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Digitalis: Its Rational Use
Medical Clinics of North America May, 1937. Mayo Clinic Number
DIGITALIS: ITS RATIONAL USE FREDRICK
A.
WILLIUS
NOTWITHSTANDING the fact that digitalis has been used by physicians for a century and a half it is probably the most misused drug in the practice of medicine. Since the days of William Withering, digitalis generally has been conceded to be the most important and the most valuable drug in the treatment of heart disease. The main reason for its misuse probably lies in the fact that we have not as yet thrown off the bonds of empiricism. We have been taught that digitalis is the sovereign remedy in heart disease, and we have been taught also its actions, its methods of administration, and certain dangers regarding its use. Our chief impression regarding digitalis is based largely on the experience that certain patients with heart disease are greatly benefited by the use of the drug. However, if we analyze our experiences with digitalis more fully, we soon recall the fact that we have frequently been puzzled when good results from its administration have not been forthcoming. The beneficial effects of digitalis in heart disease result from changes the drug produces in the various functions of the cardiovascular system. Many actions have been assigned to digitalis, and many of these have not withstood the test of time and experience, a fact which has undoubtedly contributed to the existing confusion as to its actions and indications. The effect of digitalis on the diseased heart of man is narrowed down to three definite actions, the understanding of which greatly simplifies the indications and contraindications for its use. These three actions are: 1. It depresses the function of the sino-auricular and auriculoventricular nodes, resulting in a tendency to slow the cardiac rate. Th!s is, in part, a vagal action. 2. It depresses cardiac conduction throughout the muscle and increases the refractory period of both the auricles and the ventricles. Depression of conduction, particularly 76 1
• FREDRICK A. WILLIUS
through the auriculoventricular bundle (His), occurs; this explains the striking effect of the drug in many cases of auricular fibrillation. 3. It increases the amplitude of cardiac contraction. It tends, also, to restore tonus, apparently because of its direct action on heart muscle. Digitalis does not exert a constant effect on blood pressure; a rise may occur as part. of the improvement of cardiac function and general circulation. Likewise, its effect in the production of diuresis is not a result of stimulation of the renal epithelium, as was formerly believed, but again results from the more normal behavior of the renal and the general circulation. The effect of digitalis on the diseased heart is very different from its action on the normal heart, and also from its effect on the heart of the experimental animal. In order to comprehend the action of digitalis on the impaired heart it is necessary to analyze critically the various actions that the drug may exert, and also to comprehend fully the various underlying disorders leading to heart failure. Considerable difficulty is at times encountered in definitely establishing the basis of heart failure, and not infrequently failure results from a combination of conditions that must be determined in their proper relationships. The physician is often too willing to rest after he has satisfied himself that a failing heart is the cause of the patient's symptoms, and he may make little, if any, attempt to identify the type of lesion. One of the most important factors in the misunderstanding regarding heart disease and its management has been this apparent indifference to determining the etiologic factor or factors responsible for the existing cardiopathy. The preparations of digitalis most commonly used are derived from the leaves of Digitalis purpurea, although preparations from the leaves of Digitalis lutea have been used and are presumed by some to have less tendency to produce nausea and vomiting. A tincture of digitalis of established potency and of known date of manufacture is a very satisfactory preparation. Its administration is simple, and conveniently permits changes in dosage. " The infusion is the oldest of the preparations of digitalis.
