·No text on this page.

·172
urrent Concepts
DIGITALIS THERAPY

·No text on this page.

·Current Concepts in
DIGITALIS THERAPY
Ву
BERNARD LOWN, MD.
Formerly Assistant in Medicine,
Peter Bent Brigham Hospital
and
SAMUEL A. LEVINE, MD
Chnical Professor of Medicine,
Harvard Medical School,
Physician, Peler Bent Brigham Hospital
SINCE
LONDON
J & A. CHURCHILL LTD.
101 GLOUCESTER PLACE, W1
1955

·ALL RICHTS RESERVED
This book may not be reproduced by
any means, in whole or in part, with.
out the permission of the Publishers.
PRINTED IN THE UNITED STATES OF AMERICA
AND PUBLISHED IN BOSTON BY
LITTLE, BROWN AND COMPANY
34 BEACON STREET

·Acknowledgments
The authors wish to express gratitude and acknowl.
edge indebtedness to the following, who aided in the
prosecution of these studies;
DR. M. G CRISCITIELLO
DR. A. T. CROCKER
DR J. G. GROS
DR. R. HOIGNE
DR. HD LEVINE
DR H. J. LEVINE
DR. J P. MERRILL
DR J. P. VAZIFDAR
Dr. J M. WELLER
DR N. F. WYATT
MR. W ELLIOTT
Miss EUNICE GILMAN

·No text on this page.

·CONTENTS I INTRODUCTORY REMARKS 3 6 6 8 8 10 II. THE ACTION & VD CLINICAL USE OF DICITALIS Extracardiac rffects Cardiac Action Effect on the heart rate Myocardial Action Clinical Use Physicochemical Basis for Digitalus Action Other Uses Additional Clinical Comments Choice of Digitalizing Agent III, DigitALIS INTOXICATION Subjective Manifestations Cardiac Disturbances Other Toxic Effects Cravity of Digitalis Intoxication Differences in Aiyocardial Reaction to Digualis Rising lacidence of Digitalis Intoxication 13 15 36 17 24 24 26 29 29 32 35 38 40 IV. ELECTROLYTES AND DICITALIS Calcium Magnesium Potassium Potassium Metabolism in Heart Failure V. RELATION OF POTASSIUA TO DICITALIS INTOXI. CATION Mercurial Redigitalization 43 49 49 ·58 60 Potassium Depletion Through Means Other than Mercurial Diuretics Animal Hemodialysis Human Hemodialysis 63 Clinical Problems 67 VI. PAROXYSMAL ATRIAL TACHYCARDIA WITH BLOCK 72 Electrocardiographic Features 72 Experimental Studies Production by digitalis 75 Production by potassium removal 76 Abolition by potassium administration 78 Clinical Studies 81 Incidence and predisposing factors Prognosis Idiopathic paroxysmal atrial tachycar. dia with block Differentation from other atrial mechanisms Treatment Potassium Procaine amide (Pronestyl) VII. A DIGITALIS TOLERANCE TEST Electrocardiogram as Indicator of Digitalization Chemical and Biologic Assay Methods Embryonic duck heart mcto-assay method Radioactive digitalis Acetyl Strophanthidin Tolerance Test Principle Agent Animal experiments 81 85 85 87 92 92 96 104 107 108 109 112 114 114 116 vüli

·Clinical Studies with the Tolerance Test
Material and methods
Technic
Interpretation
Results
Patients requiring digitalis
Digitalis not indicated
Uncertain and unfavorable results
Discussion
VIII Co\CLUSIONS
BIBLIOGRAPHY
INDEX
119
119
119
120
120
127
129
131
138
134
197
153

·No text on this page.

·Current Concepts in DIGITALIS THERAPY

·No text on this page.

·CHAPTER I Introductory Remarks THE use of digitalis marks the beginning of the modern era of cardiac therapy. Whole-leaf digi. talis and the punfied derivatives, the cardiac glycosides, continue as the most effective medicinal agents in the management of patients with congestive heart failure. The loss of cardiac reserve manifested by failure is the result of an imbalance between cardiac muscle strength and the work load imposed on the heart Therapy is therefore directed toward improving the function of the failing heart muscle and reducing the work load on the myocardium. The two are intertwined; affecting one influences the other Since the ultimate event in the chain leading to clinical failure occurs within the heart, the main therapeutic goal is to improve the vital function of the heart in propelling blood The digitalis drugs are the only agents known to restore compensation through such direct action on the myocardium All other measures are ancillary The need for these supplementary measures in a given case varies inversely with the efficacy of digitalis During the last decade intensive study of the pathogenesis of one of the features of congestive heart failure namely, edema accumulation has focused attention on the kidney A glomerular tubular imbalance has been suggested as the critical factor in the formation of cardiac edema,1,2 Emphasis on the (3) ·role of the kidney in increasing the cardiac load through salt and water retention has brought about a deviation from the concept of the primacy of the heart in initiating and sustaining failure. A stage has been reached at which arguments are being advanced to reassign to the heart the major role in the complex drama of congestive heart failure. The tendency to regard failure as the consequence of renal impairment has had therapeutic implications As a result therapy is sometimes based exclusively on salt manipulation achieved through various regimens of dietary salt restriction, interference with intestinal sodium absorption and the promotion of renal salt loss The mercurial diuretic and the weighing scale have been proposed as the vital implements for managing congestive heart failure : Recognition of the inseparable interaction of cardiac and extracardiac factors in the pathogenesis of failure must guide therapy Translated into practice this means that digitalis is useful, with but few erceptions, during the entire course of the evolution of cardiac failure. In the early stages major reliance is placed on digitalis Measures that diminish heart work, however, are not neglected As decompensation advances and digitalis no longer overcomes the deterioration in cardiac competence, emphasis shiſts to the restriction of salt intake and the promotion of salt loss In the initial phases of decompensation the aim of therapy is to improve the function of the heart for the requirements of normal life In the later phases the goal is to diminish the heart's burden and to bring it within the domain of limited cardiac performance. As in Withering's day, the proper use of digitalis [4] ·presents many problems. Questions of when and how to administer the drug as well as how to determine the adequacy of maintenance dosage are not yet fully answered. During the past three years new data on the action of digitalis have been acquired in our laboratory. In this report some of our work and the relevant studies of others are reviewed. These are considered from five points of view: the mode of action of digitalis and the clinical indications for its use; the toxic properties common to all therapeutically active digitalis-like preparations; the changes in the toxic threshold after alterations in body electrolytes, atral arrhythmias frequently resulting from overdosage; and a method for predicting digitalis requirement for maximum therapeutic effect before digitalization (5) ·CHAPTER II The Action and Clinical Use of Digitalis in Heart Failure Extracardiac Effects The rational use of digitalis requires an understanding of its action on human cardiovascular dynamics. The effectiveness of digitalis in heart failure has been attributed to direct cardiac as well as extracardiac actions. Withering was impressed with the diuretic properties of digitalis and attributed improvement to drug action on the kidneys. His contemporary, John Ferriar, was the first to conclude that the essential quality of the plant was exerted on the heart, Present-day concept is in accord with Ferriar's view and holds that mobilization of edemna is secondary to improved cardiac function. Kecent studies with Digoxin, however, show that this glycoside has a moderate but definite diuretic acsion. In patients without edema or with noncardiac edema a slight increase in salt and water excretion follows its administration. When normal persons are given desoxycorticosterone acetate (DOCA) and an increased salt intake until edema formas, Digoxin induces a profound diuresis comparable qualitatively and quantitatively to that observed in congestive heart failure In none of these subjects did digitalizacion produce alterations in renal or cardiac hemodynamics Digoxis may therefore exest a direct effect on the renal tubules Presumably, the drug depresses (6) ·sodium reabsorption by competition with a DOCA-like adrenal steroid that it resembles in chemical configuration. In ordinary clinical failure the improvement that occurs with digitalization frequently precedes and at times is not associated with any significant diuresis. This suggests that if a direct renal factor is operative it is in all likelihood subsidiary to the effect of digitalis on the cardiovascular system Is the clinical value of digitals derived from a peripheral or central action on the cardiovascular apparatus? The reduction in venous pressure and the enhanced cardiac output after digitalization resemble the changes produced by tourniquet application or phlebotomy McMichael and Sharpey-Schafer' therefore concluded that digitalis acts through venoconstriction They reasoned that, by augmenting periphcral venomotor tone, digitalis lowered venous pressure, decreased venous retum and lessened the overload on the heart The result was a more efficient contraction and more complete emptying of the heart When ouabain was the glycoside tested the same observers found that in half the cases of heart failure there was a definite increase in cardiac output without associated changes in venous pressure This indicated direct stimulation of the heart. Others utilizing cardiac-catheterization technics found no relation between the magnitude of fall in senous pressure and the degree of increase in cardiac output Furthermore, the increased cardiac output preceded the fall in the central venous pressure Similar studies in patients with isolated failure of the left ventricle demonstrated that with digitalization there was a significant increase in cardiac output and stroke volume [7] ·accompanied by a decrease in pulmonary arterial pres- These were achieved without alterations in right-ventricle end-diastolic pressure and could not be ascribed to the action of the drug on systemic venous pressure.10 Cardiac Action Efect on the heart rate In general there are two concepts of the mode of digitalis action on the heart One school considers that restoration of compensation is an indirect effect mediated through reduction in rate, and the other attributes it to direct action upon the myocardium Mackenzie" and Lewis'' ascribed the benefits to depression of atrioventricular conduction and vagal slowing of the heart rate Digitalis was therefore restricted to patients with atrial fibrillation and a rapid ventricular respons. The larger number of patients whose failure was accompanied by regular rhythm frequently were not treated with digitalis Such a view is no longer tenable Extensive clinical data attest to the fact that patients with normal sinus mechanism are strikingly benefited. Experience with cardiac catheterization in failure demonstrates similar hemodynamic changes after digitalis irrespective of the underlying rhythm It is now generally believed that, with the exception of certain atrial arrhythmias, slowing of the heart rate is the result of restored compensation rather than the converse in patients with sinus rhythm digitalis may improve the clinical state before a material reduction of the heart rate Therapeutic doses slow a rapid heart only in the presence of failure When increased rate occurs without decompensation, as in the sinus ( 8 ) ·tachycardias of fever, anemia and thyrotoxicosis, digitalis is notoriously ineffective. Atrial fibrillation may be an exception when rate reduction per se is a significant factor contributing to improvement. In patients with atrial fibrillation, who are highly susceptible to rate fluctuations, the ventricular rate reflects the state of compensation. When failure is accompanied by fibrillation with a rapid sentricular response, slowing invariably occurs with restored compensation. That rate reduction alone 15 a significant factor is indicated by the following observacion Occasionally, a patient with mitral stenosks and pulmonary congestion, having normal sinus rhythm, fails to improve on digitalis only to show a distinct clinical improvement with the onset of atrial fibrillation This change for the better may take place on the same dose of digitalis of the ventricular rate after the onset of fibrillation becomes slower than it was wish sinus thythm This apparently results from the ability of the drug in this instance to slow the ventrcles when the auia are fibrillating, in contrast to its failure to do so when the rhythm is regular Two mechanisms are operative in slowing the heart." When small doses of digitals are administered slowing is mediated by the vagus nerve and may be abolished by atropine or exercise. As the dose 15 increased, extravagal factors predominate The resting rate with small or large doses of digitalis may be the same When the slowing is merely vagal, however, physical exertion causes exaggerated acceleration of the heart " These facts account for the ob senation that further improvement may be achieved after more digitalis without rate alteration in p.. [9] ·tients with atrial fibrillation rate response to exercise serves as an effective gauge to the adequacy of ther. apy. Such a clear-cut indicator is absent in patients with normal sinus rhythm. This is in part responsible for the belief that digitalis is effective only in patients with atrial fibrillation. Alyocardial Action The major pharmacologic effect of digitalis is its direct action on the myocardium Digitalis increases the force of systolic contraction of heart muscle," without alteration in the diastolic fiber size. The more forceful contraction results in more complete ventricular emptying with a rise in volume output. There is also an enhanced capacity to propel blood against increased peripheral resistance 16 At the same time the duration of systole is abbreviated, allowing greater time for both ventricular filling and heart rest." The diastolic size of the heart is reduced.16 Since oxygen consumption is a function of the initial diastolic fiber length such a reduction in size diminishes the oxygen expenditure for any work output.20 The work capacity of the heart is increased, and a greater percentage of the liberated energy, therefore, is used in the mechanical processes of shortening and development of tension The over-all result is an increase in cardiac efficiency and output The basic pattern of myocardial derangement that characterizes failure is thus reversed in other words the digitalized farling heart can do the same work with less energy (oxygen utilization) or more work with the same energy expenditure than before digitalization ( 101 ·Clinical Use The cardinal therapeutic value of digitalis in failure is its ability to increase a deficient cardiac output. In the usual case of chronic congestie heart failure the clfect on the inadequate output is continuous. In the patient with incipient failure, increase in output may occur only during brief periods of the day when demunds for solume or pressure work are beyond the capacity of the myocardium Mleasurable increase in the cardiac output is not an insanable end result of digitalis therapy It occurs only in the presence of congestive heart failure Harrison and Leonardº found that, when digitalis is given to nonnal dogs, cardiac output is decreased by about 25 per cent Similar seductions were ob sened in human and animal studies in the absence of organic heart disease in the presence of heart disease, as manifested by cardiac enlargement, but in the absence of failure, digitalis is also incffective in razsing the output in a third of such patients studied at rest with cardiomegaly due to cor pulmonale and hypertension, coronary artery or sah ular heart discase, digitalis decreased the cardiac output In the remaining patients of this group output was unchanged. These results with digitalis could not be related to a previous history of congestive heart failure, to heart size or to the initial level of the cardiac output " The effect of digitalis in increasing cardiac output therefore depends on the qualitative alterations in cardiac metabolism associated with failure Although farlure is a prerequisite for the myocardial effect of digitalis, its presence does not assure ( 11 ) ·therapeutic effectiveness. The underlying process causing the failure is the critical determinant Digi. talis has little if any value when the disability is due merely to a mechanical constriction within the heart as in some cases of tight mitral stenosis with pulmonary congestion and normal sinus rhythm. Digitalis. provides no relief when the congestion derives from "pericardial embarrassment of the ventricles" interfering with ventricular filling such as that occurring in cardiac tamponade or constrictive pericarditis, unless concurrent myocardial failure cxists 23 Digitalis provides little benefit in the presence of active rheumatic carditis.24,25 It has limited value in cyanotic congenital heart disease 26 Finally, digitalis affords no improvement in the majority of cases of so-called high-output failure.3? This group is characterized by decreased peripheral arteriolar resistance Although the resting cardiac output is elevated it does not suffice for body needs altered by mctabolic or mechani. cal factors It comprises such conditions as thyrotoucosis, anemia, beriberi, osteitis deformans and arteriovenous fistulas In the majority of cases of heart failure the loss of cardiac reserve is associated with a decreased cardiac output It is in this group of so-called low-output failure that the cardiac glycosides strengthen the contractile powers of the myocardium Complete or partial resolution of failure generally occurs whether the ctiologic factor is hypertension, coronary artery, arteriosclerotic or valvular heart disease and is independent of the heart rate or the underlying atrial rhythm Why digitals is effective in failure and the [ 12 ] ·manner in which the derangement is improved remain unsolsed. Physicochemical Basis for Digitalis Action Suggestions regarding the biochemical site of digitalis action are being adduced from studies on the contractile elements of muscle According to the stimulating ideas of Szent-Gyorgyi,a' the contractile system of muscle consists of an elongated protein conjugate, myosin, and its precipitan, polymerized actin. These two proteins are attracted by colloidal forces, but are kept apart by an atmosphere of potassium ions The excitatory Impulse depolarizes the cell membrane, which thereupon becomes permeable to catrons This permits egress of potassium ions, and diffusion follows along the gradient of their sonic concentration The loss of cellular potassium promotes the union of the contractile proteins. These proteins adsorb adenosinetriphosphate (ATP) The resulting actomyosin-ATP complex becomes maximally discharged and folded, with a loss of energy The enzymatic hydrolysis of ATP follows, with myosin acting as an ATP-ase and with a release of its phosphatebond energy to recharge the contractile system and return it to a relaxed state. During the recovery phase of the cardiac cycle, catabolic processes reinvest energy into the ATP molecule so that it may serve again as the primary high-energy phosphate donor in the cell The complex process here outlined has been arbitranly divided into two phases, one of energy production, during which substrate and oxygen are utilized, ( 13 ) ·and another in which the available energy is converted into mechanical work.25,90 In low-output failure Bingia has shown that left ventricular blood flow per 100 gm. of myocardium is normal. A normal pattern of aerobic oxidation continues The glucose oxy. gen cxtraction ratio sises from a normal range of 60 to 80 per cent to an average of 100 per cent, whereas the consumption of such substrates as lactate and pyruvate remains unchanged. Furthermore, the supply of ATP is undiminished Thus, the biochemical lesion in low-output failure appears to be lodged not in the phase of aerobic energy release but rather in the conversion of the normally available energy into useful work 28,50 Presumably, the defect resides in the overstretched contractile elements of the mus. cular machine On the basis of clinical experience that digitalis acts mainly in low-output failure the biochemical site of its action is apparently limited to the energyutilization phase It may therefore be anticipated that digitalis in some manner affects either the contractile elements themselves or the concentration of intracellular potassium that mediates the contractile action In vitro studies are providing evidence of such accion Digitalis can accelerate the spiraling of miosin threads si Digitalis compounds also speed the polymerization of actın, a stage preliminary to its union with myosin This is true only of cardiac actin, but not of actin deriscd from skeletal muscle *? Friedman and St Georges studied the intracellular fate of digitoxin in heart muscle and liver by means of ultracentrifugation and assay of the fractions for their digitoxın content, utilizing the duck-heart prepara- ( 14 ) ·tion. Digitoxip was not found in the mitochondrial components where enzymes concerned with the ghcolyuc process of the Krebs cycle are situated but was abundantly concentrated in the area of the cell containing ATP, actin and myosin. This is in accord with the view that digitals acts on the contractile clements of the cardiac cell. Digitalis, furthermore, affects cellular potassium concentration Therapeutic doses are said to increase, and toxic doses to decrease, cellular potassium content"-55 These studies are unfolding the basis for the specificity of digitalis action in low-output failure Other Uses Whereas the prime value of digitalis is denied from its therapeutic action on the myocardium certain other properties find clinical use in large doses digitalis impairs conduction in the atrioventricular junc. tronal rissue and also prolongs the conducnon recosery time of atrial muscle These actions are utilized in atrial flutter and fibrillation When these arrhyth muas are being converted bs quinidine the atrial rate diminishes, thus, together with the atropine-like effect of quinidine on the vagus is conducive to increased facility of atnosentricular conduction with accelerated ventncular response The increased heart rate may necessitate interruption of quinidine therapy In such cases large doses of digtals. by delaying atrioventricular conduction, may present bouts of tachycardia In some cases of atrial flutter digitalis is directly effective in conserung the arrhythmia to more easily managed fibrillation In addition it is the agent of choice in the treatment of paroxysmal ( 15 ) ·atrial tachycardia when simpler measures of vagal stimulation have proved unavailing. Additional Clinical Comments As an illustration of the application of some of the principles discussed, one might comment on a frequent error that prevails in general practice. Many patients in the latter decades of life who complain of dyspnea are not helped by digitals The drug is given because heart disease is the usual cause of shortness of breath in the elderly person. In these cases, however, the dyspnea proves to be bronchial in origin and part of the picture of pulmonary emphysema. This error could readily have been avoided because the heart under these circumstances not only is not enlarged but also may even be smaller than normal From the previous physiologic considerations it could be inferred that if the heart is not dilated, it is very unlikely that digitalis would afford any benefit There are conditions in which certain signs and symptoms simulate heart failure but digitalis is worthless Patients may have dyspnea, rales and varied pulmonary findings owing to bronchiectasis, lung tumor or other primary respiratory lesions festations that are common in heart failure and yet occur without heart disease Similarly, an enlarged liver due to Laennec's cirrhosis or neoplasm may be confused with right-sided failure. Finally, peripheral edema has numerous causes apart from heart failure In all these cases simple hemodynamic studies, such as determinations of venous pressure and circulation time, as well as x-ray examination for vascular conmani ( 16 ) ·gestion of the lungs, may sen e lo establish the absence of heart failure A converse example in which symptoms are lacking and yet digitalis proves of value is in the patient with hypertension who exhibits a diastolic gallop Such a patient may not experience significant breathlessness or paroxysmal nocturnal dyspnea though the heart muscle is already in the early stages of failure that digitalis may remedy. Choice of Digitalızıng Agent The varying actions of the digitals drugs do not require different preparations To date no fundamental differences have been found among the digitalis glycosides in their effect on the heart The dissimilarities encountered are quantitative and related to the rapidity and degree of absorption and vanability in potency and duration of action Nevertheless, the continuing release of new digitalis preparations with claims of special efficacies causes many a physician to engage in a well-o'-the-wisp pursuit after the ideal agent The result is that he does not master the use of a single one The conclusion is that adequate experience with one purified digitalis glycoside in addition to digitalis leaf permits one to cope with nearly all clinical situations in which digitalis is indicated Powdered whole-leaf digitalis, the most widely emplayed preparation, Ines satisfactory results in the majority of patients with early and uncomplicated congestive heart failure then 12 gm is given at once, the initial effect is evident within six hours and | 17 |

·No text on this page.

·TABLE 1 AOINT Route OP 10 HINS- TRATION Ova OP Темі ACTION FOR MAXI UN LFFECT DURATION OF Crfect Properties and fode of Usage of commonly Employed Digitalizing agents. Digitalis leaf Oral MATINUM DURATION OP TOXICITY 6 hr DICITAL- IZINO Dosa 12-18 hr Gatalin (gita ligin) Oral 17 da MARY 1-2 uk 112THOD OF DIOITALIZATION KAPIO Slow (Less (3-7 DA) 7 MAY 24 Ils) Die toxin 2648 br 10-12 da 1 2-2 0 gm (1 5gm ) TV Orai T. 06 m. 30 mm 2 lar }, 12 gm /6 hr, Digoxia 2-9 ar 03 gro/da. 21 da 30-10 5 mg (57 mg ) IV Oral 0 12 Kọ. (01) 30 min 2 har 25 mg 0758 om /6 hr 9 nk + 4-6 her ! 5 ang /da. Lanatos de (Cediland) 7 da IV Oral 0 25-125 mg. (05 mg 10-30 min 1-2 da O 3 mg/da 2-3 hr Cuabais 2-3 da (375 mg 13:01 302 mois 16 les 20-30 mg 1,5 m 76 tur 005-02 mg. (01 mg) IV 1 da 5 min 15.n /da 13-32 mg 30 min (1 6 mg V 14 da 025-145 ms. (05 mg 1 2 mg 2-6 br. F,04 mg 0-30 rog (07 mg) Numbers in Durrstliesci are average values 11, initial dusi, t, follow-up dose 05-10mg 10 25 ing TO peat in 30 min F. I ung /30 min.

