrose in normal saline (the extra sodium will do good and not harm) should be started, and to the flask can be added 1 cc. of 1 :100 epinephrine (Adrenal in) or an ampule of aminophylline 0.25 gram, or sometimes both. ACTH and cortisone should not be used in the early treatment of a new case-at least until it is seen what more simple and less harmful treatment will accomplish in the first 24 hours. The majority of new patients admitted with asthma to the Massachusetts General Hospital are better on the second or third day, so that it is not necessary to submit them to the risks and dangers of the steroid hormones. When old, wellknown patients enter in status, then the steroids may be given at oncepreferably in a long, slow-running intravenous drip. Antibiotics should not be used in the acute attack-except very occasionally-for two reasons. Asthma is a slow, recurrent, chronic disorder. Antibiotics are likely to make the causative organism nonsensitive, so that further doses of antibiotics will have no effect. Secondly, patients with allergic disease have the capacity to develop sensitiveness and are likely to react to the antibiotic itself, so that it cannot be used again with any real safety. LONG-TERM MANAGEMENT
The second question which the doctor asks himself is: What causes the asthma and how can I prevent further attacks? The answer depends upon a study of the history: the age at onset, the present age, the course, whether in attacks or persistent, and whether there is relation to changes in season or environment. The whole patient must be studied and treated. Psychogenic as well as allergic and infectious causes must all be considered, and mixed causes are the rule. The problem in children is quite different from that in adults. In our study of 688 children with asthma, followed up after an interval of 20 years, Mrs. Edwards and P found that a total of 71.4 per cent were relieved of their early asthma chiefly by elimination of the offending agent. After 20 years only 10.9 per cent of all the patients were having any real trouble. Changes in environment are always important to children with asthma. To send the child to a new climate, like Arizona, has been helpful in one or two instances, but when the allergic nature of the disease was recognized, one could look back and find that the good result was due not to any positive effect of the new environment but to the negative
1308
Francis M. Rackemann
effect of escaping from the dust which had been causing trouble at home. The elimination of the dog or cat or a change to a sponge rubber mattress and pillow might have been all that was necessary. The idea can be tested by admitting the patient for a few days to the dean environment of the hospital. When the source of trouble and the patient cannot be separated, then desensitization can be attempted and may be helpful. The technique is difficult because of the wide variation in the degree of sensitiveness. In describing the "tolerance level" in the treatment of hay fever, 12 showed that among different patients differences of 100 fold in the level are found, and I implied that doses to be effective must be regulated in close accordance with the individual tolerance. "Average doses" are much too large for some and much too small for other patients. General systemic reactions occur when the tolerance is exceeded, and so the treatment is not without some danger. Vaccines have been helpful in asthma of various types, both in children and in adults. When the history shows a series of respiratory infections, the patient is considered to have a "low resistance" and vaccines are used to stimulate immunity. Not infrequently they are effective in preventing new colds. Since, however, stock vaccines are quite as effective as autogenous vaccines, and since the result is good only in case the doses produce a redness and swelling at the injection site, it becomes clear that the effect is nonspecific. Observation suggests that vaccines have another effect which is different from, or in addition to, the stimulation of immunity. This interesting problem is under study. Our technique is to inject under the skin in separate places small doses of two, or sometimes three, different stock vaccines, and then to give further treatment with the one or two which have produced the largest areas of local redness and swelling on the next day. If no reaction follows, then different vaccines are tried. Injections are given from three days to three weeks apart, depending on the patient's progress, and the amounts are so regulated as to produce each time a redness and swelling about the size of a 25 cent piece. So far I have no figures to show the results of vaccine treatment-only the impression that they are good. Swineford3 also uses vaccines. Of his 1700 eases, one-third were "cured" and another third were improved by "bacterial antigens." Stevens4 tested his patients repeatedly with "bacterial nucleoproteins" and found that the sensitivities varied from time to time. The results of his treatment were not startling, perhaps because nothing was said about the local reactions which followed his doses. One result of vaccine therapy easy to overlook is that the need for doses brings the patient to the doctor at frequent intervals, so that problems of many kinds can be discussed and dealt with together. The care of the whole patient is essential. Since 1950, ACTH and cortisone have been used more and more in
The Management of Asthma
1309
