Digitalis intoxication — management and prevention

Digitalis Intoxication Management and Prevehtion MARVIN S. ROSENBERG JOHN S. GRAETTINGER

T A B L E OF C O N T E N T S INCIDENCE

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PIIAR.XIACOLOGY O F TIIE CARDIA(2 G L Y C O S I D E S TI~E UNWANTED

E F F E C T S O F DIGITALIS

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Overdosage

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Side Effects

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I~ypersensitivity--Allergic Reactions

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~[ANIFESTATIONS OF DIGITALIS INTOXICATION . Extracardiac Manifestations . Cardiac Manifestations DIAGNOSTIC TESTS

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P r e v e n t i o n a n d R e c o g n i t i o n of P r e d i s p o s i n g F a c t o r s .

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G e n e r a l S a f e g u a r d s d u r i n g Digitalization

SUMMARY

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N o n i n d i c a t i o n s a n d C o n t r a i n d i c a t i o n s for Digitalis Administration . . . . . . . . . . . . .

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PREVENTION OF DIGITALIS INTOXICATION .

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~[ANAGE.MENT OF DIGITALIS INTOXICATION

P r o p h y l a c t i c U s e of Digitalis

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is Research Associate in Medicine at the University of Illinois College o[ Aiedlclne at Presbyterlan-St. Luke's tlospltal in Chicago. Following his intern and resldency training at Cook County lIospltal, he was Assistant in .Medicine at the University of Illinois, part of which time was spent on military leave of absence. Dr. Rosenberg was a Schweppe Fellow in Cardlology at Presbyterlan-St. Luke's Itospltal and is currently a Postdoctoral Fellow of the National tleart Institute.

is As~oclate Professor of Medicine, University of Illinois College of Medlcine. tie received his .XI.D. degree from ]Iarvard Medical School and his intern and residency training on the IIarvard .XIedlcal Service of the Boston City tIospltal. Dr. Graettlnger is Attending Physician and Director, Section of Cardlo-Resplratory Diseases, Presbyterlan-St. Luke's tIospltal, Chicago, and also Attending Physician, Veterans Administration tIospltal, IIines, Illinois.

that it [digitalis] has a power over the motion of the heart, to a degree yet unobserved in any other medicine, and that this power may be converted to salutary ends.--WiLLL~.t 9

WITiIERXNO ( 1 ).

T H E D I G I T A L I S GLYCOSIDES have been in use for centuries, but it remained for William Withering, the English physieian-botanlst, to establish their use on a scientific basis. This occurred in 1785 when, after 10 )'ears of experience with the drug, Withering's report, "An Account of the Foxglove and Somc of its Medical Uses," was published (1). A review of his monograph is quite rewarding both for its historical value and for its

lucid discussion of the preparation, clinical effects, indications and toxicity of digitalis purpurea. Withering believed that the drug was predominantly a diuretic, however, and its primary cardiac effects were not recognized until 1799 by John Ferriar. Since digitalis glycosides are the only drugs which directly improve cardiac action, there exists a tendency to use more rather than less of these drugs in patients with heart failure. Unfortunately, a limit of tolerance to these agents exists, which; if surpassed, results in a group of clinical signs and symptoms commonly referred to as "digitalis intoxication." The word "intoxication" has a combined Latin and Greek derivation meaning "intense poisoning." Poisoning, in turn, refers to the clinical situation in which lethal effects of an agent may be anticipated. If we accept the concept that a "therapeutic" agent can poison if given to excess, then it is evident that in the use of digitalis a spectrum of effects occurs, ranging from the slightest detectable effect through an optimum effect to an excessive effect. This spectrum may be divided into regions of underdigitalization, optimum digitalization and overdigitalization~; this categorization is obviously arbitrary, since there are no sharply defined points separating these various states. Furthermore, it is often difficult to place an individual patient accurately on this spectrum. Since digitalis overdosage can result in worsening of heart failure and indeed in death, knowledge of this region of the spectrum is crucial. The aim of this monograph is to discuss the available information pertaining to the diagnosis, management and prevention of digitalis intoxication.

INCIDENCE

Most authors have been impressed with the increasing number of patients with digitalis intoxication in their practices and institutions. A few of the reasons for this are: 1. An increased awareness of the clinical entity. ~The word "overdigltalization" means that an "excessive," i.e., deleterious, amount of digitalis is present which may or, unfortunately, may not be evident clinically or in the laboratory. The term "digitalis intoxication" refers to the clinical and laboratory stigmata of digitalis excess.

2. The increased longevity of the population in general and, in particular, those with cardiovascular disease. 3. Changing patterns in digitalis administration. 4. The increased utilization of diuretics and diet in the treatment of heart failure. Several years ago, it was estimated from the sales reports of various pharmaceutical companies that 600 million USP units of digitalis were consumed annually in the United States. Taking into account the average dlgitalizing and maintenance doses, it was calculated that approximately 1.5 million persons were actually being treated with digitalis (2). These figures are probably on the conservative side, and it is not surprising, therefore, that digitalis intoxication is common. Some investigators have attempted to gather morbidity data on this subject. In a 1-year period, Rodensky and Wasserman (3) found cardiotoxicity to be present in approximately 20% of hospitalized patients in their institution who were taking one of the glycosides. They quoted one study in which it was estimated that 7% of patients treated with digitalis develop toxicity, and another suggesting that 15% of hospitalized patients receiving digitalis had or developed digitalis intoxication. Most studies of this type have been made on hospitalized patients and obviously represent a selected population of the more seriously ill patients with cardiac disease. To our knowledge, a study of an unselected population on digitalis therapy, including outpatients as well as inpatients, has not been made. It is already well known that digitalis intoxication occurs mainly in older patients. In the study of Von Capeller et al. (4), tile majority of patients were over age 60, and only 7% of 148 patients with this syndrome were under age 40. The occurrence of heart disease causing congestive failure primarily in the older age groups, rather than any factor of age per se, would seem adequately to account for this incidence. Sex and race also do not seem to be primary variables in the development of digitalis intoxication. Besides morbidity data, we must examine mortality data as well. Deaths have definitely been caused by digitalis intoxication either directly or acting secondarily as "the straw that breaks the camel's back." In Rodensky and Wasserman's study, 28.4% of their patients died, 11% being directly attributable to digitalis.

Lown and Levine (5), in a discussion of digitalis-induced paroxysmal atrial tachycardia with block, stated that more than half of their patients died shortly after the onset of the arrhythmia. Deaths from suicidal attempts have also been reported. Undoubtedly, many deaths due to digitalis intoxication are never diagnosed and, in those that are, the underlying heart disease is coded as the cause of death. We are hampered further by the inability of the pathologist to detect these cases at autopsy. It is clear, then, that a valid estimate of the mortality and morbidity secondary to digitalis overdosage will have to await further studies. PHARMACOLOGY OF THE CARDIAC GLYCOSIDES

Although the pharmacology of the digitalis glycosides is quite beyond the purview of this paper, certain aspects are pertinent to a discussion of digitalis intoxication. The similarity of the commonly used glycosides with regard to their cardiotonic properties is based on their similar chemical structure. The basic molecule consists of the usual steroid nucleus, the cyclopentanophenanthrene ring, to which is attached a hydroxyl group at C1~ and an unsaturated lactone ring at G17. This portion of the molecule is called the genin or the aglycone, which by itself has only slight cardiotonic activity. T h e fully potent glycoside is formed by the addition of a sugar group at the C3 position of the aglycone. These agents act directly on the myocardium and increase the contractile force of the functioning heart; since this effect is insensitive to temperature, a physical rather than a chemical action is suggested. This action, which recent evidence indicates occurs in the normally functioning as well as the failing heart, occurs without demonstrable changes in energy production or oxygen utilization. Digitalis thus causes an increased efficiency of contraction, i.e., an increase in work without an increase in fuel. The mechanism by which these drugs bring about this increased utilization of energy is unknown. The dlgltalizing dose, as well as the maintenance dose, is related to the preparation employed and its absorption, metabolism and excretion. The potency of various preparations may vary

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from brand to brand. This is particularly true not only of the galenical preparations (extracts) but also of the crystalline preparations (digitoxin, digoxin). The possibility of a "change" in digitalis dosage must, therefore, be kept in mind when a patient's "prescription is changed. Differences in absorption obviously are important. For example, the dosage of digitoxin is essentially the same orally and parenterally, but the oral digitalizing dose of digoxin is 3-4 times greater than the parenteral dose (Table 1). After entering the body, regardless of the route, the glycosides are quite rapidly cleared from the blood and distributed throughout; cardiac muscle does not have a specific affinity for these drugs. Within the tissues, the drug has been found primarily in the supernatant fraction of the cytoplasm. These agents are metabolized to both active and inactive forms primarily in the liver. Excretion is predominantly via the kidneys and, to a lesser extent, in the bile. The duration o[ action (Table 2) of the various preparations is probably related to their molecular structures. The degree of serum binding with lipoproteins or blood lipids is inversely proportional to the polarity of the glycoside (9). Digitoxin is the least polar and, therefore, the most lipid-soluble, which accounts for its long duration. Using radioactive tracer technics, dlgitoxin has been demonstrated in the urine as long as 40 days after a single injection. Its long duration of action is reflected also by the fact that the average maintenance dose is only 1/15 to 1/17 the digitalizlng dose. By contrast, tile average oral maintenance dose of digoxin, a more polar molecule, is 1/7 the oral digitalizing dose, indicating a more rapid turnover. Since the cardiotoxicity of these drugs is an extension of their cardiotonie properties, the duration of the stigmata o[ toxicity is also most importantly influenced by the duration of their action; that occurring in patients receiving digitoxin, for example, may persist for 1-3 weeks or longer, while that resulting from acetyl strophanthidin may be of only 89 to 2 hours' duration. The individual response to the glycosides may be quite variable. Inspection of Table 1 with respec t to the ranges of both the digitalizing and maintenance doses of the various drugs will disclose differences between minima and maxima of 400% to 500% for the maintenance doses and 2 0 0 ~ to over 300% for the

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digitalizing doses. Tile m a j o r factors causing these wide ranges will be discussed later, but it is evident that the "average dose" of a digitalis glycoside is of dubious value, except as an approximate guide to therapy. T h e breadth of these ranges of maintenance dosage must mean that a large n u m b e r of patients are not receiving adequate digitalis dosage. Conversely, this same breadth of ranges is certainly one of the m a j o r reasons for the occurrence of digitalis intoxication.

THE UNWANTED EFFECTS OF DIGITALIS

A useful classification of the u n w a n t e d effects of drugs is that proposed at an international symposium in 1957 (Table 3) (10). We can immediately disregard intolerance, secondary effects and idiosyncrasy, since these effects of digitalis administration have not been demonstrated. Side effects and allergic reactions will be discussed below. Nearly all of the u n w a n t e d effects of the cardiac glycosides are due to overdosage, the manifestations of which will be discussed in a separate section. O u r present discussion conTABLE 3.--UN~,VANTEDEFFECTS OF DRUCS 1. Overdosage.--Drug levels exceed the normal threshold

A. Absolute 1. Immediate 2. Cumulative B. Relative II. Intolerance.--A lowered threshold to the normal pharmacologic action of a drug III. Side effects.--Undesirable but unavoidable effects of drugs; e.g., somnolence produced by the antihistamines A. Specific B. Nonspecific IV. Secondary effects.---An indirect consequence of a primary drug action; e.g., fungal overgrowth following broad-spectrum antibiotic administration V. Idiosyncrasy.--An inherent qualitative abnormal reaction to a drug;

e.g., primaquinc-induced hemolytic anemia VI. Hypersensitivity-allergic reactioT,s. 10

cerns only the factors which may contribute to the development of digitalis intoxication.