DIGITALIS: ITS RATIONAL USE
It has been found to be an unreliable preparation, when made by accepted methods, owing to its instability and to the great variations in its potency. Some pharmacists prepare the infusion from the fluidextract, which results in a product of a potency totally different from that of the official infusion and which is no longer comparable to it. An infusion made from the fluid extract has a greater digitoxin content than the official infusion. The relative value of the standard tincture and of the infusion of digitalis has been investigated by Weiss and Hatcher. By their method an infusion of digitalis was pre. pared that in all respects compared favorably with the standard tincture, and when it was kept in completely filled, hermetically sealed bottles it remained unaltered ~or nearly two and a half years. The use of powdered leaves of digitalis in capsules and standard tablets are also satisfactory methods of administering the drug. Digitalis may be administered intramuscularly or intravenously, although indications for the employment of these routes are less frequently encountered. These methods of administration usually presuppose the presence of an emergency in which the physician has had little or no time for the careful analysis of his patient. It is always possible in a case of acute heart failure that the basis of the condition might definitely contraindicate the use of digitalis. The intramuscular and the intravenous method may be employed with safety when the clinical status of the case is well established, but in the majority of instances it has little advantage over the oral method of administration. Pardee has pointed out that the promptness in action 'which follows injection is more dependent on the large size of the dose given than on the greater promptness with which the drug comes in contact with the heart muscle. My experience has put me in full agreement with this statement. Clarke, in a comparative study based on the rate of slowing caused by digitalis, showed that an effect was evident within three to four hours after intravenous administration, in about four hours after intramuscular administration, and in about six hours after oral administration. There is no reliable evidence that proprietary preparations of digitalis have any advantage over official preparations.
FREDRICK A. WILLIUS
The use of compound tablets containing digitalis in combination with other drugs is to be condemned, as analysis of their constituents so often reveals the presence of these drugs in such ridiculously small amounts as to be pharmacologically inactive. Studies dealing with the absorption of digitalis from the alimentary tract of man have been carried on by several investigators. It has been shown that the galenical preparations of digitalis are absorbed with sufficient uniformity to allow the establishment of an average, total therapeutic requirement of the drug, even for samples from various sources and of different activity. Eggleston and Wyckoff showed that a satisfactory, average total dose, expressed in terms of the "catunit" of activity for each pound of the patient's weight, was possible when high-grade tinctures were used. The absorption of average tinctures was variable. High-grade tinctures, in sufficiently large doses, revealed definite action on the heart of man within two to four hours after oral administration. Tinctures of less activity required five or more hours for their effects to become manifest. It must be clearly understood that the first evidence of the action of digitalis does not imply the full therapeutic effect, as this is rarely obtained in less than twenty-four or forty-eight hours, and then only when larger doses are employed. In the administration of digitalis the difficulty encountered at times in establishing a method whereby the patient is sufficiently held under the action of the drug without eliciting the toxic symptoms of overdosage is well known. The rate of elimination from the body or the degree of destruction in the body have been unknown quantities. Pardee, in studying the rate of disappearance of digitalis from the body, found that approximately 0.1 to 0.2 gm. is lost in twenty-four hours. These results would imply that at least 0.1 S gm. (1.S c.c.) would be the required daily dose necessary to maintain a digitalis effect after the- full therapeutic effect had been obtained. The establishment of the diagnosis of heart disease is frequently considered the indication for the administration of digitalis. Such a criterion is absolutely fallacious and frequently results in serious difficulty. No method of treatment is attendee!, by greater hazards than the indiscriminate and improper administration of digitalis.
DIGITALIS: ITS RATIONAL USE
The two striking indications for the employment of digitalis are the presence of congestive heart failure and the presence of auricular fibrillation with rapid ventricular rate. This statement requires modification, as at times in rapid auricular fibrillation the administration of the drug must be cautious or, perhaps, it must be withheld. As previously stated, the establishment of a definite diagnosis of the type of lesion is of primary importance. The exhibition of digitalis, in cases of acute heart failure, before the exact cause for the failure is determined is not without danger. Heart block, sudden failure from coronary occlusion, and intense hyperthyroidism, especially if crisis is present or impending, are clear-cut contraindications to its use. The presence of auricular flutter invariably demands medication with digitalis, and often very large doses and prolonged periods of administration are necessary and are well tolerated. These observations suggest that the elimination of digitalis in fluttet is perhaps more rapid than in other disorders of cardiac action. In general, although this statement is not without exception, digitalis is more effective for young and middle-aged patients, especially those with the heart failure of valvular disease, than for older patients with hypertensive, coronary, or syphilitic cardiovascular disease. There is no doubt that digitalis may be of benefit in cases of failure when the cardiac rhythm is regular. This fact was emphasized by Christian and I believe has been the experience of all who have used digitalis. My experience with digitalis has led me to be cautious in its administration to older patients, and has led me to give moderate doses over periods that have not been too prolonged. One of the signs of excessive administration of digitalis is the appearance of premature contractions or extrasystoles. When caused by digitalis, they usually occur paired with the normal beats and result in the so-called coupled rhythm. The presence of premature contractions, however, occurring in a case in which the patient has not received digitalis recently must not be considered as a contraindication for the exhibition of this drug. Digitalis has little or no value in paroxysmal tachycardia.