the treatment of the chronic reversible diseases-in asthma and eczema as well as in arthritis. They are capable of producing serious side effects, however, and are not to be used in asthma as "the first line of defense." They are to be reserved until the simple and harmless drugs-ephedrine, epinephrine and aminophylline-have been tried properly and found wanting. When, however, the disease gets "out of hand," then the risk of side effects is overshadowed by the benefit, which is usually remarkable and may be life-saving. A choice must be made between ACTH or cortisone, and it iH confusing to find that their therapeutic effects and their side effects are quite the same. In the original papers of Hench, Kendall, Slocumb and Polley,· and in Thorn's6 papers, the word cortisone is often coupled with the phrase "and ACTH." Does this mean that the stimulation of the adrenal cortex releases only cortisone, or that the other adrenocortical hormones are inert so far as the group of chronic reversible diseases is concerned? Or is it possible that ACTH is not only a stimulator of the adrenal cortex but has a direct action of its own; that it contains a steroid hormone? We do not know for certain. I find only one good report in which the effects of ACTH and of cortisone are compared directly. Bickerman and Barach 7 found that ACTH relieved the symptoms, in whole or in part, in 82.3 per cent of 130 courses of treatment given to 67 patients with asthma and emphysema; that cortisone brought relief in 86.2 per cent of 123 courses of treatment given to 61 patients; and that hydrocortisone relieved the symptoms in 95 per cent of 56 courses of treatment given to 35 patients. It is remarkable that the end results with each preparation should be so closely similar. In theory, excessive doses of ACTH can exhaust the adrenal cortices; and vice versa, excessive cortisone can inhibit the pituitary and at the same time can suppress the activity of the adrenals. The last effect explains the circulatory collapse which can follow the sudden withdrawal of steroid treatment. All authors agree that at the start of treatment large doses should be used and continued for two to four days until the asthma or the eczema is improved. One international unit of ACTH is the activity of 1 mg. of Sayer's6 preparation, which he called La-I-A, the activity being measured by the reduction of the ascorbic acid content of the rat's adrenal gland. For an adult man, the first dose is 20 to 50 units given intramuscularly or 10 or 30 units given intravenously by slow drip in 500 to 1000 ml. of physiologic saline solution. The latter method is much more effective. Most patients in status asthmaticus will improve after this dose, and then the quantity can be reduced over the course of four or five days to a maintenance dose of from 5 to 20 units per day. ACTH must be given parenterally by needle. Cortisone and hydrocortisone are absorbed by mouth, which of course
Francis M. Rackemann
1310
makes them easy to use. The quantity given in the first day or two varies from 100 to 300 mg., to be divided into four or six doses, but, as with ACTH, the amount is soon reduced to a maintenance level of between 10 and 60 mg. (Yz to 3 pills) a day. The difficulty with both ACTH and cortisone is that when the drugs are withdrawn symptoms return within two or three days: once started, it is hard to stop the treatment. Quite often, however, one can reduce the daily ration by small amounts every three or four days, and so release the patient from his bondage. Two new preparations have recently been introduced-Meticorten (prednisone), an analogue of cortisone, and Metieortelone (prednisolone), an analogue of hydrocortisone. They have two advantages: first, the dose is small-the new pill containing 5 mg. has the same therapeutic effect as the older pill containing 20 mg. of hydrocortisone-and second, the side effects are said to be less frequent. The first reports support these claims. My own experience so far is that when the quantities are so regulated as to give enough to relieve symptoms but never more than enough of the drug, the total effect, both good and bad, is not very diHerent from that of hydrocortisone. An editorialS in the New England Journal of Medicine for November 24, 1955, has a pertinent comment on a report of the British Medical Research Council and the Nuffield Foundation in which 61 patients with chronic rheumatic disease were treated, 30 with cortisone and 31 with aspirin. The results in the two series were closely parallel in nearly all respects. The comment reads: "The enthusiasm for the use of adrenal hormones in many other conditions in which they are given for indications other than replacement therapy must be treated with similar and even greater skepticism, for in most of those conditions controlled data are notably lacking." In summary, one must recognize that while ACTH and cortisone are very useful, they cannot replace the more simple and less dangerous drugs. The exciting causes of asthma are simple in only a few cases. They are mixed-allergic, infectious and psychogenic- in the great majority, and success in treatment will depend upon the study and the care of the patient as a whole person. Meantime, the real problem concerns the background of asthma: the reason why some individuals and not others are subject to attacks. REFERENCES 1. Rackemann, F. M. and Edwards, M. C.: Asthma in Children. A Follow-up Study of 688 Patients After an Interval of Twenty Years. New England J. Med. 246: 815-823 and 858-863, 1952. 2. Rackemann, F. M.: Pollen Tolerance. Its Bearing on Treatment of Hay Fever. J. Allergy. 18: 164, 1947. 3. Swineford, 0.: Observations on Use of Bacterial Antigens in Treatment of Asthma: A Brief Critical Review. Am. Practitioner & Digest of Treatment 1: 612, 1950. 4. Stevens, F. A.: Acute Asthmatic Episodes in Children Caused by Upper Res-
The Management of Asthma 5.