·talis leaves are that it produces less nausea and does not require biologic standardization On close scrutiny, however, the value of digitoxın may not be so great as it seems. Whole-leaf digitalis preparations that are now available are carefully standardized by the various manufacturers Although the absorption of digitalis from the gastrointestinal tract varies somewhat, the clinician may still detect the effect of the dose that is absorbed and alter the amounts admin. istered accordingly. The prolonged effect of digitoxın, sometimes exceeding three weeks after discontinuation of the drug, is a definite and serious disadvantage In the seriously ill cardiac patient the symptoms of dig. toxin overdosage cannot be distinguished from screasing decompensation by the simple expedient of stopping digitalis administration for a few days doses vary considerably and even 1.0 mg. as an initial dose may be excessive In Table 1 can be seen the speed and duration of its action A rapidly eliminated digitalis compound is preferred in patients with advanced heart failure who are subjected to rigid salt restriction In the presence of severe decompensation it is frequently uncertain whether optimum benefit is being derived from digitalis There is no way of telling whether more digitalis will improve myocardial function except by giving more digitalis Such manipulation of dosage incurs the hazard of overdosage Furthermore, in these pa. tients the myocardial threshold to the toxic action of [ 20 ] ·digitalis may be much reduced Esen small increases in the amount of drug gryen may result in serious intoxication (sce Chapter III, on digitalis intoxication) It is obviously desirable that the toxic action be of the briefest possible duration Digoxin, because of its rapid dissipation, is a suitable preparation for this category of patients Digoxın is a punfied glycoside of definite compostion and uniform potency derived from the leaves of digitalis lanata Purity is controlled by chemical analytic methods rendering biologic standardization unnecessary it is effective both orally and intravenously Absorption from the alimentary tract is rapid and fairly complete the digitalızıng dose, when given over a period of twenty-four to forty-eight hours, ranges from 20 to 50 mg In eighty-eight patients the average digitalızıng and toxic dose was 375 and 60 mg, respectively *7 Thus its therapeutic toxic ratio of 63 per cent approximates the value for pon. dered leaf After intravenous injection, effect, as gauged by reduction of heart rate in patients with atral fibrillation, as noted within five to ten minutes and reaches its full extent in one to two hours Aft-- ingestion digitalis action begins in one hour and maximal in sıx to seven hours !42 213 Oral digitaliza 1100 us accomplished rapidly by giving 2 0 mg at once followed by 05 mg every four to six hours · The daily maintenance dose varies from 25 to 1 25 mg About 70 per cent of patients are adequately maintained with a dose of 0 75 mg or less The most effective dose associated with the least toxicity is 05 mg per day After a single oral dose of 10 to 15 mg of Digoxin is given to patients with atrial ( 21 ) ·fibrillation and rapid heart rate, the initial tachycardia recurs in three days when full digitalization is achieved the initial level is not restored for five to seien days 142 Some have objected to the use of Digoxin because of its rapid climination It is argued that omission of the drug for a day or more will cause loss of digitalization. Symptoms of failure, however, are more effective than the admonition of the physician in disciplining the patient to take the drug with nearly unerring regularity Furthermore, periodic readjustment of digitalis dosage makes the physician aware of changing digitalis requirements As with digitalis purpurea, the keystone to the proper clinical use of Digoxin consists in tailoring the dosage to the specific needs of the patient. In case of emergency for the patient with rapidly progressing acute pulmonary edema, lanatoside C (Cedilanıd) or ouabain may be used Lanatoside C manifests its action within ten to thirty minutes after injection Peak cffect is reached within two to three hours and persists for about sixteen to thirty-sit hours, 148,147 The digitalızıng dose, when used intravenously, ranges from 12 to 32 mg Digitalization can be rapidly effected by giving 12 mg at once ſol. lowed by 04 mg every two hours Its prompt dis. sipation makes it unsuitable for oral use. Ouabain is even more rapid in action 14 It is a pure crystalline substance derned from strophanthus gratus Ouabain is hydrolyzed in the gastrointestinal tract and is therefore restricted in use to the intravenous route Effect is initiated in five minutes and reaches its maximum within an hour The digitaliz- ( 22 ) ·ing dose ranges from DG to 1.0 mg Digitalization can be rapidly achieved by giug 05 mg at once and then 0 1 mg. esery thitty minutes 1** In our exa perience it is safer to gve two doses of 0 25 mg. within a half to one hour and then follow with 01 mg Once the patient is compensated a longer-acting digitalis agent may be substituted Apparently the full digitalizing dose of ouabain is eithes destroyed or eliminated within twenty-four hours It is possible to give daily a full digitalizing dose with cumulation evsdent only after sıx to ten days Paradoxically the suppression of tachycardia in patients with atrial fibrillation and rapid rate lasts four days 150 Results with ouabain are usually certain, prompt and gratify2016 If one digitalis agent were to be recommended for its adaptability to the many and vaned clinical contingencies, we believe Digoxin would be the drug o! choice In the last analsts 11 is not the digitalis compound employed but rather facility and familianty with any single drug that permuts effective treatment of the faring heart Whatever the drug used, best results follow when a prsors notions of average dosage requirements are superseded by considerations derived from meticulous observation of the patient 123 ·CHAPTER III Digitalis Intoxication Subjective Manifestations Although idiosyncrasy or hypersensitivity rarely if ever occurs, digitalis toxicity has been a problem since the introduction of this drug Little can be added to the keen observation of Withering on the results of overdosage: L1- syncope and death, All therapeutically active digitalis preparations may produce toxicity The absence of toxic properties in a digitalis body is evidence of the cardiotonic inertness of the preparation.27 The occurrence of toxicity bears no relation to the digitalis compound employed but is conditioned by the extent of failure, the underlying etiology of the failure, the cardiac reserve, the electrolyte balance, the concurrent use of other drugs and numerous other factors Anorexia, nausea and vomiting are among the ear, liest and most common subjective manifestations of digitalis overdosage. These symptoms occur whether the drug is administered orally or intravenously." Emetic movements are not prevented by the extirpa. [ 24 ] ·tion of the gastrointestinal tract or by extensive arferent denervation of visceral structures The vomit ing is thus of central rather than peripheral ongin These symptoms may be obscured by concomitant gastrointestinal disease and may be indistinguushable from similar symptoms arising from laver and bowel congestion Advanced intoxication as evidenced by objective data sometimes occurs in the absence of all subjectne indications of overdosage 38 About 25 per cent of patients with digitals intov. cation experience either visual symptoms or dizziness The dizziness may be a true vertigo and make the am. bulatory cardiac patient bedridden The usual disturbances are characterized by blurring, dancing or Nickering dots before the eyes and color aberrations ** These symptoms are trivial in comparison with the avity of the underlying disorder Information about the presence of ocular symptoms is often not volunteered and is elicited only after careful questioning Headache is a fairly common finding and may be the sole symptom preceding disturbances in cardiac rhythm Unusual neurologic symptoms have been observed in about 9 per cent of patents suffering from digitalis intoxication These consist of pains in the lower third of the face resembling Ingeminal neuralgia associated with typical neuralgic shooting pains in the upper extremities, lower Jumbar areas and calves in patients receiving large intravenous doses of the strophanthin derivative, acetyl strophanchudin, numbness and ungling of the lips, tip of nose, cheeks and ears are frequentiv nored in the elderly and those with advanced congestise heart farlure, cen. al nervous system findings may predominate, wsth ( 25 ·lassitude, apathy, confusion, disorientation, delinum, stupor, aphasia and at times psychotic behavior patterns. Degenerative glial and gangiionic cellular changes in the brain stem and cerebellum have been found in laboratory animals poisoned with digitalis Cardiac Disturbances The most important toxic effect of digitalis is on the heart. Every form of arrhythmia and conduction disturbance has been attributed to this drug." In the presence of severe myocardial damage it is a common cause of ventricular tachycardia.“? It is probably an occasional precipitant of advanced heart blocks These extreme reactions define the toxic potential of digitalis both as a myocardial irritant and as a depressant The interaction of these two effects males possible the observed gamut of electrocardiographic anomalies Irritative phenomena resulting in ectopic rhythms have been regarded as predominantly restricted to the ventricles Recent studies dernonstrate the frequency and specific form of similar arrhythmias in the atria “ This group of atrial arrhythmias and some other toxic manifestations on the heart are dealt with in a subsequent chapter The depressant action of digitalis is mainly limited to the atrioventricular junctional tissue where the direct and indirect (vagal) actions of digitalis are synergistic. Sinoatral and intra-atrial block and standstill of the atrium are rare. This is explained by the antagonism between the vagus nerve and direct digitalis effects on conduction recovery time in Į 26 ) ·the atria.'s First-degree heart block is common. Bundle-branch block or intraventricular conduction - paitment are unusual sequelae of overdosage, possibly owing to the absence of vagal influence on the ventricular myocardium The earliest electrocardiographic evidence of digitalization consists of shortening of the QT interval, ST-segment scooping and inversion of the first porn tion of the T wave. These changes provide no index of the therapeutic adequacy of the drug nor do they permut prediction of the proximity or even the presa ence of toucity Scsere digitalis poisoning may occur in their absence" In man, except for the gastrointestinal symptoms, ventricular extrasystoles are the most common sndications of overdosage When digitalis is continued in their presence the ectopic beats assume the fired pattern of bigeminy or coupling The occurrence of bigeminal rhythm without digitalis overndulgence generally indicates serious, frequently terminal, heart disease According to McMichael" the final stage of myocardial break down has been reached when digitalis ceases to be of benefit "In its presence st is never wise to gue digitalis" This statement is valid f restricted to patients in whom bigeminy has been clearly induced bi digitals In those in whom bigemsny develops without medication adequate digitalszation may abolish the arrhythmia In such cases the ventricular premature beats are expressions of congestre heart failure, inadequate coronan perfusion and myocardial anova, with a consequent increase m ventricular irritability Distinction between the two ( 27 ) ·son The margin of safety with all preparations is limited. For any digitalis agent approximately 60 per cent of the toxic dose is required to achieve a thera. peutic effect. In this respect Digoxin, digitoxin and lanatoside C offer no advantage over digitalis Icaf 57-58 An exception may be gitalin, a water-soluble amorphous mixture of glycosides extractable from digitalis purpurea. Batterman and his co-workers $9,60 claim that with grtalın only a third of the toxic dose is required for the therapeutic effect. This finding awaits confirmation. With all digitalis compounds, once toricity emerges, a substantial percentage of the fatal dose has been administered When ventricular extrasystoles are produced in animals, from 50 to 80 per cent of the minimal lethal dose has been given 61,02 Electrocardiographic evidence of overdosage is not always present. Advanced intoxication may exist continuously with only sporadic electrocardiographic manifestation Bigeminy in such cases can be brought on by slight exertion, deprivation of oxygen therapy, straining on the bed pan or emotional upset. The electrocardiogram at one moment shows a perfectly normal rhythm whereas a few minutes later ventricular tachycardia may dominate the picture. With advancing congestive heart failure the margin between therapeutic and toxic effects decrcascs In such patients, in the absence of tell-talc ventricular premature beats to arouse suspicion of overdosage, a mercurial diuresis may be fatal Toxicity can be of prolonged duration even after digitalis is discontinued When nausea, vomiting and extrasystoles appear the practice is to stop digitalis If the symptoms persist unaltered after three or four [ 30 ] ·days or more the difficulties are attributed to the severe failure rather than to the digitalis. The resumption of digitalis under these circumstances is hazardous and further compromises a limited cardiac reserve. When critical electrolyte shifts are produced in animals digitalis toxicity usually persists for the duration of the electrolyte derangement. By this means toxicity has been prolonged forty times its usual dura. tion " If the same phenomenon held true for the human being in cardiac failure, who also suffers grave disturbances in electrolyte pattern, toxicity would last many months after digitalis had been stopped This may account for the observation that small amounts of digitalis can initiate grave arrhythmias even after L. ha lack of well defined myocardial lesions resulting from toxic doses In animals an excess of digitalis produces areas of necrosis and fibrosis, especially in the subendocardial regions of the left ventricle 64-66 The administration of atropine diminishes and that of epnephrine increases the susceptibility of the tested anımals to the pathologic lesions The underlying mechanism for the necrosis may be severe coronary vasoconstriction or a shortened period of coronary filling. No morphologic changes have been noted in man Since death from digitalis finds no pathological corroboration the significance of the digitals toxicity is often overlooked The exceptions are the rare can with continuous electrocardiographic tracion just before death There are only 6 induced ventricular fibrillation: ( 31 ) ·son. The margin of safety with all preparations is limited for any digitalis agent approximately 60 per cent of the toxic dose is required to achieve a therapeutic effect. In this respect Digoxin, digitoxin and lanatoside Coffer no advantage over digitalis lcaf.**** An exception may be gitalın, a water-soluble amorphous mixture of glycosides extractable from digitalis purpurea. Batterman and his co-workers59,6o claim that with gitalin only a third of the toxic dose is required for the therapeutic effect This finding awaits confirmation. With all digitalis compounds, once tor: icity emerges, a substantial percentage of the fatal dose has been administered. When ventricular extrasystoles are produced in animals, from 50 to 80 per cent of the minimal lethal dose has been given 65,63 Electrocardiographic evidence of overdosage is not always present Advanced intoxication may exist continuously with only sporadıc electrocardiographic manifestation Bigeminy in such cases can be brought on by slight exertion, deprivation of oxygen therapy. straining on the bed pan or emotional upset. The electrocardiogram at one moment show's a perfectly normal rhythm whereas a few minutes later ventricular tachycardia may dominate the picture With advancing congestive heart failure the margin between therapeutic and toxic effects decreases in such patients, in the absence of tell-tale ventricular prcsnature beats to arouse suspicion of overdosage, a mercurial diuresis may be fatal Toxicity can be of prolonged duration even after digitalis is discontinued When nausea, vomiting and extrasystoles appear the practice is to stop digitalis If the symptoms persist unaltered after three or four ( 30 ) ·standing the large amount of digitalis, he experienced no subjective evidence of intoxication and exhibited only a few extrasystoles lasting for nine minutes. A TIME 0 OUABAN 0 ATRAL RATE 260 THIẾT 1 am incinnat 2 50 1 3 ms 260 --- برر۔ عمیر نام سیبر FIGURE 1 Electrocardiograms in a Trenty-Year-Old Man without Organic Heart Disease but with a Spontaneous Eprsode of Fluttet A shows the tracing on maintenance digitalis therapy, and B the tracing after 13 mg of ouabain had been given intravenously to induce further ventricular slowing Occasional premature ventricular beals occur over a period of nine minutes contrasting experience is shown in Figure 2. A patient with severe right-sided and left-sided failure due to coronary-artery disease and previous anterior and posterior myocardial infarctions* had been off digitalis for about five months because of nausea and vomiting. To test his responsiveness to digitalıs, he was given 1 2 mg of acetyl strophanthidin intrave- *Thus case a more fully discussed by Enselberg et al. ( 33 )

·No text on this page.