OVERDOSAGE Either relative or absolute overdosage may occur. The former concerns the presence of factors which modify the pharmacology of the drug, the latter tile absolute amount of digitalis within the body. Ahhough these two types exist, there are no differences in the manifestations of digitalis intoxication resulting from them and, indeed, they may coexist. In both, there exists excessive digitalis activity, and in both the type and dose of preparation prescribed, ~ the route of administration, absorption; distribution, metabolism and excretion of the glycoside have a bearing on whether therapeutic or toxic levels will prevail. The importance of these factors varies from patient to patient since no two patients are exactly alike in their handling of digitalis. ABSOLUTE OVERDOSAOE.--This probably occurs most commonly in digitalized patients who begin to do poorly, are thought to be underdigitalized and, therefore, are given additional digitalis. It may occur during initial digitallzation when the excessive use of parenteral preparations is most often at fauh (12) or when onedose digitalization is attempted. It is our opinion that the latter procedure is dangerous and should never be attempted. T o prevent overdosage during initial dlgitallzation, oral preparations should be prescribed whenever possible. Absolute overdosage may be further subdivided into immediate and cumulative. Immediate overdosage occurs when an inordinately large dose is administered by the physician or, less commonly, when ingested by accident or with suicidal intent. In these instances, the manifestations of poisoning occur relatively quickly, dependent on the rapidity of onset of the effect of the digitalis preparation employed (Table 2). A gross overdosage may occur as a result of an error in the prescription or due to a patient's misunderstanding. ~The type of preparation used is important only insofar as the time of onset and offset of digitalis intoxication is concerned since we are in agreement with others that there are no qualitative differences among the various cardiac glycosides. ll

Several deaths due to the ingestion of large single doses of one of tile cardiac glycosides have been reported. Most occurrences of this nature are relativcly innocuous, especially in individuals with nonfailing hearts due to the relative insensitivity of such hearts "to these drugs. In some of the fatal cases reported, death occurred suddenly and was assumed to be due to ventricular fibrillation, which is the common cause of death in overdigitalized experimental animals. Recently, a case of intrauterine digitalis intoxication was reported in which a single dose of 8.9 mg. of digitoxin was ingested by a 7~-months-pregnant woman, resulting in bradycardia and bigeminy in tile fetus. The infant died at the age of 3 days, 1 week after the ingestion of the drug, apparently from intrauterine anoxia (11). Previous studies have demonstrated that the cardiac glycosides do cross the placenta. CUMULATIVE OVEROOSAOE.----Thlsresuhs from the prescription of too large a maintenance dose. Probably the most frequent cause is tile use of 0.2 rag. of digitoxin for maintenance. Although some patients require such a large dose, it is wiser to prescribe smaller doses at first and then to increase tile amount as necessary. The exact maintenance dose for an individual patient can be determined only by careful trial and hopefully minimal error. Therapeutic measures frequently used in conjunction with the cardiac glycosides, i.e., bed rest, diuretics, sedation and a lowsodium diet, may in themselves abolish the stigmata of congestion. It is not surprising, therefore, that marked improvement may occur in the clinical state of tile patient while he remains underdigitalized. In patients in whom this occurs and, in addition, are given too large a maintenance dose, the onset of digitalis intoxication may not become apparent for a relatively long period after the initiation of tim drug. RELATIVE OVERBOSAGE.--The incidence of digitalis intoxication ifi patients receiving tim "average" digitalizing or maintenance doses of one of tixe glycosides is considerable. In some individuals these "average" doses may produce absolute overdosage. In others, however, toxicity is precipitated by the presence of one or more modifying factors which make the patient more susceptible to the effects of digitalis. These are cases of relative overdosage in that the actual body level of digitalis may be relatively low. These predisposing factors may be divided into cardiac, renal, 12

hepatic, pulmonary and electrolyte factors, each of which, either alone or with the others, may play a major role in relative overdosage. The cardiac effects of digitalis are related to the state of the myocavdium. As has been stated earlier, tile normal myoeardium is rather insensitive to digitalis and quite large doses may be given without tile development of toxicity. On the other hand, patients with severe heart failure may develop digitalis intoxication with the addition of quite small doses, e.g., 0.25 rag., of digoxin. Animal studies in which large doses of one of tile cardiac glycosides were administered before and after the experimental production of heart failure have corroborated this clinical impression. Animals developed digitalis toxicity at significantly lower doses after the production of failure than in the control state and, indeed, intoxication occurred in some in whom it could not be induced while their hearts were normal (13). The usual therapeutic dose of digitalis is approximately 60% of the toxic dose (6). In patients with severe and usually intractable heart failure, the therapeutic dose may approach the toxic dose, and, indeed, digitalis intoxication may be unavoidable. Other measures in the management of such patients will have to be relied on until the glycosides may be reinstituted safely (12). Since the digitalis glycosides are 60-80% excreted by the kidneys, a significant degree of renal failure may lead to relative overdosage. It should be appreciated that this problem may arise not only in the patient with obvious renal failure but also in the elderly and in patients with marked congestive heart failure. In the latter circumstances, 2 or 3 days after the initiation of treatment the renal abnormalities may be slgnifieantly improved and digitalis again handled more nearly normally. This is another reason not to use a one-dose digitalization program in patients with marked congestive heart failure. The importance of renalfailure is borne out by the fact that over 10% of Lown and Levlne's patients with paroxysmal atrial taehycardia with block had renal failure (5). The interrelationship between renal function and body potassium will obviously affect the state of digitalization. This will be discussed later, as will the effect of renal dialysis on the production of digitalis intoxication. The liver serves to break down digitalis into its active and 13

inactive metabolites. Therefore, any significant degree of liver impairment may decrease the detoxification of these preparations, thereby reducing their excretion. This then may be another factor in the production of relative overdosage and perhaps con-tributes to the irrcreased susceptibility to digitalis often seen in patients with acute myocardial infarction and in those with congestive failure where anoxia and decreased hepatic blood flow are commonly present. Patients have been studied in whom marked susceptibility to digitalis has been present in the postoperative period when acute hypoxla was present. Improvement in the patient's condition after relief of the etiologic factors, e.g., airway obstruction or atelectasls, has been associated with recover)' of the usual preoperative tolerance to digitalis. Other studies have shown that the occurrence of digitalis intoxication in patients with chronic pulmonary disease is related to the degree of peripheral arterial unsaturatlon. In patients with significant unsaturation, digitalis intoxication was promptly induced with doses which did not produce toxicity in less unsaturated patients. A particular problem is presented in elderly patients undergoing chest surgery in whom a relatively high incidence (20-30% in some series) of postoperative rapid atrial arrhythmias is found. Since many of these patients may be on digitalis, the differentiation between digltalis-lnduced arrhythmias and those unrelated to the drug must be made and is often difficult. Some of the differentiating features will be discussed later. The relationship between the serum and tissue electrolytes, in particular potassium, calcium and magnesium, has received considerable emphasis in recent )'ears. Potassium is probably the most important; certainly its role in digitalis intoxication has received much attention. It is well known that hyperkalemic animals are protected from the development of intoxication even after large doses of one of the cardiac glycosides; conversely, if the same animal is made hypokalemic, quite small doses may prove lethal. This relationship is also true in humans. It is important to recognize, however, that myocardial sensitivity to digitalis is not related to the serum level per se but to total body potassium and potassium balance. It is quite likely that the level of the gradient of potassium across the myocardial cell membrane 14

or the intracellular potassium concentration is the major factor. The physician's reliance on the manipulation of electrolytes in the treatment of heart failure has no doubt been a major factor in the increased incidence of digitalis intoxication in recent }'ears. Diuretic agents such as the mercurials, carbonlc-anhydrase inhibitors, ammonium chloride and the numerous thiazide preparations frequently induce hypopotassemia to tile point where digitalis intoxication becomes manifest. The term "mercnrial rcdlgitalization" has been used to refer to cases of digitalis intoxication precipitated by a mercurlal-induced diurcsis. This effect was thought to be due to the mobilization of glycoside stored in the extracellular fluid. Subsequently, edema fluid has been shown t o contain no significant levels of digitalis; therefore, this term has been abandoned. Digitalis intoxication in these cases results from the potassium diuresis which accompanies the sodium and water diuresis. Severe dietaD' restriction of sodium and the administration of adrenal corticosteroids and cation exchange resins also are known to induce negative potassium balance. At times, the most minor change in potassium may be important; e.g., digitalis intoxication may occur after the ingestion of a high-carbohydrate meal. This is due to the entrance of potassium with glucose into cells, which may produce enough of a change in myocardial potassium to precipitate digitalis intoxication. These same events may occur in diabetics during tile treatment of acidosis; therefore, digitalis should be withheld, if possible, until after the intracellular potassium deficit has been corrected. In patients already on digitalis, the occurrence of an arrhythmia should be anticipated. A rapid heart rate should not simply be ascribed to a sinus tachycardia, but electrocardiographic confirmation of the heart rhythm is mandatory. In these patients, inspection of the T-waves in the electrocardiogram may be helpful in evaluating the serum potassium level as well. Elevation of body calcium has long been considered to augment the action of the cardiac glycosides, although this has not been proved. Conversely, the production of hypocalcemla has been felt to be antagonistic to digitalis activity. These purported relationships have been used as the bases of tests to evaluate the state of digitalization and will be discussed later. If synergism does indeed exist, it would seem to be of little practical importance except perhaps where heart failure is coexistent with dis15

eases associated with hypercalcemia, such as hyperparathyroidism, multiple myeloma and certain malignancies. Hypomagnesemia has been shown to be a predisposing factor in the appearance of digitalis intoxication. Whether this action "is due to the magnesium level per se or perhaps an accompanying change in potassium is not yet known.

SIDE ~FFECTS Gastric irritation with epigastrlc pain or nausea is not infrequently seen with large doses of the galenical digitalis preparations and usually precludes their being used in rapid oral digitalization. These symptoms are less common with the crystalline preparations. Only rarely are these symptoms troublesome at the small doses necessary for maintenance. These gastric symptoms should not be confused with the gastrointestinal symptoms of digitalis intoxication or of congestive failure. Gynecomastia is a well-documented side effect. The mechanism of its production is unknown, hut it is known to occur in the absence of congestive heart failure or abnormal liver function. Some authors have postulated that the steroid nucleus of the glycosides has an estrogen-like action while others have stated that there can be no such relationship because of the unique structure of the glycosides, which does not permit their conversion into any of the estrogen compounds in the body. Although a clear explanation of etiologic factors is lacking, withdrawal of the drug relieves the swelling. Digitalis increases the sensitivity of the carotid sinus by its parasympathomimetic action. In some patients, eyeball pressure, e.g., when surgical dressings are applied to the eye, or the performance of the Valsalva maneuver while straining at stool, may produce transient arrhythmlas and even sudden cardiac standstill. Side effects, such as the production of angina pectoris or acute myocardial infarction, have not been documented to our satisfaction and will not be discussed further.

