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Common Problems in Management of Pneumonia
COMMON PROBLEMS IN MANAGEMENT OF PNEUMONIA H. CORWIN HINSHAW
THE medical literature of recent years is richly supplied with authoritative information on practical and theoretic aspects of sulfonamide treatment of pneumonia. The choice of drugs, the methods of administration and information concerning toxic manifestations of these drugs are well described in several publications which have been widely read l1-nd are extensively followed. It should be our aim, not to emphasize these well-known principles further or to suggest any important amendments to them, but rather to review some of the common problems which the attending physician must solve when utilizing sulfonamide preparations in the treatment of pneumonia. It would also be of interest to note trends of investigation which may indicate what further developments may occur. TRENDS OF
INVESTI~ATION
The therapeutic advances in treatment of pneumonia made during recent years have been unparalleled but there is no evidence that progress has ceased. It seems more probable that advances will continue at their present rapid rate toward the goal of an ideal therapeutic procedure. Preliminary reports suggest that antibiotics, such as penicillin, may represent the closest approach to an ideal therapeutic agent yet to be revealed. When the chemical composition of such preparations has been determined, the way may be opened to the synthetic production of many compounds of new chemical groups with ever-increasing advantages. A substance which will control hacterial infection rapidry and effectively without harm or inconvenience to the host would have appeared totally impracticable only a few years ago, hut today it appears well within the range of practical attainment. These chemotherapeutic agents have such a profound effect upon the hasic metabolism of bacteria of many divergent species that it seems quite possihle that eventually all types of bacterial disease may yield to this fundamental approach. Even at this time there are few important bacterial diseases not affected in greater or less Iheasure by preparations of the sulfonamide group. Drugs of the diaminodiphenylsulfone group· attack still other organisms. The development of a still different group of compounds related to penicillin may be accomplished and these compounds may deal effectively with many of the remaining types of bacterial infection. 804
COMMON PROBLEMS IN MANAGEMENT OE PNEUMONIA
805
POSITION OF CHEMOTHERAPY IN PRESENT-DAY TREATMENT
It no longer needs to be emphasized that chemotherapy is the treatment of choice for typical pneumonococcic pneumonia. An enormous literature has accumulated which presents overwhelming evidence that, when pneumonia is definitely attributable to pneumococci or is of lobar type, no delay should be permitted in instituting chemotherapy in full dosage and continued for adequate periods. This great and proper emphasis upon pneumococcic lobar pneumonia has sometimes been misinterpreted to suggest that in cases of pneumonia without pneumococci in the sputum, bronchopneumonia, postoperative pneumonia and other secondary or 'unusual types of pneumonia the patient need not receive drug treatment. However, I should agree heartily with the widely held belief that in most of the latter cases of pneumonia chemotherapy in full dosage should be given an adequate trial . for at least two to four days before one reaches any decision that the infection is not amenable to this type of treatment. Pneumonia of the so-called virus or atypical group does not respond to chemotherapy. These cases may often be recognized with fair accuracy but usually only during epidemic conditions and only by those who have had unusual experience with this group of diseases. The clinical and roentgenographic diagnosis of virus pneumonia is open to such a high degree of error that in my opinion it is rarely permissible to make such a diagnosis until after adequate trial of chemotherapy has failed to control the infection. My colleagues and I regard present-day chemotherapy as a procedure of such safety and potential efficacy that it may be employed with proper safeguard in a tentative manner in nearly all cases of pneumonia, including those which are suspected of being of nonbacterial origin. It is a fair rule to state that, when any reasonable doubt exists, a trial of chemotherapy seems to be indicated. We have repeatedly seen chemotherapy used with notable success in cases that had all of the clinical features of so-called virus pneumonia and we have also seen it fail in what appeared to be typical lobar pneumonia. The decision to institute chemotherapy does not seem to be a difficult one when pneumonia is known to exist. However, the decision to discontinue treatment when it is found ineffective is one much more difficult to make and is frequently delayed too long. Before one discontinues chemotherapy it is necessary to ascertain that truly adequate doses of the drug have been administered. The definition of adequate dosage should not depend upon the individual physician's previous experience but should be that dosage recommended in the medical literature for the particular drug, as based upon cumulative pooled experi-