·conduction" (olff-Parkinson-\Vhite syndrome) fol. lowed Shortly thereafter, a ventricular prefibrillatory rhythm developed, The severe intoxication lasted for about thirty minutes Two days later half the dose of acetyl strophanthidin again evoked marked toxicity, These 2 patients demonstrate both the difficulty and the case of producing intoxication. The underlying status of the myocardium is one of the important factors responsible for this difference. The nor mal, therefore, differs from the failing heart both in response to beneficial and in toxic actions of digitalis It may be that toxicity is but an extension of the therapeutic effects at the cellular level. Rising Incidence of Digitalis Intoxication With the introduction of the purifed glycosides it was expected that the incidence of intoxication would durinish The patient on such maintenance therapy is assured a constant dosage because the uncontrollable variation in the potency of digitalis-leal preparations is removed The converse, however, has been true given are that the glycosides are more toxic than leaf and that the premonstory symptoms are infrequent or absent Both these contentions are without clinical substance. The pattern of toxicity is the same irrespective of the drug employed The therapeutic-toxic ratio, the only valid way of comparing digitalis compounds, is approximately the same for nearly all these drugs 951 ·The increasing frequency of intoxication, we believe, is related to the current manner of digitalis usage and the changing methods in the management of patients with congestive heart failure. With the punified glycosides rapid intravenous diitalization has become a common practice. As a rule this route is not justified. Digitalis intoxication more often follows intravenous medication; furthermore, the oral route permits prompt and effective achievement of the same result. A more serious problem derives from dogmatic oversimplification in dosage prescription A single-dose method for digitalızing with dígitoxin has been promulgated. Patients are given 1.2 mg of digitoxin at once and are maintained on 02 mg daily. The administration of equivalent amounts of digitalis leaf or tincture is not possible because of the high incidence of prompt gastrointestinal upset from direct local irritant action." This method has gained vogue because of its simplicity The practice is of little hazard to the ambulatory cardiac patient with early failure, especially since 1.2 mg of digitoxın, as shown by DeGraff and his associates, is a subdigitalizing dose in most cases. Intoxication, however, has been repeatedly observed even with this dose?? For the patient with serious cardiac disability the dangers multiply. Much of the toxicity reported since the introduction of the glycosides has been due to digitoxin. The validity of the single-dose method holds for the "average" cardiac patient Clinically, such patients are seldom encountered This approach creates pharmacologic rigidity for the patient with congestive heart failure Until a simple procedure has been devised for predicting digitalis require. [ 36 ] ·tnents responsible practice demands empirc individuslization in dosage schedule for each patient. Another factor responsible for the increase in toxicity is the expanding life span of patients with heart disease. Antibiotics, salt restriction, surgery and application of newer physiologic principles to therapy have contributed to the lengthening of life The patients who are salvaged by these means have prolonged life expectancies with greater opportunity for Men severer heart failure to develop It has already Lxen emphasized that these sicher patients are more prone to toxicity Perhaps the most important reason for the rise in the incidence of digitalıs intoxication is the increasing dependence of treatment on electrolyte manipulation Restriction of salt ingestion and administration of mercurial diuretics, ammonium chloride, cation-erchange resins, carbonic anhydrase inhibitors and cortisone are becoming part of the therapy for failure All these measures induce changes in electrolyte metabolism and may alter the threshold of the myocardium to digitalis intoxication. Such electrolyte shifts will increasingly complicate digitalis treatment of congestive heart failure. This problem is dealt with in the next chapter. ( 37 ) ·CHAPTER IV Electrolytes and Digitalis Calcium The classical studies of Ringer? -9,153 demonstrated the dependence of cardiac contraction on the electrolyte environment. In these early experiments with the perfused frog heart, it was learned that calcium and potassium ions were antagonistic in their effects on contraction. When the concentration of calcium in the perfusing medium was raised, a more vigorous systole ensued. When the concentration of potassium was raised, increased relaxation resulted in the ab. sence of calcium the effects of potassium prevailed and the heart stopped beating in diastole On the other hand, increasing the concentration of calcium caused systolic arrest of the heart, the so-called "calcium rigor" In the intact animal raising the serum level of calcium by intravenous injection causc bradycardia and T-wase changes. The reduction in heart rate is probably of vagal origin since it is reversed by atropine Continued administration of calcium results in ventricular fibrillation and death 154,155 The injection of calcium salts in human beings induces bradycardia, sinus arrhythmia, shifting pacemaker, various degrees of heart block and multiple extrasystoles of large and unusual for There may also occur a flattening of the T and P waves These effects are transient.156,197 Low levels of serum cal. [ 38 ) ·fole 188 cium are associated with prolongations of the QT in. terval. The increased duration of electrical systole is not accompanied by a prolonged mechanical sys- Calcium and the digitalis glycosides act synergisti cally to increase contractility of the frog's ventricle. At any given calcium level there is an optimal concentration of potassium at wluch contraction is maxima] The cardiac glycosides behave as though they were substituted for a certain amount of calciumn The complex interrelations betiscen calcium, potassium and ouabain have been expressed in a d'Ocagne shortened the survival time of the preparations.100 This has not been corroborated in the intact anımal organism When calcium was administered to both digitalized and nondigitalized dogs no differences were detected in the electrocardiograms at the same serum levels Furthermore, the mode of death, the lethal dose and the serum level of calcium at which fatality occurred were the same in the two groups The conclusion drawn from this study was that calcium and digitals were neither synergistic nor even completely additive. 101 In digitalized patients deaths have been reported following intravenous injection of calcium 182 The mechanism responsible for fatality is uncertain It is possible that the falling heart may be more sensitive to the toxic action of calcium The relation between [ 39 ] ·calcium and digitalis in patients with heart disease remains to be explored. Alagnesium Magnesium salts depress the contractility of voluntary and cardiac muscle. 163-166 High serum concen. trations produced by parenteral administration cause bradycardia, conduction disturbances and cventually cardiac arrest.103 The depressant action of magnesium is not mediated by the vagus nerve since it persists after vagotomy or atropinization 165-367 Death ensues from respiratory failure A consistent effect noted after intravenous mag nesium administered to patients is a feeling of intense heat in the throat which radiates downward through the body and is associated with visible blushing. i** It has been claimed that magnesium is effective in preventing ventricular tachycardia and fibrillation after large intravenous doses of mercurial diuretics 170 The capacity of magnesium to abolish digitalis intoxication was first dernonstrated by Zwillinger." He successfully treated a patient with ventricular flutter after intravenous strophanthın by the intracardiac administration of magnesium. He also reported the protective action of magnesium against digitalis poison. ing in frogs and dogs However, ventricular tachycardia and fibrillation can be provoked in dogs despite high concentrations in the blood.'' Enselberg and co-workers found that 20 cc of 20 per cent solution of magnesium sulfate when given sapıdly by intrave. nous route to cardiac patients abolished or reduced the frequency of extrasystoles due to digitalis 16The [ 40 ] ·effect was nearly instantaneous, but of very short dura- The therapeutic usc of magnesium for digitalis intoxication is limited by its transient action and by its occasional undesirable effects Potassium The importance of potassium ions for heart function was pointed out by physiologists near the turn of the century.76.19 These observations were overlooked or neglected unul clinical associations called attention to them Of all the ionic alterations encountered in man, those due to potassium have the most pronounced effects on the heart. One of the properties that differentiate potassium from other cations is its high rate of mobility across cell membranes." This may be the basis for the critical role of potassium in muscular excitability and conductivity It appears that the migration of potassiun ions links the electric phemomenon of excitation with the biochemical process of energy release essential for the mechanical event of contraction, Changes in body potassium content when accompanied by alterations in extracellular concentration are reflected in the electrocardiogrami The effects of both hyperkalemia and hypokalemia on the heart have been adequately reported A profound relation exists between digitals and potassiuryl. Digitals affects the potassium concen tration of the myocardial cell There is general agree ment that toxic doses of digitalis liberate potassium ( 41 ) ·from heart muscle 80,51 Skeletal muscle also loses po tassiurn when poisoned with digitalis 174 Digitalis sensitizes the heart to acetylcholine and vagus-nerve in. hibition; these two factors have been shown to be associated with a decreased intracellular concentration of potassium "** It may be that liberation of cellular potassium is the result of the depletion of energy-rich phosphates that occurs with digitalis overdosage 178 No agreement exists on the effects of therapeutic doses of digitalis on cellular potassium concentration. The whole range of possibilities from no change in potassium**.*l to cellular loss and gains,has been reported. Boyer and Poindexters attribute the ther. apeutic action of digitalis to restoration of cellular potassium and improved cellular hydration The resemblance between digitalis and adrenal steroids in chemical structure prompted the suggestion that there may also be a similanty in function in that digitalis acts to maintain potassium within the cell. Other similarities have been noted The cardiac glycosides as well as the adrenal cortical hormones protect rats, mice and cats against lethal doses of potassium and prolong the life of adrenalectomized animals.1** A converse relation also exists: changes in potas. sium concentration influence the action of digitalis At present, data are available primanly on the toxic effect When the isolated striated muscle of a frog is treated with ouabain there is an initial rise in tension and heat production, followed in time by loss of ex. citability Immersing the muscle in Ringer's solution, which contains potassium, causes a reversal of 10t. icity ? When rabbits are given potassium salts the lethal dose of ouabain is increased. Similarly, when 1 42 } ·the isolated duck heart is perfused with fluid of high potassium concentration the toxic action of digitalis is inhibited $This inhibition may be due either to depression of myocardial irritability by potassium or to the interference with the escape of cellular potassium when the heart is exposed to large amounts of digitalis In man potassium salts reduce or abolish ventricular extrasystoles and at times reverse paroxysms of ventricular tachycardia 86 The effectiveness of potassium is not contingent on the precipitating factors of the arrhythmia Castleden 177 found that epinephrneinduced ventricular premature beats were prevented when the patient was pretreated with potassium He was also successful in preventing extrasystoles occasioned by insulin hypoglycemia in a diabetic patient Sampson,97 who first introduced potassium in the treatment of clinical arrhythmia, noted that its action 15 more effective when the disturbance of rhythm is caused by digitalis Other investigators have confirmed that potassium is promptly effective against many of the arrhythinias produced by digitalis *184,80 It has been reported that potassium salts also eliminate the symptoms of overdosage and rapidly promote a sense of well-being in patients with digitalis poison- Ing 88 Potassium Afetabolism in Heart Failure Electrolyte and water abnormalities in congestive heart failure are due both to derangements in heart function and to the therapeutic procedures in current use In heart failure the excretion of sodium is impaired ( 43 1 ·from heart muscle.80,81 Skeletal muscle also loses po tassium when poisoned with digitalis 179 Digitalis sensitizes the heart to acetylcholine and vagus-nerve in hibition; these two factors have been shown to be associated with a decreased intracellular concentration of potassium.'" It may be that liberation of cellular potassium is the result of the depletion of energy-rich phosphates that occurs with digitalis overdosage 173 No agreement exists on the effects of therapeutic doses of digitalis on cellular potassium concentration. The whole range of possibilities from no change in potassium*0,81 to cellular loss and gain*.' has been reported. Boyer and Poindexterås attribute the therapeutic action of digitalis to restoration of cellular potassium and improved cellular hydration The resemblance between digitalis and adrenal steroids in chemical structure prompted the suggestion that there may also be a similarity in function in that digitalis acts to maintain potassium within the cell Other similarities have been noted The cardiac glycosides as well as the adrenal cortical hormones protect rats, mice and cats against lethal doses of potassium and prolong the life of adrenalectomized animals.it A converse relation also exists: changes in potassium concentration influence the action of digitalis. At present, data are available primarily on the toxic effect When the isolated striated muscle of a frog is treated with ouabain there is an initial rise in tension and heat production, followed in time by loss of excitability Immersing the muscle in Ringer's solution, which contains potassium, causes a seversal of 107 icsty 62 When rabbits are given potassium salts the lethal dose of ouabain is increased. Similarly, when (42) ·the isolated duck heart is perfused with fluid of high potassium concentration the toxic action of digitalis is inhibited & This inhibition may be due either to depression of myocardial irritability by potassium or to the interference with the escape of cellular potas. sium when the heart is exposed to large amounts of digitalis In man potassium salts reduce or abolish ventricular extrasystoles and at times reverse paroxysms of ventricular tachycardia **** The effectiveness of potassium is not contingent on the precipitating factors of the arrhythmia Castleden"" found that epinephrineinduced ventricular premature beats were prevented when the patient was pretreated with potassium He was also successful in preventing extrasystoles occasioned by insulin hypoglycemia in a diabetic patient Sampson, ? who first introduced potassium in the treatment of clinical arrhythmia, noted that its action 18 more effective when the disturbance of rhythm is caused by digitalis Other investigators have confirmed that potassium is promptly effective against many of the arrhythmjas produced by digitalis *1,89,89 It has been reported that potassium salts also eliminate the symptoms of overdosage and rapidly promote a sense of well-being in patients with digitalis poison- Ing 88 Potassium Metabolism in Heart Failure Electrolyte and water abnormalities in congestive heart failure are due both to derangernents in heart function and to the therapeutic procedures in current use In heart failure the excretion of sodium is impaired [ 43 ] ·plasm potassium is essential, in rats potassium deprivation induces myocardial lesions and causes death from congestive heart failure.! 101 Present-day therapy also contributes to the deranged electrolyte picture. It has been stated that electrolyte abnormalities in the serum are absent in the untreated patient.102,105 Low-salt diets and druretics are the chief agencies that disturb normal electrolyte equilibrium The injection of mercurial diuretics promotes the excretion of a bicarbonate-frec chloride-rich urine. After administration of mercurial diuretics the urinary chloride and potassium concentrations are significantly higher and the sodium lower than their respective values in the serum. With extensive diuretic therapy bsypochloremic hypokalemic alkalosis may result, 27,104 The composition of the diuretic urine and the lack of change in scrum sodium and potassium levels indicate that potassium leaves while sodium enters the cellular compartment. The edematous patient who has been on rigd solt restric. tion for a long time is more likely to respond to mercurial agents with increased potassiuin diuresis *'s The patient with advanced failure is therefore more likely to experience serious tasses of potassium The protracted administration of ammonium chloride by itself may result in potassium depletion. Userally, aminonium chlonde is employed to synergize the action of mercurial diuretics. The excretion of potassium is increased by such pretreatment Potassium concentration in the diuretic unne is raised by about 15 milliequiv per liter when ammonium chloride is given to enhance the action of mercurial diuretics 105 Recently introduced methods for removing sodium (46 ·from thc body exert pronounced effects on the potassiurn balance. Dock z first showed that cațion-ex change resins will increase fecal elimination of gastrointestinal sodium These resins are now widely employed in the treatment of cardiac edema. The resins in use have a greater affinity for potassium than for sodium, and unless a potassiumn-cycle resin is incorporated in the mixture183,154 or adequate potassium is provided, serious deficits may occur. Hypokalemia may be encountered even when resins containing po. tassium are utilized.185 Another agent now being used as an oral diuretic is the sulfonamide denvative Diamox (2-acetylamino- 1,3,4-thiadiazole-5-sulfonamide) The sulfonamides have been found to be specific carbonic anhydrase inhibitors.186 Such inhibition of renal carbonic anhydrase prevents the tubular secretion of hydrogen on and its reabsorption of sodium 18+ Schwartz185 found that sulfanilamide caused diuresis in patients with congestive failure, Diamoe is from fifty to four hun. dred times more potent as a carbonic anhydrase inhibitor than 15 sulfanilamide 169 Furthermore, it is much less toxic These properties are finding clinical application 180 From the standpoint of potassium, both experimental and human studies reveal that Diamox causes substantial increases in its urinary excretion 180,191 In patients with heart failure the underlying pathologic process and the therapeutic regimens for its management constitute the two general categories of factors that deplete both cellular and myocardial potassiurn It is unknown to what extent potassium depletion contributes to the biochemical lesion and ( 47 ) ·aggravates the clinical state of congestive failure It has been demonstrated that the loss of potassium sigo nificantly affects the body's threshold to the toxic action of digitalis and may be an important cause for the rising incidence of digitalis toxicity. [ 48 ] ·CHAPTER V Relation of Potassium to Digitalis Intoxication Alercunal Redigitalization Evidence that potassium loss from the body may precipitate digitalis intoxication was first gained in a study of the postmercurial redigitalization phenome- From twenty-four to forty-eight hours after diuresis a digitalized patient may experience nausea, vomiting, giddiness, headache and considerable weakness Electrocardiograms may demonstrate any of the changes that occur with an overdose of digitalis The mobilization of digitalis-containing edema has been implicated as the mechanism Two quantitative studies have been carried out to date Miller: determined the amount of digitalis in ascitic and pleural fluid by means of the Hatcher cat assay technic In digitalized patients with heart failure he found the tremendous concentration of 0 46 to 09 cat units per 100 cc of edema Schnither and Levine206 utilized the frog assay method and also noted significant quantities of drug in the extravascular fluid accumulations of digitalized patients They presumed that as much as 01 gm of digitalis leaf or equivalents may be present in a liter of edema It was their conclusion that the postmercurial manifestations were due to the dosage after diuresis [ 49 ] ·If the explanation is valid, the administration of an extra amount of digitalis, without any, diuretics, to patients who tend to develop this syndrome should precipitate toxicity The additional amount required would be predictable from the size of the diuresis (assuming that a liter of edema contains as much as 01 gm, of digitalis bodies). When a dose of digitalis is given equivalent to the maximum amount presumed mobilized no toxicity follows. If, for example, a pa. tient who experiences postmercurial redigitalizations with diuresis of about 1500 cc, receives in addition to his maintenance dose 0 15 to 0 3 gm of digitalis leaf, no toxicity is produced. There is a further objection to this theory If digitalis-laden edema is the causa. tive factor, the onset of the syndrome should relate to the magnitude of the diuresis Schnitker and Le. vine108 observed no such relation Direct evidence of the absence of digitalis glycosides in edema fluid has been provided in a recent study by the micro-assay technic utilizing the embryonic duck-heart prepara. tion 195 These investigators found that edema fluid removed from 8 patients digitalized with digitoxin revealed a maximal digitoxin content of 20 micrograms per liter of edema, In half the patients no digitoxın was detected Even massive diuresis, therefore, could not mobilize sufficient digitalis to account for the postdiuretic intoxication phenomena, A mechanism **---'an mitet operate to chang tion of some of enon suggests another explanation The patients who exhibit such postmercurial difficulties invariably have advanced congestive failure They have been main. ( 50 ) ·tained on rigid salt restriction and are usually receiving ammonium chloride to improve the response to mercurials.106 These are the patients who are likely to excrete substantial quantities of potassium in response to diuretics, It may be that the heart's threshold to the toxic properties of digitalis is reduced by potassium depletion, as is true in isolated heart preparations ) If potassium loss is responsible for the toxicity, potassium administration should abolish it. This is indeed the case The action of potassium on the postdiuretic symptoms and signs is no different from its action in stopping other manifestations of digitalis poisoning After the ingestion of potassium chloride the first effects are noted within twenty to thirty min. utes Peak action occurs in one to three hours, at the tirne when the highest serum level is achieved Dissipation of effect follows within four to eight hours. Occasionally, digitalis-induced arrhythmias are permanently eliminated, usually there is a recurrence within the above-indicated time interval after a single dose of potassium. The nonspecificity and transiency of the potassium effect would lead one to conclude that the action of potassium is pharmacologically in the nature of a dea pression of myocardial irritability rather than the result of a correction of deficits resulting from the diuresis This conclusion is contradicted by the following experience when a patient who consistently develops redigitalization is given potassium during the diuresis the later occurrence of symptoms and signs is prevented Since the duration of the effect of potassium is about eight hours, whereas toxicity usually ( 51 ) ·Mercaptomerin, which had been supplemented by ammo nium chloride This time the response to 12 mg of acety! strophanthidin was qualitatively different (Fig 3B). Within 5 minutes of the injection multifocal ventricular pre mature beats appeared, with runs of bigeminy and trigeminy One bour after the strophanthidin the patient experienced nausea and vomiting, Toxıcıty persisted for about 90 minutes, whereas the therapeutic slowing continued lor 4 hours Study of the potassium balance revealed a loss of 83 milliequiv after the ammonium chloride and mercaptomerin, without any significant changes in the serum po tassium concentration, AR, a 20-year-old woman with mitral stenosis, had normal sinus rhythm and right-sided and left-sided failure. On 2 occasions, 1 month apart, she was digitalized with small fractional doses of ouabain ta end points of mild toxicity. Each digitalization followed a mercurial-induced diuresis that resulted in excretion of significant quantities of potassium (Table 2) The atrial mechanisms at the time of the 2 tests were different, and yet the requirements of Quabain were nearly the same (Fig 44) With 06 mag and 07 mg of ouabain Dausea, vomiting, changing atrial pace makers and rare ventricular premature beats developed The arrhythmias persisted for several hours When ouabain was given in an identical manner but after a positive potassium balance, achieved by the ingestion of 7.5 mg of potassium chloride daily for 10 days, the dose for toxicity was nearly doubled (Fig. 4B) This occurred despite a 20 per cent reduction in weight After 12 mg of the drug the patient erhibited the same toxic end point As previously, and with a total dose of 13 mg she experienced nausea and vomiting Ventricular extrasystoles were not observed The changing auricular pacemaker persisted for only 1 hour Two patients in similar studies who did not sustain losses of potassium alter diuresis showed no changes in threshold to the action of acetyl strophanthidin 107 The postmercurial redigitalization phenomenon may be defined as a state of increased myocardial sensitivity to the toxic properties of digitalis resulung from a negative potassiura balance precipitated by diureuc ( 54 ) ·Dan Devo TABLE 2. Successive Digitalization with Prachonal Doses of Ouabarn to the Earliest Electrocardiographic Evidence of Intoxication POTASSIUM BALANCE May 3 Rody WOMT milluquio -100 POTASSIUM SUK mulequi /aler 51 AMOUNT OY OUARAIN FOR ToXICITY June 5 June 13 Mercaptomer (2ce Mercaptomerin (2 ct ) Pocasacura chloride (75 g per day for 10 dayu) DULATION 07 TOXICITY Ar. - 70 +210 36 07 39 32 06 35 3 12 1 On May 3 and June 3 ouabarn administered 24 fu after the production of negative potassium balance by means of mercurial-induced doutril Se rum polassrum values an morning of digitalization not altered by previous mercury duresw On June 13 ouabain again given, thu lume alter trn days of potanium suppletne lation and positive balance (see also Figures 44 and B) Note inimesed tolerance to kebarn forded by adminuiratio of polst

·7
MAY 3, 1950 TIME O QUABANO
DIE OLIITITIT
90 MIN
0.6ye.
2
120
0.7
3
JUNE 3,1950
0
O
077
90
0.6
FA
120
07
3
171113
FOURZ 4A Electrocardiograms in AR

·JUNE 13,950, TIME O QUARAINO, PIL 190 MIN try 1 Owo. 240 1.2 3 270 1.3 300 5 TOVRK 4B Electrocardiograms in HR A and B represent different occasions uhen ouabann was gnen intravenously In each a prior mercurial injection had been followed by substanhal diuresis and potassium excretion (Table 2) A are control tratings, 2 and 3 were obtained Therdy minutes after 6 and 17 mg ovabatn Nausea and romising followed both digitalizations In B, after 7.5 gm potassium chloride daily for ten dap, ouabain was again administered with same dosage, schedule as previously Toric protective action of potassium) ·therapy. In its presence digitalis should be discontinued and potassium adininistered by mouth until the evidence of overdosage disappears Serious dis. turbances of thythm and even death will be prevented if diuretics are withheld when the patient gives any evidence of digitalis intoxication. Potassium Depletion Through Afeans Other than Ater. curial Diuretics Losses of potassium, irrespective of cause, potentiate the toxic action of digitalis, Both desoxycorticosterone acetate and cortisone may produce negative potassium balance and alter the threshold of the heart to digitalis.1,107 We have observed a case in which postmercurial redigitalization developed only after corti. sone had been started. Symptoms and signs were controlled by oral potassium supplementation. Mfarled disturbances of rhythm may result from small doses of digitalis when patients have sustained chronic potassium depletion through either the renal or the gastrointestinal route. In these patients, especially when the serum potassium level is depressed, even small amounts of digitalis can prove fatal. Generally, there is no reliable correlation between serum potassium concentration and digitalis requirement. The increased sensitivity that at times follows diuresis is not reflected by the serum level The serum potassium value is usually normal in the presence of digitalis intoxication. When the manifestations of overdosage are reversed with potassium there is no significant or sustained rise of the serum potassium concentration A relation, however, exists between body potassium balance and the heart's sensitivity ( 58 ) ·to digitalis This sensitivity increases with a negative balance and decreases with a positive one. There is one exceptional circumstance where lowering of the serum potassium concentration without reducing body stores sensitizes the myocardium to the toxic action of digitalis. The intravenous administration of glucose and insulin to digitalized patients and animals may provohe digitalis-tihe arrhythmias. 507,104 Within five to ten minutes after injection there is a fall in the serum potassium level The hypokalemia is transient and is caused by the withdrawal of extracellular potassium necessary for the deposition of glycogen in cellular depots 195 The arrhythmia is closely correlated in onset and termination with the altera. tions in the serum potassium values It is possible that in this special example cellular deficits of potassium are also involved in the fundamental mechanism The cellular compartment is not a single homogeneous reservoir Factors governing concentration of the bulk ions no doubt are differn entiated to subsene specific tissue function, so that concentration will vary from tissue to tissue with changes in internal and external environment The internal shifts in this case might increase the potassium in tissues where glycogen is being deposited while de. creasing it in the myocardium The sharp gradient in potassium concentration existing between cells and interststal fluid may require cellular oxidative energy for its maintenance It can be postulated, therefore, that in the presence of tissue anoxia or interference with celular nutrition Minor Huctuations in extracellular potassium concentration critically affect the concentration ratio between the two compartments The ( 591 ·patient with congestive heart failure thus may be predisposed to release myocardial potassium when the serum level is abruptly lowered. Animal Hemodialysis The studies cited above do not establish with finality a relation between the myocardial threshold to digitalis toxicity and the potassium balance of the body. In all cases multiple and complex electrolyte changes in addition to those due to potassium were either induced or present at the time of the digitalization. This limitation can be overcome by the use of the artificial kidney Ilernodialysis mahes possible selective alterations of individual ions while controlling other variables. Furthermore, the availability of acetyl strophanthidın* as the digitalizing agent permits numerous discrete digitalizations to identical end points in the course of a single day The combination of these methods enables one to effect biologic titration of digitalis requirement while body potassium is being increased or decreased. 8,196 The relation of digitalis to potassium was investigated in 11 dors by means of the artificial hidncy and acetyl strophanthidın During this study, which con- $1$ted of four phases spaced one to two weeks apart, 178 individual digitalizations were carried out to end points of sentricular tachycardia, In the first phase 5 separate digitalizations were accomplished, with fractional doses of acetyl strophanthidin at two-hour intervals. During the second phase the digitalizations were repeated while the dog was being hemodialyzed against a normal bath, with electrolytes in the dialysate *Kindly supplied by E4 Li and Company. Indianapolis, Indiapu. [ 60 ] ·ABLE 3. Dosages Required to Produce Ventricular Tachycardia in Dogs in 178 Digitalizations before and during Hemodialysis, with Alterations in Body Potassium FERIOD No or DIOITALIZATIONS AVERADE SERV'NE POTASSIUM Doss or ACETYL STROTILANTHIDIN REQUIRED FOR TOXICITY mallu quiv liter 82 074 55 0 47 Delore dialysis During dialysis, with nortaal bath potansum concentration 140 milliequiv per liter) During dialysis, with low bath por 110 concentration (01 milliequiv per liter) During dialysis, with high bath potassum concentration 100 mliequiv per liter) 19 2.17 0,19 22 70 1,15 Note the large dose of acetyl atrophantbıdın (115 mg.) needed when potassium is high and the imall dosa (o 19 mg ) wlien potaulura low, Extraction, 25 milliequiv.

·adjusted to their respective serum concentrations. The third procedure was limited to extensive potassium extractions by hemodialyzing against a bath without potassium. The final phase, the titration dialysis, again consisted of 5 digitalizations, 1 carried out before and 4 during the dialysis of the 4 digitalizations on the artificial kidney, 1 followed two hours of potassium extraction, another followed the addition of potassium, and 2 were accomplished while the potassium was maintained at a normal salue The data indicated that the quantity of acetyl strophanthidin necessary for toxicity remained con. stant of the dogs were digitalized every two hours With the start of hemodialysis there was a reduction in the dose needed to produce ventricular tachycardia Thereafter, irrespective of the duration of dialysis, the dose remained constant as long as no electrolyte alterations were induced During the potassiun extraction phase, which lasted over four hours, the serum level was lowered to about 1.9 milliequiv and an average of 48 milliequiv. was removed from the body Although specific electrocardiographic changes involving auricular and ventricular complexes were produced, no arrhythmias or conduction disturbances resulted, 196 When body potassiurn was increased during the titration dialysis, the dose of acetyl strophanthidin for toxicity rose to 240 per cent of the normal dialysis re. quirements Toxicity Jasted a few seconds. Atrial standstill was usually produced prior to disturbance in the ventricular rhythm. When massive doses were administered interventricular block and cardiac arrest rather than ventricular tachycardia followed 151.196 [ 62 ] ·When digitalization was carried out after the removal of potassium striking qualitative and quantitative changes ensued Dunng the titration dialysis the serum potassium was lowered to 21 milliequiv., and 25 milliequiv was removed (or about half the amount eliminated from the body during the longer extraction phase) The dose of acetyl strophanthidin necessary for toxicity was lowered by 60 per cent compared with digitalizations during normal dialysis (Table 3). The reduction in the amount of acetyl was consistently greater than 40 per cent. There was also a significant prolongation of the duration of toxicity Without changes in body potassium ventricular tachycardia persisted for a maximum of fifteen minutes When the potassium was lowered toxicity lasted several hours A further difference was the emergence of multifocal premature beats, bigerniny and bidirectional ventricular tachycardia (Fig 5). Hitherto, such rhythms have not been induced with digitalis in the intact mammalian heart in situ ** It can be concluded that dogs depleted of potassium respond to digitalis in a manner similar to that observed in the cardiac patient in failure there is a significant reduction in the dose that will cause intoxication, toxicity once produced is of prolonged duration, and there is an appearance of multifocal ventricular rhythms Human Hemodialysis Patients with renal shutdown are improved by hemodialysis In some cases the procedure may be lifesaving If the relation between digitalis and potassium described in dogs holds for human beings [ 63 ]

·No text on this page.