FREDRICK A. WILLIUS
The preoperative digitalization of patients with cardiac disease is to be condemned as a routine practice. Several objections to this become evident at once. In the majority of instances, the preoperative administration of digitalis is unnecessary and involves, therefore, an unnecessary loss of time for the patient, with the attendant financial burden. As previously stated, many older patients do not tolerate digitalis well, and if it is indiscriminately given, they may be in a less favorable condition to meet operation. If it is recalled that little can be anticipated from the exhibition of digitalis except in cases in which heart failure is present or has recently been present, the chief contraindication to this procedure becomes evident. If heart failure exists, operative intervention is positively contraindicated, and then only after cardiac function has been reestablished by proper treatment. It is my belief, therefore, that the indications for the routine preoperative digitalization of patients with heart disease lack scientific and clinical confirmation, and that this routine ~hould be discouraged. Likewise, the routine administration of the drug in cases of pneumonia is not to be encouraged. Controlled studies have failed to demonstrate any justification for continuance of the procedure. When heart disease and pneumonia coexist, and the situation is such that under ordinary circumstances the heart would demand digitalis, or the additional load imposed by pneumonia threatens heart failure, it should be employed intelligently. We must not, lose sight of the fact that the patient with pneumonia may be extremely toxic, and that the addition of a toxic drug in a full therapeutic dose may lead to disaster. As previously stated, the oral method of administration of digitalis is the one of choice. Many patients have failed to receive benefit because too little digitalis has been given; less frequently, harm has resulted from its administration in excessively large doses. Eggleston demonstrated the possibility of giving relatively large doses of the drug, and his method of administration is known as the Eggleston method. The strength of the preparation employed is determined in cat units, and from this the dose is calculated for man. When the standardized tincture is used, the average requirement in oral administration for production
DIGITALIS: ITS RATIONAL USE
of the full therapeutic effect or minor toxic action is about 0.146 c.c. for each pound of the patient's weight. For example, a patient weighing 150 pounds (68.1 kg.) would require 21.9 C.c. of the tincture. The calculated total dose is given in divided portions: the first dose is half the total dose; the second, which is given six hours later, is half the remainder, and the third and fourth doses, given at intervals of six hours, are half the second dose. Eggleston's method has been modified in numerous ways, although the general principle of the method has been maintained. These methods of administering relatively large doses of digitalis over short periods are not without objection. Their justification implies that the patient has been carefully examined and that the cause of heart failure has been fully determined. After the total calculated dose has been given, means do not exist whereby the action of the drug may be modified, and notwithstanding various opinions the onset of toxic symptoms is highly undesirable, and at times, hazardous. In the majority of cases of cardiac disease in which digitalis is indicated, sufficient time may safely be consumed to administer smaller individual doses over a longer period of time. Experimental studies have shown that full therapeutic effects, without toxic symptoms, can be obtained with standard preparations in doses of 1. 5 gm. (22 grains) of the leaf, or 15 c.c. (225 minims) of the tincture. These therapeutic effects may be obtained even if digitalis has been employed in the same case; however, at least two weeks without digitalis must be allowed to elapse between the two periods of administration of the drug. The administration of 1 to 17~ grains of the leaf or 1.5 to 2 C.c. of the tincture three times daily is a satisfactory and safe method in most cases. After the development of the therapeutic effect, the problem of maintaining the action of digitalis without the onset of toxic phenomena presents itself. Numerous methods of administering the drug have been employed, but in general two plans are adopted. Digitalis may be given daily, in doses sufficiently large to maintain its effect over relatively long periods of time; or larger doses may be employed, and may be given for a few consecutive days each week with regular periods of withdrawal.