806
H. CORWIN HINSHAW
ence of many physicians. It is true that some physicians have found doses much smaller than those usually recommended to be reasonably adequate for many infections and, in consequence, have evolved practices that, however adequate they may be to deal with mild infections, are inadequate to deal with more severe infections. To many physicians the determination of the concentration of sulfonamide drugs in the blood stream appears to be an unnecessary refinement for average patients who are responding properly to treatment. All will agree that the most important indication for studies of the concentration of sulfonamide compounds in the blood is in the case of the patient who is not responding to therapy in the anticipated manner. In such instances treatment should not be discontinued until the concentration of sulfonamide compounds in the blood has been determined to exclude the possibility that either inadequate absorption or inadequate dosage is responsible for the failure of the drug. Under these circumstances, parenteral administration may offer a rapid, satisfactory solution to a perplexing problem. DIAGNOSTIC PROBLEMS
Most difficult diagnostic and therapeutic problems arise during the course of epidemics of febrile respiratory diseases, such as influenza. Not only must the physician be on guard to detect complicating secondary bronchopneumonia at such times; he must also realize that cases of primary pneumonia of conventional type do occur independent of influenza epidemics. Not only primary pneumonia but other respiratory diseases, including the acute exacerbations of symptoms in such chronic diseases as tuberculosis, bronchiogenic carcinoma, pulmonary abscess and so forth, may resemble influenza. Every epidemic of influenza yields an increased number of cases of such chronic diseases in which diagnosis has been unfortunately but often unavoidably delayed. The only apparent solution of the problem would depend upon the physician's warning his patients that continued contact should be maintained between physician and patient until an obvious state of normal health is regained. This routine practice might prevent repetition of instances in which early symptoms of pulmonary tuberculosis or other chronic disease of the lungs have been confused with epidemic influenza, or indeed in which the symptoms may have been those of epidemic influenza which rekindled a former latent symptomless disease. It seems probable that acute epidemic diseases of the respiratory tract may lead to serious exacerbations of such diseases as tuberculosis and that spon-
COMMON PROBLEMS IN MANAGEMENT OE PNEUMONIA
807
taneous recovery or prolonged periods of asymptomatic disease would have continued had not the influenzal infection been superimposed. Influenza is such a serious complication of tuberculosis that some have suggested that the great influenza pandemic of 1918 destroyed many persons who had previously latent tuberculosis, reducing the sources of contagion sufficiently to have been a factor in the recent statistical decline of this disease. Many laboratories have adopted the practice of staining for acid-fast organisms all specimens of sputum presented for pneumococcic typing for pneumonia and have discovered a surprising number of patients whose symptoms were those of pneumonia but who had tubercle bacilli in their sputum: VALUE OF ROENTGENOGRAPHY
A rational approach to treatment in a difficult case of pneumonia requires precise knowledge of the character and extent of the pathologic process and serial examinations to detect trends of progression or retrogression of the disease. Only accurate and repeated roentgenologic examinations can supply this information, and often the interpretation of results in difficult situations will require the skilled services of a trained roentgenologic consultant. These facilities are usually obtainable only in modern and well-equipped hospitals. Fortunately, such hospitals are numerous in this country and available for nearly every serious case of pneumonia. The factor of expense is likely to be cited as a restricting factor in conducting roentgenographic examinations, but when such examinations are used freely early during the course of questionable infections of the respiratory tract they may lead to early detection and prompt treatment by chemotherapy. It will then be recognized that the expense of treating such a disease as pneumonia will depend upon prompt treatment and it is felt that free use of roentgenographic methods of diagnosis will be a moneysaving practice as well as a livesaving practice. Roentgenographic examination is of great value, not only in selecting those cases which are likely to require chemotherapy when symptoms of acute disease of the respiratory tract are present, but also in watching the process of resolution and in detecting the development of complications. It should be urged that all persons who have any type of pulmonary infiltration, as revealed by roentgenography, should continue to have serial roentgenographic examinations until such lesions have disappeared completely. In many instances this procedure will require a period of several weeks or more of continued observation.