HYPERSENSITIVITY

ALLERGIC REACTIONS

Allergic reactions are most likely the result of an antigenantibody reaction in which one of the cardiac glycosides is the 16

allergen. Several reasonably well-documented cases have appeared in the literature, but their occurrence is quite rare. Hypersensitivity reactions are mainly confined to skin phenomena which may become manifest as erythematous, scarlatiniform, papular or urticarial eruptions. Cases of facial edema associated with urticaria and angioneurotic edema have been reported. Other manifestations, such as prolonged fever, arthralgia, bronchial asthma and thrombocytopenic purpura, have also been reported. Tile antigen is not known. In occasional patients the substitution of another digitalis preparation results in complete relief. This suggests that, in at least a few cases, a chemical other than the glycoside used in the manufacture of the final preparation may be at fault. The cyclopentanophenanthrene ring which forms part of the nucleus of all digitalis preparations has been incriminated in those patients where tile glycoside itself is thought to contain the allergen. In summary, the unwanted effects of the digitalis preparations are nearly all related to overdose, either relative or absolute. The differentiation between these two types is important in planning appropriate therapy. It should be recalled that, when the usual patient is adequately digitalized, approximately 6 0 ~ of the toxic dose has been given. Furthermore, when toxicity is present, 4 0 ~ of the lethal dose is present. The prevention and early recoomaition of these unwanted effects is of obvious importance. MANIFESTATIONS OF DIGITALIS INTOXICATION

The manifestations of digitalis excess may be divided into two groups, the cardiac and the extracardiac. The latter are troublesome to the patient, but in themselves are rarely the cause of serious incapacity or death. The serious consequences result from cardiotoxicity, and, ahhough they frequently follow or accompany the extracardiac symptoms, they may occur alone. EXTRACARDIAC

I-'~ANIFESTATIONS

GASTROINTESTINAL SYSTEM.--The earliest and most c o m m o n symptoms of digitalis excess are anorexia, nausea and vomiting,

which usually appear in this order. Diarrhea is seen less com17

monly. These effects occur whether the drug is given orally or parcnterally and have been shown to arise in the central nervous system. This central mechanism involves the vomiting center and a chemoreceptor trigger zone in the dorsolateral part of the reticular formation, both of which are in the medulla. Vomiting may also occur secondary to local gastrointestinal irritation, particularly with tile galenical preparations, and to congestive heart failure. These should not be confused with that due to digitalis excess, but occasionally their differentiation may be difficult. Recently, Gazes, et al. (14) reported 11 cases of acute hemorrhage and necrosis of the small intestine which they believed were related to digitalis. These patients presented with abdominal pain mimicking the picture seen with mesenteric artery occlusion or mesenteric vein thrombosis. At autopsy, neither of these lesions was present, but marked venous congestion was seen which was thought to be the cause of the necrotic intestine. The authors pointed out that all of their cases were on high doses of digitalis and that 7 had other evidences of digitalis excess. It was postulated that hepatic-vein or sinusoidal-sphincter constriction with resulting portal splanchnic venous congestion might have b e e n the mechanism whereby digitalis produced this syndrome. The validity of attributing this syndrome to digitalis cannot be judged until more cases are reported, but, for the present, this mechanism should be considered when a patient develops abdominal pain while on large doses of digitalis, and unnecessary surgery may thus possibly be avoided. NERVOUS SVSTV.~I.--Visual aberrations are well-known s}wnptoms of digitalis excess but are often missed unless the patient is specifically questioned about their presence. These disturbances consist of blurred vision, the presence of flickering objects and illusions of color. Most commonly, objects appear yellow or green, but any color may be present. It is thought that these changes are cerebral in origin rather than originating in the retina or optic nerve. Total but reversible blindness secondary to bilateral toxic retrobulbar neuritis has also been reported. Neuropsychiatric manifestations also may occur. Dizziness, occasional vertigo, headache and facial pains resembling trigeminal neuralgia have been described. After intravenous acetyl strophanthldin, Lown and Levine noted transient numbness and tingling 18

of the lips, nose, cheeks and ears (6). In older patients in particular, acute confusional psychoses, often referred to as "digitalis delirium," may develop. Other behavioral changes, such as lassitude, apathy, confusion, disorientation, stupor and aphasia, may also occur. The true cause of these symptoms may go unrecognized, particularly when they are part of a complex picture. Neuralgic-type pains in the extremities as well as low-back pain may develop. Generalized muscular weakness has also been described.

CARDIAC I-~{ANIFESTATIONS We have stressed the consideration that the effects of digitalis on the heart are quantitative and may be regarded as being on a spectrum which ranges from insignificant effects through optimum effects to frank poisoning of the heart. The therapeutic goal of the clinician obviously is to adjust the administration of the drug to the level at which the pumping action of the heart is most efficient and to withhold the drug when it causes toxicity. The undesirable cardiac effects could arise either from a direct action on myocardial contractility with a decrease in stroke volume or secondarily from a decreased cardiac output caused by certain abnormal cardiac rhythms. Although congestive failure may seem to worsen in certain patients receiving increasing amounts of digitalis without the development of an arrhythmia, we are not aware of data which confirm that, clinically, even large amounts of digitalis ever decrease myocardial contractility.

The usual undesirable cardiac effect o/ digitalis intoxication is the occurrence o / a n arrhythmla. This may not result in symptoms; therefore, the detection of an arrhythmia at the bedside or in an electrocardiogram usually leads to tile suspicion of digitalis excess. Electrocardiography, therefore, is indispensable for the following of patients in whom any suspicion of digitalis excess exists, particularly since some of the arrhythmias are characterized by normal rates and a regular rhythm. We have not found it useful, however, to base a diagnostic or therapeutic classification of digitalis intoxication on electrocardiographic criteria alone. The electrocardiogram in a patient with digitalis overdosage may vat)' considerably from hour to hour. We have seen 19

serious cardiac arrhythmias [or only a Jew minutes at a time in patients receiving high doses of a long-acting digitalis preparation in whom the electrocardiogram was being monitored over a period of several hours. Obviously, such a patient must be regarded "as being toward the dangerous end of the spectrum of digitalizatlon despite the absence of the arrhythmla for even long periods. Since the presence or absence of the arrhythmia depends on the time at which the electrocardiogram is taken in such a situation, the limited usefulness and, indeed, the potential hazard of deciding whether or not digitalis intoxication is present by electrocardiographic criteria alone is evident. Another limitation of electrocardiography is that it can reveal only the nature of an arrhythmia, not its cause. Since digitalis may either cause or be useful in the treatment of many arrhythmias, the significance of an arrhythmla cannot be decided on electrocardiographic criteria alone; therefore, although the clinician must use the electrocardiogram, he cannot depend on the electrocardiographer for the diagnosis of digitalis intoxication or for therapeutic suggestions. The assessment of the degree of digitalization and the diagnosis of digitalis intoxication is an obligatory clinical responsibility which must be carried by the physician with the aid of the electrocardiogram. The essentiality of constant suspicion backed by electrocardiography, particularly in ill patients receiving digitalis, cannot be overemphasized. Prerequisite to a discussion of the electrocardiographic stigmata of digitalis excess is an appreciation of the S T - T changes which may occur during the administration of digitalis. These changes are important to recognize since, although commonly related to dosage in any given patient, the relationship is not quantitative and cannot be used to assess the degree of digltalization. Repolarizatlon of the ventricles is hastened by digitalis and, indeed, most probably occurs earlier with respect to the onset of depolarization in the total heart, i.e., while some regions of the myocardium are still undergoing depolarization, repolarlzatlon may be under way in others. The electrocardiographic consequences of this phenomenon are shortening of the QT duration and a "curving" of the ST s%mnent away from the major direction of the QRS deflection. Since the QRS is usually upright in the llmb leads and left precordial leads, a convex-downward 90

depression occurs in these leads followed by a small upright T ; in leads in which QRS is negative, which commonly occurs in leads V1 and V.o, a convex-upward elevation of S T may be seen (Fig. 1). In tile differential diagnosis of these ST segment deviations, it is helpful to keep in mind that, when caused by digitalis, the most marked deviation is in the middle of the segment; the ST junction and early portion of the segment are not as much deviated in contrast to those reflecting ischemia, in which straightening and depression, often including the ST junction, are commonly found, and the Q T duration is usually normal or prolonged. The appearance of these S T - T and Q T changes in the electrocardiogram of a patient receiving digitalis does not, even when they are marked, mean that an undesirably high level of digitalization is present, and they are commonly referred to as "digitalis effect." Conversely, the absence of marked changes (or, indeed, any changes) of this kind does not mean that a serious digitalis-induced arrhythmla may not soon develop. The effect of digitalis on the heart rate was recognized long ago in Withering's observation that "the rapid pulse doth moderate." Digitalis does not directly affect the rate of the heart to any significant degree, however, when the sinus node is the pacemaker unless atrioventricular block occurs (vide in/ra). When sinus tachycardia slows during digitalization of a patient with congestive heart failure, the rate decrease is due to an improvement in circulatory function, i.e., the rapid rate was a compensatory mechanism to maintain cardiac output in the face of an inadequate stroke volume. In some patients with a severe myocardial infarct, acute rheumatic carditis or severe aortic stenosis, tile heart rate does not slow because tile damaged heart cannot respond with an increase in stroke volume. If increasing amounts of digitalis are given to such patients in an effort to slow the heart rate, serious arrhythmlas may occur. We believe that the basis of the commonly held belief that digitalis administration is unwise in these patients is the not infrequent intoxication produced by continuing the drug to toxic levels because a compensatory sinus tachycardia does not slow. Although digitalis does not have a clinically significant effect on heart rate by a direct effect on the sino-atrial node, certain slno-atrlal abnormalities may be seen in digitalis intoxication 21

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Fro. l . - - E f f e c t s of digitalis in atrial fibrillation. This elderly female presented in severe conge~tlve failure with a history of being ill for only a few days. She denied ever having taken digitalis. T h e electrocardiogram in column I shows a very rapid and predominantly irregular r h y t h m . In Vx, however, the rhythnl is perfectly regular, with a rate of 167 heats per mlnnte. Definite fibrillation ~aves cannot be identified. T h e Q R S duration is 0.12 second a n d suggests either a n intraventrlcular conduction defect or ventricular tachycardia. T h e t h i r d a n d fourth beats in L3 are faster a n d of different configuration and, thus, a p p e a r to be ectoplc ventricular brats, sshich tends to exclude the diagnosis of ventricular tachycardla. F u r t h e r m o r e , carotid sinus massage slowed the rate. T h e only previous tracing available showed normal sinus r h y t h m ~sith a normal Q R S duration and, therefore, was not helpful. T h e diagnosis of atrial fibrillation ~,ith complete left bundle b r a n c h block was made, a n d dlgltallzation with lanatoslde C was carried out. In column 2, the ventricular rate is slowed, definite atrial fibrillation is present, a n d left bundle branch block persists. Digitalis effect appears in the tracing, as evidenced by the scooping a n d depression of the ST segment in leads I a n d V s a n d the reciprocal changes in L a a n d Vx, where more p r o n o u n c e d S T elevation appears.