FREDRICK A. WILLIUS
In order to obtain satisfactory results, the method of administration must be selected to meet the needs of the individual case. In my experience, the second method has proved satisfactory. The individual dose, administered three times daily for the necessary number of consecutive days each week, is readily adapted to varying conditions. The daily administration of ridiculously small doses of digitalis is without scientific support and should not receive encouragement. It is important to emphasize the great discrepancies in dosage that may occur from the use of ordinary medicine droppers. This unreliable method is to be condemned, as it has been a significant factor in the inadequate administration of digitalis. Some physicians have presumed that a minim of the tincture of digitalis, as measured in a calibrated vial, corresponds to a drop as delivered by the average medicine dropper. That this method is unreliable can be proved by anyone by filling a calibrated vial to a given capacity in minims, using several droppers. Discrepancies of from five to fifteen drops will be observed. The position in which the dropper is held, vertically, obliquely, or horizontally, also results in a discrepancy. Graduated vials are readily available and one should be prescribed with the digitalis; it is easy to instruct the patient in its use. Under certain conditions digitalis may be given satisfactorily by rectum. This method of administration is particularly applicable if nausea and vomiting are present from other causes. Essentially the same dosage used in oral methods may be used. In order to simplify this procedure, the total daily dose may be given at one time, with 20 to 25 C.c. of water added. The intravenous and intramuscular injection of digitalis has already b~en discussed, and I wish to emphasize that the indications for this mode of administration occur only occasionally. TOXIC. EFFECTS
Every physician should understand the toxic effects of digitalis. Certain symptoms of overdosage are well known; namely, anorexia, nausea, vomiting, and diarrhea. The occurrence . 9f Qoupled beats as toxic manifestations has also received con-
DIGITALIS: ITS RATIONAL USE
siderable emphasis, and likewise the occurrence of partial or complete heart block. Other toxic effects are not so well known and merit considerable emphasis, owing to the fact that they often occur independent of such well-known symptoms as nausea and vomiting. Occasionally, during the administration of digitalis, paroxysms of tachycardia occur which have been known to terminate in death. The paroxysms have been identified as arising in the ventricles. The occurrence of these phenomena during the course of administration of digitalis in a case in which the patient was not hitherto subject to them, indicates a profoundly toxic effect of the drug. The toxic effects of digitalis on the brain and certain nervous tissues are important to recognize, as the continued administration of the drug when toxic effects are present, often results fatally. Prominent among these are disturbances in vision. They consist of dimness of vision, inability to focus the eyes, difficulty in identifying objects, and the presence of scotoma, diplopia, and so forth. Yellow and green vision are striking, and are often alarming manifestations of intoxication with digitalis. Toxic cerebral effects of digitalis are not as yet fully appreciated and are of the utmost importance owing to their seriousness. In older medical writings, allusions are found to the so-called cardiac psychoses, some instances of which were probably the result of intoxication with digitalis. The first symptoms usually are restlessness and increased nervous irritability; periods of disorientation regarding time and place soon follow. These manifestations are frequently supplanted by stupor, from which the patient does not recover. Visual disturbances mayor may not be associated phenomena. Toxic cerebral symptoms may occur without the more usual signs of poisoning by digitalis. The onset of any of these symptoms clearly indicates immediate discontinuance of the drug, for the time at least, and the prompt clearance of the tissues; this may at times be possible by the daily intravenous administration of hypertonic glucose solution. VOL. 21-49
DIGITALIS: ITS RATIONAL USE FREDRICK
A.