·Arease, the final decision was to administer potassium une Clinical Problems Digitalis intoxication may simulate conditions that require digitalis for control, and, conversely, arrhythmias caused by various agencies besides digitalis may resemble digitalis intoxication At times, prompt recognition of the underlying nature of the cardiac disturbance may be lifesaving The following cases illustrate these points His improved status Period he lost 14 kg of edema became does of digitalis his heart rate an withstanding Mathin systolic BVC AN, a 47-year-old man with mitral stenosis and regurgtation, for 8 years had had right-sided and left-sided fail. ure with atrial fibrillation During the year before admnis. sion he began to experience angina-like chest pain and be At the time of entry to the Peter Bent Brigham Hospital he was in severe fasure, with marked orthopnea, chronic pulmonary congestion, ascites and + + + + peripheral edema. Shortly after adpussion because of the development of a nodal tachycardia llis To assess the degree of digitalization, a digitalis tolerance test (described in Chapter VII) was carried out, indicating that he would benefit from full digitalization This was accomplished within 24 hours Thereafter, improvement was progresa 2-week permitted the performance of val. vuloplasty Two days after the operation, regular At this time he was cyanotic, moist rales were present at the lung bases, the was less than 90, and he appeared in peripheral nodal tachycardias may be caused by digitalis over. 30 milliequrt of potassium chloride had been gren by vein the rhythm reverted to atrial fibrillation (Fig. 6) The patient's immediate status improved The next day, without recering any digitalis he was nauseated and vomited, and the electrocardiogram exhibited a trigeminal rhythra and blood The regularization of the ventricular response in ( 67 ) ·rapid (Fig. 7). At the end of 1 hour his blood pressure rose to 124/78, and he began to have a copious dureus Thereafter, recovery was continuous and uneventful. A blood sample drawn before therapy revealed a potassium concentration of 7.5 milliequiv, per liter, corroborating the impression of hyperkalemia. These patients illustrate two contrasting situations. Superficial examination of A N. would have led one to give more digitalis. The patient, indeed, was showing an increasing heart rate, and the general circulatory state was deteriorating Further digitalis might verv well have proved lethal. The regularity of the rapid ventricular response in a previously fibrillating patient was the special feature that suggested overdigitalization for that reason potassium was given and was effective In E M the lack of P waves again led the attending staff to the diagnosis of nodal rhythm caused by an overdose of digitalis The administration of potassium was considered However, the possibility of digitalis intoxication was dismissed for two reasons in human beings digitalis intoxication does not cause intraventricular-conduction impairment, and when complete atrioventricular dissociation or nodal rhythm results from an overdose of digitalis, the ventricular response is usually regular When it is irregular, interference from sporadıc conduction of the atrial impulse is evident. A slow irregular ventricular rhythm with intraventricular block and atrial paralysis strongly sug. gests potassium poisoning This is to be considered even in the absence of the characteristic changes in the T contour Advanced hyperkalemia may be present without peaked T waves 110 In EM, the rapid { 70 ) ·infusion of bank blood under pressure may have produced hemolysis and thus provided an exogenous source of potassium The control of the hyperkalemic effects on the heart by the combination of hypertonic sodium solution, glucose and insulin permitted the kidneys to excrete the excess potassium without further deleterious sequelae. (71] ·CHAPTER VI Paroxysmal Atrial Tachycardia with Black The relation between the potassium balance of the body and the toxic action of digitalis called attention to parovysmal atrial tachycardia wsth block. This arrhythmia frequently resulted from eitlier an absolute overdose of digitalis or a relative overdose conditioned by a changed cardiac threshold. Study corroborated and amplified the interaction of potassium and digitalis“ Digitalis in toxic amounts has been reported to produce the whole gamut of cardiac arrhythmias encountered clinically Il Disturbances in ventricular rhythm arc well recognized consequences of digitalis intoxication. Abnormal atrial mechanisms, however, are regarded as rare and nonspecific in our experia ence paroxysmal atrial tachycardia with block is a common, serious and specific clinical entity that usually results from digitals intoxication 112 Electrocardiographic Features While the presence of paroxysmal tachycardia with bloch can be suspected on purely clinical grounds, its identification is not possible without an electrocardio gram It is a hybrid arthytlimia partaking of the characteristics of both atral tachycardia and flutter The atnal rate varies from 120 to 250, the usual rate range being between 150 and 190. The onset and offset are gradual and sequential. Unlike untreated ( 72 ) ·flutter, in which 2:1 block is the rule, 113 only 30 per cent of cases of paroxismal atnal tachycardia with block show such a response. 122 In the remainder the degree of block varies and is often inconstant The Wenchebach type of conduction is a common finding Consecutie PR intervals may differ significantly in I FIGURE 8 Typical Electrocardiographic Pattern of Digitalts-Produced cpusode of Paroxysmal Tachycardia with Clock The atrial rate is 190 Ventricular response is variable P waves are upright in the limb leads Note 10-electric base line in Leads 2 und 3 and Lenincular premature beat in Lead duration, giving the impression of complete atrioventricular block When the evolution of the arrhythmia 13 continuously observed a 11 atrioventricular response invariably precedes the emergence of the block The impaired conduction is increased by Sagal suimulation and diminished or abolished by atropine or exercise ( 73 ) ·The P waves, when discernible, are upright in Leads 1, 2 and 3 They inay be indistinguishable from the P waves originating in the sinus node, but generally differ in contour and amplitude In some cases the P wave is notched or peaked and of great size. In others it is extremely diminutive, barely ruffling the base line. The PR interval may not be constant; those incorporating a QRS complex are at times of shorter duration. Unlike flutter, in which the base line is in continuous motion, in this arrhythmia an iso-electric interval separates the atrial complexes (Fig. 8). Evidence of digitalization is usually present. The ST segment may be depressed, with inversion of the first portion of the T wave and QT-interval shortening In addition ventricular premature beats are observed in most patients These may occur singly or assume bigeminal patterns and at times give way to brief or prolonged runs of unidirectional or bidirectional ventricular tachycardia, Experimental Studies In dogs paroxysmal atrial tachycardia with block has been produced by an overdose of acetyl strophanthidin and by the removal of potassium from the digi. talized animal The administration of glucose and insulin to dogs who have been digitalized evokes atrial tachycardias. The phases in the emergence of these arrhythmias are similar to those observed in clinica! Cases 197 If paroxysmal atrial tachycardia with block, as ob. served in the cardiac patients, is caused by digitalis, it should be possible to demonstrate the following the production of this arrhythmia by digitalis when the [ 74 ] ·intervention of other factors is excluded; the precip:- tation of paroxysmal atrial tachycardia with block in the digitalized patient by the loss of potassium from the body; the abolition of paroxysmal atrial tachycardia with block by the administration of potassium and the failure to abolish auricular arrhythmias, including paroxysmal atrial tachycardia with block, when digitalis is not a factor in their genesis Production by digitalis Heyl" was the first to demonstrate that digtalis was a causative factor of this arrhythmia On three separate occasions he was able to induce paroxysmal atrial tachycardia with block in a patient with congestive heart failure by the administration of digitalis leaf. When the drug was discontinued normal sinus rhythm was re-estab. Iished The arrhythmia exhibited all the essential features described above (Fig 8) The role of digitalis and quinidine was later also suggested by Decherd, Herrmann and Schwab115 on the basis of a study of 40 patients of this group, 33 had received digitals, and in 23 the amounts were regarded as excessive by the authors In a study of 1247 patients with acute myocardial infarctions, Asheyil? observed 5 with supraventricular tachycardia Two of the patients showed the typical features of paroxysmal atrial tachycardia with block In these 2 and in 2 others digitalis was implicated in production of the arrhythmia In these clinical experiences many factors were operating, and the role of digitalis was conjectural If a relation between digitalis and paroxysmal atrial tachycardia with block exists it is necessary to demonstrate its operation without the intervention of other important variables This was made possible by the use ( 75 ) ·of acetyl strophanthidin, which permits digitalization in the course of a few minutes. To date we have observed 3 patients in whom paroxysmal atrial tachycardia with block promptly followed the intravenous administration of acetyl strophanthidin. No other drugs were utilized The maximum interval for the emergence of the arrhythmia was twelve minutes and its development was a gradual sequential process identical in the 3 patients There were roughly four phases in this development The first consisted of an increase in atrial rate frequently associated with a slight or prominent alteration in the contour and magnitude of the P wave but not in its direction. This represented the usurpation of pace-setting function by a more excitable ectopic focus. A gradual acceleration of the atrial mechanism followed, with a continuation of a 1:1 ventricular response. The third phase consisted of migration of the P waves with increasing atrioventricular block Lastly, when the rate had reached a critical level, 2:1 or greater or less degrees of atrioventricular block developed (Fig 9) The critical rate at which block ensued differed from patient to patient and in any one patient under varying circumstances The experience in these 3 patients clearly indicates the association with digitalis Production by potassium removal. In digitalized patients the loss of body potassium may have the same effect as the administration of additional digitalis In the study with the artificial kidney discussed above, 7 of the digitalized patients gave evidence of intoxication during the removal of potassium by hemodialysis, In 2 of these patients paroxysmal atrial tachycardia ( 76 )

·TINE 0
RATE 130
ACETYL S O 3
1
احمد
اسی
5 MIN
116 NO
ir mon
LIITILIN!
ini
175
ATRIAL. KATE 200
PLP
FIGURE 9 Production of Paroxysmal Atstal 1 achycardia with
Blouk by the Administration of Acetyl Strophanthıdın in a
Digitalized Patient
The earliest event consists of a change in pacemaker and
acceleration of ratt (2) This is followed by continued 17.
Tuve u «UV

·of acetył strophanthidin, which permits digitalization in the course of a few ininutes. To date we have observed 3 patients in whom parorysmal atrial tachycardia with block promptly followed the intravenous administration of acetyl strophanthidin. No other drugs were utilized. The maximun interval for the emergence of the arrhythmia was twelve minutes, and its development was a gradual sequential process identical in the 3 patients. There were roughly four phases in this development. The first consisted of an increase in atrial rate frcquently associated with a slight or prominent alteration in the contour and magnitude of the P wave but not in its direction This represented the usurpation of pace-setting function by a more excitable ectopic focus. A gradual acceleration of the atrial mechanism followed, with a continuation of a 1:1 ventricular response. The third phase consisted of migration of the p waves with increasing atrioventricular bloch. Lastly, when the rate had reached a critical level, 2:1 or greater or less degrees of atriot entricular block developed (Fig 9) The critical rate at which block ensued differed from patient to patient and in any one patient under varying circumstances. The experience in these 3 patents clearly indicates the asa sociation with digitals Production by potassium removal In digitalized patients the loss of body potassium may have the same effect as the administration of additional digitalis. In the study with the artificial kidney discussed above, 7 of the digitalized patients gave evidence of intoxication during the removal of potassium by hemodialysis. In 2 of these patients paroxysmal atrial tachycardia ( 76 )

·Tim D
RA 13
ACTYL S O 30
1
5
(m
175
10
190
H2H
-~-
32
ATRIA KATE 2
FOURE 9 Production of Paroxysmal Atrial Tachycardia with
Block by the Administration of Acetyl Strophanthidin in a
Digitalized Patient
The earliest event consists of a change in pacemaker and
acceleration of rate (2). This is followed by continued 17-
Iute V 21.

·with block developed, and in a third its maturation was stopped by potassium administration. The evolution of the arrhythmia was gradual and followed the same sequence as in the patients who received acetyl strophanthidin. A change in pacemaker was the first harbinger of the tachycardia This was followed by acceleration of rate and increasing atrioventricular-conduction impairment, which finally resulted in second-degree heart bloch (Fig 10). In 2 of the 3 patients other evidence of digitalis intoxication also developed The reduction in the serum potassiura concentration at which the arrhythmias began averaged 1 milliequv. per liter. In all 3 patients, however, the values were above 35 milliequiv, and in 1 it was 56 milliequiv. per liter. Elevation of the serum potassium level to its value before the ar. rhythmia did not promptly reverse the tachycardia Abolition by potassium administration. When paroxysmal atrial tachycardia with block is caused by digitalis potassium is rapidly effective in restoring a normal mechanism (Fig 11) In 10 episodes induced na'. En '--'iv, (1,5 to orally or Table 5). The process of reversion of the arrhythmia by potassium was a chronologic mirror image of the stage in its evolution The first change consisted of a slight slowing of the ectopic focus, with establishment of a 1:1 atrioventricular response. This was associated with a sudden increase in ventricular rate and with aggravation of symptoms of dyspnea and palpitation A diminution in atrioventricular block followed, with visible migration of the P wares and continuous re- ( 78 ) ·0 duction in the heart rate, An abrupt change in the P-wave contour then resulted in the re-establishment Twt ATRAL RAR Srryx POTASSIUX 75 malliaqury /later 1 LOUILIELL 45 145 2 52 156 الالعاب 3 3 HI 59 168 4 TO 60 170 6,6 LVL 5 IT TIITTI Sicure 10 Production of Paroxysmal Atrial Tachycardia with Block by the Removal of Potassium in a Digitalized Uremia Patient Phases in der elopment and similar to those when the arrhythmia us produced by an overdose of digitalis of a sinus rhythm" (Fig 11) Potassium is ineffective in the absence of a back- ( 79 ) ·I 15 MIN. 186 2 20 172 Fift 3 30 156 . FIFT TUN 40 120 זיויד OT Law 80 106 4.2 T! 6 FIOURE 11. Abortion of Paroxysmal Atrial I achycardia uith Block by the Administration of Potassium With slouing of atnal rate 1 1 atrioventricular response develops, wih paradoxic ventricular accelesatson (2). Atrioventricular block diminishes with decrease in afrial rate (3, 4,5) Finally, abrupt change 19 contour of P wate with reconftitution of normal sinus rhythm See Iteunes 9 and 10 ·ground of digitalis intoxication. This is true even if the mechanism is paroxysmal atrial tachycardia with bloch. In 6 cases of atrial arrhythmias not due to digitalis, 3 of which were paroxysmal tachycardia with block, the administration of 40 to 200 milliequiv. (30 to 150 gm ) of potassium chloride did not alter the atrial mechanism Potassium was ineffective even though hyperkalemia was produced in 3 of the 6 patients (Table 5) It can therefore be concluded that an overdose of digitalis affects atria as well as ventricles The atrial manifestations of advanced digitalis intoxication assume the specific form of paroxysmal tachycardia with block The laws relating potassium to the myocardial threshold for digitalis toxicity operate in this arrhythmia as in other cases of digitalis poisoning Clinical Studies Incidence and predisposing factors in a period of cleven years at the Peter Bent Brigham Hospital 66 episodes of paroxysmal atral tachycardia with block were obser ed in 51 patients 112 Half the episodes occurred during the past three years in 12 of the bouts of tachycardia digitalis was not a factor in the remainder, all of which were associated with digitalis, the evidence suggested either absolute or relative overdosage (Tablc 6) Of the 54 episodes 36 were due to a distinct overdose, 8 were precipitated by a massive mercunal diuresis while the patients were on maintenance digitalis therapy, and in 10 others a variety of factors involved were believed to have sensitized the patients to digitalis toxicity In 6 of these substantial losses of potassium, resulting either from intrinsic ( 81 ] ·TABLE 5 Effect of Potassium Administration on Atnal Arrhythmias.* ReSULTS OF POTASSIUN ADMINISTRATION HYPZ- KAIZMIA POTASSIUK GIVEN RAVERSION OP ARRHYTHMIA No. of cases TYPE OF ARRHYTHMIA EPISODES OT ARRHYTHMIA no, of cases No OP PATIENTS CAUSS OF Ашитики miliegwia. 10 0 20-100 10 Digitales Induced 6 0 Paroxysmal atna! tachycardia with block Paroxysmal atrial lachycardia with block (3 cases) Flatter. (3 cases) Nodal, lachycardia (1 case) 40-200 $ 6 "SpontaDeOUS" 6 "Nou that potatum reverses only arrhythmias produced by digitalis.

·renal lesions or from extraction by hemodialysis, were the factors In 3 of the remaining 4 the administration of cortisone, insulin or calcium precipitated the arrhythmia, whereas in the fourth the predisposing factor appeared to be a 100-pound weight loss. Thus, in slightly over 80 per cent of the episodes, digitalis was involved in the emergence of paroxysmal atrial tachycardia with block In all patients in whom digitalis was implicated the arrhythmia ceased when the drug was discontinued. The data indicate a continuing increase in the observed incidence of paroxysmal atrial tachycardia with block. Although the heightened awareness and recognition of this mechanism is a factor, in all likelihood an actual rise in frequency has occurred. No doubt the conditions discussed above, at the beginning of this section, as responsible for the augmented incidence of digitalis intoxication also account for the increased incidence of tachycardia with block. An additional reason may be that potassium loss favors the development of this arrhythmia Of the 7 patients exhibiting digitalis poisoning during hemodialyszs, 2 had paroxysmal episodes and another demonstrated the early stages of the arrhythmia In nearly half the patients, therefore, digitalis intoxication assured the form of paroxysmal atrial tachycardia with block In a study of electrocardiographic changes during 13 consecutive hemodialyses Kohn and Kiley126 observed arrhythmias in 3 In 2 of these digitalis was implicated One patient, who sustained potassium extraction, showed mcreasing digitalis effect and then an atrial tachycardia In the other patient, in whom the potassium shift was small but other electro- ( 83 ) ·TABLE 6 Causes of Paroxysmal Atrial Tachycardia unth Block in 66 Episodes Occurring in 51 Patients, NO OF PATIENTS PAPDISPOSING FACTOR NO OF LPISODES PERCENTAGE OF TOTAL EPISODES 39 81 8 54 5 OUC Attack Avociated with digitalis Overdose of digitalis Mercury druresis and digitalis maintenance Miscellaneous actors and digitalis maintenance Renal potassium losa Hemodialysis Corticle administration Inulin administration Calcuum administration Weight kus Idiopathic wicach ---- Nettet 18 2 12 ·lytes, including calcium, were corrected, a brief paroxysm of ventricular tachycardia des eloped Although the samples are small they indicate a much higher percentage of atrial arrhythmias than would be found in a random population with digitalis intoxication Since potassium depletion is becoming an increasing problem in patients with congestise heart failure a continuing rise in the incidence of paroxysmal atral tachycardia with block is to be anticipated Prognosis Patients in whom this arrhythmia is due to digitalis usually have serious heart disease All 5 patients with supraventricular tachycardia studied by Askeytit died shortly after the inception of the arrhythmia in the senes of 40 patients described by Decherd, Hermann and Schwab118 55 per cent died during their hospital sojourn Of the 39 patients studied at the Peter Bent Bugham Hospital, 23 (60 per centdied shortly after the onset of the tachycardia Perusal of the clinical records of the Brigham patients leaves little doubt that the high mortality was related to the continued administration of digitalis, at times in increasing doses Since paroxysmal atrial tachycardia with block is associated with ventricular rates of over 100, the tendency is to give more digitalis to slow the ventricles in the critically ill cardiac patient this usually induces more profound toxicity and eventually death Idiopathic paroxysmal atrial tachycardia with block The 12 patients in whom the arrhythmia was idiopathic differed in a number of respects from those patients in whom it was due to digitalis 11 No etiologic agents or predisposing conditions were evident Six of the 12 patients had not received digitalis for 1 85 ) ·at least a month before the onset of the tachycardia. A digitalis effect was not present on the electrocardiogram, and only 1 patient manifested ventricular extrasystoles. Three had no demonstrable organic heart disease. The arrhythmia lasted in 6 of the 12 more than a month and in 3 for over a year. It had been present for nineteen years in 1 case and almost continuously for twenty-five years in another. In only 1 of the 39 cases due to digitalis had the paroxysmal tachycardia with block been present for longer than a month The mortality rate was significantly lower in the idiopathic group Two patients died (17 per cent), and in both death appeared unrelated to the atrial abnormality Idiopathic paroxysmal tachycardia with block is a benign condition. When it occurs in young people it is compatible with a long, healthy and active life Digitalis therapy is not contraindicated if congestive heart failure is present. When a 1.1 response develops digitalis is the drug of choice for slowing the ventricular rate Pronestył, potassium or quinidine is ineffective in restoring a normal sinus mechanism. A convincing explanation of the mechanism that operates in idiopathic paroxysmal atrial tachycardia with block is laching A basis for the pathogenesis of this arrhythmia may be an organic or functional defect in the atrioventricular conduction system The nervous mechanisms controlling heart rate are related to the effective cardiac output When the output is inadequate because of ventricular bradycardia, reflex atnal acceleration will follow Since only a fraction of atrial beats get through, rates in excess of 150 may be necessary to sustain output The persistence of the ( 86 } ·atrial tachycardia when 1:1 conduction occurs fol. lowing exercise or emotion may be due to the prolonged continuance of the rapid atrial rate, which conditions a new level of equilibrium of atrial muscle automaticity There is another type of paroxysmal almal taclıya cardia that is not related to digitalis When atrial fibrillation or flutter is being converted to sinus slythm with quinidine a transition phase may develop that exhibits the features of tachycardia with block. This is a transient electrocardiographic patter devoid of clinical significance Diferentialion from other alrial mechanisms, Parorysmal atral tachycardia with block may resemble nearly every atrual mechanism. Before the onsct of block, when the arnal rate is slow and no previous tracings are available for comparison of P waves, it may be indistinguishable from a sinus tachycardia. When the rate exceeds 150 but the arrhythmia i still in a 1 i response phase, it is usually considered as a supraventricular tachycardia This is clearly demonstrated in Figure 12 The patient, FC, whner underlying condition was a potassiumi-losing nephritis and malignant hypertension, had fare episodes of cachycardia with block while on digitalis. The first bout (Fig 11) was precipitated by a mercurial diuret. rapid heart action sale ulio vue appeared critically sweet palpitation extreme anxiety and advancing pulmonary edema ( 87 ) The electrocardic

·Tisz
ATRIL RATE
165
Strum POTASSIUM
27 mulluqt10 /lifer
15 MIN.
135
20
124
3
30.
106
4
40
100
3.4
Ficust 12 Electrocardiograms in FG
On the basis of trecing (1) supraventricular tachycardia
was diagnosed, and digitalis suggested Housier, the hus
tory of potassium-losing nephritts and precious puodes of
paroxysmal atrial tachycardia ų tih block suggested the L AS
all response phase of the latter arrhythmud Oral polos.
sium was effective int rapidly restoring sinus rhythm