6.
7. 8.
1311
piratory Bacteria During Colds, with and without Bacterial Sensitization. J. Allergy 24: 221, 1953. Bench, P. S., Kendall, E. C., Slocumb, C. H. and Polley, H. F.: Effect of a Hormone of the Adrenal Cortex, Cortisone (l7-Hydroxy-ll-Dehydrocorticosterone: Compound E), and of Pituitary Adrenocorticotropic Hormone on Rheumatoid Arthritis and Acute Rheumatic Fevl'L Tr. A. Am. Physicians 62: 64, 1!J49; Proc. Staff Meet., Mayo Clin. 24: 181, 1949. Thorn, G. W. and others: Pharmacologic Aspects of Adrenocortical Steroids and ACTH in Man. New England J. Med. 248: 2.-32-245, 284-294, 323-337 and 369-378 (Feb. 5, 12, 19 and 26), 414-423 (Marc~h 5), 588-601 and 632-646 (April 2 and 9), 1953. Bickerman, H. A. and Barach, A. L.: Comparative Results of Use of ACTH, Cortisone and Hydrocortisone in Treatment of Intradable Bronchial Asthma and Pulmonary Emphysema ..r. Allergy 25: 312, 1954. Cortisone Versus Aspirin in Early Rheumatoid Arthritis. Editorial. New England J. Med. 25.'3: 935, 1955.
266 Beacon Street Boston 16, Massachusetts
THE gaps in our knowledge of asthma are still large. The first, and most important, concerns the background of the disease. How and why does asthma develop in the first place? Why do certain individuals become "allergic"? Until there is knowledge of the chemical and physiologic changes which can occur in susceptible patients, and which do not occur in normal persons, treatment of asthma, and eczema too, will be largely symptomatic and therefore unsatisfactory. THE SHORTCOMINGS IN ETIOLOGIC DIAGNOSIS
In young people the exciting cause may be simple and well defined. As soon as the patient and his family learn of the clinical sensitiveness to the cat, for example, the symptoms will clear and the patient will be well as long as further contact with the offending substance in dust-or sometimes food-is avoided. Unfortunately such simple cases are the exception. Mixed causes-allergic, infectious and psychogenic-are present together in almost every case, and unless each one of these factors is considered the results will not be satisfactory. In a number of cases with positive skin tests, the patient shows no evidence of a clinical sensitiveness until a "stress" of some kind is experienced. New colds can lower the threshold to make a slight degree of allergy become effective, and the patient will wheeze. The concept is demonstrated by the subsequent history: when the kapok pillows, for example, are found and removed, then the new cold is no longer accompanied by asthma. Physical stress-exposure to cold, undue exertion, or just plain fatigue-can result in asthma, and psychogenic stress can cause asthma, but only in those patients who have the background for asthma. Certain children appear able to produce an attack of asthma in order to escape a distasteful task, and we suspect that adults can do the same. If this is true, the mechanism presents a very interesting and important problem in itself. In another group of cases the skin tests are quite negative, and one assumes that the patient has a "bacterial allergy," but this is not easy to prove. The improved prognosis in this group (the attacks subi"ide at
* Member, Board of Consultation, Maswchusetts General Hospital; Former Lecturer in Medicine, Harvard Medical School, Boston. 1305
1306
Francis M. Rackemann
an earlier age) suggests a mechanism different from that of simple allergy-one that depends upon the nature of the offending agent. Bacteria are good antigens: they produce antibodies and immunity. They are, however, poor allergens in that positive skin tests are difficult, though not impossible, to obtain. Animal danders are both antigenic and allergenic, while extracts of pollens produce immunity rarely but positive skin tests easily: they are allergenic primarily. Skin tests are not the answer to the asthma problem or to the treatment of the particular patient. Again, and always, one must emphasize the necessity for a good history, with its orderly chronological account of the whole disease and with the dates and ages for each event or change in symptoms recorded. A good history has seven parts, and each of the seven must be covered. The Present Illness takes most of the time and most of the paper, but then comes the General Health or the System Survey, to be correlated later with a careful physical examination to find what other troubles are present besides asthma. Some of them might be connected with the cause of the asthma. The Past History and Family History come next, and the fifth is the Residence. What sort of place is it? Who else lives there? Who sleeps in the same room? Are there animals? What about the furniture and the bedding? The sixth step in taking a history is to inquire of the Occupation, since the details might be important. The patient works in a bakery, but he does not mix flour-he drives a delivery truck; or, vice versa, he is technically a truck driver, but he helps to load bags of flour in a bakery storeroom. Sources of dust in the home, including hobbies, can be important. Finally, the patient is questioned on Previous Treatment, for what has been prescribed before without success need not be repeated unless the early technique of dosage was unsatisfactory. TREATMENT OF THE ACUTE ATTACK