WILLIUS
NOTWITHSTANDING the fact that digitalis has been used by physicians for a century and a half it is probably the most misused drug in the practice of medicine. Since the days of William Withering, digitalis generally has been conceded to be the most important and the most valuable drug in the treatment of heart disease. The main reason for its misuse probably lies in the fact that we have not as yet thrown off the bonds of empiricism. We have been taught that digitalis is the sovereign remedy in heart disease, and we have been taught also its actions, its methods of administration, and certain dangers regarding its use. Our chief impression regarding digitalis is based largely on the experience that certain patients with heart disease are greatly benefited by the use of the drug. However, if we analyze our experiences with digitalis more fully, we soon recall the fact that we have frequently been puzzled when good results from its administration have not been forthcoming. The beneficial effects of digitalis in heart disease result from changes the drug produces in the various functions of the cardiovascular system. Many actions have been assigned to digitalis, and many of these have not withstood the test of time and experience, a fact which has undoubtedly contributed to the existing confusion as to its actions and indications. The effect of digitalis on the diseased heart of man is narrowed down to three definite actions, the understanding of which greatly simplifies the indications and contraindications for its use. These three actions are: 1. It depresses the function of the sino-auricular and auriculoventricular nodes, resulting in a tendency to slow the cardiac rate. Th!s is, in part, a vagal action. 2. It depresses cardiac conduction throughout the muscle and increases the refractory period of both the auricles and the ventricles. Depression of conduction, particularly 76 1
• FREDRICK A. WILLIUS
through the auriculoventricular bundle (His), occurs; this explains the striking effect of the drug in many cases of auricular fibrillation. 3. It increases the amplitude of cardiac contraction. It tends, also, to restore tonus, apparently because of its direct action on heart muscle. Digitalis does not exert a constant effect on blood pressure; a rise may occur as part. of the improvement of cardiac function and general circulation. Likewise, its effect in the production of diuresis is not a result of stimulation of the renal epithelium, as was formerly believed, but again results from the more normal behavior of the renal and the general circulation. The effect of digitalis on the diseased heart is very different from its action on the normal heart, and also from its effect on the heart of the experimental animal. In order to comprehend the action of digitalis on the impaired heart it is necessary to analyze critically the various actions that the drug may exert, and also to comprehend fully the various underlying disorders leading to heart failure. Considerable difficulty is at times encountered in definitely establishing the basis of heart failure, and not infrequently failure results from a combination of conditions that must be determined in their proper relationships. The physician is often too willing to rest after he has satisfied himself that a failing heart is the cause of the patient's symptoms, and he may make little, if any, attempt to identify the type of lesion. One of the most important factors in the misunderstanding regarding heart disease and its management has been this apparent indifference to determining the etiologic factor or factors responsible for the existing cardiopathy. The preparations of digitalis most commonly used are derived from the leaves of Digitalis purpurea, although preparations from the leaves of Digitalis lutea have been used and are presumed by some to have less tendency to produce nausea and vomiting. A tincture of digitalis of established potency and of known date of manufacture is a very satisfactory preparation. Its administration is simple, and conveniently permits changes in dosage. " The infusion is the oldest of the preparations of digitalis.