808
H. CORWIN HINSHAW ADVANTAGES OF HOSPITAL CARE
The modern hospital has much to offer the patient suffering from severe acute disease of the respiratory tract. Diagnosis may be arrived at rapidly and accurately by roentgenographic and other means. The bacteriologic examination of the sputum is more conveniently and more precisely accomplished if the patient is in a hospital than if he is elsewhere. Expert nursing care will assure accurate medication and is an important aid in assuring proper intake of fluids and measurement of urinary output, which are such important factors in prevention of complications when chemotherapy is employed. Oxygen therapy may frequently be helpful in shortening the course of the disease, and may even be lifesaving in unusual and complicated cases. The early detection of complications of pneumonia is greatly facilitated and prompt treatment of such complications assured. Serious toxic effects of chemotherapeutic agents employed in pneumonia, such as renal concretions, hematologic idiosyncrasies, drug rashes, drug fever and so forth, will be much easier to detect and to treat under hospital conditions of medical practice than under other conditions. Inadequate dosage or excessive concentrations of the chemotherapeutic agent in the blood are less likely to occur when the patient is under hospital observation and supervision than when he is not. At the present time there is an inadequate number of physicians for civilian practice in many communities and each physician must take advantage of those facilities which will permit him to treat the maximal number of patients with maximal efficiency and minimal expenditure of time. When acutely ill persons are confined to hospitals many details of care may be delegated properly to interns, nurses and even lay employees with gain in efficiency of treatment. The physician in charge may visit a large number of patients during the time which might have been consumed in making only a few house calls. In some communities the shortage of hospital beds may be a limiting factor in the realization of this aim, especially during times of epidemics of disease of the respiratory tract as influenza. CHOICE OF SULFONAMIDE DR:UG
Of the several sulfonamide drugs which are available and are known to be effective against pneumococcus infections, my colleagues and I have a preference for sulfadiazine at the present time. Sulfadiazine is easy to administer, yields very satisfactory blood levels, rarely produces undesirable side reactions and, above all, appears to be as effective as any of the other sulfonamide preparations which are available at this time. Our preference for it is also dependent upon the fact that our
COMMON PROBLEMS IN MANAGEMENT OE PNEUMONIA
809
experience with this drug is more extensive at the time of writing than our experience with other sulfonamide compounds. The principal potential hazard in sulfadiazine therapy is the danger of precipitation of crystals in the urinary tract. However, it is possible to avoid precipitation of the drug in the renal tract by free administration of fluids, often supplemented by large doses of sodium bicarbonate. If the urine is alJmline in reaction and if the volume of urine excreted equals or exceeds 1,200 cc. in twenty-four hours, the danger of renal complications is reduced to a minimum. The most frequent error is to watch fluid intake rather than .fluid output in judging requirements. It is obvious that only the factor of output is significant and that crystallization will occur only when the volume of outflow is inadequate to carry away the excreted drug. Since both the free and the combined form of the drug are much more soluble in alkaline than in acid or neutral urine, the advantage of administration of sodium bicarbonate is clearly seen. There is usually no objection to alkalinization as a r
810
H. CORWIN HINSHAW
Sulfapyridine is rarely used by my colleagues and me at the present time in the treatment of pneumonia. British publications continue to refer to sulfapyridine in such a manner as to lead to the belief that the drug is still favored in England and in Canada. This preference may be due to the fact that sulfathiazole and sulfadiazine are not so readily available in these countries as sulfapyridine. However, definite information on this point is not available to us at the present time. Sulfapyridine has the very definite disadvantage of producing nausea and vomiting among a large proportion of patients who receive therapeutically effective doses. Furthermore, I do not know of any convincing evidence of any therapeutic property of this drug which is not possessed to an equal or greater degree by more recent sulfonamide derivatives. Sulfamethazine has properties similar to those of sulfamerazine with even greater solubility in urine. Preliminary studies have also shown a high degree of therapeutic efficacy of this preparation but its complete clinical evaluation has not been accomplished at the present time and the drug is not available on the market. Sulfanilamide has been supplanted completely in cases of pneumococcic infections and should not be employed in such cases, as it is distinctly inferior to the newer derivatives. Diaminodiphenylsulfone has been shown experimentally to possess a great therapeutic power but its toxic reactions are very severe and dangerous and the drug has not been released for sale because of this fact. Derivatives of diaminodiphenylsulfone have been prepared that have marked reduction of toxic potentialities but none of these are available in the market at the present time and these derivatives need not receive further discussion unless they become available to the medical profession. The ideal chemotherapeutic agent for treatment of pneumonia remains'to be developed, but progress toward that goal has been rapid and is continuing at an accelerated pace.