(Figs. 2 and 3). Sino-atrial nodal depression may result in sinus bradycardia, sinus arrhythmia or wandering atrial pacemaker. Sinus arrest, either fixed or intermittent, may also occur in which the ventricles may be driven by a slow atriovcntricular nodal or, rarely, an idioventricular pacemaker. The development of sinus arrhythmia, particularly if nonphasic with respiration, should also lead to a consideration of digitalis excess. Finally, a "wandering pacemaker" may be seen in which a variation of the configuration of tile P-wave occurs. In addition to the secondary slowing of the heart rate resulting from the improvement of fai!ure, digitalis may primarily slow the heart rate by its familiar effect on the atrioventricular conduction velocity. This effect is initially mediated via the vagus nerves, can be blocked by atropine and may be augmented by parasympathomimetlc drugs, e.g., prostigxnine. With increasing levels of digitalization, a direct action not blockable by atropine is seen. Although slowing of the rapid heart rate by this action is undoubtedly one of the most salutary effects of these agents, this effect on a-v conduction may become quantitatively excessive. Since the maintenance of cardiac output in the presence of bradycardia must depend to a major extent on a considerable stroke volume, very slow rates are undesirable in patients with diseased hearts in whom the ability to increase stroke volume is limited. In most patients with sinus rhythm, even large or toxic doses of digitalis usually do not cause delayed atrioventricular conduction. In some patients, however, various degrees of a-v block may appear. This most often occurs in patients with ischemic or rheumatic heart disease. A prolonged a-v conduction time reflected electrocardiographically by a prolonged PR interval without dropped beats (first degree a-v block) may be seen early in the course of digitalizatlon but is of no consequence since this does not slow the heart rate. Higher degrees of a-v block may be seen in which some, but not all, of the sinus beats pass through to the ventricles (second degree a-v block) (Figs. 2 and 3), or complete (third degree) a-v block may occur, in which none of the sinus beats pass the a-v system and the ventricles are driven at a slow rate either by the a-v node or an idlovcntricular pacemaker. May we emphasize here that we are discussing slowing 23

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F~. 3.4evere di~h~lls intoxication with sinus arrest. This patient is an elderly white male who entered the hospital with uremia and congestive heart failure. Prior to admission, he had been maintained on digitoxin and quinldine sulfate, the latter since a successful conversion to sinus rbytbm from atrial fibrillation some months before. On admission on 2-19-62 he was noted to have bradycardia. An electrocardiogram showed no atrial activity and a slow, regular, nodal pacemaker. Digitalis was stopped. No potassium chloride was given, since the patient had hyperkalemia. The following day (2-20-62), sinus arrest persisted, but the nodal rhythm was irregular and U-waves were seen. Later the same day, P-waves were thought to be present in the routine electrocardiogram. This was confirmed in lead Ve, which demonstrated a definite sinus arrhythmla with first degree A-V block. At times, this rhythm was nonphasic in relation to the respiratory cycle. On the folloss~ng day (2-21-62), normal sinus rhythm with first degree A-V block was present. Three days later, the patient had improved conslderably and 0.25 rag. of digoxln was given, which promptly induced second degree A-V block of the Wenckebach type. Digoxin was again stopped, and normal A-V conduction reappeared. Throughout this whole period, quinidine was continued, since the admission electrocardiogram disclosed no evidence of toxicity to this drug (widening of QRS). It in interesting that thln patient was in digitalis intoxication despite hs~erkalemia (which was never apparent in the electrocardiogram) and actually improved as the potassium was falling toward normal levels.

of tile heart as a result of antegrade a-v block in tile presence of a sinus mechanism. These various degrees of atrioventricular block may be seen in heart disease even without digitalis and may be increased or -made manifest by the parasympathomlmetic action of the drug at any level of digltalization in any given patient. This phenomenon is important to appreciate, since second or third degree a-v block may occur in such patients receiving digitalis at dosage levels far below those at which toxic effects on the myocardium might be anticipated. Indeed, even low doses of digitalis may have to be discontinued because of the slow heart rate. In patients with atrial fibrillation and flutter, digitalis slows tile heart rate by its direct cardiac action on tile a-v node. It is in these two conditions, when tile ventricular rate is rapid, that the drug is most efficacious. When these arrhythmlas are not tile consequence of digitalis, the slowing of tile ventricular rate to normal by increasing the "physiologic" second degree a-v block "~ is a most important indicator of the level o f dlgitalization (Fig. I). In atrial flutter, in which the a-v block is greater than 2:1 prior to digitalization, disease of tile a-v node is suggested. Digitalization should be performed carefully in these patients to prevent complete heart block and possible ventrlcular standstill, which may be precipitated by the additional a-v blocking effect of digitalis. In judging the degree of second degree block and the adequacy of digltalization, the relationship between digitalis and the autonomic nervous system must be kept in mind. Often during the course of dlgitalization in a hospitalized patient with atrial fibrillation, for example, the early morning resting ventricular rate will be found to be slow, e.g., 55-65, and the patient will be thought to be "digitalized." If the patient is then made to exert slightly, such as by sitting up a few times, the ventricular rate may become quite rapid. This means that more digitalis should be given with the goal of control of the ventricular rate when the patient is active since the ordinary state of man is not basal. If, on the other hand, the ventricular rate during activity *Some degree of second degree atrioventrlcular block is always present in atrial fibrillation and nearly always in atrial flutter since the a-v node usually cannot transmit impulses at a rate faster than 200 beats per minute. 26

is below 50 per minute, it is probably wise to omit one or morc doses of digitalis since arrhythmias, particularly atrioventricular nodal escape rhythms, may occur and, as has been mentioned, marked bradycardia is undesirable. There is one clinical situation, the Wolff-Parklnson-White syndrome, in which the administration of digitalis to less than toxic levels may be associated with a paradoxical increase in heart rate. In tiffs condition, an anomalous atrioventricular pathway exists which is not depressed by digitalis as is the normal a-v node. Any significant a-v nodal depression, e.g., by digitalis or vagal stimulation, favors conduction through the abnormal and accelerated pathway resulting in a broad QRS complex and a narrow P - R interval. Supraventricular arrhythmlas of all types are common in this syndrome when conduction through the anomalous pathway is established, which accounts for the "paradoxical" acceleration of the heart rate. To convert these arrhythrajas, quinidine, which depresses conduction along the anomalous pathway, is often necessary. Quinidinization while digitalis is withheld allows normal sinus rhythm with normal a-v conduction to resume. Small maintenance doses of both of these drugs may be useful in the prevention of recurrent episodes. While the above-mentioned effects of digitalis on the heart rate may become quantitatively excessive and force diminution or discontinuation of the drug, they are usually not life-threatening. On the other hand, let us now consider disturbances of impulse initiation which, by their very presence, often portend serious consequences and which usually necessitate more active therapy. The mechanisms by which digitalis produces these arrhythmias are probably by an increase in automaticity and a decrease in conduction velocity, thereby favoring the initiation and continuation of ectopic activity. ATRIAL ARRHYTttMIAs.--Atrial prcmature beats are occasionally seen. Paroxysmal atrial tachycardia (usually with 2:1 a-v block), atrial flutter and atrial fibrillation also occur in digitalis intoxication, the latter two uncommonly, but the first is one of the most frequent of the serious digitalis-induced arrhythrajas. The differentiation between paroxysmal atrial tachycardia with block and atrial flutter must be made. This is of great importance since tim former is usually digitalis-induced 27

while atrial flutter usually requires more digitalis, although, rarely, it too results from digitalis intoxication. Knowledge of the salient features of paroxysmal atrial taehyeardia with block and of atrial flutter usually allows easy differentiation, but occasionfilly this is quite difficult using electrocardiographic criteria alone. Several differences are helpful in making the correct diagnosis (5). In flutter, atrial rates below 250 are rare unless quinidine has been given, while in paroxysmal atrial tachycardia the atrial rate is usually less than 200. In atrial flutter, the atrial "F" waves appear in a continuous positlve-negative "saw-toothed" wave form with the result that the tracing is in continuous motion without an isoelectric interval between atrial waves. By contrast, in atrial tachycardia discrete P-waves with an isoelectrlc inter~'al between them are seen (Fig. 4). This difference is seen most clearly in leads 2, aVF and 3; the two atrial rhythms may appear quite similar in the other leads, particularly in the central precordial leads. The occurrence of prominent U-waves in atrial tachycardia may cause the tracing superficially to resemble flutter, but the lack of continuous, absolutely regular, atrial activity will become apparent if calipers are used as dividers to trace over supposedly corresponding portions of the tracing. It should be kept in mind that the P-wave form in atrial tachycardia may appear normal but will commonly differ from that seen in other tracings in a given patient. When atrial tachycardia occurs as a manifestation of digitalis intoxication, a 2:1 atrioventricular block is usually present, and the resultant ventricular rate (with atrial rates commonly being 170 to 200) is 85 to 100. The rate of a-v conduction may vary with the result that a slight variation, usually 0.02 to 0.10 second, may occur between successive R - R intervals in the electrocardiogram. In atrial flutter occurring in the absence of digitalis, a constant 2:1 atrioventricular block usually occurs with a perfectly regular ventricular rate (with atrial rates commonly being 220 to 280) of 110 to 140. By contrast, when flutter is digitalis-induced, a 4:1 or greater a-v block is usually found. When atrial flutter is present either with a 2:1 or variable a-v block up to a 4:1 block, therefore, it is unlikely that the arrhythmia is digitalis28

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t Fro. 4.--Parox)'smal atrial tachycardla ~dth 2:1 atrloventrlcular block shinning the effect of carotid sinus pressure in a 77-year-old female ~*ith arteriosclerotic beart disease and a history of recurrent episodes of tach)'cardla for which d gltalls a n d quinldine were being administered. T h e above tracing was taken during an episode of tachycardla following an increase in her dlgltalls dosage. T b e standard llmb leads show a slightly irregular Ventrlcular rate of approximately 115 beats per minute. T h e P-was'es have the same axis as was present during a previous normal tracing; bowever, the u p w a r d deflections following the Q R S complexes in leads 2 a n d 3 were not present before. These deflections a p p e a r exactly halfway between the obvious P-waves and, indeed, are P-waves tbemselves. T h e diagnosis was paroxysmal atrial tach)cardla with 2:1 A - V block. T h i s was confirmed by carotid slnux massage, xdtich clearly identified the atrial taehyeardla at a rate of 230 beats per minute. T h e flat base llne between P-waves and the slightly irregular vcntrlcular rate help to differentiate this a r r h y t b m l a f r o m atrial flutter with a 2:1 A - V block.

29

induced, and additional digitalis to the point of a 4:1 block is usually indicated. Finally, in differentiating between atrial flutter and atrial tachycardia, carotid sinus pressure during monitoring of the electrocardiogram is invaluable in that a higher degree of atrioventricular block may be induced, and the character of the atrial activity will become clearly evident (Fig. 4). Uncommonly, atrial fibrillation may be digitalis-lnduced. Although this is probably quite rare and cannot be proved, the sudden development of atrial fibrillation with a rapid ventricular rate in a digitalized patient who has had sinus rhythm should bring up this possibility and lead to a re-evaluation of his digitalis status. Since digitalis is efficacious in controlling the ventricular rate in the treatment of patients with paroxysmal as well as fixed atrial fibrillation, such a patient may present quite a therapeutic dilemma. In most of these cases, a rapid nodal tachycardia with irregular block rather than true atrial fibrillation is present. Paroxysmal atrial tachycardia with an irregular atrioventricular block may mimic atrial fibrillation at the bedside; therefore, electrocardiographic confirmation is mandatory. ATRIOVENTRIGULAR NODAL ARRHYTHMIAs.--Nodal premature beats, nodal rhythms and nodal tachycardia are commonly seen at high digitalis levels. Indeed, in our experience these abnormalities are much more common than atrial tachycardia with block. Nodal beats, nodal rhythm and nodal tachycardia are diagnosed electrocardiographically by either the absence of P-waves or P-waves indicating retrograde depolarization of the atria (Figs. 5 and 7). If tile retrograde impulse depolarizes the atria before tile antegrade spread depolarizes the ventricles, a retrograde (usually inverted) P-wave preceding the QRS will be noted. If the retrograde and antegrade spreads result in simultaneous atrial and ventricular depolarization, the P-wave will be buried in the QRS. If the retrograde spread depolarizes the atria after the antegrade spread has depolarized the ventricles, a retrograde P-wave will be seen following the QRS. Nodal beats and rhythms tend to occur as "escapes," i.e., when a long sinus pause occurs, an "atrioventricular nodal escape beat" will often restart the heart. 30

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Fro. 5.--Atrioventricular nodal tachycardia in a middle-aged male with muhivalvular rheumatic heart disease and persistent congestive heart failure, lie has had known atrial fibrillation for several years and bad heen on maintenance digitalis. On !-5-fi2 nausea, anorexia and diarrhea were present, and "regularizatlon" of his rhythm was noted. An electrocardiogram showed a regular rh~'thm at 125 beats per minute. No P-waves could be identified. Depressed ST segments and terminally upright T-waves were seen, compatible with digitalis effect. In La, two ectoplc ventricular beats of different origin were seen. A diagnosis of digitalis intoxication with a nodal tachycardla ("middle-nodal") was made. Digitalis was stopped, and potassium chloride was given by mouth. A tracing on i-8-62 demonstrated the resumption of a slow, irregular, ventricular response and lessened digitalis effect. Frequently, muhifocal, ectoplc ventrieular beats are associated with the various dlgitalls-induced arrhythmias and may be helpful in arriving at the correct diagnosis.