In considering treatment, the doctor asks himself two questions: The first is: What shall I do now-tonight-to relieve the bronchial obstruction? All too often the interest in the cause and nature of the asthma overshadows the immediate practical requirements. The nebulizer charged with a bronchodilating aerosol, like epinephrine 1 :100 or Isupre11 :200, may be a godsend. Pills containing ephedrine 25 mg., often combined with aminophylline or theophylline 100 to 150 mg., may be good, but if the patient needs "shots" of epinephrine 1 :1000, he should have them: his mother or his wife can learn easily to boil the needle and syringe and inject the dose under the skin. The dose need not produce pallor and jitters if the quantity is small, 0.20 to 0.40 cc. at the start, increasing later if no relief occurs, and the dose can be repeated in 30 minutes if necessary. But not over four or five injections should be given in 24 hours. If epinephrine is not effective, then the patient needs to have aminophylline injected intravenously. The dose of 0.25 gram comes dis-
The Management of Asthma
1307
solved in normal saline in ampules containing 10 cc. It is important to give the injection slowly, taking at least three minutes for it. Severe asthma, called status asthmaticus, must be treated in a hospital, partly because of the clean environment but more because good nursing care is so necessary. As soon as such a patient arrives in the hospital an intravenous drip of 100 cc. of 5 per cent dextrose in normal saline (the extra sodium will do good and not harm) should be started, and to the flask can be added 1 cc. of 1 :100 epinephrine (Adrenal in) or an ampule of aminophylline 0.25 gram, or sometimes both. ACTH and cortisone should not be used in the early treatment of a new case-at least until it is seen what more simple and less harmful treatment will accomplish in the first 24 hours. The majority of new patients admitted with asthma to the Massachusetts General Hospital are better on the second or third day, so that it is not necessary to submit them to the risks and dangers of the steroid hormones. When old, wellknown patients enter in status, then the steroids may be given at oncepreferably in a long, slow-running intravenous drip. Antibiotics should not be used in the acute attack-except very occasionally-for two reasons. Asthma is a slow, recurrent, chronic disorder. Antibiotics are likely to make the causative organism nonsensitive, so that further doses of antibiotics will have no effect. Secondly, patients with allergic disease have the capacity to develop sensitiveness and are likely to react to the antibiotic itself, so that it cannot be used again with any real safety. LONG-TERM MANAGEMENT
The second question which the doctor asks himself is: What causes the asthma and how can I prevent further attacks? The answer depends upon a study of the history: the age at onset, the present age, the course, whether in attacks or persistent, and whether there is relation to changes in season or environment. The whole patient must be studied and treated. Psychogenic as well as allergic and infectious causes must all be considered, and mixed causes are the rule. The problem in children is quite different from that in adults. In our study of 688 children with asthma, followed up after an interval of 20 years, Mrs. Edwards and P found that a total of 71.4 per cent were relieved of their early asthma chiefly by elimination of the offending agent. After 20 years only 10.9 per cent of all the patients were having any real trouble. Changes in environment are always important to children with asthma. To send the child to a new climate, like Arizona, has been helpful in one or two instances, but when the allergic nature of the disease was recognized, one could look back and find that the good result was due not to any positive effect of the new environment but to the negative
1308
Francis M. Rackemann