DIGITALIS: ITS RATIONAL USE
It has been found to be an unreliable preparation, when made by accepted methods, owing to its instability and to the great variations in its potency. Some pharmacists prepare the infusion from the fluidextract, which results in a product of a potency totally different from that of the official infusion and which is no longer comparable to it. An infusion made from the fluid extract has a greater digitoxin content than the official infusion. The relative value of the standard tincture and of the infusion of digitalis has been investigated by Weiss and Hatcher. By their method an infusion of digitalis was pre. pared that in all respects compared favorably with the standard tincture, and when it was kept in completely filled, hermetically sealed bottles it remained unaltered ~or nearly two and a half years. The use of powdered leaves of digitalis in capsules and standard tablets are also satisfactory methods of administering the drug. Digitalis may be administered intramuscularly or intravenously, although indications for the employment of these routes are less frequently encountered. These methods of administration usually presuppose the presence of an emergency in which the physician has had little or no time for the careful analysis of his patient. It is always possible in a case of acute heart failure that the basis of the condition might definitely contraindicate the use of digitalis. The intramuscular and the intravenous method may be employed with safety when the clinical status of the case is well established, but in the majority of instances it has little advantage over the oral method of administration. Pardee has pointed out that the promptness in action 'which follows injection is more dependent on the large size of the dose given than on the greater promptness with which the drug comes in contact with the heart muscle. My experience has put me in full agreement with this statement. Clarke, in a comparative study based on the rate of slowing caused by digitalis, showed that an effect was evident within three to four hours after intravenous administration, in about four hours after intramuscular administration, and in about six hours after oral administration. There is no reliable evidence that proprietary preparations of digitalis have any advantage over official preparations.
FREDRICK A. WILLIUS
The use of compound tablets containing digitalis in combination with other drugs is to be condemned, as analysis of their constituents so often reveals the presence of these drugs in such ridiculously small amounts as to be pharmacologically inactive. Studies dealing with the absorption of digitalis from the alimentary tract of man have been carried on by several investigators. It has been shown that the galenical preparations of digitalis are absorbed with sufficient uniformity to allow the establishment of an average, total therapeutic requirement of the drug, even for samples from various sources and of different activity. Eggleston and Wyckoff showed that a satisfactory, average total dose, expressed in terms of the "catunit" of activity for each pound of the patient's weight, was possible when high-grade tinctures were used. The absorption of average tinctures was variable. High-grade tinctures, in sufficiently large doses, revealed definite action on the heart of man within two to four hours after oral administration. Tinctures of less activity required five or more hours for their effects to become manifest. It must be clearly understood that the first evidence of the action of digitalis does not imply the full therapeutic effect, as this is rarely obtained in less than twenty-four or forty-eight hours, and then only when larger doses are employed. In the administration of digitalis the difficulty encountered at times in establishing a method whereby the patient is sufficiently held under the action of the drug without eliciting the toxic symptoms of overdosage is well known. The rate of elimination from the body or the degree of destruction in the body have been unknown quantities. Pardee, in studying the rate of disappearance of digitalis from the body, found that approximately 0.1 to 0.2 gm. is lost in twenty-four hours. These results would imply that at least 0.1 S gm. (1.S c.c.) would be the required daily dose necessary to maintain a digitalis effect after the- full therapeutic effect had been obtained. The establishment of the diagnosis of heart disease is frequently considered the indication for the administration of digitalis. Such a criterion is absolutely fallacious and frequently results in serious difficulty. No method of treatment is attendee!, by greater hazards than the indiscriminate and improper administration of digitalis.
DIGITALIS: ITS RATIONAL USE
The two striking indications for the employment of digitalis are the presence of congestive heart failure and the presence of auricular fibrillation with rapid ventricular rate. This statement requires modification, as at times in rapid auricular fibrillation the administration of the drug must be cautious or, perhaps, it must be withheld. As previously stated, the establishment of a definite diagnosis of the type of lesion is of primary importance. The exhibition of digitalis, in cases of acute heart failure, before the exact cause for the failure is determined is not without danger. Heart block, sudden failure from coronary occlusion, and intense hyperthyroidism, especially if crisis is present or impending, are clear-cut contraindications to its use. The presence of auricular flutter invariably demands medication with digitalis, and often very large doses and prolonged periods of administration are necessary and are well tolerated. These observations suggest that the elimination of digitalis in fluttet is perhaps more rapid than in other disorders of cardiac action. In general, although this statement is not without exception, digitalis is more effective for young and middle-aged patients, especially those with the heart failure of valvular disease, than for older patients with hypertensive, coronary, or syphilitic cardiovascular disease. There is no doubt that digitalis may be of benefit in cases of failure when the cardiac rhythm is regular. This fact was emphasized by Christian and I believe has been the experience of all who have used digitalis. My experience with digitalis has led me to be cautious in its administration to older patients, and has led me to give moderate doses over periods that have not been too prolonged. One of the signs of excessive administration of digitalis is the appearance of premature contractions or extrasystoles. When caused by digitalis, they usually occur paired with the normal beats and result in the so-called coupled rhythm. The presence of premature contractions, however, occurring in a case in which the patient has not received digitalis recently must not be considered as a contraindication for the exhibition of this drug. Digitalis has little or no value in paroxysmal tachycardia.