31

Pick, Langendorf and Katz (15) have emphasized that in patients with atrial fibrillation, when digitalis intoxication develops, tile slow and irregular ventricular rate may be superseded by the escape of a regular nodal pacemaker. A functional complete 9atrioventrictdar block is present in that none of the atrial fibrillatory activity passes to the ventricles. If this arrhythmia is not recognized and more digitalis is given, nodal tachycardia may result (Fig. 5) followed by a nodal tachycardia with irregular block or the serious alternating bidirectional tachycardia (Fig. 6). As a general rule, it is important to remember that digitalis intoxication is usually present in any patient with chronic fibrillation who develops "regularization" of his rhythm since spontaneous conversion to a sinus mechanism is uncommon. Often, when a patient with heart failure develops a rapid, regular pulse accompanied by increasing failure, a sinus tachycardia secondary to the failure is thought to be present, and more digitalis is given. An electrocardiogram under such circumstances is mandatory to establish the presence or absence of a dlgitalis-induced arrhythmia, most commonly a nodal rhythm or a paroxysmal atrial tachycardia with 2:1 block. It cannot be stressed too strongly that frequent examinations and electrocardiograms are necessary, particularly in t h e patient in whom relative overdosage is likely to develop and, most particularly, in the patient with "regularization" of his rhythm. When tile atria and the ventricles are beating at different rates, a semantic as well as a clinical problem is commonly present. We have already discussed those instances in which the atrial rate is [aster than the ventricular rate in that only some or none of tile atrial impulses pass to the ventricles. These occurrences are called "atrioventricular block" (Figs. 2 and 3). If the block is complete, a subatrial pacemaker must obviously be present and may be in the a-v node or below. In normal sinus rhythm, if an atrioventricular nodal rhythm is present at a rate slower than atrial activity, it has taken over because o/ tile failure of higher pacemaker activity to reach the ventricles. In the case of a-v nodal rhythm with atrial fibrillation, the a-v node has again taken over because of complete a-v block. In these circumstances, we are thus considering a-v nodal rhythms as a consequence of antegrade block. 32

Atrioventricular nodal rhythm and tachycardia may occur in yet another way if a retrograde, i.e., "ventriculoatrial," block is present. If the a-v nodal impulses do not pass in retrograde fashion to depolarize the atria, the phenomenon of a-v dissociation is-present; the atrial mechanism, whatever its site, drives the atria usually at a slower rate, and the nodal pacemaker drives

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L2 FIG. 6.--tMternatlng hldirectloiial A-V nodal tachycardla in an elderly female who entered the hospital in a stuporous condition with marked congestive heart failure. At 1:30 P.~i. of the day of admission, the electrocardiogram showed atrial fibriIIatlon with a sllghtly rapid ventrlcular rate. At 4:30 v.M., 0.5 rag. of dlgoxin was glven.Six hours later, a regular tachycardla was not-cal.An electrocardlogram demonstrated a rate of 175 beats per minute without definite P-waves. Two types of QRS complexes Were present, both less than 0.12 second; they were bidirectional and alternated with every other beat. The R-R interval between these two kinds of complexes was the same. The upright complex was identical to the patient's normal QRS contour. Thls represents an alternating bldirectional nodal tachycardla, which is considered pathognomonle o[ severe digitalis intoxication. In other instances, one or both of the complexes may be greater than 0.12 second, and then an alternating bidirectional ventrlcular tachycardla is said to be present. Whether this arrhythmla represents a double nodal tachycardla or a nodal tachycardla with aberrant conduction of every other beat has not been decided in the literature.

the ventricles. If the retrograde and antegrade blocks are complete-i.e., if there are no instances of either an atrial impulse passing the a-v node and "capturing" the ventricles or, conversely, of a nodal beat "capturing" the atria and depolarizing them in retrograde fashlon--the dissociation is said to be "complete." If such captures do occur, "incomplete a-v dissociation" is said to be present. If the nodal pacemaker completely controls the atria, then nodal tachycardia is present (Fig. 7). Unfortunately, file term "interference dissociation" has been used in several dif33

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ferent senses in this general field of a-v dissociation and probably is best discarded. Tile antegrade and retrograde blocks seen in digitalis intoxication tend to be transient and hence have been called "functional" in contrast to tlle more constant antegrade atrioventricular blocks, first, second or third degree, seen as a consequence of heart disease. Furthermore, since the a-v nodal rates at which a-v dissociation develops are often considerably faster than usual nodal rhythms in complete heart block~ a heightened rhythmicity of the a-v node is suggested. "' Various rather intricate electrical phenomena may be seen in atrioventricular dissociation when the atrial and ventricular rates are close and captures occur. A kind of "regular irregularity" o f . rhythm may occur. These elegant arrhythmias have been discussed in recent textbooks of electrocardiography and require expert interpretation, but in patients with atrial fibrillation the general dictum that "regularization of rhythm suggests digitalis intoxication" m u s t be remembered if fatalities from overdosage are to be reduced. VENTRICULAR ARRtPt'TttMIAS.----The most frequent manifestation of digitalis excess is the occurrence of ectopic vcntricular beats (Figs. 5 and 8). In early stages, these complexes with a QRS duration over 0.19 second are classically of the same form and follow the preceding normal beat by a constant interval, which suggests a single focus of origin. When regular sinus or nodal rhythm is present, the ectoplc beat is usually "premature" and is followed by a full compensatory pause since the ventricle is still refractory at the time the next sinus impulse arrives or because it has discharged tile next building nodal impulse. At times, however, when tile sinus rate is slower, an ectopie premature ventricular beat may be "interpolated" between two regular beats not followed by a compensatory pause and truly be an "extrasystole" (Fig. 8). With increasing intoxication, multifocal, bidirectional, ectopic ventricular beats, often in pairs, may develop. If intoxication progresses, short runs of ventricular tachycardia usually occur which may eventually develop into an alternating bidirectional ventricular tachycardia, ventricular tachycardia of the usual variety (unidirectional) and ventricular fibrillation (Fig. 9). It should be kept in mind that ectopic 35

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L Fro. B.--Digitalis-induced trlgemlnal rhythms in a mlddle-aged woman who had been receiving digitalis /or )'ears. On 3-8-62, a trlgeminal rhythm due to coupled premature ectoplc ventrlcular beats is present, while on 3-9-62 trlgemlny due to interpolated ~entrlcular beats (extrasystoles) is seen. In the latter strip, the P-~,ave o! the last complex of each triplet is seen partially buried in the T-wave o! the ventrieular beat. On 3-12-62 the patient underwent major abdominal surgery. The following morning, 3-13-62, digitalis intoxication was still present, but ST segment depression and prolongation of the QU duration is noted, with large U-waves superimposed on the ends of the T-waves. Because of these changes, the diagnosis of cellular h)popotassem~a was made, and the Serum potassium was 3.0 rag.% Digitalis was stopped, and intravenous potassium chloride was given. By 3-14-62 the arrhythmla had disappeared, and the S T - U segments were less abnormal. On 3-16-62, an electrocardiogram (not shown) demonstrated a normal sinus rhythm s~ith only small U-waves similar to those present in the tracing of :3-8-62.

36

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Lead 2 Fio. 9,--Absolute digitalis overdosage. This was a 3-month-old infant with cyanotic congenital heart d/sease, ~ bo underwent paillatlve cardiac surgery on November 3, 1960. She had been previously digitallzed and was maintained on 0.03 rag. of d/goxin daily. Two hours postoperatively, 0.5 rag. of digoxln was given intramuscularly at 1:20 p..xt. The first 4. tracings demonstrate increaxlng digitalis effect (depression and scooping of the ST segment with inversion of the T-wave). Sinus t~chycard/a is present at 2:25 and 2:48 v.sL, while an unusual rh)thm is present at 3:07 and 3:09 r..xf. This consists of a blgemlnal rhyt}gm where every second beat is initiated by a premature atrial systole (of the same configuration as the sinus ILwaves) followed by a PR interval longer than the alternate sinus beats. One interpretation of this arrh~thm~a is that it represents a sinus tachycard~a with alternating .dnus premature beats. At 3:09 P.Sf., a ventrlcular extrasystole is also seen. At 3:12 P.Sr., ventricdar fibrillation appeared which was followed by a slow and irregular id/oventrlcular ~hythm (3:15 P..~L). Potassium chloride and open cardiac massage were without benefit.

37

ventricular beats, particularly when multifocal and bidirectional, are frequently associated with the digitalis-induced supraventricular arrhythmias and, thereby, provide a clue to the correct diagnosis (Fig. 5). The development of life-threatening ffrrhythmias, such as ventricular tachycardia and ventricular fibrillation, need not follow a definite pattern of progression from less severe arrlwthmias. Indeed, they may occur de novo in the absence of any of the extracardiac manifestations and even without electrocardiographic evidence of digitalis effect. In the differential diagnosis of abnormal ventricular impulse initiation, suggested by wide QRS complexes of aberrant form, the possibility of a supraventricular origin of the beats in question accompanied by an abnormally delayed intraventricular conduction must be kept in mind. Atrial ectopic premature beats may be accompanied by conduction delay or complete bundle branch block and thus resemble vcntricular ectoplc beats. As in atrial premature beats without aberration, the abnormal P-wave can usually be found, and the pause following the beat is not fully compensatory. More difficult is the occurrence of a supraventricular tachycardia with bundle branch block which may closely simulate ventricular tachycardia. The ventricular rate is usually quite regular, however, and the complexes often look like bundle branch block, in contrast to the often slightly irregular rate and bizarre complexes of ventricular tachycardia (Fig. 1). An almost absolute diagnosis of ventricular tachycardia can be made if atrial activity at a slower rate can be identified. The use of bipolar exploration of the central prccordial region, e.g., CR1, CIR2 leads, high and low, and the use of an esophageal lead are often most helpful in disclosing slower atrial activity and thus establishing a ventricular tachycardia. The one possible exception would be the occurrence of a complete atrioventrlcular dissociation in which a normal sinus rhythm and an a-v nodal rhythm with bundle branch block were present. Every effort to establish the diagnosis of digitalis-lnduced ventricular tachycardia must be made, since it represents an absolute contraindication to digitalis and demands immediate specific treatment, while supraventricular tachycardia with bundle branch block or nondigitalis-induced ventricular tachycardia require quite different measures. 38

It should be kept in mind that digitalis may both cause and revert atrial fibrillation, atrial tachycardia, atrioventricular nodal rhythm and ventricular ectopic activity. T h e clinical circumstances of the occurrence of these arrhythmlas and, if necessary, the use of diagnostic and therapeutic tests will determine whether digitalis is to be given or withheld. DIAGNOSTIC TESTS