effect of escaping from the dust which had been causing trouble at home. The elimination of the dog or cat or a change to a sponge rubber mattress and pillow might have been all that was necessary. The idea can be tested by admitting the patient for a few days to the dean environment of the hospital. When the source of trouble and the patient cannot be separated, then desensitization can be attempted and may be helpful. The technique is difficult because of the wide variation in the degree of sensitiveness. In describing the "tolerance level" in the treatment of hay fever, 12 showed that among different patients differences of 100 fold in the level are found, and I implied that doses to be effective must be regulated in close accordance with the individual tolerance. "Average doses" are much too large for some and much too small for other patients. General systemic reactions occur when the tolerance is exceeded, and so the treatment is not without some danger. Vaccines have been helpful in asthma of various types, both in children and in adults. When the history shows a series of respiratory infections, the patient is considered to have a "low resistance" and vaccines are used to stimulate immunity. Not infrequently they are effective in preventing new colds. Since, however, stock vaccines are quite as effective as autogenous vaccines, and since the result is good only in case the doses produce a redness and swelling at the injection site, it becomes clear that the effect is nonspecific. Observation suggests that vaccines have another effect which is different from, or in addition to, the stimulation of immunity. This interesting problem is under study. Our technique is to inject under the skin in separate places small doses of two, or sometimes three, different stock vaccines, and then to give further treatment with the one or two which have produced the largest areas of local redness and swelling on the next day. If no reaction follows, then different vaccines are tried. Injections are given from three days to three weeks apart, depending on the patient's progress, and the amounts are so regulated as to produce each time a redness and swelling about the size of a 25 cent piece. So far I have no figures to show the results of vaccine treatment-only the impression that they are good. Swineford3 also uses vaccines. Of his 1700 eases, one-third were "cured" and another third were improved by "bacterial antigens." Stevens4 tested his patients repeatedly with "bacterial nucleoproteins" and found that the sensitivities varied from time to time. The results of his treatment were not startling, perhaps because nothing was said about the local reactions which followed his doses. One result of vaccine therapy easy to overlook is that the need for doses brings the patient to the doctor at frequent intervals, so that problems of many kinds can be discussed and dealt with together. The care of the whole patient is essential. Since 1950, ACTH and cortisone have been used more and more in
The Management of Asthma
1309
the treatment of the chronic reversible diseases-in asthma and eczema as well as in arthritis. They are capable of producing serious side effects, however, and are not to be used in asthma as "the first line of defense." They are to be reserved until the simple and harmless drugs-ephedrine, epinephrine and aminophylline-have been tried properly and found wanting. When, however, the disease gets "out of hand," then the risk of side effects is overshadowed by the benefit, which is usually remarkable and may be life-saving. A choice must be made between ACTH or cortisone, and it iH confusing to find that their therapeutic effects and their side effects are quite the same. In the original papers of Hench, Kendall, Slocumb and Polley,· and in Thorn's6 papers, the word cortisone is often coupled with the phrase "and ACTH." Does this mean that the stimulation of the adrenal cortex releases only cortisone, or that the other adrenocortical hormones are inert so far as the group of chronic reversible diseases is concerned? Or is it possible that ACTH is not only a stimulator of the adrenal cortex but has a direct action of its own; that it contains a steroid hormone? We do not know for certain. I find only one good report in which the effects of ACTH and of cortisone are compared directly. Bickerman and Barach 7 found that ACTH relieved the symptoms, in whole or in part, in 82.3 per cent of 130 courses of treatment given to 67 patients with asthma and emphysema; that cortisone brought relief in 86.2 per cent of 123 courses of treatment given to 61 patients; and that hydrocortisone relieved the symptoms in 95 per cent of 56 courses of treatment given to 35 patients. It is remarkable that the end results with each preparation should be so closely similar. In theory, excessive doses of ACTH can exhaust the adrenal cortices; and vice versa, excessive cortisone can inhibit the pituitary and at the same time can suppress the activity of the adrenals. The last effect explains the circulatory collapse which can follow the sudden withdrawal of steroid treatment. All authors agree that at the start of treatment large doses should be used and continued for two to