·graphic diagnosis of her arrhythmia was supraventricular tachycardia. Since the rhythm resembled a phase in the recession of paroxysmal atrial tachycardia with block, instead of digitalis she was given 20 milliequiv. of potassium chloride orally. Within fifteen minutes her heart rate dropped to 135, and within forty min- IVF V6 Coretic-Sinus Pressure FICURE 13 Electrocardiograms in CW For over a year the rhythm appeared regular on auscultation, and electrocardiograms were interpreted as showing nodal Thythm The perfectly 150-electric base line in all leads raised suspicion, however, of the underlying mechanism When carotid naus pressure was applied while a V lead was being taken the presence of paroxysmal atrial tachycardia with block was revealed utes sinus rhythm was restored, with abatement of the signs of failure When P waves are not in evidence in the standard or unipolar leads and the ventricular rate is slow because of atrioventricular block, nodal rhythm is the likely diagnosis Patient C W represents such a case of electrocardiographic misinterpretation (Fig 13). [ 89 ) ·This sixty-six-year-old man with rheumatic mitral and aortic disease had had atrial fibrillation for eleven years. For more than a year the ventricular rhythm had been perfectly regular on auscultation The electrocardiogram during this time was interpreted as showing nodal rhythm However, the application of carotid-sinus pressure, while a precordial lead was maintained in the Vi position, revealed the true nature of the arrhythmia. Atypical flutter is another name used by some for paroxysmal atrial tachycardia with bloch This is a misnomer, for it implies that the two mechanisms are nearly identical expressions of a common underlying process 45 Aside from important differences in pathogenesis and treatment there are significant electrocardiographic and clinical differences The patient in whom flutter develops is on the average a decade older than the one with tachycardia with bloch. He is less likely to have severe heart failure. He has not been on rigid salt restriction and has not received frequent mercurial injections before the onset of the rapid heart action. In flutter the atrial rate exceeds 250, except during quinidine administration; in paroxysmal atrial tachycardia with block it is invariably less The following electrocardiographic features ſurther differentiate the two arrhythmias: in untreated flutter, atrioventricular block is usually 2-1, the Wenckebach type of conduction is rare; in nearly 70 per cent of the cases the P waves are inverted in Leads 2 and 3,4 the base line between P waves is not iso-electric but has an undulant, sometimes seesaw quality, and ventricular premature beats are rare The prognosis in flutter is more favorable and ( 90 ) ·is about the same as that in the idiopathic variety of tachycardia with block. Paroxysmal atrial tachycardia with block is at times confused with atrial fibrillation The diminutive P waves and changing degrees of atrioventricular block conduce to misinterpretation The development of tachycardia with block is not precluded by many years of chronic fibrillation Some of the cases of atrial fibrillation reported in the literature after digitalis overdosage may hase been examples of paroxysmal atrial tachycardia with block Although atrial fibrillation as quite rare in patients with syphılıtıc heart disease, Resnik198 observed 7 cases in which there appeared to be fibrillation due to digitalis intoxication It is to be noted that at the time of this report electrocardiograms were limited to three standard limb leads In these leads the two arrhythmias are frequently indistinguishable It is of interest that 2 of the patients at some time in the evolution of their fibrillation cx. hibited varying degrees of atrioventricular block In ! patient 3 2 block occurred the first time digitalis was administered, this was followed by complete atrioventricular dissociation The second time digitalis was tried "atrial fibrillation" developed, lasting for twentysix days and finally stopping six days after the discontinuation of strophanthin When a very small dose of digitalis was given a third time the drug induced "atrial ſlutter," the rate of the “flutter" being unusual. ly slow, 165 The patient died the same day 198 It is therefore more than likely that some of the digitalisinduced "fibrillations" were actually instances of paroxysinal atrial tachycardia with block When the ventricular rate of a patient with long. [91] ·standing fibrillation accelerates and regularizes after a diuresis or an increased dose of digitalis, tachycardia with bloch should be suspected. When the routine leads do not show this mechanism, exploration of the precordium with CR leads may demonstrate the blocked P waves Mild cxercise may be helpful diagnostically. In the presence of fibrillation the irregularity will be increased; the converse is true in paroxysmal atrial tachycardia with block Carotid-sinus pressure may prove rewarding: it frequently enhances atrioventricular block, revealing the presence of non. conducted P waves Finally, if in a so-called case of fibrillation small ff waves are scen coming at a ratc of about 200 per minute, paroxysmal atrial tachycardia should be suspected. Nevertheless, a significant number of cases remain in which identification of the mechanism is difficult. In such patients a test dose of potassium or a digitalis tolerance test may identify the arrhythmia Treatment The treatment of paroxysmal atrial tachycardia with block does not differ from the methods of managing other manifestations of digitalis intoxication Digitalis is stopped, and diuretic measures are suspended until all evidence of overdosage has disappeared The patient's activity is restricted To suppress toxicity either one of the salts of potassium or procaine amide (Pronestyl) is employed Potassium The cffectiveness of potassium salts has been pointed out A few comments are necessary on the indications for its use, methods of administration ( 92 ) ·and the hazards that attend therapy In the ambulatory patient with digitalis overdosage the daily administration of 50 to 75 gm. of potassium chloride in divided oral doses suffices for the control of intoxication This dose should be reduced or stopped after a therapeutic result has been achieved When the episode of intoxication is severe 50 gm of potassium chloride may be given at once This amount, when the compound is dissolved in a chilled fruit beverage, In patients develops 50 sen given in divided daily doses on the day of, and the day after, the diuretic When acidosis is present the acetate or citrate salts of potassium can be used instead of the chloride Drastic depletion of this electrolyte should be avoided in the digitalized patient with uremia The elevated serum potassium level in these patients coexists with normal or reduced body stores In a number of circumstances we prefer the intravenous route for potassium administration The advantages are that the action is prompt and results are certain, and when the electrocardiogram as continuously observed, it is safer than the oral route Once an oral dose is ingested one is committed to that dose When the potassium is given intravenously, however, the infusion is halted at the first evidence of peaking or tenting of the T wave, 110 and the hyperkalemia promptly disappears For intravenous use he employ a solution containing 40 milliequiv of potassium chloride in 500 cc of 5 per cent glucose and water This is given in the course of an hour and repeated if [ 93 ] ·necessary until a total dose of 120 milliequiv. has been given Once a therapeutic end point has been reached, oral maintenance is started. We have given potassium intravenously to the fol. lowing types of cases: first, to patients in shock due to ventricular tachycardia precipitated by digitalis or to patients exhibiting prefibrillatory ventricular rhythms that may result in sudden death; second, to elderly patients with heart failure and digitalis overdosage, since such patients are prone to develop poisoning even with small doses of potassium; third, to patients with paroxysmal atrial tachycardia with block, in order to present a prolonged 1:1 response phase that may aggravate the congestive heart failure; and fourth, when data were required to ascertain wheth. er an abnormal cardiac mechanism was due to digitalis. Should the cardiac patient in failure be maintained on small supplements of potassium? The release of myocardial potassium in failure, through the pathologic process itself as well as through the therapeutic methods now in vogue, appears to provide a rationale for such use. However, the loss of the cation in failure is in all likelihood a secondary expression of chronic lesions in intracellular physicochemical processes The liberation of potassium is therefore a component of the pathologic impairment, and replenishment of the accrued cellular deficits depends on correction of the lation of the levels in the extracellular compartment would be effective against a nearly thirtyfold cellular ( 34 ) ·concentration gradient To date there is no clinical evidence that long-continued administration modifies or benefits the course of congestive heart failure Furthermore, when appetite is normal, in the absence of renal or gastrointestinal potassium loss, the ubi. quity of potassium assures an abundant supply of this cation Potassiurn supplementation is indicated only in the presence of any of the serious manifestations of digitalis overdosage or when acute loss is superposed upon the chronic underlying disease Even under these circumstances the continued administration of large doses is hazardous It has been stated that in the absence of anuria the body can excrete large ingested amounts so rapidly that toxic levels cannot be produced 128,120 Other observers have found that ingested potassium may produce intoxication in patients with heart disease 122-124 Brown, Tanner and Hecht,124 who gave 200 milliequiv (8 gm ) of potassium orally, reported striking differences between normal subjects and patients with congestive failure Although the peak serum level nomally occurs within two hours of ingestion, in persons with heart failure it is reached within three hours, and the level is correlated with the degree of failure The serum level rose 26 per cent (to 55 muulliequiv per liter) in normal persons, 43 per cent (to 60 milliequiv per liter) in patients with compensated heart failure and 67 per cent (to a value of 74 milliequiv per liter) in decompensated subjects Not only are these peals reached later but they persise longer when the failure is uncontrolled In the patient without heart disease such a potassium load will be excreted within four hours, in the patient ( 95 ) ·with decompensation it may require twenty-four hours or longer. These differences are due to low renal clearances in patients with failure. 124 In our experience the ingestion of even a lesser single dose of potassium may induce severe hyperkalemia This is especially true in elderly cardiac patients. Although they may have normal concentrat. ing capacities and urea clearances they handic potassium as though afflicted with advanced renal impairmncnt. Since the hazards are real and the benefits are dubious routine administration of potassium should be restricted to cases in which its use is clearly indicated. It should be given in moderate doses with electrocardiographic supervision for the limited period of need. Procaine amide (Proncstyl). A new agent, the amide analogue of procaine, is proving effective in controlling the arrhythmias due to overdoses of digitalis, For a number of years surgeons and anesthetists have employed procaine to control heart rhythm, cspecially during cardiac and thoracic surgery 100,200 The clinical use of procaine has been restricted because of rapid hydrolysis in the scrum and a tendency to stimulate the central nervous system in the unanesthetized patient Procaine amide, unlike procaine, is stable within the body and in therapeutic doses is devoid of convulsant action To date, procaine amide is the most effective agent in protecting dogs under cyclopropanc anesthesia from the arrhythmias caused by epinephnne 125 The antiarrhythmic property of procaine amide resides principally in its ability to depress cxcitability ?! [96] ·elevates the threshold to electric stimulation in all arts of the dog's hcart Procaine amide also depresses nduction in both atria and ventricles and prolongs e absolute and relative refractory periods The detee of these changes is a function of the plasina level the drug 201 Such quinidine-like effects are also oted in the turtle and human hearts 202,203 In conast to quindıne, however, myocardial contractility is ot depressed even with high concentrations of proaine amide 202 Procaine amide is completely and rapidly absorbed om the intestinal tract and can thus be given either cally or parenterally Peak levels after an oral dose re achieved in about ninety minutes 124 After intraenous administration effects as assessed by the proongation of the QT interval are noted within four inutes 127 The drug is slowly metabolized and exreted Plasena levels decline approximately 15 per ent an hour Roughly 60 per cent is excreted unhanged in the urine On repeated oral doses a -lateau is reached after thirty-six to forty-eight ours 126 The electrocardiographic effects, which re. emble those of procaines or quinidine, 16 consist of R and QT prolongation, T-wave flattening and QRS widening The immediate hemodynamuc effects of the intraenous injection of procaine amide have been studied 7 10 patients by cardiac catheterization There vas a reduction in systemic and pulmonary artery ressure, with a prolongation of the mean circulation me These values returned to control levels within bout thirty minutes in half this group of patients he cardiac output fell The hemodynamic changes ( 97 ) 203 ·were related to the presence of heart disease and were least evident in patients with normal hearts Procaine amide finds its most cllective chnical application in the control of ventricular arrhythmias. It promptly abolishes most bouts of ventricular tachycardia and diminishes or eliminates scntricular premature beats. 127,122,205-201 In some cases it will control ventricular tachycardia when quinidine has been un. successful. The action of procaine amide on abnormal atrial mechanisms has been less spectacular In some cases recently established bouts of atrial fibrillation are reverted to sinus rhythm 130.133 Irrespective of whether such restoration is effected a slowing of the atrial rate follows. The ff waves become coarsened and widened and resemble flutter waves in their configuration. Prom caine amide, like quindine, exerts an atropine-like effect on the vagus nerve, with accelrration of the ventricular rate in the inadequately digitalized patient.202 Procaine amide has been used with good results in nodal tachycardias, with variable results in supraventrc. ular mechanisms and with little effect in most in. stances of flutter Many of the arrhythmias successfully treated with procaine amide have been precipitated by an overdose of digitalis 137 130 Stearns, Callahan and Ellis**t were able to abolish by intravenous procaine amide nearly every arrhythmia due to digitalis. The doses ranged from 60 to 400 mg In 2 such patients with multiple ventricular extrasystoles the administration of procaine arde permitted the continuation of both digitalis and diuretic measures, with good effect. The specific interaction between procaine amide and toxic doses of digitalis was experimentally studied [98] ·by Lown and Crocker,131 who found that in dogs procaine amide was promptly effective in stopping ven. tricular tachycardias produced by an overdose of acetyl strophanthidin Such arrhythmias usually lasted from three to fifteen minutes. When 100 mg of procaine amide was given intravenously the tachy. cardia was abolished within a minute, without further recurrence of the tachycardia or ventricular extrasystoles To test further the effect of procaine amide on the toxic threshold of digitalis in dogs the following study was carried out Dogs were digitahzed with acetyl strophanthidin 5 successive times at two-hour intervals to an end point of ventricular tachycardia The first 2 digitalizations served as controls Before the remaining 3 digitalizations 100 mg of procaine amıde was given intravenously (Table 7) In 38 control digitalizations in 7 dogs an average dose of 0 95 mg of acetyl strophanthidin was required to produce ventricular tachycardia After pretreatment with procaine amnide the dose was increased to 169 mg. or 178 per cent of the control value When digitalization was carried out two hours after the administration of procaine amide the requirement of acetyl strophanthidin was still 37 per cent above the control level When small amounts of acetyl strophanthidin were injected just as an episode of ventricular tachycardia ended spontaneously there was an immediate resumption of the arrhythmia When procaine amide was used to stop such a bout of tachycardia, however, it was possible to administer nearly 65 per cent of the control dose of the drug before the abnormal mechanism was again induced (Table 7) 208 ( 99 ) ·were related to the presence of heart disease and were least evident in patients with normal hearts Procaine amide finds its most effective clinical application in the control of ventricular arrhythmias. It promptly abolishes most bouts of ventricular tachycardia and diminishes or climinates ventricular premature beats 127,132,209-207 In soine cases it will control ventricular tachycardia when quinidine has been un. successful. The action of procainc amide on abnormal atrial mechanisms has been less spectacular. In some cases recently established bouts of atrial fibrillation are reverted to sinus rhythm 130,132 Irrespective of whether such restoration is effected a slowing of the atrial rate follows. The ff waves become coarsened and widened and resemble flutter waves in their configuration Procaine amide, like quindinc, exerts an atropine-like effect on the vagus nerve, with acceleration of the ventricular rate in the inadequately digitalized patient.301 Procaine amide has been used with good results in nodal tachycardias, with variable results in supraventricular mechanisms and with little effect in most instances of flutter Many of the arrhythmias successfully treated with procaine amide have been precipitated by an overdose Stearns, Callahan and Ellis207 were able to abolish by intravenous procainc amide ncarly every arrhythmia due to digitalis The doses ranged from 60 to 400 mg In 2 such patients with multiple ventricular extrasystoles the administration of procame amide permitted the continuation of both digitalis and diuretic measures, with good effect The specific interaction between procaine amide and toxic doses of digitalis was experimentally studied [ 98] of digitalis 121,220 ·by Lown and Crocher,191 who found that in dogs procaine amide was promptly effective in stopping ven. tricular tachycardias produced by an overdose of acetyl strophanthidin Such arrhythmias usually lasted from three to fifteen minutes When 100 mg of procaine arnide was given intravenously the tachycardsa was abolished within a minute, without further recurrence of the tachycardia or ventricular extrasystoles To test further the effect of procaine amde on the toxic threshold of digitalis in dogs the following study was carried out Dogs were digitalized with acetyl strophanthıdın 5 successive times at two-hour intervals to an end point of ventricular tachycardia The first 2 digitalizations served as controls Before the remaining 3 digitalizations 100 mg of procaine amude was given intravenously (Table 7) In 38 control digitalızations in 7 dogs an average dose of 095 mg of acetyl strophanthidin was required to produce ventricular tachycardia After pretreatment with procaine arnide the dose was increased to 169 mg or 178 per cent of the control value When digitalization was carried out two hours after the administration of procaine amide the requirement of acetyl strophanthidin was still 37 per cent above the control level When small amounts of acetyl strophanthidin were injected just as an episode of ventricular tachycardia ended spontaneously there was an immediate resumption of the arrhythmia. When procaine amide was used to stop such a bout of tachycardia, however, it was possible to administer nearly 65 per cent of the control dose of the drug before the abnormal mechanism was again induced (Table 7).208 ( 99 ) ·were related to the presence of heart disease and were least evident in patients with normal hearts. Procaine amide finds its most effective chnical application in the control of ventricular arrhythmias. It promptly abolishes most bouts of ventncular tachy. cardia and diminishes or climinates ventricular premature beats 127,132,205-207 In some cases it will control ventricular tachycardia when quinidine has been unsuccessful The action of procaine amide on abnormal atrial mechanisms has been less spectacular. In some cases recently established bouts of atrial fibrillation are reverted to sinus rhythm.130,132 Irrespective of whether such restoration is effected a slowing of the atrial rate follows The ff waves become coarsened and widened and resemble flutter waves in their configuration Procaine amde, like quinıdınc, exerts an atropine-like eflect on the vagus nerve, with acceleration of the ventricular rate in the inadequately digitalized patient.201 Procaine amide has been used with good results in nodal tachycardias, with variable results in supraventricular mechanisms and with little effect in most instances of flutter Many of the arrhythmias successfully treated with procaine amide have been precipitated by an overdose of digitalis 1.7150 Stearns, Callahan and Ellis07 were able to abolish by intravenous procaine amido nearly every arrhythmia due to digitalis The doscs ranged from 60 to 400 mg in 2 such patients with multiple ventricular extrasystoles the administration of procaine amide permitted the continuation of both digitalis and diuretic measures, with good effect The specific interaction between procainc amide and toxic doses of digitalis was experimentally studied (98) ·by Lown and Crocher,"11 who found that in dogs procaine amide was promptly effective in stopping ventricular tachycardias produced by an overdose of acetyl strophanthidin. Such arrhythmias usually lasted from three to fifteen minutes When 100 mg of procaine amide was given intravenously the tachycardia was abolished within a minute, without further recurrence of the tachycardia or ventricular extrasystoles To test further the effect of procaine amide on the toxic threshold of digitalis in dogs the following study was carried out. Dogs were digitalized with acetyl strophanthidin 5 successive times at two-hour intervals to an end point of ventricular tachycardia The first 2 digitalizations served as controls Before the remaining 3 digitalizations 100 mg of procaine amide was given intravenously (Table 7) In 38 control digitalizations in 7 dogs an average dose of 0 95 mg of acetyl strophanthidin was required to produce ventricular tachycardia Aſter pretreatment with procaine annide the dose was increased to 169 mg or 178 per cent of the control value When digitalization was carried out two hours after the administration of procaine amide the requirement of acetyl strophanthidin was still 37 per cent above the control level When small amounts of acetyl strophanthıdın were injected just as an episode of ventricular tachycardia spontaneously there was an immediate resumption of the arrhythmia When procaine amide was used to stop such a bout of tachycardia, however, it was possible to administer nearly 65 per cent of the control dose of the drug before the abnormal mechan. ism was again induced (Table 7) 209 ( 99 ] ·cessfully prevented the occurrence of ventricular tachy. cardia in 1 patient by the daily oral administration of 3.0 gm , he has been receiving procaine amide for two years without evident harm. As experience is accumulating in the use of this drug, it is becoming clear that procaine amide frequently causes toxicity and may cven cause death. Flushing of the face, giddiness, weakness, bad taste in the mouth, thirst, apprehension, nausea and vomiting are some of the milder reactions 201 Febrile cpisodes,200,210 allergic reactions127.211,21: and agranulocytosis with fatal outcomc215,214 have been described The most common untoward reaction with intravenous use is hypotension Significant lowering in systolic and diastolic pressures, which forced discontinuation of therapy, was observed in 40 per cent of the patients treated by Stcarns, Callahan and Ellis 207 While the rate of infusion may be a factor, it occurs with all dosage schedules and may follow an injection rate of 25 mg per minute 207 Intraventricular conduction disturbance is a common manifestation in some instances of ventricular tachycardia, it may accelerate the ventricular rate and induce prefibrillatory rhythms 215 Sudden death after a total intra cnous dose of 300 mg has been reported 1* Procainc amide 15 prone to induce ventricular fibrillation in patients with complete atrioventricular dissociation 215 It is also contraindicated in patients with asthma 207 The elderly patient with advanced cardiac failure is more susceptible to the toxic side effects, especially with intravenous use In such patients the drug should be Procaine amide is an important adjunct to the (102] given orally ·management of the arrhythmias due to an overdose of digitalis. It resembles potassium in its effect. Its action may be due to alteration in membrane per. meability, facilitating the entry of potassium into the cell.

·CHAPTER VII A Digitalis Tolerance Test The problem of how to digitalize, how much druge to use and when to use it dates to Withering The studies of Egglestons provided a rational approach to digitalization and indicated that the quantity of drug required is a function of body weight. In practice, however, the high incidence of both overdigitalization and underdigitalization, when the weight formula was rigidly applied, led to the recognition that the dose of digitalis for maximum therapeutic effect cannot be predicted in advance but must be derived for each patient in the trial-and-error process of digitalization Although empiric dosage determinations suffice for the majority there are increasing numbers of cases in wluch even fractional digitalization is fraught with danger At times the very question of administering more digitalis is uncertain. Will additional digitals aggravate or improve failure? Are the symptoms of nausea and vomiting due to overdosage or to advanced decompensation? Are ventricular premature beats indexes of toxicity or evidence of myocardial anoxia from increasing failure? Is an episode of paroxysmal rapid heart action an expression of too much digitalıs or an indication for more? Thesc and similar ques. trons frequently confound the clinician and are conducive to indecision and contradictory hall measures The following «rpertence illustratcs one of the problems mentioned; ( 104 ) ·MO, a 36-year-old woman, manifested ventricular tachy. cardia and peripheral vascular collapse 48 hours after a mutral valvuloplasty She had been on maintenance digitalis therapy, and her previous rhythm had been that of atrial fibrillation The cause of the tachycardsa was uncertain She was treated with large doses of procaine amide, followed by, intravenous injection of quinidine and potassium chlo ride, without reversion These measures further aggravated the ventricular tachycardia by accelerating the rate, increasing intraventricular block and establishing multifocal sites for the arrhythmia (Fig 14) The ineffectiveness of both procaine amide and potassium indicated that digitalis was not a factor in the ventricular tachycardia It was suggested that decompensation with impaired coronary perfusion and resulting myocardial anoxia stimulated an irritable myo cardial focus produced by the trauma of valvuloplasty and thus precipitated the ectopic rhythm If the initiating factor was increasing failure, digitalss, by restoring compensation, would prove effective where other measures failed She was therefore given small amounts of ouabain (01 mg) every 30 minutes (Fig 14). After a dose of 0 3 mg atrial fibrillation emerged as the dominant rhythm After another 03 mg all evidence of ventricular irritability had disappeared The patient however, died 24 hours later Ventricular tachycardia is regarded as one condition in which digitalis is absolutely contraindicated In this patient digitalis was effective in reversing the arrhythmia If there had been a method for determining the digitalis status and rapidly effecting digitalization, death might have been prevented We have seen a number of similar cases in which, in retrospect, it seemed likely that if digitalis had been given promptly and in adequate dosage, the irreversible failure or tachycardia might have been controlled The converse has also been our experience digitalis was given, with harmful consequences, and in retrospect it appeared that the patient's deteriorauon in the first place was due to overdosage The problem is therefore one of evolving a method for de- ( 105 )

·TIME
10 [im
MEDICATIONS
يه
والے بل اس لیے
11.30A.M' pronesty1 =1.8qm Quinidine
2
3.30 PM.
Ouobain 0.1mg
قو
WWW
4,30 PM
0.3 mg
630 PM
0.6 m4:
عالم الاسلام امرالی
FIGURE 14 Ventricular Tachycardia Following Afro l'al.
vuloplast) 19 & Patient on Alaintenance Duguralis
Procaine amide, quinidine and potassium chloride aere ed.
minutered intra invisl) without effect Ouabain caused
seession to atrial fibrilattan

·termining rapidly and without excessive hazard the patient's digitalis status and requirements. We have desiscd a test that provides such information. Before delineating the method and its clinical use other approaches to the problem will be briefly reviewed. Electrocardiogram as Indicator of Digitalization When Cohn, Fraser and Jamiesonat first reported that digitalis caused a characteristic alteration in the form of the T wave, it was hoped that the electrocardiogram would provide information on the degree of digitalization Pardee suggested that the T wave might be used as a measure of digitalis action in man 218 Other correlative studies then followed. Bronner and Blumgart" found that the earliest alteration of the T wave occurred when about 50 per cent of the total therapeutic dose had been ingested They concluded that T-wave changes sened as a quantitative index of the amount of digitalis present in the body It was also reported that QT shortening might be employed as a measure of digitalization 270,271 Some investigators even suggested that the electrocardiographic changes were not only specific for digitalis but were characteristic for each type of digitalis preparation employed 141,222,223 Contrary viewpoints were also expressed Geiger and co-workers found that in digitalized patients the electrocardiographic changes were neither uniform nor consistent When progressive digitalization was studied by serial electrocardiograms no quantitatre correlation was observed between the amount of drug and the resultant changes in the ST segment and Twave contour Gold and his group, in attempting to ( 107 ) 225 ·evolve an electrocardiographic method for the bio-as. say of digitalis preparations, found that carefully sclectod normal subjects at rest scre required to giie a satisfactory dosage-response cunc The ST segments and T waves are highly variable parameters of the electrocardiogram. They are affected by alteration of body position, exercise, temperature, infection, excitement, hyperventilation, clectrolytes and a host of other factors Myocardial injury and ventricular hypertrophy give patterns frequently in. distinguishable from those duc to digitalis It has already been pointed out that advanced poisoning may occur without the tell-tale electrocardiographic effects of digitalis The conclusion to be drawn is that in the absence of intoxication, the electrocardiogram is without value in assessing the degree of digitalization in the cardiac patient. At best it may suggest the presence of digitals in the body Chemical and Brologic Assay Methods Until very recently there was no reliable microchemical method for detecting digitalis and its glycosides in the minute quantities that are active biologically Chemical determinations were a thousandrold Icss sensitive than the tissue concentration at which the drug is cflective The earliest chemical study was that of Keller and Killiani 246 The presence of digitalis was ascertained by the formation of a blue ring characteristic of digitoxose at the interphase of test fluid and sulfuric acid The test was capable of detecting up to 005 mg of digitoxin A more sensitie determination depended on the red color forned by the interaction between the unsaturated lactone ring [ 108 ) ·tion.15 of digitoxin and allaline dinitrophenol.*The biochemical studies of the digitalis content of body fluids were complex and cumbersome, and the results were not reproducible *** The absence of a suitable chemical test led to the use of animal hearts for the bio-assay of digitalis 2-9-231 At first, intact animals such as frogs, guinea pigs and cats were employed as test objects The determination was based on the production of cardiac standstill in a prescnbed time 232-234 The use of the isolated frog heart or the heart-lung preparation, and recently the cat's papillary muscle, enhanced sensitivity of detec- 25 235 236 A still more sensitise test object was pro vided by the embryonic chick heart 237 239 The heart was immersed in the test fluid containing digitalıs, and the concentration was judged by the production of cardiac irregularities Embryonic duck-heart muto-assay method. An approach similar to the chick-heart method was employed by Fredman, Bine and co-workers, za who adapted the embryonic duck heart for the bio-assay of digitoxin They were able to detect concentrations as low as 0 05 microgram per gram of tissue Would this test pernit evaluation of the digitalized state? Before answering the question it is necessary to review briefly some of the findings of these and other ini estigators concerning the distribution and concentration of digi. talis in the animal body 240-944 Digitoxin is completely absorbed from the intestinal tract Absorption is not impaired by the presence of right-sided failure Once digitoun enters the blood a considerable fraction is physically bound to plasma albumin 245-249 Three minutes after intravenous ad- [ 109 1

·No text on this page.