An all-too-frequent problem is trying to decide whether a patient has had too much or too little digitalis, i.e., determining the state of dlgitalization. By the use of complex bioassay technics, the daily urinary excretion of digitoxin and its metabolites can be determined, and, if over a certain value, digitalis excess may be assumed to be present. Unfortunately, there is no practical laboratory examination which will tell us the total body level of cardiac glycosides. Such a test would obviously be important but would be of only limited value, since many clinical problems center around relative overdosage. Until such time as a useful test is available, we must rely heavily on clinical judgment. Usually this empiricism is adequate. Furthermore, fortunately, it is the unusual patient in whom digitalis cannot be stopped for a few days and the patient observed for any improvement or worsening of his condition, thus permitting a decision as to whether under- or overdosage is present. It is obviously much safer to err on the side of withholding digitalis rather than of giving an excess if the patient's condition permits. Several tests have been devised to aid in the differentiation between digitalis excess and underdigitalization which are of value when an immediate answer to this problem is mandatory. Carotid sinus stimulation. This maneuver can frequently be of great value in deciding the state of digitalization and is of little danger if performed for periods of no longer than 5 seconds. It has been well established that the parasyrnpathomimetic effect of carotid sinus stimulation becomes more evident after the administration of the cardiac glycosides. This phenomenon can be of considerable clinical value in the diagnosis of arrhythmias related to digitalis intoxication, as it is in the diagnosis of other arrhythmias. Carotid sinus massage or other vagal-stimulating tech39

nics (eyeball pressure, Valsalva maneuver, etc.) will frequently convert ectopic atrial tachycardias to sinus rhythm. If these measures fail, digitalization is usually the treatment of choice. However, one need not necessarily wait until digitalis converts the arrhythmia. Since these agents augment vagal effects on the heart, carotid sinus massage performed at the time of the peak effect of the glycoside or before each subsequent dose may produce conversion to normal sinus rhythm. In this way, conversion may be produced earlier and with smaller doses of digitalis. In patients receiving digitalis, this synergistic action between carotid sinus stimulation and the drug may often aid in the diagnosis of incipient digitalis intoxication. During massage, heart block, nodal rhythm, ectopie ventricular beats or ventrlcular bigeminy may emerge and indicate that digitalis should be stopped or reduced or that any factors predisposing to relative di~talis excess should be corrected. In patients with chronic atrial fibrillation receiving digitalis a n d reserpine, however, the appearance of these arrhythmias does not necessarily constitute evidence of digitalis excess, since reserpine has been found to increase the sensitivity of the heart to carotid sinus stimulation to a greater degree than that attributable to digitalis alone (16). In digitalized patients who develop rapid and regular rhythm, the electrocardiogram alone may not allow differentiation among the various supraventricular arrhythmias. In the patient with sinus tachycardia, carotid sinus stimulation produces a gradual slowing during massage with return to the same rate after it is stopped. In paroxysmal atrial tachycardia, either no change or conversion to sinus rhythm may occur in some patients, but in others, particularly in those with paroxysmal atrial tachycardia with 2:1 atrioventricular block, this maneuver, by the production of increased a-v block, may allow the recognition of the ectopie P-waves (Fig. 4). In other patients, the a-v block caused by carotid sinus stimulation may disclose flutter waves which were inapparent or buried in the QRS complexes or Twaves. When the differentiation between paroxysmal atrial tachycardia with block and atrial flutter cannot be made, carotid sinus massage often proves helpful in demonstrating the nature of the base llne and the morpholog3z of the atrial waves present. Carotid sinus stimulation can be of value in still another way. 40

In patients with atrial fibrillation and rapid ventricular rates, marked slowing during carotid sinus massage with persistence of a totally irregular ventricular response is indicative of the need for more digitalis. On the other hand, if slowing is due to the development of a slow nodal rhythm, which, in contrast to slow fibrillation, is regular, this is a sign of impending digitalis intoxication. Observation of tile electrocardiogram during these procedures is, therefore, quite important. This test may be particularly helpful in critically ill patients in whom the persistence of a rapid heart rate may induce serious consequences but in whom tile inappropriate administration of more digitalis with resultant toxic arrhythmlas would be even more serious. We shall now consider the several digitalis tolerance tests which have been developed to evaluate the state of digitalization. None of these tests is perfectly reliable, and none is without danger. It is our belief that, for other than investigative purposes, their use should be limited to the more critically ill patients in whom the correct answer to the question of too little or too much digitalis must be known quickly. Furthermore, these tests should be performed only under circumstances in which equipment, drugs and personnel to manage any untoward effects are readily available. ACETYL STROPttANTHIDIN TEST.--This test consists of titrating the patient with small intravenous doses of acetyl strophanthidin to an end point of toxicity determined in the continuously monitored electrocardiogram. This cardiac glycoside has an ultra-fast onset of action beginning approximately 30 seconds after administration, a peak action in 5-12 minutes and complete dissipation of effect in 2-3 hours. The usual range of the dlgitalizing dose is 1.2-1.8 rag. If intoxication is induced, its duration is limited to 30 minutes, which is the great advantage of this preparation over the other glycosides. Tile test as originally performed has been modified to increase its safety, since several deaths have been attributable to acetyl strophanthidin. The test as currently performed by Lown and Levine (17) is as follows. Two ampules, each containing 0.6 mg. of acetyl strophanthidin, are diluted to 20 cc. in 5% glucose in water for a concentration of 0.06 mg. per ml. In patients in whom digitalis intoxication is seriously suspected, 0.075-0.15 mg. of acetyl strophanthidin (1.25-2.5 ml.) is in41

jected every 5-10 minutes while in most other patients 0.15-0.3 nag. (2.5-5.0 ml.) is given at the same time intervals. The drug is continued until improvement or nausea, vomiting or cardiotoxiclty is demonstrated in the electrocardiogram. Obviously, a physician knowledgeable in dectroeardiographir interpretation must be in attendance. No more than 1.2 nag. is given to any patient. If toxicity develops after the injection of 0.075-0.3 rag., overdosage is presumed to be present. If toxicity appears after 0.6 rag., the patient is considered to be adequately digitalized. When therapeutic effects occur after 0.6-0.9 rag., the patient is regarded as being underdigitallzed, and more digitalis is given. If the full 1.2 rag. is required, full digltallzatlon is carried out. In the monitoring of the electrocardiogram during an acetyl strophanthldin test, it must be remembered that an ectople atrial tachycardia may develop at a rate only slightly faster, e.g., 130160, than a pre-existing sinus tachycardia and be manifest only by a change in the contour of the P-waves in addition to the moderately increased rate. Although any toxicity produced is fleeting in nature, if life-threatening arrhythmias develop, potassium or procaine amide should be given at once. Therefore, these agents must be readily available for immediate infusion during the performance of this test. T h e results of Lown and Levine with their modified test have been excellent in that they reported no deaths in 25 patients and found the test extremely useful and quite accurate. Occasionally, in patients in whom the clinical impression was at variance with the state of digltalizatlon as suggested by the test, management of the patient according to the result of the test proved to be correct.

The two diagnostic tests just discussed may be of extreme value when used together. This was true in the management of the following critically ill patient with rheumatic heart disease and chronic atrial fibrillation. H. LaF. is a 48-year-old white housewife who recently underwent cardiac catheterization in our laboratory for evaluation of her mltral stenosls. Prior to admission, she had been taking 0.25 rag. of gltalin daily. Following a routine right heart catheterization, a percutaneous left atrial puncture was attempted using the dorsal approach; instead, the needle entered the right atrium and right ventricle and, when with42

drawn, the patient immediately went into profound shock without loss of consciousness. Norepinephrine was immediately begun with a prompt elevation of her blood pressure to the normal range. There was no evidence of heart failure, hemopericardium, hemothorax or pneumothorax, n.or did any of these complications develop subsequently during her course. Her ventricular rate was quite rapid ( 140-160 beats per minute) and failed to slow despite control of the blood pressure. Lanatoside C was given slowly intravenously in a dose of 0.4 mg. This slowed the rate to between 1I0 and 115 beats per minute over the next I ~ hours. During the following 1 ~ hours, the rate rose again to between 140 and 160 beats per minute. At this point, we were concerned that the persistence of the rapid heart rate might precipitate acute pulmonary edema and thought perhaps more digitalis was in order. We were equally concerned with the precipitation of digitalis intoxication since a month earlier cardiac catheterization had been postponed because of dlgltalis-induced ventricular bigeminy. In order to help solve this dilemma, an acetyl strophanthidin tolerance test was performed, using a conservative dose of 0.075 rag. every 10 minutes. Ventricular blgeminy appeared after the third dose (accumulative dose of 0.225 rag.). This was treated with an infusion of approximately 400 rag. of potassium chloride. Thereafter, her rate slowed to between 80 and 100 beats per minute but rose again to between 120 and 130 beats per minute ~ hour later. No further cardiac glycoside was given, since digitalis intoxication had been precipitated by such a small dose of acetyl strophanthidin. Three hours after the last dose of acetyl strophanthidin was given (nearly 7 hours after shock had developed), the rate was 140 beats per minute. It was noted that carotid sinus pressure induced prompt slowing to under 100 beats per minute without the development of any signs of digitalis intoxication. This suggested to us that more atrioventricular block would be advantageous. In order to substantiate the need for more digitalis, a second acetyl strophanthidin test was performed. After 3 doses (again 0.075 mg. every 10 minutes), the rate had slowed to 110, no electrocardiographic evidence of digitalis intoxication ensued, and repeat carotid sinus stimulation still produced slowing. Since the peak effect of the Lanatoside C was now over, 0.5 rag. of dlgoxin was given intravenously over a 2-minute period. Shortly thereafter, the rate stabilized and persisted at 90-100 beats per minute. Several hours later, frequent episodes of ventricular bigeminy occurred (continuous monitoring of the electrocardiogram on an oscilloscope was maintained for over 24 hours), which were treated with small doses of intravenous potassium chloride via a slow drip of 5% 43

dextrose in water, which was maintained in readiness for immediate infusion. Twenty-four hours after the onset of shock, her blood pressure remained normal without vasopressors, as did her ventricular rate. Over the next several days, she was maintained on 0.25 rag. of digoxin daily without complications. The patient left the hospital in 10 days and has done well at home. The exact etiology of her shock has not been determined. T h e above case clearly illustrates the value of these tests in the minute-to-minute management of a critically ill patient. The first acetyl strophanthldin test indicated that digitalis intoxication was near and that it should be withheld; the second test, used in conjunction with carotid sinus stimulation, supported the need for more as indicated previously by the latter test alone. Obviously, one need not reserve carotid sinus stimulation for only critically ill patients; it may be helpful in any situation where the state of dlgitallzatlon must be determined promptly. CHELATION OF c a l c i u M . - - T h i s test utilizes the intravenous injection of the mono-, dl- or trlsodium salt of ethylene-diaminetetra-acetate ( E D T A ) . Since digitalis and calcium are synergistic, when ionized calcium is acutely lowered by the chelating compound, digitalis becomes less effective, and digitalls-lnduced cardlotoxlclty is rapidly reversed. I t is hypothesized that this chain of events is related to the lessened ability of extracellular potassium to cross the myocardial cell membrane during digitalis overdosage; however, a direct calcium effect has not been ruled out. Several studies utilizing this test have been reported in the literature. Gubner and Kallman (18) converted digitalls-lnduced arrhythmias with 600 rag. or less of N a 2 E D T A given over a half hour period. Cohen et al. (19) used doses up to 1.5 Gm. in a 15-mlnute period with conversion of digitalls-induced ventricular arrhythmias. They concluded that this drug was ineffective in atrial arrhythmias. Since their study included only 2 patients with digitalis-induced supraventricular arrhythmias, this point would seem unsettled. They concluded that response to N a E D T A was a poor guide to the status of digitalization; therefore, E D T A was unreliable as a test agent, but it was valuable in the treat44