four days until the asthma or the eczema is improved. One international unit of ACTH is the activity of 1 mg. of Sayer's6 preparation, which he called La-I-A, the activity being measured by the reduction of the ascorbic acid content of the rat's adrenal gland. For an adult man, the first dose is 20 to 50 units given intramuscularly or 10 or 30 units given intravenously by slow drip in 500 to 1000 ml. of physiologic saline solution. The latter method is much more effective. Most patients in status asthmaticus will improve after this dose, and then the quantity can be reduced over the course of four or five days to a maintenance dose of from 5 to 20 units per day. ACTH must be given parenterally by needle. Cortisone and hydrocortisone are absorbed by mouth, which of course
Francis M. Rackemann
1310
makes them easy to use. The quantity given in the first day or two varies from 100 to 300 mg., to be divided into four or six doses, but, as with ACTH, the amount is soon reduced to a maintenance level of between 10 and 60 mg. (Yz to 3 pills) a day. The difficulty with both ACTH and cortisone is that when the drugs are withdrawn symptoms return within two or three days: once started, it is hard to stop the treatment. Quite often, however, one can reduce the daily ration by small amounts every three or four days, and so release the patient from his bondage. Two new preparations have recently been introduced-Meticorten (prednisone), an analogue of cortisone, and Metieortelone (prednisolone), an analogue of hydrocortisone. They have two advantages: first, the dose is small-the new pill containing 5 mg. has the same therapeutic effect as the older pill containing 20 mg. of hydrocortisone-and second, the side effects are said to be less frequent. The first reports support these claims. My own experience so far is that when the quantities are so regulated as to give enough to relieve symptoms but never more than enough of the drug, the total effect, both good and bad, is not very diHerent from that of hydrocortisone. An editorialS in the New England Journal of Medicine for November 24, 1955, has a pertinent comment on a report of the British Medical Research Council and the Nuffield Foundation in which 61 patients with chronic rheumatic disease were treated, 30 with cortisone and 31 with aspirin. The results in the two series were closely parallel in nearly all respects. The comment reads: "The enthusiasm for the use of adrenal hormones in many other conditions in which they are given for indications other than replacement therapy must be treated with similar and even greater skepticism, for in most of those conditions controlled data are notably lacking." In summary, one must recognize that while ACTH and cortisone are very useful, they cannot replace the more simple and less dangerous drugs. The exciting causes of asthma are simple in only a few cases. They are mixed-allergic, infectious and psychogenic- in the great majority, and success in treatment will depend upon the study and the care of the patient as a whole person. Meantime, the real problem concerns the background of asthma: the reason why some individuals and not others are subject to attacks. REFERENCES 1. Rackemann, F. M. and Edwards, M. C.: Asthma in Children. A Follow-up Study of 688 Patients After an Interval of Twenty Years. New England J. Med. 246: 815-823 and 858-863, 1952. 2. Rackemann, F. M.: Pollen Tolerance. Its Bearing on Treatment of Hay Fever. J. Allergy. 18: 164, 1947. 3. Swineford, 0.: Observations on Use of Bacterial Antigens in Treatment of Asthma: A Brief Critical Review. Am. Practitioner & Digest of Treatment 1: 612, 1950. 4. Stevens, F. A.: Acute Asthmatic Episodes in Children Caused by Upper Res-
The Management of Asthma 5.
6.
7. 8.
1311
piratory Bacteria During Colds, with and without Bacterial Sensitization. J. Allergy 24: 221, 1953. Bench, P. S., Kendall, E. C., Slocumb, C. H. and Polley, H. F.: Effect of a Hormone of the Adrenal Cortex, Cortisone (l7-Hydroxy-ll-Dehydrocorticosterone: Compound E), and of Pituitary Adrenocorticotropic Hormone on Rheumatoid Arthritis and Acute Rheumatic Fevl'L Tr. A. Am. Physicians 62: 64, 1!J49; Proc. Staff Meet., Mayo Clin. 24: 181, 1949. Thorn, G. W. and others: Pharmacologic Aspects of Adrenocortical Steroids and ACTH in Man. New England J. Med. 248: 2.-32-245, 284-294, 323-337 and 369-378 (Feb. 5, 12, 19 and 26), 414-423 (Marc~h 5), 588-601 and 632-646 (April 2 and 9), 1953. Bickerman, H. A. and Barach, A. L.: Comparative Results of Use of ACTH, Cortisone and Hydrocortisone in Treatment of Intradable Bronchial Asthma and Pulmonary Emphysema ..r. Allergy 25: 312, 1954. Cortisone Versus Aspirin in Early Rheumatoid Arthritis. Editorial. New England J. Med. 25.'3: 935, 1955.
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