·Unlike other mammals, which did not excrete sig. nificant amounts of digitoxin, man eliminated through the kidney from 40 to 50 per cent of a single dose as cardiac glycoside.243,360,361 This elimination occurred at a rate of 5 per cent of the administered dose during the first twenty-four hours and lesser amounts there- SI---------- r the urine It has been accordingly postulated that the state of complete digitalization is characterized by a daily excretion of 30 to 50 micrograms (003 to 005 mg) of digitoxin 23 The presence of acute left-sided failure or chronic decompensation did not diminish renal excretion During the first twenty-four hours after the onset of acute right-sided failure, excretion decreased about 50 per cent and thereafter reached control values Increases in renal excretion of digitoxin occurred consistently in patients with subjective or objective symptoms of overdosage Patients with digitalis intoxication excreted about twice as much in twentyfour hours as the compensated cardiac patient The embryonic duck-heart preparation has been used in difficult cases to determine whether adequate or excessive digitalization existed as The duck-heart preparation provides a valuable method for investigating the metabolism of digitalis It has limited applicability, however, in assessing the clinical state of digitalization The test is complex, time-consuming and requires special facilities shares with other bio-assay technics the disadvantage of excluding substances which might adversely affect the ( 111 ] ·embryonic heart This necessitates a cumbersome chemical process of extraction of the digitalis agent Furthermore, in order to overcome the extreme Variation which characterizes biologic testing, 5 or more hearts have to be employed for each determination. This apparently does not assure consistency of results, for Friedman and co-workers253 had to employ eggs derived from a single hatchery which lias maintained a thoroughbred strain for over two decades. A fundamnntni nhiantian in push nnnnnnnchthar than tibility of the myocardium to digitalis Such data are critical for correct clinical evaluation Radioactive digitalis With the development of radioisotope technics, reversion to the chemical inethod of studying the metabolism of digitalis has become possible The biosynthesis of radioactive digitalis has been achieved through exposure of digitalis purpurea plants to an atmosphere of radioactive carbon dioxide 262 The tracer technic permits great sensitivity for detecting minute amounts of labeled drug, it is possible to assay as little as 002 microgram of radioactive digitoxin This method can be adapted to follow metabolic products of the parent compound by distinguishing between unchanged digitoxin and other cardio active principles 24 In 1950 Geiling and co-workers, 202 utilizing this technic, reported that dogs excreted up to 46 per cent of a single dose of digitoxin in the urinc, Fischer and associates264 found that cats and rats eliminate a nearly similar amount of unchanged digitoxin and metabolites through the urinary route. [ 112 ) ·The finding of the importance of the kidncy as a major pathway for elimination of digitalis and its breakdown products contradicts the results of carlier investigations s6-258,265,266 but agrees with the duckheart method. When digitoxin labeled with radioactive carbon is administered to cardiac patients, 60 to 80 per cent is eliminated by the Lidneys either as unchanged digitoxin or as its metabolic densatives.*61 After a single intravenous dose there is a marked in itial excretion of digito un lasting for two days; this is followed by a gradual leveling off after the fifth day. During the initial three-day period 20 per cent of the administered dose is eliminated, and about half this amount is excreted in the first twenty-four hours Most of the carbon-14 from the labeled drug is excreted as metabolic products Only 6 to 10 per cent of the original drug is elımınated as unchanged digiloxin, and this occurs mainly in the first six hours after injection. A minute amount of unchanged digitoxin can be detected in the urine for as long as forty days after administration, and carbon-l4 products continue to be present in the urine up to the seventyfourth day 3 The cumulative effect of digitoxin apa pears to be related to its persistence in the body The sigmficance of these radioactive metabolites is uncertain Their high specific activity suggests direct deriva. tion from digitoxın rather than resynthesis from the bodily carbon dioude pool, where some of the carbon- It is conceivable that tracer technics may be adapted for clinical ise to assess bodily disposition of digitails By giving radioactive digtalis and determining urinary excretion and specific activity over the myocar- ( 13 ) 14 enters ·dium the digitalis status may be delineated At present these methods are not of practical significance for the patient with congestive heart failure. Acetyl Strophanthidin Tolerance Test Principle. The purpose of the test is to ascertain the degree of digitalization and myocardial sensitivity to digitalis in patients whose digitalis status is in doubt. Since there is currently no clinical method for determining cardiac susceptibility to digitalis, except through the act of digitalization, such a procedure is employed. Acetyl strophanthidin, the agent uscd, has a short latency, pcal effect is achieved in the course OT HCO 1 CO 2 3 H10 GOH Strophanthidin of several minutes, and dissipation is rapid The amount of drug nccessary for a therapeutic or toxic end point determines whether digitalis is to be used and the approximate dosage for optimal effect Agent Acetyl strophanthidın is an ultrarapiu-acting synthetic ester of the cardiac aglycone, strophanthidin. It has been proved possible to introduce various radi- ( 114 ) ·cals on the steroid-ring system of thic strophanthidin molecule by utilizing the highly reactive properties of the secondary hydroxyl group at the carbon-atom 3 position. Several derivatnes of strophanthidın have been prepared by interaction with various acids and glucose molecules 265,269 Wedd and Blair's recently cast doubt on tlic digtalis-like properties of this agent. They found that acetyl strophanthidin failed to shorten tlic refractory period, interpreted as the QT interval, without impairing contractility Since digitalis glycosides shorten the QT interval, they concluded that acetyl stroplianthidin is not a digitalis-like substance and that its therapeutic action is due to vagus-nerc stimulation Greiner and Reilly,270 however, convincingly demonstrated the digitalis-lihe properties of this drug When hypodynamic papıllary muscles of cats' hearts were exposed to acetyl strophanthidin there was a marked increasc in the force of contraction The response was qualitativcly similar to that with other digitalis bodies, but quan. titatively this drug was the most powerful of all the preparations tested Although the relation between the clectric activity and therapeutic action of digitalis is not clear, it is likely that the critical properties that distinguish the digitalis drugs are due to positive inotropic action on the myocardium In tests on human subjects acetyl strophanthidin has been found to be a potent digitalis-like agent "* 114 It is much more rapid in effect and dissipation than ouabain, generally conceded as the most rapid-acting of all cardiac glycosides 135,137-140 A comparison of some of the clinical properties of the two drugs is presented in Table 8 The earliest effect of acetyl [ 115 ] ·strophanthidin, during 154 trials in 125 patients, occurred within one to five minutes, with an average of three and a half minutes 154 In a number of pa. tients we have observed an effect as early as thirty seconds after administration."** When the drug was given over a five-minute period 70 per cent of the maximum action, as gauged by the slowing of the ventricular rate of atrial fibrillation, was evident at the end of injection. The effect persisted for about an hour, and in no case was it present after four hours. 136 In dogs it is possible to digitalize at two-hour TABLE 8 Comparison of Speed of Action and Dissipation of Ouabain and Acetyl Strophanthidin Data EARLIEST EFFECT PZAK ACTION PERSISTENCE of EFTCT DIZATIOY OF TOXICITY MIR MIR $-20 60-120 Several br Ouabain Acetyl strophanthidin 3 hr - 5 days 2 hr 72-5 12 30 min *Note that action of acetyl atrophanthidin w more rapid and more transicnt than that of ouaban intervals without evidence of cumulation." Toxicity lasts for about thirty minutes. Enselberg and his coworkers, 156 who have had the most extensive clinical expenence with this agent, reported toxicity in a quarter of the trials However, they gave the whole digitalızıng dose at once. In experiments on both dogs and human beings acetyl strophanthudin is about half as potent as ouabain--that is, 01 mg of ouabain is equivalent to 0 2 mg. of acetyl strophanthidın 135,168 Animal experiments. A number of problems re- ( 116 ) ·mained to be solved before the application of acetyl strophanthidin as a testing agent in man: the development of methods for eliminating or controlling toxicity; determination of whether the action of acetyl strophanthidin on the heart is quantitatively additive to that of any other digitalis preparation already in the body--the critical point of the tolerance test; and ascertaining of whether the state of prior TABLE 9. Summary of Ouabain Assay with Aceryl Strophanthıdın in 4 Dogs No or DEVIATION IN PREDICTED ASSAYS Dosk or QUABAN PROM AMOUNT GIVEN DURATION OF TOXICITY ACZTYL ACETYL STROPHANTASDEN STROTRANTEIDEN AND DVARAIN men 6 B 13 20 digitalization modifies the toxic pattern of acetyl strophanthidin either in quality or in duration These problems were studied in dogs It was found that administration of small increments of acetyl strophanthidın at brief intervals produced significant slowing or rare extrasystoles without serious toxicity If toxicity was precipitated intravenous injection of procaine amide was also immediately effective in abolishing the arrhythmias 131 When ouabain was present in the body the additional administration of acetyl strophanthidin to the point of toxicity did not alter the toxic pattern or prolong its duration (Table The possibility of determining the quantity of dig?- ( 117 ) 9) ·talis in the body by means of acetyl strophanthidin was tested in dogs When acetyl strophanthidin is given at two-hour intervals the dose for the production of ventricular tachycardia remains constant. Il, how ever, a dose of ouabain is administered between successive doses of acetyl strophanthidin, there is a reduction in the dose of acetyl strophanthidin equivalent to the amount of ouabain given A typical example, one of a group of identical experiments, is presented in Figure 15. Four doses of acetyl strophanthidin 10 Acetyl strophonthidin Ouaboin given Quobaini bady - 01 Aam STROFAAYTHIDIN mg. OVARAIY mg UM TUTTI TIX IN HOURS FIGURE 15 Declining Doses of Acetyl Strophanthiden for the Production of Ventricular Tachycardia Iihen Increasing Amounts of Oucban Accumulate in the Body were given to the same tosic cnd point two hours apart The first time the dose required was slightly in excess of 20 mg When acetyl strophanthidin was again grien, but this time preceded by 05 mm of ouabain administered an hour earlier, it required ( 118 ) ·only 50 per cent of the first digitalizing dose to produce ventricular tachycardia Each time ouabain was injected the reduction in the dose of acetyl strophanthidin for toxicity was nearly equivalent to the amount of ouabain administered The over-all results in 20 similar assays are shown in Table 9 The average deviation in the predicted amount of ouabain from the amount actually gren was 13 per cent This was the same as the magnitude of deviation in successive digitalizations with acetyl strophanthidin when no ouabain was given This method permits accurate appraisal of the quantity of a digitalis preparation present within the body With these preliminary observations it was considered justified to employ the acctyl strophanthidin tolerance test in man Clinical Studies with the Tolerance Test Material and methods The test was employed in patients with congestive heart failure whose digitalis status was in doubt or in whom myocardial sensitivity to the drug was believed to be increased To date 20 tests have been carried out in 18 patients the inajority of whom were critically or terminally ill 140 Technic The procedure of the test was quite simple Two ampoules, each containing 06 mg of acetyl strophanthidin, were diluted 10 20 cc in 5 per cent glucose and water If the patient to be tested had received little or no digitalis 03 mg of acety! strophanthidin (or 5 cc of the dilution i was given intravenously eser five minutes until the achievement of either a therapeutic effect or a mild toxic response In the presence of possiblr digitalis intoxication the schedule was modified Esther the interval 1 119) ·between doses was increased to ten minutes or the initial two increments of acetyi strophanthidin were reduced to 0.15 mg. In the presence of an arrhythmia that was most probably due to digitalis potassium was first given and, if ineffective, followed by a tolerance test. The electrocardiogram was continuously observed during the test. One-minute strips were taken before each injection. With the onset of evidence of intoxication, nausea excepted, the test was stopped. If the toxic pattern consisted of ventricular premature beats small amounts of procaine amide were given intrave. nously until all extrasystoles had disappeared. Interpretation Interpretation of the test was based on the amount of acetyl strophanthidin required and on the patient's qualitative response If toxicity developed after the first injection of 0.15 mg. or 03 mg overdosage was presumed to be present, and no further digitalis was administered. If toxicity ensued after 0.6 mg without the intervention of any thera. peutic effect the patient was regarded as adequately digitalized When therapeutic action occurred after 06 mg or 09 mg fractional doses of any one of the commonly used digitalis preparations were given until the same effect had been achieved If the patient required 12 mg or more full digitalization was carried out. Results In 18 of the 20 tolerance tests the information provided served as an immediate and accurate guide to further therapy The results were uncertain in 1, and another patient died soon after the complction of a test Twelve of the tests indicated that the patients could profit from more digitalis either in full or partial dosage, and seven of the tests were inter- ( 120 ) ·preted as contraindicating digitalis (Table 10). Although the findings of the tolerance test frequently contraindicated clinical impressions, the patients' subsequent courses corroborated the conclusions of the test in all instances Patients requiring digitalts. Of the 12 patients re- Taple 10 Results of 20 Assays in 18 Patients. EFFECT UNCERTAIN DIGITALIS REQUIRED NO 07 ASSAYS Full digitalization 8 Parual digitalization 4 DIGITALES Nor REQLIRED NO OP 1394YJ Toricity 3 Full digitalization 2 Increased sensitivity 1 No therapeutic effect 1 7 Total 12 1" "Patient exhibited bidirectional ventricular tachycardia before test. quiring digitalis 9 were on maintenance doses Two had received no digitalis and it was uncertain whether 1 had taken any Some of these cases are reported below CC, a 54-year-old man with hypertensive cardiovascular and coronary artery disease, had sustained 2 episodes of myocardial infarction before entering the hospital After his 2d infarct right-sided and left-sided falure developed HA W. the last thrl. losf and main- He also h before He had marked hycardia - ( 121 ) ·plaud trety 1 BULES Alter insilly se beydi Vomit agaia At this point the heart rate had decrease about 20 per cent, and the extrasystales had disappeare (Fig 16) The test was interpreted to denote that needed full digitalization. Within the next 95 hours, hreceived 4.0 mg of Digoxin This dose controlled his fail ure and iurther slowed his rate Tint Rasa VPES ActTyl Stor KONTHEDEN 30/1y. 3 w ) HA 327 BB min 12mg 2 196 nr 78 7/ min. Dsporin 40 mg 3 FIOCRF 16 Tracings in C The acetyl strophanthiden tolerance test indicated the need of full digitalization. When the had been accomplished failure was controlled, and extrasystoles diminuhed Without an acetyl strophanthidin tolerance test there appeared to be no way of determining this patient's digitalis necds The nausca, vomiting and mulufocal ventricular extrasistoles suggested over dosage and urged discontinuation of the drug. The unfavorable course, the increasing pulmonary and tiepatic congestion and the background of myocardial infarction intimated that a possible basis for the ( 122 ) ·clinical picture was increasing failure that might be remedied by more digitalis Even though it was concluded that he needed more digitalis, the amount required would have remained uncertain and inadequate dosage might have vitiated effective action The therapy during the month before hospitalization was characterized by vacıllation between half measures and resulted in sapping of the patient's wellbeing and the physician's morale. GG, a 49-year-old man, had syphilitic aortic insufficiency Twelve hours before ador.ission dizziness, marked weakness, dyspnea and palpitation developed Asupraventricular, tachycardia with a rate of 180 was found to be the cause of his fymptoms Sedation, carotid-sinus pressure and Prostig. ALA - L-J. -1.. . rate thereupon slowed, and there was an abrupt reversion to sinus rhythm At this point he exhibited 2d-degree heart block, a changing pacemaker and ventricular premature beats Intravenous injection of procaine amide in a dose of 300 mg controlled these manifestations The tolerance test is not only a diagnostic procedure but also, in some cases, a therapeutic measure Reversion of supraventricular tachycardias requres a digitalis 'preparation that has short latency, prompt peak action and rapid dissipation of toxicity, acetyl strophanthidin has these properties Enseiberg and his co-workers186 caused 11 of 12 cases of supraventricular tachycardia to revert to sinus rhythm with acetyl strophanthidin, the majority within one to three minutes in 1 refractory case the patient had "auricular tachycardia with high degree atrioventricular block" ( 123 1

·In patient G.G. the onset and progress of pulmonary
edema due to the rapid heart action demanded
prompt digitalization. Since he had received some
TIME
ATRIAL RATK
Acetyt
STROPI UNTitlov
03
1
20min
130
1.5mg
2
24 min.
300 mo Pronssty!
3
27 min
FOURT 11 Electrocardiograms in GG, Showing that are
fyl Strophanthidin Caused the Arrhythmia to Revent to
Sinus Rhythm.
digitalis the amount to be
even was uncertain If
ouabaın' had been used the equivalent dosage would
( 124 )

·have been 07 mg. to 08 mg. This dose could not has been administered with safety in less than two or three hours, and the longer period might have jeopardized the patient's life. The problem with some cases of suprasentricular tachycardia is that a toxic amount of digitalis may be necessary for reversion, as in this patient. When toxicity develops before the arrhythmia is controlled it is hazardous to continue with more digitalis Furthermore, the touc reaction may be more serious and prolonged than the initial arrhythmia These difficulties are either lacking or at a minimum when acetyl strophanthidın is used AN (whose history was presented on page 67) had severe right-sided and left-sided failure, a nodal tachycardia and ventricular premature beats at the time of hospitalization for mitral- alve surgery After digitalis had been stopped the rhythm reverted to atrial fibrillation, but he continued to have premature beats and runs of regular ventricular rhythm His condition had by this time deteriorated, and he was regarded as terminally ill The consensus was that he was . In this patient clinical judgment was contradicted by the results of the tolerance test No basis eusted before the test for assuming that he required full dig?- talization All therapeutic measures were ineffective in controlling his advancing failure, and it was expected that he would die within a few days The proper [ 125 ] ·use of digitalis not only improved his status but also permitted him to be operated on The experience of patients requiring partial digitalization is illustrated in AN, and in GR (p 128) After the valvuloplasty AN exhibited marked sensitivity to both overdigitalization and digitalis inadequacy in both circumstances a nodal tachycardia, with aggravation of the TIME ACETYI. STROPHANTHIDIY 148 0 RATE 0 ! 0.3 mg 132 11 3 min. 2 1 omg. 105 48 min. 1 1 Digoxin 3.5mg 100 24 hr. + F th HLRt 18 Ilectuadograms in 4N Auch struphanthidin tult rare test indicated the need for full digitalization It hen this was achie.ed failure was controlled failure deatherd Immedone after operation he had a nodal tuh Jid: wuh was due to on crosit and was Oriculd by the inu (?BERS dittlun u polusin ( 126 ) ·(See Fig 6) When digitalis was stopped for a few days a nodal tachycardia again des cloped Because clectrocardiographically it appeared to be identical to the previous arrhythmia, notwithstanding the fact that he was off digitalis the tachycardia was again ascribed to digitalis intoxication The intravenous administration of 35 milliequiv of potassium chloride was ineffective (Fig 19) An acetyl tolerance TINE POTASSIL RATE 139 0 I 60min. 35 milliequiv 136 1. Acetyl Strophanthidin 0.3 mg. O 3 136 8 min. 0.6 mg. 64 BELGELT FIGURE 19 Nodal Tachycardia after Metral I al wluplasty 19 4 N ---Not Helped by Potassium Acetyl strophanthıdın tolerance fest indicated the need for mote digitalis test was carried out Within 8 minutes after a total dose of 06 mg the rate dropped precipitously from 136 10 61 per minute, and was maintained there by I mog of Digoxin ( 127 ) ·In this case identical electrocardiographic arrhyth mias were caused by diametrically opposite conditions, and a correct appraisal required the use of both potassium and acetyl strophanthidin. GR, a 32-year-old woman with rheumatic mitral stenosis and atrial fibrillation, entered the hospital as an emergency admission to the surgical service. Four hours earlier she had experienced sudden, severe pain and numbness in the right leg She was anxious, sweating profusely and complain of Awenner wala 'n whic the f .L.L.1- ate p howe range maintenance digitalis for 3 years, 2 days before hospitalization her daily digitoxin dose was increased to 02 mg Since she had some ventricular premature beats, a tendency to regularity in the fibrillation and what appeared to be P waves in Lead V. the possibility of digitalis overdosage was considered An aceryl strophanthidin tolerance test was carried out She received 03 mg of the drug every 10 minutes (Fig 20) After 06 mg there was a material reduction in heart rate, and she experienced nausca She was then given 05 mg of Digoxin intravenously and taken to the operating room Her rate did not rise over 100, and a successful embolectomy was performed In this patient the test again provided diagnostic information and proved of therapeutic value. The rapid heart rate was precipitated by the peripheral cmbolization The daily digitalis intake, sufficient for usual needs, was inadequate in this emergency. A small increment of drug controlled the tachycardia; thereafter, the digitalis needs receded to the former level of requirement The special value of acetyl strophanthıdın in this case was the rapidity of its effective action within twenty minutes the patient was prepared for operation ( 128 )

·No text on this page.

·sidered. An acetyl tolerance test was carried out. After the first 0 3 mg there was a change in atrial pacemaker and a slight acceleration of rate. This was not noted at the Ти! RATE 130 ACETYL STROPITAYTHODY 0 0 1 Omin, 190 0.6 mg. 2 A=2003 V100 min 111 PL 3 32 min. 128 Pronesty! 1 I'ICURE 21 Electrocardiograms in RT Tolerance test induced parorysmal atrial Sachycardia with block, which was controlled with procaine amide Digitalis was not considered indicated time and another 03 ms was given Paroxysmal atrial tachycardia with block resulted (Fig 9) This reverted to a sinus tachycardia on the intras enous injection of 750 mg of [ 130 ) ·procaine amide (Fig 21) It was concluded that the pa. tient had had adequate digitalis and was bordering on intoucation The sinus tachycardia was the result of failure and could not be controlled until the failure was abolished She was given much sedation and morphine. Within a few hours the pulmonary edema began to abate, and a reduction rate followed She recovered, and some days later a mitral valvuloplasty restored her nearly to full acta. ity A long-acting digitalis preparation might have prolonged the toxic response, and the pulmonary edema might have impeded or prevented restoration of compensation Within a few minutes, through use of the tolerance test, it was evident that digitalis was not to be employed Uncertain and unfavorable results In 1 patient the results were uncertain The patient came in with left-sided failure and atrial fibrillation with a ventricular rate of 160 A dose of 16 mg of Ccdıland intravenously did not slow the rate The next day he experienced a cerebrovascular accident, with frequent grand-mal seizures During the convulsion he had bidirectional ventricular tachycardia To ascertain whether digitalis would slow the rapid fibrillation acetyl strophanthidin was given However, the sporadic recurrence of bidirectional ventricular tachycardia prevented judgment whether the patient was underdigitalized or overdigitalized Acetyl strophanthidin accelerated the death of another patient, who was terminally all with left-sided and right-sided failure unresponsive to all measures While she was on maintenance digitalis an episode of rapid heart action interpreted as supraventricular tachycardia with left-bundle-branch block developed The arrhythmia was terminated with procaine amide ( 131 ) ·Two days later, because of a ventricular rate of 120, it was decided to carry out a tolerance test. Within thirty seconds of the injection of 03 mg of acetyl strophanthidin multifocal ventricular premature beats developed, and within a minute progressed to ventricular tachycardia. It was now evident that the previous arrhythmia had also been an episode of ventricular tachycardia. The cerebral symptoms, the anorexia and the extreme regularity of the atrial fibrillation appeared as the obvious stigmas of ad. vanced digitalis intoxication She was therefore given 200 mg of procaine amide intravenously, with reversion to rapid and regular fibrillation However, about nine minutes after the acetyl strophanthidin and sa minutes after the procaine amide she grew cyanotic, with gasping respiration The electrocardiogram revealed ventricular fibrillation. Whether the terminal episode was due to acetyl strophanthidin, procaine amide or other factors will never be established with finality. Deaths after small intravenous doses of procaine amide have been reported 130 The chain of circumstances in this patient demands that her death be ascribed to the tolerance test It seems to us that a number of errors of judg ment were committed in this case In the first place the initial arrhythmia was not recognized as ventricular tachycardia Secondly, the symptoms, as well as the regular and rapid ventricular response in a patient with atrial fibrillation, should have indicated that she was still seriously intoxicated at the time of the test. In the presence of overt digitalis intoxication the administration of potassium is the procedure of choice. Without the tolerance test it is likely that the patient ( 132 ] ·would have received more digitalis and probably the outcome would have been identical. Discussion The amelioration of disease by therapeutic means that alter internal biologic processes carries with it the constant possibility of injury In deciding the justification of any new drug or procedure one must weigh the benefits to be accrued against the hazards to be encountered in relation to the seriousness of the underlying problem in the treatment of advanced cardiac disease situations in which the patient's wellbeing depends on an accurate appraisal of digitalis needs frequently arise No method has been available to date for this purpose The test outlined above provides an indication whether digitalis can be safely given or must be withheld Our experience has impressed us with both its great value and its potential danger Its use is justified only in the most carefully selected cases There must be real doubt concerning the digitalis requirements that cannot be resolved by simpler clinical means before the test is employed [ 133 ] ·CHAPTER I'III Conclusions In recent years a great deal of new information has accumulated on the mode of action of digitalis and on its benefits and dangers in the treatment of congestive heart failure of clinical importance is the recognition of the existing relation between digitalis and potassium. Depletion of body potassium lowers the myocardial threshold to the toxic action of digitalis This finding is especially significant today when the management of heart failure is based in large measure on the manipulation of electrolytes that is attended by loss of body potassium It is likely that the altered treatment of heart failure contributes to the rising incidence of digitalis intoxication. Digitalis overdosage affects atria as well as sen. trícles In the former it gives rise to a specific arrhythmia, paroxysmal tachycardia with bloch, which is readıly controlled by the salts of potassium or procaine amide The variation of the response of the heart to digitalis in any one patient, the frequency of conditions in which underdigitalization and oserdigitalization are indistinguishable and the similarity of paroxysmal atrial tachycardia with block to many nondigitalis-induced arrlithmias have made necessary a procedure for providing information on the digitalis status of the cardiac patient A digitalis tolerance test that provides ( 134 ) ·such data has been devised It is based on a biologic assay of myocardial sensitivity to an ultrarapid-acting, digitalis-like drug, acetyl strophanthidin The newer methodologies employed, including cardiac and coronary-sinus catheterization, renal hemodialysis, micro-assay of digitoxin with the embryonic duck-heart preparation and radioactive digitalis compounds, promise a further extension of Inowledge concerning the mechanism of heart failure and the mode of action of digitalis. The introductory words of Withering to his treatise, which ushered in a new era in the care of patients with congestive heart failure, form an apt conclusion to our study: These remarks consist partly of matter of fact and Partly of opinion The former will be permanent, the latter must vary with the detection of crror or improve. ment of knowledge I hazard them with diffidence and hope they will be examined with candor not by contrast with other opinions but by an attentive comparison of the phenomena of disease ( 135 )

·No text on this page.