ment of ventricular arrhythmias secondary to digitalis intoxication. Eliot and Blount (20), in a larger study, concluded that many of the failures and equivocal results reported in previous studies were due to the small doses administered. These authors will not accept a therapeutic failure Unless 3.0 Gin. of E D T A have been given within a 12-minute period or until clinical evidence of hypocalcemia has developed. T h e solution they used was 4 Gm. of NaaEDTA dissolved in 250 cc. of 5 ~ glucose in water, which resulted in a 16 mg./ml, solution. This was infused at an average rate of 255 reg./rain, with a range of 50-800 mg./min. The end point was the occurrence of a change in rhythm or conduction in the electrocardiogram. Arm pain, circumoral paresthesias and apprehension occurred in 4 0 ~ of their patients. Massage and warm packs relieved tile arm pain while the other symptoms were controlled by slowing the rate of infusion. In one patient, tetany occurred and was treated with intravenous calcium, which produced irreversible ventricular fibrillation; the authors warn against the use of intravenous calcium in such patients even for the treatment of hypocalcemic tetany. Others have reported the occurrence of a hemorrhagic diathesis and renal toxicity with the use of EDTA. Eliot and Blount found the drug to be quite effective only in patients with digitalis-induced arrhythmias but not in others. Thus, the differentiation of arrhythmias due to digitalis intoxication and those due to other etiologies could be made. Although the effect of E D T A was quite transient, by stopping digitalis and administering potassium, the beneficial response could be maintained. They concluded that E D T A was a valuable tool which could not be used to determine the state of digitalization, but was of great benefit in tile diagnosis and treatment of dlgitalis-induced cardiotoxlcity. The specific effectiveness of E D T A on only digitalis-induced arrhythmias cannot be fully accepted as yet since other studies have suggested that this is a nonspecific effect. Lown agrees with this and, furthermore, has found potassium chloride more effective than EDTA as an antiarrhythmic agent. The proponents of EDTA, on the other hand, feel that this drug is safer than intravenous potassum. Obviously, more studies both in man and in 45

animals need to be made before more definite conclusions can be reached. CALCIUhl ADMINISTRATION.----This test is based on the same premise as calcium chelation, i.e., the synergism of digitalis and 6alcium. In tiffs test, however, intravenous calcium is given, and digitalis-induced arrhythmias are used as an end point. This test, then, seeks to obtain information similar to that derived from the acetyl strophanthidin test, and the indications for performing these tests are essentially the same. Nalbandian et al. (21), who first reported the use of this test, advocate the administration of calcium intravenously according to a strict schedule consisting of 0.5 ml. of 10% CaCI_o every 2.5 minutes for 4 doses, then 1.0 ml. every 2.5 minutes until the end point is reached or until 9 doses totaling 7.0 ml. of CaCl.o have been given. If electrocardiographic evidence of digitalis intoxication occurs and persists for more than 1 minute or if the resuhant arrhythmia is a serious one, 10% Na2EDTA is administered promptly, the dose being calculated from the amount of CaCle needed to produce the end point. The authors have developed a formula which is designed to predict, from tile dose of CaCI2 given during tile "Calcium-Digitalis Tolerance Test," the maximum safe dose of additional digitalis which can be given. Lown et al. (22) have criticized the experimental design of these studies and are of the opinion that the synergism between these two drugs on cardiac excitability in the intact animal with and without heart failure has not been adequately demonstrated. Further data concerning the usefulness of this test would seem desirable. POTASSIUM "ADMINISTRATION.--Inpatients thought to be in digitalis intoxication, particularly when arrhythmlas are present, potassium chloride may he administered in an attempt to correct the arrhythmlas. Since the serum potassium does not bear a known relationship to myocardial intracellular potassium, a normal concentration of serum potassium does not preclude the effectiveness of this drug. The intravenous administration of KCI under constant electrocardiographic monitoring is preferable to oral administration. The dose of KCI which may be used is similar to that for the treatment of known digitalis intoxication and will be discussed below. Unfortunately, even if a favorable effect is seen, this does 46

not prove that the arrhythmia is digitalis-induced since KCI is an effective antiar,'hythmic drug regardless of the arrhythmia's etiology. NEOSTIOMrNE TEST.--A recent test reported by Harrison et al. (23) utilizes neostigmine to predict the dose of digitalis required to slow the ventricular rate in patients with the recent onset of atrial fibrillation or flutter who were already digitalized while they were in normal sinus rhythm. Neostigmine is a parasympathomimetic agent which has a prominent vagal effect on the atrioventricular node and thus acts in a manner similar to the early effects of digitalis. When a digitalized patient develops either of these atrial arrhytlunias, one wishes to administer the smallest dose required to slow tile ventricular rate. The authors feel that their test can predict this dose and, thereby, expedite the treatment of these patients without danger of producing digitalis intoxication. Tile test is performed by injecting 0.25 rag. of neostigmine intravenously every 5 minutes until the ventricular rate slows at least 30 beats per minute or until 3 doses have been given. They found that 0.25 rag. of neostigmlne has the same slowing effect as 0.25 mg. digoxin or 0.1 nag. digitoxin. Therefore, after completion of the test, one of these glycosides is given intravenously in an equivalent dose, e.g., if the rate slowed after the second dose of neostigmine, 0.5 rag. of digoxin or 0.2 rag. of digitoxin would be administered. In this way, the slowing was maintained for 6-12 hours. In 14 patients, the test was found effective and without untoward side effects. The authors mention the obvious contraindications, i.e., active peptic ulcel, bronchial asthma and pulmonary insufficiency, but also include the presence of any unstable cardiac state in which ventricular irritability exists or is likely to develop. It is in this latter group, which includes patients with electrolyte imbalance and ventricular irritability, that the determination of the state of digitalizatlon is so important. Perhaps, future experience with this test will demonstrate its safe and effective use in such patients and thereby increase its usefulness. At present, however, it would seem to have only limited use. Carotid sinus stimulation, as mentioned earlier, will give the same qualitative information but cannot be used to quantitate the dose of digitalis which ,t7

may be given safely. The actyl strophanthidin test would also give similar information. In summary, several pharmacologic tests are available to help the physician assess the state of digitalizatlon in his patient, particularly when arrhytlmaias are present. The best of these is probably the acetyl strophanthldin test. In most cases, however, clinical judgment based on the meticulous observation of the patient's clinical state, together with the judicious use of carotid sinus pressure, will be sufficient. This course of action may make it unnecessary to perform any of these potentially hazardous tests, but their use in critically ill patients may be necessary and valuable. MANAGEMENT OF DIGITALIS INTOXICATION

If, inadvertently, the doses of the foxglove should be prescribed too largely, exhibited too rapidly, or urged to too great a length, the knowledge of a remedy to counteract its effects would be a desirable thing. Such a remedy may perhaps in time be discovered (1). Although several substances are now being investigated, 175 years after Withering's comment no direct digitalis antagonist is currently available. At present, therefore, the therapy of digitalis intoxication varies from simply eliminating a few doses of the glycoside to the employment of potentially dangerous drugs. The complexity of the treatment is directly proportional to the type and severity of the intoxication, to the over-all clinical state of the patient and to the digitalis preparation at fault. It behooves us all to anticipate the onset of digitalis intoxication and to prevent it or, having failed to prevent it, to recognize it in its earliest form. It should be expected particularly in the aged, in patients with severe heart disease and in patients in whom predisposing factors are present or likely to develop. As is the case in most of therapeutic medicine, the treatment of digitalis intoxication is relatively clear-cut once the diagnosis is definitely established. When this is not possible, the safest and most expeditious course of action should be taken. If the clinical state of the patient is deteriorating, the use of one of tile diagnostic tests mentioned above may be necessary. If not, withdrawal 48

of tile drug will commonly result in lessening of the intoxication or its complete relief in 3--4 days. In tile presence of mild nausea or vomiting or evidence of mild cardiotoxicity, e.g., infrequent premature ventricular beats, bradycardia or marked first degree atrioverrtricular block, all that is necessary is omission of a few doses until the toxic signs or symptoms are gone, after which the cardiac glycoside can be reinstituted at a lower dosage. Indeed, in patients with sinus rhythm and mild congestive symptoms, it is often necessary deliberately to produce toxicity of this degree in order to determine if adequate digitalization has occurred. If mild toxicity occurs secondary to relative overdosage, correcting the predisposing factor (if amenable to therapy) is usually all that is necessary without a change in digitalis dosage. If no predisposing factors are present when digitalis intoxication develops, it is important to avoid any measures which might produce them. Once the diagnosis of digitalis intoxication is entertained, therefore, all diuretics should be stopped temporarily in order to avoid hypopotassemia. Restriction of activity is valuable in preventing progression of the toxic state. An increased frequency of ectopic beats or the development of runs of nodal or even ventricular tachycardia may be seen during mild activity or excitement in patients with digitalis excess. The importance oi sedation is evident. Although even in the presence of more serious cardiotoxlcity cessation of digitalis is often all that is necessary, other therapeutic measures are usually indicated. These include the administration of potassium chloride, procaine amide or EDTA. POTASSIU~MCtILORIDE.--As mentioned earlier, one of the specific defects in digitalis intoxication is thought to be intracellular myocardial hypopotassemia. Whether this is tn~e or other factors are of equal or greater importance, the administration of KC1 to these patients is often beneficial. This is true in the presence of a normal as well as a low serum potassium. It should be recalled that KCI may abolish arrhythmias of any etiology, but, when atrial and nodal tachycardias and ventricular tachycardia convert during administration of KC1, one may infer that they were induced by digitalis. Either the oral or intravenous routes may be used. Oral KC1 is available in enteric coated tab49

lets and in liquid form. The tablets may be used in the prevention or treatment of relative digitalis overdosage in doses of 3.06.0 Gm. daily. In patients prone to develop digitalis intoxication after mercurial injections, 5.0-7.5 Gm. KCI given in divided -doses on tile day of and the day after the diuretic will usually prevent its occurrence. Tile tablets may not dissolve in the gastrointestinal tract, and, therefore, the liquid preparation is preferred in the treatment of moderate or severe digitalis intoxication. This is given in chilled fruit juice to increase its palatability and to decrease its gastric irritation. Potassium chloride may be efficacious in still another way. In those patients with severe myocardial disease in intractable heart failure who develop toxicity prior to the development of a full therapeutic effect, the administration of potassium with digitalis may be advantageous. It is thought that perhaps tile combination of these drugs lowers the therapeutlc-toxic threshold so that effective levels of digitalis may be safely reached. This form of therapy may be tried even when no evidence of hypopotassemia is demonstrable. In these cases, 5.0 Gm. are usually given in a single dose and are followed by 2.0-2.5 Gm. every 4-6 hours as needed. It is best not to exceed 10 Gin. in any 24-hour period. It has been well documented that there is relatively poor renal handling of potassium in elderly patients and in those with marked congestive heart failure regardless of age. For these reasons, oral potassium may cause the serum potassium to rise rapidly to dangerous levels. Although it may appear paradoxical, intravenous KCI may be safer in such situations. In the more critically ill patients, in those with serious arrhythmias and when it is being used as a diagnostic agent, this rotate is preferred. During the intravenous administration of potassium, continual electroeardiographie monitoring is mandatory. With such close observation, tile conversion of the arrhythmia, improvement in the patient's symptoms or the onset of hyperpotassemia, as judged by tenting or peaking of the T-waves, may be identified within minutes of their occurrence. For these reasons, this rotate is probably the safer and certainly leads to the desired effect much more quickly than the oral route. The intravenous solution usually used is 3.0 Gm. of KC1 (40 mEq.) added to 500 ee. of 5% glucose and water. This is infused 50