FREDRICK A. WILLIUS
The preoperative digitalization of patients with cardiac disease is to be condemned as a routine practice. Several objections to this become evident at once. In the majority of instances, the preoperative administration of digitalis is unnecessary and involves, therefore, an unnecessary loss of time for the patient, with the attendant financial burden. As previously stated, many older patients do not tolerate digitalis well, and if it is indiscriminately given, they may be in a less favorable condition to meet operation. If it is recalled that little can be anticipated from the exhibition of digitalis except in cases in which heart failure is present or has recently been present, the chief contraindication to this procedure becomes evident. If heart failure exists, operative intervention is positively contraindicated, and then only after cardiac function has been reestablished by proper treatment. It is my belief, therefore, that the indications for the routine preoperative digitalization of patients with heart disease lack scientific and clinical confirmation, and that this routine ~hould be discouraged. Likewise, the routine administration of the drug in cases of pneumonia is not to be encouraged. Controlled studies have failed to demonstrate any justification for continuance of the procedure. When heart disease and pneumonia coexist, and the situation is such that under ordinary circumstances the heart would demand digitalis, or the additional load imposed by pneumonia threatens heart failure, it should be employed intelligently. We must not, lose sight of the fact that the patient with pneumonia may be extremely toxic, and that the addition of a toxic drug in a full therapeutic dose may lead to disaster. As previously stated, the oral method of administration of digitalis is the one of choice. Many patients have failed to receive benefit because too little digitalis has been given; less frequently, harm has resulted from its administration in excessively large doses. Eggleston demonstrated the possibility of giving relatively large doses of the drug, and his method of administration is known as the Eggleston method. The strength of the preparation employed is determined in cat units, and from this the dose is calculated for man. When the standardized tincture is used, the average requirement in oral administration for production
DIGITALIS: ITS RATIONAL USE
of the full therapeutic effect or minor toxic action is about 0.146 c.c. for each pound of the patient's weight. For example, a patient weighing 150 pounds (68.1 kg.) would require 21.9 C.c. of the tincture. The calculated total dose is given in divided portions: the first dose is half the total dose; the second, which is given six hours later, is half the remainder, and the third and fourth doses, given at intervals of six hours, are half the second dose. Eggleston's method has been modified in numerous ways, although the general principle of the method has been maintained. These methods of administering relatively large doses of digitalis over short periods are not without objection. Their justification implies that the patient has been carefully examined and that the cause of heart failure has been fully determined. After the total calculated dose has been given, means do not exist whereby the action of the drug may be modified, and notwithstanding various opinions the onset of toxic symptoms is highly undesirable, and at times, hazardous. In the majority of cases of cardiac disease in which digitalis is indicated, sufficient time may safely be consumed to administer smaller individual doses over a longer period of time. Experimental studies have shown that full therapeutic effects, without toxic symptoms, can be obtained with standard preparations in doses of 1. 5 gm. (22 grains) of the leaf, or 15 c.c. (225 minims) of the tincture. These therapeutic effects may be obtained even if digitalis has been employed in the same case; however, at least two weeks without digitalis must be allowed to elapse between the two periods of administration of the drug. The administration of 1 to 17~ grains of the leaf or 1.5 to 2 C.c. of the tincture three times daily is a satisfactory and safe method in most cases. After the development of the therapeutic effect, the problem of maintaining the action of digitalis without the onset of toxic phenomena presents itself. Numerous methods of administering the drug have been employed, but in general two plans are adopted. Digitalis may be given daily, in doses sufficiently large to maintain its effect over relatively long periods of time; or larger doses may be employed, and may be given for a few consecutive days each week with regular periods of withdrawal.