·Bibliography* 1 Weston, L. G. Je, Anslow. W P Js, and Smith, HW, Excretion of strong electrolytes Bull New York Acad. Med 21 586-606, 1919 2 Grouan, J. Weston, E, Halpeno, J. P, and Leiter, L 5 7 # 2.927-933, 1948 9 Bloomfield, R. A, et al Effects of cardiac glycosides upon dynamica of circulation in congestive heart failure / Clonin. vestigahan 21 588 599, 1948 10 1-.. P. V rothrat PT Richarry pw 17 11 12 13 14 1941." 15 Cattl, M, and Gold, H Influence of digital glucoudes on force 16 11. 18 Coho, A E, and Stewart, H J Evidence that digitalu infuences *Additional relerences (unnumbered) are listed by chapter on pages 148-151, ta the order in which they pertain to the text ( 137 ) ·contraction of beart in man ). Clin. lepestigation 1 97.125, 1984 19. Starling, H. The Linacre Lecture on the Law of the Hearl. 27 20. Grenels, II. Zur Physiologie und Pharmakologie der Energetik des Saugetierberzens. Arch f. erger Path - Pharmakol, 169 689-723, 1933 21. Harnson, T. R., and Leonard, B. W Effect of digital on cardiac outout of dogs and its bearing on action of drug in heart disease. 1. Clin Intestigation 3 1-36, 1926 22. larvey, R. BY, Ferrer, l, Cathcart, R. T. and Alexander, J. K."Some effects of digoxin on heart and circulation in thao dugoxin in enlarged hearts not in clinical congestive failure Corctlation 4 366-377, 1951. 23. Harvey, R. M, et al Mechanical and procardial factors in chronic 24 Schwartz, S. P. and Levy. ) Digitalis studies on children with heart disease cffects of digital on edema of children with theupatic lever and chronic valvular disease in presence of snus rhythm Am. ) Du Chud 42 1349-1363, 1931, 25 Taran, L A Therapeutic regunen for arute rheumatic heart discase in children 1. Pediat 33 226-241, 1349 26. Nadas, AS, Rudolph, A., and Reinhold, DL. Use of digitalis in infants and children clinical study of patients in con gestive heart failure New Eng. Aled 248 98-105, 1953 27 Friedberg, C K. Ducasts of the Wrarl, 1081 PP Philadelphia Saunders, 1950 28. Szent-Gyorgyl, A Contraction in heart muscle fibre Bull Nee York Acad fod 28 3-10, 195? 29 Wollenberger, A Energy metabolism of failing heart and metabolic action of cardiac glycosides I Pharmacol Esper, Therap. 97 30 Olson, E, and Schwartz, W B Myocardial metabolisa un con- 30a Bang, RJ, et al Cflect of strophanthus on coronary blood flow and cardiac oxygen consumption of normal and failing humas 31. Bowen, w. Effect of digoxin upon rate of shortening of myoun 32 Horváth, 1. Kiraly, c, and Sterb, Action of cardiac glycosides 33 Friedman, M. and St George, S Cardiac and hepatic antracellular late of digitoxin Chin Inbarligason 32 569, 1953 34 Lagen, PS Effects of daglandin varying dogage upon potar #um and water content of rabbit heart muscle Pharmacal Exper Therap 67 50-55, 1939 35. Boyer, PK, and Poindexter, CA Influence of digitalis on slectrolyte and water balance of heart muscle Am Heart / 20 36 Wood, E, and lfoe, G K Electrolyte and water content of ventricular bousculature of heart lung preparation with special refsrence to effects of cardiac glycosides Am Phynol 135 515-573, 37. Matcher, R., and Weiss S Scat of emetic action of digitalis bodiet Arch Int Ared 29 690-704, 1922 38 Larvin, 11 M Paro tymal ventncular tachycardia with alternating complete due to digitales intoxication Am Heart] 21-52. 1928 39. Sprague IIB White, PD, and Kellogs, F'Disturbances of vuron dur to digitalu Tersew of Sterature and report of cases LAMA 15 716-720, 1925 10 liueper, WC, and Ichosowske CT Experimental studies in [ 138 ) ·<? Red, W D Toxic effects of digitalis JANA #1 35-439, 1923 43. toe, y clinical aspects of complete auricutoventricular heats binci clinical analysis of 11 cave As IniAd 12 510-523, 3950, 4. Luoma, B. Wyatt, NF, Crocker AT, Goodale, WT, and 45 6 fleremans, &, Desherd C. M, and AlcKinley, W. F 49 49 50, 51 I. $3. 34 Lewann, E 1 Gynecomastia shising digital therapy report of sahtlitsonal cases with liver-fuschion studies New Eng / Nad 2 6 316-320, 1953 35 Arkey. J and Neurath, 1, dog wala and cated myocard al infarclon! AU 03-218 3945 56 Pete, S. On effect of digitalis, its ophanthi and mercurui diuretics on blood coagulation preliminary report Ann med Int Fannya 36 124 144, 1947 57 Kose OA, Sasteran RC and Definit, Ac Cinical muders, on daypain, purabed slegialus glycusedt Am Hrari | 24 43-457, 1952 18 DeGrast, A, C Borman RC, and Rose, DA Digitoxin it evaluakson for anal dignalization of patient with corgextive heart Laulus 14 13 115-49 1949 59 Bartoman P DeGran AC and Rose, O A Therapeutic 60 62 RoSun, G C, and Wilson Quantitative study of effect of digitalis on heart of cat T Pharmacol Exp! Theray 10 49 507, 1918, { 139 ) ·6. Levine, S A, and Cuaningham, T. D Afargin al ualety of intrenous digrali ta cals Arck. Ini, died. 26 293-29, 1920. 63 Lown, B, et al. Unpublished daza. 64, 1 65 67. ES 70, 21. 11 17 74 75 76 Ringer, s, and Afurre!), W Concerning effects on frogs of arrest al circulating, and explanation of action of pocash walls on anbal body / Physiol 72-93, 1878 77. 78 79 BO 81 BZ 83 85 VigAUJI 86. Je W Serrud Third edition 2 vol. 1735 pp Philadelphu F A Davis Co. $913 Pp 3193-1229 87 Sarapson, 11. Anon EC, Asd honda, Egert on man of potassium adiitration in relatna to digitalo glycon sider with specul reference to blood xnvw polassiuen, electro- ( 140 ) ·cardiogram and ectopic beats. Am. Heart26 164-179, 1943 88. Bull, 1 E Ure of pocais chloride and dieoxo" 10 cogere hesti lailure South 42 1037-1941, 1945 89. Enxebery, CD, Summons, IG, and Munia, A. A Efect of Dolassium upon beart, with special reference 10 Presbyluty of treatment of toxic arrhythias Bup to digitales. Art. Heart . 3 713-729, 1950 9. Fox, CL, Jr, Fredburg. CK, and Wute, A. G. Electrolyte sortor.sites a chronic congesisve kent la Jure effect of de minuiration of porassom and sodom salt. Clappstipation u 701, 1919 91. JJ, 1JUJ 93. iuri, LT, Boyle. A , Rosow, WA, Cryffin, R., and Eng- Etrcm, Fletabolus studied during treatment of severe congestive Scart falurt with 30 ogon sodium dict Clin. lubenicahon 23 $25 19%) 94. Burrows, BA, ad Sasson, I K Measurement of total body potassium by radiowotope dilution technique J Clin Inpassanon 29 BUS, 1951 45. Alangan, Gand Myers, V, Crause, porasum sad 1 95. 97. hemical nature of C Further studies ble uoplications of 1 99 100 101. 102. 103 104. 100. 1 106 Schmitker, 14., and Levine, SA Presence of digtalu in body funds of digitalized patirtis Arch Int Bed 60 241 250, 1937, ( 141 ) ·107. Lown, B, Salzberg, 11 , Engelberg, CD, and Weston, R. E. Interrelation between potassjum metabolism and digitalis toxicity in heart failure Proc Soc. Exper Biol & Afod 76 97-801, 1951 108 Lown, B., Weller, JM, Wyatt, N., Jſoigne, R, and Merrill, JPCHects of alterations of body potassium on digitalu toxicity, Clin Investigation 3} 648, 1952 109 Lown, B, et al Unpublished data. NO Levine, II D, Vazıldar, IP, Lown, Band Merrill, J. P. Tent-shaped" 'T waves of normal amplitude in potassium intoxication. Am Heart) (3 437-450, 1952 Cohen, B M Digitalis pouoning and als treatment New Ext J. Sed 245 225-230, 1952 !12 Wyatt, NF, Levine, HD, and Lown, B Unpublished data. 113 Desonin-Santander, A, Pack, A, and Langendorf, RA-V conduction in auricular flutter 'Curculation 2 604-616, 1950 114 leyl, A F Auricular paroxy mal tachycardia caused by digitales report of case Ann Int Aed 5 858-872, 1932 115 Decherd, GM, Jr, Herrmann, GR, and Schwab, ER Paroxysmal supraventricular tachycardia with A.V block Am. Heart ) 26 416-472, 1943 116 kohn Rand kiley, I F Electrocardiographic changer dur ang hemodialys, with observations on contribution of clectrlyte disturbances Lo digitalis torCHY An In Med 39 38, 1953 117 Askey, M Auricular paroxystal tachycardia in association with myocardial infarction Am Heart) 37 425-434 1919 118 Lown. B and Levine, HD Unpublished data 119 Darrow, D Dody.Rurd physiology role of potassium in clinical disturbances of body water and electrolytes New Ens I Afed 242 978-983 and 1014 1018, 1950 120 Finch, C A, Sawyer, CG, and Flynn, J. Clinical tyndrome of potaurum intoxication im Bled 1 337 352, 1946 121 Blum, L Recherches sur le rôle des sel alcalins dans la patho genic des oedere l'action diurétique du chlorure de potassium Presse med 28 685 688, 1920 122 Stewart, II J. and Smith, JJ Changes an electrocardiogram and in cardiac rhythm during therapeutic use of potassium salts Am Sc 201 177 197, 1941 123 Thomson, WAR Firect of potassium on heart in man Drui ilea ] 1 369 282, 1939 124 Brown, II, Tanner, GL and Heche,,!! I Cileus of potassium salts in subjects with heart disease I 'Iob Clon Aled 37 506- 511, 1351 125 Mark, LC, et al Action of procaine amide (N1-2 diethylamiga ethyl)-p-aminobenzamide) on ventrcular arrhytharias Phar. 126 Idom Physiological disposition and cardix, effects of procaine amide Pharmacol Esper Therap 102 5 15 1951 127 Berry and (efter, Wil'se of propesty! in treatment of ectopic rhythang treatment of marty eight episodes in sevenir erghi patients 1{ed 1 431 441, 1951 128 Long T H Oppenheurer MWebster A Rand Durant, TR1 Firest of initasenuus procaine on leart frothenology 10 404-415, 1949 129 Sagall, E L, llorn, CD and Risesa, FF Studies on artion of quinidine in man measurestent of speed and duration of effect following oral and intramuscular administration Arch Inf Med 7! 460-473, 1913 130. DicCord, M. C. and Taguchs, J T. Study of effect of pt ·imide bydrochloride in supraventricular artbyemizi. Cuculation 4 381-393, 1951, 131, Low Bad Crocker, A, T. Lapublished blata, 112. Kayden, li , Steele, js, Lat, L C. and Brodie, B B. Uk of procaint amid is cardiac arrhythmias. Circulation 4 13 22, 1951 133 Eggleston, C. Digitala dosage Arch Int Jed 16.1-32, 1915 134 Gold, H, Ono, HL. Modell, W. and Halpera, S.L. Pe bavior of synthetic esters of strophanthidin acetate, propionate, butyrate, and benzoate, so man). Pharmacol & Esper Therap 36 301-3179, 1946 133 ma IT 136 127 www.lu ugluu LILUNCUL OL Lugesuve De AIL fasture Am_Heart] 20 43-453, 1941 138. Gold, R. Treatment of cardiac failure with digitalis glcondes 139. tion of ouabain 140 gitalis tolerance 141 .-4112 Lkquod legtapte aucunacal study of Saratos de c. Am Heart / 24 472, 1912 142. Wayne, EJ Clinical observations on two pure glycosides of digitalis, digoxin and digitalnum verum Cin Sc 163, 1933 143 Schwab, EPA Clinical observations on pura glycoside of Dig tala lanata, dignxin Texas Siale I Med 35 619 194) 144 Fyans, W. Dick, P, and Evans, B Rapid digitalization, Bril 145 14. B! H. 146. 147 1'3 143 1 150. 151 152 153 + 1883 1.54 flot E, and Nahum, L H Analysis of cardiac uregutarties produced by calcaum, and their prevention by yodium antal 155 Hloft, H E, Sztb, P K and Winkler, A W Electrocardo ( 143 ) ·ographic changes and concentration of calcium in serum following intravenous injection of calcium chloride Am. 1. Physiol. 125 162, 1939 156. Berliner, K Effect of calcium injections on human heart Am I. M. Sc. 191 117, 1936 137. Clarke, N. Action ! calcium or bumse electrocardiogram Am Heart ) 22 367, 1911. 158 Barker, P, S, Johnston, P P. and Wilson, F. N. Duration of 159 1 160 161 162. 1151, 1936 163 Smith, P. K. Winkler, AW, and Hoff, II. E Electrocardiographuc changes and conceptration of magnesium in krum lol. lowing intrasenous injection of magnesium satu Am I Physiol. 126.720, 1939 164 1. 165 166 . 167. I. روی دی، د 168 Enselberg, CD, Simmons IG, and Mintz, A Afflects of magacin upon cardiac arrhythmias Am Ilearl / 39 703, 1954 169. Poes, N, and href, M 2 Alagnesium sulfate in treatment of angiospasm Larcel I'577, 1933 170 Pipety 1. Sanabria, A, and Arriens, R T Mercurial durelia additior of magnesium sulfate to prevent touc effects of their intraveno is adminstration Bril Heart J 197, 1914 171 Szekely, P, and Wynne, N A Effects of magnesium on cardiac arthy tlumat caused by digitalis Cian Sc JD 241, 1951 172 Zwillinger. Uber die Wagnenumwarkung auf das Hert. Klin 173. Cattell, M, and Goodell, 11 On mechanism of action of digitalus glucoside on muscle Science 86 106, 1937 174. Howell, WH, and Duke, 1Y W Effect of vagas inhibition on output of potassium from beart mPhysiol 21 51, 1900 175 Wollenberger, A Effect of ouabain and digovun on energy-r.ch phosphate store of beart Federation Proc 7 266, 1948 176 Zwemner, RL, and Lowerstein, B E Cortin-like effects of sterord glycosides on potassrum. SCHERC# 31 75, 1940 177 Castleden LM Effect of potassium salt on cardiac Irregue Lartes, Bra ASI 17, 1441 178 Calboue, J A, Culics, G E Clasbe, , and Ilarruon, T. R ( 144 ) ·Studies in congestive heart failure effect of overwork and other factor en potassium contest ol cardiac muscle J. Clin Investiga Hon 9 393, 1930 9 Reunder, LC Boyle, AJ, Iser, L. T. McCaughey, RS, and Meyer, G Electrolyze and water content of cardiac and 10 11. 4 HJ. IJU 12 Dock, W Sodium depletion as a therapeutic procedure value of 10n-exchange resins in withdrawing sodium from body To A Am. Physician 23 282, 1946 13. Kahn, s s, ard Emerson, K, Jr Experience with the use of Catron exchange reains in the treatment of edema. J Clin Invest Fallon 29 827, 1950 # Tartz, B L., Kohlstaedt, KC, and Helmer, O M Use of combination of anion and cation exchange resina in treatinent of edema and ascites Cirrulation 5 524, 1932 55 Gull, R. and Duncan, C G Arterial hypertension therapeutic effects of cation-exchange rends New Eng Med 247 271, 1952 36 lann, , and Keilin, D Sulfanilamide u specific intubstor of 17 38 39 U i 10, 90 Fredber, C.K. Taymor, R, Minor, B, and Halpro, M Use of diamox, carbonic anhydrase inhibitor_as oral diuretic to Patients with congestive heart failure New Eng Med 241 883 1953 91. Berbner, RW, Kennedy, TJ. Jr, and Orlof, J Relatorulup between acidification of urine and potassium metabolism effect of carbonic anhydrase inhibition on potassium excretion Am] MIcd 11274, 1951 2. taller, G, and Smith, FM The presence of digitalis in dema fud and its possible conical ugnificance ) Clar Invest Barion 10 666, 1931 33 SC George, S, Naegele, C F, French, F., Rosenman, RH: 34 35 في 1 الی 97 99 ( 145 ) ·199. Beck, C. S, and Mantz, F. R Control of heart beat by surgeon with special reference to ventricular fibrillation occurring during operation 4 Surg 105 525, 1937, 200. Burstein, C. Utility of intravennw procaine ! anesthetic mindrement of mode..... 201, . 202. wwd, : 203. Wedd, A M , Blair, II A., and Warner, R S Action of procunt amide og bestt Am Heart 42 399, 1951 204. McClendon, RL, Hausen, W. R, and Kinsman, J 11 lemon dynamic changes following procaine amide adounistered intra venously Am ) Sc. 222 375, 1951 205 - .'L . T1 . 206. 18 . 207. 208 209 210. 11. 211. 212. 4.14 0.1JJJ 213 Inouye, M. M.lar, J, and Townsend, JH, Agranulocytosis following maintenance dosage of pronestyt report of severe case with recovery TANA 147 652, 1951 214. Miller, H, Pollock, RC, and Criffth, G C Fatal agranulog Imus terulting from procasbe derivative Lab & Clom Aled 18 850, 1951 215. Denny, J. L, Miller, II Guffith, G. C. and Nathanson, At It Ventricular acceleration following procaine amide bydrochloride 216, 217. 1. 10 10 1 1.1 لار ده 218, Pardec, II EB. Standardization of digitals by its action on human heart AM4 81 186, 1423 219 Bromet, AW, and Blumgart, IL Maintenance dose of digi tale electrocardigraphic study IANA 92 204, 1949 220. Dicuade, F R Tung. C Land Buen, V Study of standardszation of digitalis 1 Method for clinical standardization Chin Tolestigate 14 725, 1935 221. Larsen, Neukirch, F, and Nielsen XA Plecimcardigraphic changes in oormal adults following digitalis odabestration Am Heart J 13 163, 1937 2.2. Tandonsky R Anderson, N, and Vandeventer, J K Electro cardipgraphic and clinical study of various socalled cardiac drukt Am 1/181] 28 288, 1914 ( 146 ) ·273 Wegria, R, Geyer, J H, and Brown, B S Fibrillation threshold after administration of digitals and ouabain Pharmacol & Exper. Therap 71 336, 1941 224 Geiger, A J. Blaney, L F. and Druckemiller, W. H Quanta. tative electrocardiographic Etudy of digitalization Am Hari 22 230, 1911 225 Gold, H, Cattell, M, Otto, IL, kwit, NT, and Kramer, A1 L ltethod Int broassay of digitals in humans Pharmacol & Exper Therap 75 190, 1942 226 227 5 . LUJE ! 228 Pratt, EL Calorimetric method for estimation of digitoun 229 230 231 232 233 latcher, R. A, and Brody, J G Biological standardization of drugs / Pharm 82 360, 1910 234 T 7 235 236 237 238 DAH MP 239 240 DIIK, , , , HL, web, ww, 241 242 243 244 245 of serum and other soluble tissue proteins of rabbit / Pharmacol & Exper Thetap Ba 193 1944 [ 147 ) ·246 Farah, A. Combination of cardioactive glycosides with serum po ftsns. . Pharmacot & Exper Therap 143, 1945 247, Haartrany, 1. korlmaclier, H, and Lendle, L. Bedingunge der Bindung von Digitalisglykosiden auf die Scrure we stoffe Arch. 1 expet Path Pharmakol, 194 223, 1940 248. Suter, Elber die Bindung herzwirksamer Gold 249. m Im 11, . . 230. 1 251. 252. o 253 Frtedroan, A?, St George, S, and Bine, , Sc. Behavior and late of digitoxin in experimental animal and man. Afedicine 33 15. 1954 254 llatcher, RA, and Exeleston C Sud 255 256 ISL. 257. Lendle, L. Uber die Elumanationsgeschwindigkeit und Kumula Lionsneigung von Digitalisglykosiden und Struphanthin Arch / exper Park · Pharmako 180 518, 1936 258 259 260 261 St George, S, Bine, RJ, Friedman, M. and Bland, C Rena! excretion of digitorin 10 rabbit and dog Proc Soc. Expe Bol & Med 78 504, 1951 262 Geiling, K, et al Biosynthesis of radioactive medicinally . 263 IA IJJ- 264. .. 263 Gold, II Digitalis elimination Arch Int Afed 32 779, 1973 266 Eggleston Some newer concepts in digitalis therapy Am I $ISG 625. 1920 267 Chen K, und Elderfield Rc Synthetic dertvatives of strophanthidin I Pharmacol Exper Therap 76 81, 1942 263 Stelde, FA, Anderson, RC, Maze, N, and Chen, K K Action Proc Sos Espar Diol sled 33 198, 1943, of atrophanthudin-3-propionate, butyrate, und -benzoate 10 man. ( 148 ) ·269 Wedd, AM, and Blau, II A. The action of acetyl-strophanthydo os beurt muscle Pharmace & Exber Therat 104 334, 1952 270 Greider, T, and Rally, J Inotropic action of acetyl atrophanthi din, ttrophanth do, and tryptamine strophanttudun Prec Soc Exper Biot & died &1 141, 1952 ADDITIONAL REFERENCES Chapter 11 Stead, EAJr, Warren, J V, and Brangon, ES Effect of anatode Con circulation of patients with congestive laulure Arch IR Med 81 282, 1948 Werked, and Lagerlol, 17 "ilerzkatheterisserung" Nord med 36 1163, 1918 Cold, 1, witt, N.T, Otto, L, and Fox, T Physiological adaptatians an cardiac zlowing by digitalis and then bearing on problema of digitalization in patients with auricular fibrilation 7 Pharmacol Exper Therap. 67 224, 1939 Cu! Diputalu and Its Ka : inthosid on ela & Med 40 B, Stewart, Crane, N F, Deitrick, E, and Thompson, W. Action of digitalis 10 uncompensated heart disease Arch Int Mid LaDu, ls, and Fahr, G Effect of miravenous admonustration of and mechanical effi- 5 344, 1943 cabolum of heart in art J 11 273, 1936 14. ure in completely 461, 1939 een cardiac size and ration of digitalis 10 1 Effect of digitala Investigation $ 125, TH IL 141 Bing, R. and Taschler, M Cardiac failure and cardiac muscle Goodale, W T Olson, R E, and Haeckel, D B Myocardial glucose. lactate, and pyruvate of metabolism of normal and failing hearts studied by coronary venous catheterization saman Federation Pros Wallenberger Energy metabolissa of failang heart and metabolic ac- Biörck, G Clinical aspect of energy problems of heart murcle Scandinau Clen & Lab Investigation 2 242, 1950 ( 149 ) ·Friedman, M, St George, S, and Ishida, T. Intracellular distribution of digitoun Proc Soc. Exper. Bol & Aled #7 318, 1953. Chapter III Wolle, L S, and Geger, A J. Urticaria due to drugs of digitalis scrie New Eng Aled 248 148, 1953 Cohen, R V., and Brodsky, XY LAllergy to digitalis / Allergy 12 69, 19410 Ilatcher, RA, and Eggleston, Studies a elimination of certain digitalis bodies frou antgal organism ] Pharmacol & Exper Therap. 12 405, 1919 Dresbach, M Further experiments in attempt to lixcate site of cmc action of digitalis glycosides. Pharmacol Exper. Therap! Gelland, AL Visual symptoms alter digitoxin therapy. J 4.11A 107 1231, 1951 Batterman, KC, and Gutner, L B Phitherto undescribed neurological manifestations of digitales toxicily Am Heart / 36 50.2, 1918 Gichrist. A R Paroxysmal ventricular tachycard Am. Heart II 546, 1926 Schuensen, C. Ventricular uchycardia as result of administration ol digitalis Ileart 9 191, 1922 Luten, P. Clinical studies of digitalis advanced toxic sbythms Arena Int Afed 35 87, 1925 Williams, C. and Ellis, LB, Ventriculur tachycardia analysis of thirty Freundlich, J Paroxysmal ventricular tachycardia. Am Heari / JI 537 1946 Gallavardin, L Rhythme couple digital que et extrasystolique ventriculare des cardiopathues grasci (Slade préfibrilatoire du ventrale ) de med de Lyon 7 419, 1926 Reid, W Ventricular fibrillation following ectopic ventricular tachy Froment, R Lui tachycardies parorystiques vantnculares. Paru Massan, Penal, F Elektrokardiographischer Befund von llerafımmera bed plocz. Lichem Herztod Kunwch schr 12 1249, 1933 Meyer, Mort subite par fibrillation sentriculare au cour d'une oro cardite chronique enregistree à l'électrocardiographe Archd mal. du coeur 27 1, 1934 Zwillinger, L Uber, die Magnesiumurkung auf das Herz Alus lychnsiar 14 0429, 1935 - ... A ministration of D FT. Af ann. Mlassic, E, Stillerman S, Wright, CS, and Winnich, Y. Lect, Administration of digitalis on coagulabıbly of human blood Arch DeTakat), a Trump, K A, and Gilbert, NC Effect of digitalis on cIntung Gechanism 14 [25 810, 1944 Sokoloff, L, and Herrer AT [fect of digitalization on coagulation Proc Soc Expe! Biel 1924 19 303, 1945 | 1501 time in man ·Ruurt 11 I. LD I! plov . Dea NI N. 1920 Duvaor, X2Poller, L. Desoille, H, und Caultier, M Deux aus der Har Vau Rifle Palomer. * $. and White, PD Paroxysmal ventricular tachycardia with stylhoue skesnac on dsection of ventricular complexrt in Chapter IV Winkler, AW, 110, 11 E, and Smith, P K Electrocardiographic changes and concentration of potassa se following intre Venous insectos of potassiuoa chloride 4m 1 Phynol 174 178 19:59 Kerth, NM, Outerberg. A, E, and Burch, Some effects of potassium salt in man *** In Med 379 392 Shaspry Shafer, E P Potasssum effects on T wave in version to ouro cardial infarction and preponderance of ventricle Bru Moart 1 BU, 1943 1 1.4, IA Beurt, S, Striert, W A, Nadler, Cazu PCand Lanning, M Electrocardiographic patterns hypnpocassert observatori co keventy-nine parents "Am A$ $. 21: 142, 1959). ( 151 )