THE medical literature of recent years is richly supplied with authoritative information on practical and theoretic aspects of sulfonamide treatment of pneumonia. The choice of drugs, the methods of administration and information concerning toxic manifestations of these drugs are well described in several publications which have been widely read l1-nd are extensively followed. It should be our aim, not to emphasize these well-known principles further or to suggest any important amendments to them, but rather to review some of the common problems which the attending physician must solve when utilizing sulfonamide preparations in the treatment of pneumonia. It would also be of interest to note trends of investigation which may indicate what further developments may occur. TRENDS OF
INVESTI~ATION
The therapeutic advances in treatment of pneumonia made during recent years have been unparalleled but there is no evidence that progress has ceased. It seems more probable that advances will continue at their present rapid rate toward the goal of an ideal therapeutic procedure. Preliminary reports suggest that antibiotics, such as penicillin, may represent the closest approach to an ideal therapeutic agent yet to be revealed. When the chemical composition of such preparations has been determined, the way may be opened to the synthetic production of many compounds of new chemical groups with ever-increasing advantages. A substance which will control hacterial infection rapidry and effectively without harm or inconvenience to the host would have appeared totally impracticable only a few years ago, hut today it appears well within the range of practical attainment. These chemotherapeutic agents have such a profound effect upon the hasic metabolism of bacteria of many divergent species that it seems quite possihle that eventually all types of bacterial disease may yield to this fundamental approach. Even at this time there are few important bacterial diseases not affected in greater or less Iheasure by preparations of the sulfonamide group. Drugs of the diaminodiphenylsulfone group· attack still other organisms. The development of a still different group of compounds related to penicillin may be accomplished and these compounds may deal effectively with many of the remaining types of bacterial infection. 804
COMMON PROBLEMS IN MANAGEMENT OE PNEUMONIA
805
POSITION OF CHEMOTHERAPY IN PRESENT-DAY TREATMENT
It no longer needs to be emphasized that chemotherapy is the treatment of choice for typical pneumonococcic pneumonia. An enormous literature has accumulated which presents overwhelming evidence that, when pneumonia is definitely attributable to pneumococci or is of lobar type, no delay should be permitted in instituting chemotherapy in full dosage and continued for adequate periods. This great and proper emphasis upon pneumococcic lobar pneumonia has sometimes been misinterpreted to suggest that in cases of pneumonia without pneumococci in the sputum, bronchopneumonia, postoperative pneumonia and other secondary or 'unusual types of pneumonia the patient need not receive drug treatment. However, I should agree heartily with the widely held belief that in most of the latter cases of pneumonia chemotherapy in full dosage should be given an adequate trial . for at least two to four days before one reaches any decision that the infection is not amenable to this type of treatment. Pneumonia of the so-called virus or atypical group does not respond to chemotherapy. These cases may often be recognized with fair accuracy but usually only during epidemic conditions and only by those who have had unusual experience with this group of diseases. The clinical and roentgenographic diagnosis of virus pneumonia is open to such a high degree of error that in my opinion it is rarely permissible to make such a diagnosis until after adequate trial of chemotherapy has failed to control the infection. My colleagues and I regard present-day chemotherapy as a procedure of such safety and potential efficacy that it may be employed with proper safeguard in a tentative manner in nearly all cases of pneumonia, including those which are suspected of being of nonbacterial origin. It is a fair rule to state that, when any reasonable doubt exists, a trial of chemotherapy seems to be indicated. We have repeatedly seen chemotherapy used with notable success in cases that had all of the clinical features of so-called virus pneumonia and we have also seen it fail in what appeared to be typical lobar pneumonia. The decision to institute chemotherapy does not seem to be a difficult one when pneumonia is known to exist. However, the decision to discontinue treatment when it is found ineffective is one much more difficult to make and is frequently delayed too long. Before one discontinues chemotherapy it is necessary to ascertain that truly adequate doses of the drug have been administered. The definition of adequate dosage should not depend upon the individual physician's previous experience but should be that dosage recommended in the medical literature for the particular drug, as based upon cumulative pooled experi-
806
H. CORWIN HINSHAW