FREDRICK A. WILLIUS
In order to obtain satisfactory results, the method of administration must be selected to meet the needs of the individual case. In my experience, the second method has proved satisfactory. The individual dose, administered three times daily for the necessary number of consecutive days each week, is readily adapted to varying conditions. The daily administration of ridiculously small doses of digitalis is without scientific support and should not receive encouragement. It is important to emphasize the great discrepancies in dosage that may occur from the use of ordinary medicine droppers. This unreliable method is to be condemned, as it has been a significant factor in the inadequate administration of digitalis. Some physicians have presumed that a minim of the tincture of digitalis, as measured in a calibrated vial, corresponds to a drop as delivered by the average medicine dropper. That this method is unreliable can be proved by anyone by filling a calibrated vial to a given capacity in minims, using several droppers. Discrepancies of from five to fifteen drops will be observed. The position in which the dropper is held, vertically, obliquely, or horizontally, also results in a discrepancy. Graduated vials are readily available and one should be prescribed with the digitalis; it is easy to instruct the patient in its use. Under certain conditions digitalis may be given satisfactorily by rectum. This method of administration is particularly applicable if nausea and vomiting are present from other causes. Essentially the same dosage used in oral methods may be used. In order to simplify this procedure, the total daily dose may be given at one time, with 20 to 25 C.c. of water added. The intravenous and intramuscular injection of digitalis has already b~en discussed, and I wish to emphasize that the indications for this mode of administration occur only occasionally. TOXIC. EFFECTS
Every physician should understand the toxic effects of digitalis. Certain symptoms of overdosage are well known; namely, anorexia, nausea, vomiting, and diarrhea. The occurrence . 9f Qoupled beats as toxic manifestations has also received con-
DIGITALIS: ITS RATIONAL USE
siderable emphasis, and likewise the occurrence of partial or complete heart block. Other toxic effects are not so well known and merit considerable emphasis, owing to the fact that they often occur independent of such well-known symptoms as nausea and vomiting. Occasionally, during the administration of digitalis, paroxysms of tachycardia occur which have been known to terminate in death. The paroxysms have been identified as arising in the ventricles. The occurrence of these phenomena during the course of administration of digitalis in a case in which the patient was not hitherto subject to them, indicates a profoundly toxic effect of the drug. The toxic effects of digitalis on the brain and certain nervous tissues are important to recognize, as the continued administration of the drug when toxic effects are present, often results fatally. Prominent among these are disturbances in vision. They consist of dimness of vision, inability to focus the eyes, difficulty in identifying objects, and the presence of scotoma, diplopia, and so forth. Yellow and green vision are striking, and are often alarming manifestations of intoxication with digitalis. Toxic cerebral effects of digitalis are not as yet fully appreciated and are of the utmost importance owing to their seriousness. In older medical writings, allusions are found to the so-called cardiac psychoses, some instances of which were probably the result of intoxication with digitalis. The first symptoms usually are restlessness and increased nervous irritability; periods of disorientation regarding time and place soon follow. These manifestations are frequently supplanted by stupor, from which the patient does not recover. Visual disturbances mayor may not be associated phenomena. Toxic cerebral symptoms may occur without the more usual signs of poisoning by digitalis. The onset of any of these symptoms clearly indicates immediate discontinuance of the drug, for the time at least, and the prompt clearance of the tissues; this may at times be possible by the daily intravenous administration of hypertonic glucose solution. VOL. 21-49