·Merill. Significance of electrocardiogram in electrolyte duxturbe
ances Am. Heart]. (1 634, 1952.
Chapter V
Merril, J P Smith, S, IT, Callahan, E. 1. III, and Thorn, C. W
Uw of allificial Idney dmcal experience / Chn Javithawn
29 425, 1950
Chapter 11
Scbwastt, W B, and Levine, S A. Case of paroxysmal auricular
tachycardia prexnt almost continuously lor twenty-five year Cir
Fulation 1 936, 1950
( 152 )

·INDEX to, 34 ACETYL STROPHANTHIDIN procaine amide in, 130, animal experiments with, 131 60-63, 116-119 results of, 120 bigeminy with, 34 technic of, 119 chemical formula of, 114 toxicity in, 25, 117 cumulation of, 116 unfavorable results of, duration of action, 116 131 carlest effect of, 116 agus nerve and, 115 excretion of, 52 ventricular flutter and, 34 Intoxication, 34 ventricular tachycardia intraventricular block due and, 62, 64, 118, 132 Acetylcholine, 42 mercurial redigitalization Acidosis, 45, 93 studies and, 52-54 Actin, 13-15 ouabain and, 115, 116, 124 Acute pulmonary edema, papillary muscle and, 115 digitalization in, 23 paroxysmal atrial tachy Adenosinetriphosphate cardia with block due to, (ATP), 13-15 76 Adrenal steroids, resempharmacology of, 114 blance to digitalra, 42 procaine amide and, 99, Aerobic oxidation, of myo- 117 cardium, 14 QT interval and, 115 Ammonium chloride, 37, tolerance test, 114-133 46, 51 case reports of, 121, Anema, 9, 12 123, 125, 126, 128, 129 clinical studies of, 119 Animal experiments, with acetyl strophanthidin, 60- digitalis not indicated, 129 63, 116-119 extrasystoles, ventricu- Anomalous atrioventricular lar, in, 120 conduction (Wolff-Parkininterpretation of, 120 son-White syndrome), 34 potassium therapy in, Anorexia, 20, 24 120 Arteriovenous fistulas, 12 principle of, 114 Askey, J M, 29, 75, 84 [ 153 ] ·Assay methods for digitalis Atrioventricular conduction, biological, 108-111 8. 15, 64, 86 chemical, 108, 109 Atrioventricular dissociation, clectrocardiographic, 107, 70 108 Atropine, 9, 32, 73 embryonic duck-heart, Atypical flutter, 90 109-112 Auricular. See Atris) pharmacologic, 114-133 radioactive compounds in, BATTERMAN, R. C, 30 112 Beriberi, digitalis in, 12 Asthma, procaine amide Bidirectional ventricular and, 102 tachycardia, 41, 63, 64, 74, ATP, 13-15 131 Atrial fibrillation Bigeminy brgeminy in, 28 acetyl strophanthidin and, digitalis indicated in, 8, 15 34 exercise and, 10 atrial fibrillation and, 28 hemodialysis and, 66 digitals and, 28, 30, 32 mitral stenosis and, 9 duration of, 28 myocardial infarcuon and, hemodialysis and, 64 digitalis in, 29 nondigitalis-caused, 28 paroxysmal atrial tachy ouabain and, 28 cardia with block difa paroxysmal atrial tachy. ferentiated from, 91 cardia with block and, 74 syphuic heart disease precipitating factors in, 30 and, 91 rheumatic heart disease veatricular regularization and, 28 and, 67, 92, 132 Biliary excretion, of digi- Atrial ſlutter toxin, 110 digitalis in treatment of Bing, RJ, 14 15, 32 Blast, II A, 115 electrocardiogram in, 90 heart rase in, 30 Blumgart, HL, 107 Paroxysmal atrial tachy. Boyer, P K, 42 cardia compared to, 74 Brain, digitalis concentraprognosis of, 90 tron in, 110 Atnal paralysis, 69, 70 Bronchiectasis, simulating Atrial tachycardia, 66, 83, heart failure, 16 87, 88 Brown, 11, 95 Atrioventricular block, com Bundle-branch block, digiplete, 73 talis intoxication and, 27 ( 154 ) ·CALCIFIC AORTIC STEA0$15, sions, in digitalis intoxica- 69 tion, 25, 26 Calcium, 38-40 Chemical assay methods for death due to, 38 digitalis, 108, 109 digitalis intoxication and, Coagulation time, digitalis 39 Intoxication and, 29 digitalis synergism with, Cohn, A E, 107 39 Congestive heart failure electrocardiogram and, 38 Sex Ileart failure low serum level of, 39 Coronary artery disease, digpotassium antagonism of, Italis and, 12 38 Cortisone, 58 ventricular fibrillation Crocker, A T, 99 and, 38 Crystodigin See Digitoxin Calhoun, J A, 45 Cyanotic congenital heart Callahan, E J, 111, 98, 102 disease, digitalis in, 12 Carbonic anhydrase inhibi. tors, 37 Deatz Cardiac efficiency, 10 due to calcium, 38 Cardiac falure. See Heart due to digitals, 28, 35 failure due to procaine aprude, Cardiac output, 7, 11, 12 101 Cardiac tamponade, digia Decherd, GM, Jr, 75, 85 talis in, 12 Decompensation Se Heart Carotid-sinus pressure, 92 failure Case records DeGrafl, A C, 36 acetyl strophanthidin tol. Desoxycorticosterone acetate erance test, 121, 123, (DOCA), 6, 58 125, 126, 128, 129 Diamos, 47 digitalis intoxication, 67 Diastolic fiber length, 10 mercurial redigitalization, Diastolic gallop, digitaliza- 52-57 tion and, 17 potassium Intoxication, 68 Diastolic heart size, 10 ventricular tachycardia, Digitaline Nativelle See 105, 106 Digitoxin Castleden, LIM, 43 Digitalis Cation-exchange resins, 37, acetylcholine and, 42 47 action of, 6-23 Cedilaad Sec Lan itoside C acute pulmonary ederna Central nervous system leand, 22 [ 155 ] ·Digitalis intoxication. See Intoxica. adrenal steroids' resem. tion, digitalis blance to, 42 intravenous use of, 36 anemia and, 9, 12 kidney effects of, 7 arteriovenous fistulas and, lethal dose, 30 12 liver concentration of, 110 atrial fibrillation, 29 low-output failure and, 12 atrioventricular conduc magnesium, 40, 41 tion and, 15 mitral stenosis and, 12 beriberi and, 12 myocardial effects of, 10 bigeminy, 28 normal sinus rhythm and, brain concentration of, 8, 12 110 osteitis deformans and, 12 cardiac efficiency and, 10 cardiac output and, 7, 11 paroxysmal nocturnal cardiac tamponade and, dyspnea and, 17 12 physicochemical basis for cellular potassium and, 15 action of, 13-15 choice of agent, 17-23 pericardial constriction concentration in tissues, and, 12 110 potassium concentration in congenital heart disease myocardium and, 41 and, 12 potassium relationship, 41 death from, 28 purpurea. See Digitalis diastolic fiber size and, 10 leaf diuretic action of, 6 quardınc therapy and, 15 dyspnea and, 16 radioactive, 112-114 edema content of, 49, 50 requirements, and serum electrocardiogram and, 27, potassium correlation, 58 66 rheumatic carditis and, 12 clectrolytes and, 38-48 site of action, 13 extracardiac effects of, skeletal muscle potassium 6-8 and, 42 gonadal steroids' resem T waves in, 107, 108 blance to, 29 titration experiments with, heart rate and, 8 60, 62 hcart size and, 10 therapeutic value of, 12 heart slowing and, 9 tolerance test See Acetyl high-output failure and, strophanthıdın, tolerance 12 test idiosyncrasy, 24 toxic properties of, 24 ( 156 ) ·111 Digitalis kidney concentration of, thrombosis, intravascular, 110 and, 29 liver concentration of, 110 thyrotoxicosis and, 12 maintenance dose, 19, 20 vagus stimulation by, 9, metabolic products of, 113 42 protein-binding, 109 venous pressure and, 7 radioactive, 113 ventricular emptying and, therapeutic-toxic ratio of, 10 110, 111 ventricular fibrillation urinary excretion of, 110, and, 28 Digitalis leaf Digoxin atrial tachycardia with administration, route of, block and, 75 21 elirdination of, 18, 19 adrenal steroids and, 6 hypersensitivity to, 24 digitalization with, 19, maintenance dose, 17-19 21, 22 therapeutic-toxic ratio of, duration of action, 19, 20 30 excretion of, 22 toxicity, duration of, 18, maintenance dose, 19, 21 19 renal tubules affected by, Digitoxin 6 absorption of, 109 speed of action, 19, 21 administration, route of, therapeutic-touc ratio of, 18 21, 30 bigeminy with, 28 Diuresis, 6, 28 biliary excretion of, 110 Dizziness, 25 blood level of, 110 Dock, W, 47 brain-tissue concentration Dosage-schedule determinaof, 110 dıgıcalization with, 18-20 Dyspnea, 16 disadvantages of, 20 ederna-fluid concentration ECTOPIC BEATS See Extraof, 110 systoles embryonic duck-heart as Ederna, 3, 6, 16, 49, 50 say for, 109 Eggleston, C, 104, 110 excretion of, 111, 112 Electrocardiogram fecal concentration of, 110 atrial flutter and, 90 intoxication, incidence of, calcium infusion and, 38 36 digitalis effect in, 27, 66, intracellular fate of, 14 107, 108 ( 157 ) tron, 36 ·Electrocardiogram FERRIAR, J., 6 digitalis intoxication and, Fischer, C. S, 112 30, 49 Fraser, F, R, 107 digitalization determined Friedman, M, 14, 110, 112 by, 106 hemodialysis and, 66 GEIGER, A. ), 107 hyperkalemia and, 69, 70 Guiling, E. M K., 112 idiopathic atral tachycar. Gitalın, 19, 30 dia with block and, 86 Glomerular-tubular imbal. myocardial injury and, ance, 3 108 Glucose paroxysmal atrial tachy. consumption of, by myocardia with block and, cardium, 14 72, 73, 130 digitalis toricity and, 59 potassium and, 41 hypokalemia and, 59 PR interval, 73, 74, 77 insulin and, 59, 69, 74 procaine amide and, 97 Glycogen, 59 QT interval, 27 Gold, H, 107 ST segment, 27 Gonadal steroids, 29 T wave, 27 Greiner, T., 115 ventricular hypertrophy Gynecomastia, 29 and, 108 Electrolytes, 38-48 HARRISON, TR, 11 Ells, LB, 98, 102 flatcher, RA, 110 Embryonic duck-heart micro Ileadache, 25, 49 assay method, 50, 109-112 Heart block, 26, 27, 65 Emphysema, 16 Heart failure Enselberg, C D., 116, 123, cardiac output and, 12 140 cation-exchange resins Excretion, of digitalis, 22, and, 47 110-112 coronary artery discase Extracardiac action, of dig. and, 12 italis, 6-8 digitalis intoxication con- Extrasystoles fused with, 30, 31 digitalis and, 33, 122 electrolytes and, 44 magnesium and, 41 hypertension and, 12 multifocal, 28 idiopathic atrial tachy. potassium and, 43 cardia with block and, procaine amide and, 98 86 ventricular, 27, 30, 43, 63, myocardial potassium and, 65 ( 158 ) ·94 27 Heart failure Intoxication, digitalis, 24-37 nutrition and, 45 absence of electrocardiopotassium and, 14, 43-48, graphic effects in, 27, 30 acetyl strophanthidin and, renal impairment in, 4 34, 117 sodrum excretion an, 43 anomalous atrioventricutheories of, 3, 4 Iar conduction and, 34 valvular heart disease bidirectional ventricular and, 12 tachycardia in, 63, 64 vomiting and, 25 bigeminy and, 27, 30, 32 work of heart and, 4 bundle-branch block and, Heart rate, 8 Hecht, H H, 95 calcium and, 39 Hemodialysis cardiac disturbances in, animal, 60-63 26-28 atrial tachycardia during, central nervous system 83 manifestations of, 25, 26 human, 63-66 coagulation time in, 29 ventricular tachycardia dizziness in, 25 during, 85 Hemodynamics duration of, 30, 31 digitalis and, 7, 10, 12 electrocardiogram and, procaine amide and, 97 27, 49 Heparin tolerance, 29 electrolyte manipulation Herrmann, GR, 75, 85 and, 37 Heyt, A F, 75 extrasystoles in, 32, 122 High-output failure, 12 gravity of, 29, 31 Hyperkalemia, 69, 70,96 gynecomastia in, 29 Hypersensitivity, digitalis headache in, 25, 49 and, 24 Hypokalemia, 46, 47, 59 heart disease simulated by, 32 IDIOPATHIC heart failure differenti- ATRIAL TACHY- CARDIA WITH BLOCK, 85, ated from, 31 86 heparin tolerance and, 29 Idiosyncrasy, digitalis and, incidence of, 36, 37 intraventricular block in, Intravenous administration 34 of digitalis, 36 magnesium and, 40 Intraventricular conduction, muscle weakness and, 29 impairment of, 70 myocardial injury and, 32 [ 159 ) 24 ·Intoxication, digitalis digitalization with, 19, 22 myocardial reserre and, maintenance dose, 19, 22 31, 32 therapeutic-toxic ratio of, nausea in, 122 30 normal heart and, 32, 35 Left ventricle, blood flow in, ouabain and, 33 pathologic lesions in, 31 Leonard, BW, 11 prefibrillatory state in, 35 Levine, S. A, 49 potassium and, 41-43, 92 Lewis, T, 8 procaine amide in, 96 Low-output failure, 12-14 sinoatrial block and, 26 Lown, B, 99 subjective manifestations in, 24-26 MACKEYZIE, J., & suicide and, 32 McMichael, J, 7, 27, 32 titratson hemodialysis and, Magnesium, 40.41 62, 65 Mercurial diuresis, 4, 29, 30, trigeminal neuralgia and, 10, 46, 49, 81 25 Mercurial redigitalization, ventricular extrasystoles 49-50, 93 and, 27 Miller, G. II, 49 ventricular fibrillation Mitochondria, 15 and, 31, 131 ventricular flutter in, 34 Mirral stenosis, 9, 12 entricular tachycardia in, Multifocal ventricular extra- 26 systole See Extrasystoles visual symptoms in, 25 Muscular weakness, 29 vomiting in, 49, 121 Myocardium weakness in, 49 aerobic oxidatron of, 14 energy liberation and, 14 JASSESON, RA, 107 digitalis action on, 10 digitalis concentration in KELLER, A F, 108 32, 110 Kiley, J E, 83 digitalis intoxication and, Killani, H, 108 31, 32 Krebs cycle, 15 digitalis sensitivity of, 114 Kohn, RM, 83 glucose consumption of 14 LAENNEC'S CIRRSIOSIS, sim infarction of, 29, 75 ulating heart failure, 16 lactate metabolism of, 14 Lanatos.de C oxygen consumption of, 33 blood level of, 110 potasstum and, 43, 43, 31 ( 160 ) ·Myocardium atrial fibrillation diffcr- Pyruvate metabolism of, entiated from, 91 14 atrial flutter differenthreshold to digitalis intiated from, 90 toxication, 52 atral tachycardia differwork load of, 3 entiated from, 87, 88 Myosin, 13, 14, 15 atrioventricular block, complete, in, 73 NAUSEA, 49, 122 atropine for, 73 Neurath, O, 29 bidirectional ventricular Yodal rhythm, 70, 89, 90 tachycardia and, 74 Nodal tachycardia, 67, 98, bigeminy and, 74 127 carotid-sinus stunulation Normal heart, digitalis inin, 90 toxication and, 35 differential diagnosis of, Normal sinus rhythm, 8, 9, 87 10, 12 digitalis leaf and, 75 electrocardiographic fea- OSTEITIS DE FORMANS, 12 tures of, 72, 73, 130 Overdosage See Intoxica experimental studies in, 74 tion, digitalis glucose and insulin in, 74 Ouabain, 22, 23 incidence of, 81, 85 acetyl strophanthidin mercurial diuretics in, 81 compared with, 115, 116, nodal rhythm and, 89 124 P waves in, 74, 89, 92 bigeminy and, 28 dosc, 19, 22, 23, 55, 118 phases in development of, 76 intoxication, 33 persistence of action, 23 potassium and, 76, 78, 80, Oxygen consumption, by 82, 92 myocardrum, 10 PR interval in, 73, 74, 78 predisposing factors, 81, P WAVE, 77, 78, 92, 93 83 Papıllary-muscle preparaprocaine amide for, 101 Lion, 115 production of, 75, 77 Pardee, H E B, 107 prognosis of, 85 Paroxysmal atrial tachycarquinidine and, 87 dia with block, 72-103 QT interval in, 74 acetyl strophanthidin in, ST segment in, 74 76 T Waves in, 74 animals and, 74 treatment of, 92–103 [ 161 ) ·Tita, 17 Paroxysmal atrial tachycar. maintenance therapy with, dia with block 91 vagal stimulation in, 15, membrane permeability 73 of, 41 ventricular extrasystoles mercurial redigitalization in, 74 and, 51, 93 ventricular rate in, 85 muscle excitation and, 41 ventricular tachycardia myocardıurn and, 13, 43, and, 74 51 Wenckebach conduction onset of action, 51 in, 73 paroxystnal atrial tachy Paroxysmal nocturnal dysp cardia with block and, 78, 80, 82 Pathology of digitalis intoxi pharmacology of, 41 cation, 31 procaine arnide and, 101 Pere, S, 29 ventricular extrasystoles Pericardial constriction, dıg. and, 43, 94, 102 italis in, 12 PR interval, 73, 74, 78 Poindexter, C. A, 42 Prefibrillatory rhythms, 28, Potassium, 41-43 35 administration, methods Procainc amide (Pronestyl), of 93 96-103 calcium antagonism of, acetyl strophanthidin and, 117, 130, 131 Cellular concentration of, admunistration, method of, 14, 15, 44 101 depletion, 45, 47, 48, 58, atrial arrhythmias and, 98 76 contraindications, 102 Diamox and, 47 death due to, 132 digitalis intoxication and, digitalis intoxication and, 41, 42, 43, 67, 92 98, 99 dosage, 42, 93 dosage, 101 duration of action, 51 electrocardiogram and, 97 electrocardiogram and, 41 extrasystoles treated by. excretion of, 46 98 Blycogen deposition and, hemodynamic effects of, 59 97 hazards of use, 95 nodal tachycardia and, 98 beart failure and, 43-48 paroxysmal atrial tachy. indications for, 93-95 cardia with block and, intoxication, 69, 70 101 ( 162 ) 38, 39 ·66 Procaine amide (Pronestyl) Schwartz, W B, 47 pharmacologic properties Serum potassium level, 58, of, 96, 97 potassium and, 101 Sharpey-Schafer, E P., 7 quin.dine contrasted with, Single-dose method, for digi- 97 talization, 36 toxicity of, 102 Sinoatrial block, 26 urinary excretion of, 97 Sinus tachycardia, 8 vagus nerve and, 98 Skeletal-muscle potassium, ventricular fibrillation due 42 to, 102 Sodium, 43, 44 ventricular tachycardia ST segment, 27, 66, 74, 107, and, 98, 102 108 Purodigin See Digitoxin Stearns, N S, 98, 102 Pyruvate, in myocardial St George, S, 14 metabolism, 14 Subjective manifestations of digitalis intoxication, 24-26 QT INTERVAL, 27, 66, 74, Suicide, digitalis and, 32 107, 115 Sulfonamides, as carbonic Quindine anhydrase inhibitors, 47 atrial fibrillation and, 15 Szent-Gyorgyi, A, 13 atrial Autter and, 15, 90 digitalis and, 15 T WAVE, 27, 66, 74, 107, 108 paroxysmal atrial tachy- Tachycardia Se. Atria), cardia with block, 87 Paroxysmal, and Ventric procaine amude and, 98 ular tachycardia RADIOACTIVE DIGITALIS, 112- Tanner, L, 95 Therapeutic-toxic tation, 21, Reilly, J, 115 30, 35 Renal disease, potassium de- Thrombosis, intravascular, pletion and, 58 digitalis and, 29 Resnik, W. H, 91 Thyrotoxicosis, digitals and, Rheurnatic carditis, active, 12 digitals in 12 Tossue anoxia, 59 Ringer, S , 38 Titration dialysis, 62 Tolerance test See Acetyl SAGALL, E L, 28, 32 strophanthidin, tolerance Salt restriction, 4, 46 test Schnitker, 1 A, 49, 50 Schwab, E, 75, 85 UREMIA, 93 114 ·Ventricular tachycardia, 26, 28, 40, 62, 63, 64, 65, 74, 85, 94, 99, 105, 106, 118, 132 Visual symptoms, in digitalis intoxication, 12, 25, 49, 122 VAGUS NERVE acetyl strophanthidin and, 114 digitalis action and, 9, 42 procaine amide and, 98 paroxysmal atrial tachy. cardia with block and, 73, 90 Valvular heart disease, digitalis and, 12 Venous pressure, 7, 16 Ventricular emptying, 10 Ventricular extrasystoles See Extrasystoles Ventricular fibrillation, 31, 38, 102, 132 Ventricular flutter, 28, 34 Ventricular regularization, in atrial fibrillation, 67 WZAKRESS, in digitalis intoxication, 49 Wedd, A M, 115 Weight formula, for digitalization, 104 Wenckebach conduction, 73 Withering, 1, 4, 6, 24, 104, 135 Wolff, L, 28, 32 ZWILLINGER, L, 40

·No text on this page.