ence of many physicians. It is true that some physicians have found doses much smaller than those usually recommended to be reasonably adequate for many infections and, in consequence, have evolved practices that, however adequate they may be to deal with mild infections, are inadequate to deal with more severe infections. To many physicians the determination of the concentration of sulfonamide drugs in the blood stream appears to be an unnecessary refinement for average patients who are responding properly to treatment. All will agree that the most important indication for studies of the concentration of sulfonamide compounds in the blood is in the case of the patient who is not responding to therapy in the anticipated manner. In such instances treatment should not be discontinued until the concentration of sulfonamide compounds in the blood has been determined to exclude the possibility that either inadequate absorption or inadequate dosage is responsible for the failure of the drug. Under these circumstances, parenteral administration may offer a rapid, satisfactory solution to a perplexing problem. DIAGNOSTIC PROBLEMS
Most difficult diagnostic and therapeutic problems arise during the course of epidemics of febrile respiratory diseases, such as influenza. Not only must the physician be on guard to detect complicating secondary bronchopneumonia at such times; he must also realize that cases of primary pneumonia of conventional type do occur independent of influenza epidemics. Not only primary pneumonia but other respiratory diseases, including the acute exacerbations of symptoms in such chronic diseases as tuberculosis, bronchiogenic carcinoma, pulmonary abscess and so forth, may resemble influenza. Every epidemic of influenza yields an increased number of cases of such chronic diseases in which diagnosis has been unfortunately but often unavoidably delayed. The only apparent solution of the problem would depend upon the physician's warning his patients that continued contact should be maintained between physician and patient until an obvious state of normal health is regained. This routine practice might prevent repetition of instances in which early symptoms of pulmonary tuberculosis or other chronic disease of the lungs have been confused with epidemic influenza, or indeed in which the symptoms may have been those of epidemic influenza which rekindled a former latent symptomless disease. It seems probable that acute epidemic diseases of the respiratory tract may lead to serious exacerbations of such diseases as tuberculosis and that spon-
COMMON PROBLEMS IN MANAGEMENT OE PNEUMONIA
807
taneous recovery or prolonged periods of asymptomatic disease would have continued had not the influenzal infection been superimposed. Influenza is such a serious complication of tuberculosis that some have suggested that the great influenza pandemic of 1918 destroyed many persons who had previously latent tuberculosis, reducing the sources of contagion sufficiently to have been a factor in the recent statistical decline of this disease. Many laboratories have adopted the practice of staining for acid-fast organisms all specimens of sputum presented for pneumococcic typing for pneumonia and have discovered a surprising number of patients whose symptoms were those of pneumonia but who had tubercle bacilli in their sputum: VALUE OF ROENTGENOGRAPHY
A rational approach to treatment in a difficult case of pneumonia requires precise knowledge of the character and extent of the pathologic process and serial examinations to detect trends of progression or retrogression of the disease. Only accurate and repeated roentgenologic examinations can supply this information, and often the interpretation of results in difficult situations will require the skilled services of a trained roentgenologic consultant. These facilities are usually obtainable only in modern and well-equipped hospitals. Fortunately, such hospitals are numerous in this country and available for nearly every serious case of pneumonia. The factor of expense is likely to be cited as a restricting factor in conducting roentgenographic examinations, but when such examinations are used freely early during the course of questionable infections of the respiratory tract they may lead to early detection and prompt treatment by chemotherapy. It will then be recognized that the expense of treating such a disease as pneumonia will depend upon prompt treatment and it is felt that free use of roentgenographic methods of diagnosis will be a moneysaving practice as well as a livesaving practice. Roentgenographic examination is of great value, not only in selecting those cases which are likely to require chemotherapy when symptoms of acute disease of the respiratory tract are present, but also in watching the process of resolution and in detecting the development of complications. It should be urged that all persons who have any type of pulmonary infiltration, as revealed by roentgenography, should continue to have serial roentgenographic examinations until such lesions have disappeared completely. In many instances this procedure will require a period of several weeks or more of continued observation.
808
H. CORWIN HINSHAW ADVANTAGES OF HOSPITAL CARE
The modern hospital has much to offer the patient suffering from severe acute disease of the respiratory tract. Diagnosis may be arrived at rapidly and accurately by roentgenographic and other means. The bacteriologic examination of the sputum is more conveniently and more precisely accomplished if the patient is in a hospital than if he is elsewhere. Expert nursing care will assure accurate medication and is an important aid in assuring proper intake of fluids and measurement of urinary output, which are such important factors in prevention of complications when chemotherapy is employed. Oxygen therapy may frequently be helpful in shortening the course of the disease, and may even be lifesaving in unusual and complicated cases. The early detection of complications of pneumonia is greatly facilitated and prompt treatment of such complications assured. Serious toxic effects of chemotherapeutic agents employed in pneumonia, such as renal concretions, hematologic idiosyncrasies, drug rashes, drug fever and so forth, will be much easier to detect and to treat under hospital conditions of medical practice than under other conditions. Inadequate dosage or excessive concentrations of the chemotherapeutic agent in the blood are less likely to occur when the patient is under hospital observation and supervision than when he is not. At the present time there is an inadequate number of physicians for civilian practice in many communities and each physician must take advantage of those facilities which will permit him to treat the maximal number of patients with maximal efficiency and minimal expenditure of time. When acutely ill persons are confined to hospitals many details of care may be delegated properly to interns, nurses and even lay employees with gain in efficiency of treatment. The physician in charge may visit a large number of patients during the time which might have been consumed in making only a few house calls. In some communities the shortage of hospital beds may be a limiting factor in the realization of this aim, especially during times of epidemics of disease of the respiratory tract as influenza. CHOICE OF SULFONAMIDE DR:UG
Of the several sulfonamide drugs which are available and are known to be effective against pneumococcus infections, my colleagues and I have a preference for sulfadiazine at the present time. Sulfadiazine is easy to administer, yields very satisfactory blood levels, rarely produces undesirable side reactions and, above all, appears to be as effective as any of the other sulfonamide preparations which are available at this time. Our preference for it is also dependent upon the fact that our
COMMON PROBLEMS IN MANAGEMENT OE PNEUMONIA
809
experience with this drug is more extensive at the time of writing than our experience with other sulfonamide compounds. The principal potential hazard in sulfadiazine therapy is the danger of precipitation of crystals in the urinary tract. However, it is possible to avoid precipitation of the drug in the renal tract by free administration of fluids, often supplemented by large doses of sodium bicarbonate. If the urine is alJmline in reaction and if the volume of urine excreted equals or exceeds 1,200 cc. in twenty-four hours, the danger of renal complications is reduced to a minimum. The most frequent error is to watch fluid intake rather than .fluid output in judging requirements. It is obvious that only the factor of output is significant and that crystallization will occur only when the volume of outflow is inadequate to carry away the excreted drug. Since both the free and the combined form of the drug are much more soluble in alkaline than in acid or neutral urine, the advantage of administration of sodium bicarbonate is clearly seen. There is usually no objection to alkalinization as a r
810
H. CORWIN HINSHAW
Sulfapyridine is rarely used by my colleagues and me at the present time in the treatment of pneumonia. British publications continue to refer to sulfapyridine in such a manner as to lead to the belief that the drug is still favored in England and in Canada. This preference may be due to the fact that sulfathiazole and sulfadiazine are not so readily available in these countries as sulfapyridine. However, definite information on this point is not available to us at the present time. Sulfapyridine has the very definite disadvantage of producing nausea and vomiting among a large proportion of patients who receive therapeutically effective doses. Furthermore, I do not know of any convincing evidence of any therapeutic property of this drug which is not possessed to an equal or greater degree by more recent sulfonamide derivatives. Sulfamethazine has properties similar to those of sulfamerazine with even greater solubility in urine. Preliminary studies have also shown a high degree of therapeutic efficacy of this preparation but its complete clinical evaluation has not been accomplished at the present time and the drug is not available on the market. Sulfanilamide has been supplanted completely in cases of pneumococcic infections and should not be employed in such cases, as it is distinctly inferior to the newer derivatives. Diaminodiphenylsulfone has been shown experimentally to possess a great therapeutic power but its toxic reactions are very severe and dangerous and the drug has not been released for sale because of this fact. Derivatives of diaminodiphenylsulfone have been prepared that have marked reduction of toxic potentialities but none of these are available in the market at the present time and these derivatives need not receive further discussion unless they become available to the medical profession. The ideal chemotherapeutic agent for treatment of pneumonia remains'to be developed, but progress toward that goal has been rapid and is continuing at an accelerated pace.