slowly over a 1-hour period unless one of tile above-mentioned effects occurs. If no change or an incomplete change is seen, then this dose may be repeated until 9.0 Gm. have been given. Once tile desired effect has been reached, the intravenous drip is stopped, and oral maintenance is begun. Often, the therapeutic end point is reached at a very critical potassium level. Subsequent to stopping the infusion, the signs of digitalis intoxication may reappear in a relatively short time. One must be aware of this and continue close observation of the patient until the orally administered potassium has had time to be absorbed, which is usually 2 hours. PROCAINE AMIDE.--One of the most effective antlarrhythmic agents is procaine amide. Its major effectiveness has been in tile conversion of ventricular arrhythmias. It has not been as useful in supraventricular arrhythmias except in the presence of digitalisinduced paroxysmal atrial tachycardia with block and nodal tachycardias where it has proved very valuable. Its use is indicated when potassium is not available, when potassium has failed to convert tile arrhythmia in question or when potassium administration is dangerous, e.g., when azotemia is present. In the latter case, it may be used following pretreatment with less than effective doses of potassium. In this way, conversion is produced with smaller amounts of both potassium and procaine amide. For intravenous use, 50 rag. are given by drip every 9 minutes until 300 rag. are given, then 50 rag. every 4 minutes until toxicity or conversion occurs. Tile maximum dose is 1,000 mg. in 1 hour. Acute hypotenslon may occur during its infusion, and therefore tlle blood pressure should be taken before each dose. Norepinephrine should be available for immediate infusion in the event that the pressure fails to rise promptly with slowing or stopping of the drug. Of course, continuous monitoring of tile electrocardiogram is necessary to detect any changes in rhythm as soon as they occur and to watch for the onset of any serious toxic effect of procaine amide, such as marked QRS prolongation. The oral route has been proved to be quite effective and is preferred in most cases. The dnlg is completely absorbed in tile gastrointestinal tract and reaches maximum levels within 90 minutes. A single dose of 750-1,000 rag. (250 mg. per capsule) may 51

be given followed by 500 mg. every 3 to 6 hours. If necessary, maintenance doses to prevent recurrence of the arrhythmia may be given until the body level of digitalis has decreased below toxic levels or until any predisposing factors lmve bcen corrected. E D T A . - - T h e use of calcium chelating agents provides one more approach to tile treatment of digitalis intoxication. Present studies suggest that they are probably inferior to potassium chloride, but future investigation may not confirm this. They must, of course, be given intravenously and should be reserved for patients with serious digitalis-induced arrhythmias. Their dosage and administration have been discusscd fully in a previous section. Finally, tile failing heart may become unresponsive to the therapeutic effects of digitalis, and, indeed, toxic effects may appear before any therapeutic effect is obtained. This is not due to the development of tolerance to the glycosidcs. It should be remembered that the cardiac glycosides do not correct tile basic defect present in the failing myocardium. Their effect is only temporary, and sooner or later rcfractory heart failure will appear. In these cases, it is important that we do not hasten this process by allowing digitalis intoxication to develop or to go undiagnosed and untreated. PREVENTION OF DIGITALIS INTOXICATION

One of medicine's prime objectives is the prevention of disease or of its consequences, if already present. In therapeutics, tile achievement of tile optimum effect of a drug with prevention of its unwanted effccts is tile main objective. In general, prevention may be classified into two categories: primary and secondatT. In the former, attempts to prevent the first episode of digitalis intoxication arc made. In the latter, tile goal is the prevention of repeated episodes of digitalis intoxication, which definitely tend to occur more frequently after an initial episode. In this regard, it is important to remember that individuals tend to develop the same toxic manifestations during different episodes of digitalis intoxication. For example, some patients will develop cardiotoxic signs without the electrocardiographic characteristics of digitalis cffect. Obviously, these patients must be watched much more 52

carefully than those in whom anorexia, nausea and vomiting develop prior to any serious impulse or conduction disturbances. If it is difficult to examine a patient receiving digitalis as often as one would like, the patient or a responsible member of the family chn be taught to record the heart rate and report any significant changes. At times, it may be desirable to request the sexxices of a Public Health nurse or the visiting nurse when more highly trained observation is needed.

NONINDICATIONS AND CONTRAINDICATIONS FOR DIGITALIS ADMINISTRATION

Obviously, digitalis intoxication may be prevented in those patients in whom glycoside therapy is not indicated, but to whom it is sometimes given. Certain arrhythmias and the signs and symptoms of congestive failure in patients with evidence of organic heart disease constitute tile major indications for glycoside therapy. Digitalis should not be used routinely in patients with dyspnea, fatigue, edema, shock or sinus tachycardia since, obviously, patients with these signs and symptoms do not necessarily have heart failure. In many patients with organic heart disease in whom cardiac function is quite adequate, digitalis is not indicated. When one cannot decide clinically whether early heart failure is present, simple diagnostic tests may be used, such as the venous pressure before and during hepatic pressure, the circulation time, the vital capacity, shifts in weight compatible with edema accumulation and response of the heart rate to exercise (particularly in patients with atrial fibrillation). When these aids are inconclusive, a trial of digitalis therapy is often justified. It is our belief that no harm can be done by digitalizatlon as long as serious digitalis intoxication is avoided. Digitalis is not indicated in patients with acute myocardial infarction unless heart failure is present. In third degree atrioventrieular block without failure, digitalis is of no known benefit, and, indeed, in the patient who vacillates in and out of second and third degree block, digitalis may be harmful in that Stokes-Adams attacks may be precipitated. 53

1)ROPIIYLACTIC USE o F DIGITALIS Tile prophylactic use of tim cardiac glycosides is sometimes of value. Digitalization on this basis was discouraged in the past because of the concept that digitalis was detrimental to tile nonfailing heart, but recent investigation has shown tiffs not to be the case. Prophylactic digitalization has its greatest benefit in preoperative patients. Any patient with chronic atrial fibrillation in whom cardiac surgery, or probably any major surgelT, is contemplated should be digitalized preoperatively and, if already receiving digitalis, should be evaluated to assure optimum therapy throughout tim operative and postoperative period. Preoperative digitalization may also be valuable in elderly patients with cardiomegaly without definite evidence of failure. We do not agrce, however, with those who advocate prophylactic digitalization for all patients over 60 )-ears of age in whom chest surgery is planned. By prophylactic digitalization the development of a rapid ventrlcular rate in fibrillating patients or in those who fibrillate during or shortly after surgery ma t, be prevented. Serious cardiac failure also may be avoided in those who ma t' develop it as a result of the multitudinous factors present during the surgical and postsurgical periods. These patients should be digitalized slowly with oral preparations, preferably digoxin because of its relatively short duration, at least 9 weeks prior to elective surgery. By sucl-t foresight, operative or postoperative rapid digitalization by parenteral routes may be avoided.

GENERAL SAFEGUARDS DURING DIGITALIZATION

Several general rules concerning digitalization will usually prevcnt digitalis intoxication: KNOW XVtIAT TO EXPECT FRO.~I DICITALIS.--~'[ost patients we see with atrial fibrillation and acute congestive failure respond very well to digitalization. Indeed, it may be difficult to discern whether the bed rest, low-salt diet, diuretics or digitalis produced the desired result, since these therapeutic approaches are usually used simtdtaneot,sly. In other patients with compensatory sinus tachycardia, the heart rate may not decrease to normal, and 5a

digitalis intoxication may be induced if an attempt to "control the rate" is the goal of digitalization. Some patients with sinus rhythm may become compensated at rates of 80 or 90 or more. In any patient with congestive failure and sinus tachycardia, control of the stigmata of congestive failure in toto, not just the heart rate, must be the goal. KNOW YOUR P R E P A R A T I O N . ~ E v e r y physician should be acquainted with probably three types of preparations: a rapid, parenteral agent, such as Lanatoside CI, to be used in emergencies; a rapid-acting oral preparation, such as digoxin, which is of particular value where predisposing factors to relative digitalis overdosage exist or when the drug may have to be given in near-toxic amounts for the treatment of certain arrhythmias; and a more stable, longer-actlng compound, such as digitoxln or digitalis leaf, for the usual patient who does well once he is compensated. Although the differences among these drugs are only quantitative, their time of onset, peak effectiveness and duration should be well known to the physician (see Table 2). NEVER GIVE DIGITALIS P A R E N T E R A L L Y

X,VHEN AN ORAL ROUTE

WILL SUFFICE.--~Vhen digitalis intoxication occurs during initial digitalizatlon, in nearly all cases the drug has been given parenterally. The need for parenteral preparations is limited to a few occasions, such as rapid arrhythmias with the patient in extreme distress or in some critically ill patients with acute pulmonary edema. Patients unable to take oral preparations on the day of surgery, in the immediate postoperative period or because of vomiting, will obviously require a parenteral preparation, but this should ahvays be given intramuscularly rather than intravenously. Oral preparations, such as digoxin, take effect within a few hours, and there are relatively few patients in whom such a brief delay is hartnful. Indeed, waiting a few hours may save the patient the added morbidity of digitalis intoxication. At other times, we must anticipate the need for digitalis so that slow oral digitalization may be performed. The efficacy and indications for prophylactic dlgitalizatlon have already been discussed. AVOID SINGLE-DOSE DIGITALIZATION.----Althoughthe "average" digitalizing dose of a particular preparation is safe in the majority of patients if administered as a single dose, it will be opti55

mum only in the "average" patient and, in some, digitalis overdosage may be induced. We see no advantages to this method and, indeed, it is potentially hazardous. D U R I N G DIGITALIZATION, START ~VITII T I I E LARGEST DOSE FIRST.

--Progressively diminishing dosages should be used. A relatively large dose, such as one-half the usual digitalizing dose, may be given initially, followed by one-fourth the digitalizing dose on the next occasion. This is usually followed by smaller doses, perhaps twice the usual maintenance dose, given once or twice a day until digitalization is complete (see Table 1). DO

N O T O R D E R I~IORE DIGITALIS U N T I L T H E

P R E V I O U S D O S E IIAS

REACHED ITS BIAXIMU~I EFFECT.---The timing of the doses of digitalis will obviously depend on the preparation used (see Table 2). With Lanatoside C, repeat doses may be given after only a few hours, but with digitoxin, where the maximum effect is not reached for 4---12 hours, ordering a repeat dose sooner than this may precipitate digitalis intoxication. DO

NOT VCRITE ADVANCE ORDERS FOR DIGITALIS EXCEPT FOR

I~IAINTENANCEDOSES.--Since each digitalization is an in vivo experiment to titrate the patient to his own individual end point, the effect of previous doses must be evaluated before more is ordered. Even if digitallzation is being carried out slowly with oral medication, this rule still applies if the heart block due to unusual digitalis sensitivity of a diseased conduction system is to be noted. P R E V E N T I O N AND R E C O G N I T I O N OF PREDISPOSING FACTORS

The importance of a careful history of a patient's medications is obvious. An unfortunately large group of patients are not aware that they have been receiving a dlgitalls'preparatlon, which is not surprising if one considers how the short list of pharmacologic names of the various compounds has been lengthened by the use of proprietary names. Parenthetically, we believe that every patient who is receiving a digitalis preparation should be told this by his physician. As has been emphasized, patients with severe myocardial impairment, renal disease, liver disease and electrolyte problems are 56

predisposed to relative digitalis overdosage. If these abnormalities are present and cannot be immediately corrected, digitalization can be carried out more slowly and the maintenance dose carefully established. Potassium depletion secondary to diuretics, adrenal corticosteroids, Sodium restriction, diet, poor nutrition, diarrhea or vomiting should be anticipated and potassium supplemented. It is also necessary to refrain from increasing potassium loss, e.g., by giving a diuretic if ventricular ectopic beats are present, until it has been determined whether or not they are digitalis-induced. Patients in severe heart failure frequently have mild hypopotassemia due to a relative electrolyte dilution secondary to hypervolemia. The total body potassium is usually normal in these cases. Therefore, vigorous attempts at raising the potassium level should not be made. This is particularly true in patients with failure, who often handle potassium loads quite poorly. In patients scheduled for major surgery, in particular for pulmonary or cardiac surgery, if the patient has been on a longacting cardiac glycoside, we prefer to change to digoxin at least 1-2 weeks prior to surgery. If arrhythmlas develop during surgery or in the postoperative period, their evaluation, i.e., whether they represent digitalis intoxication or not, and treatment are thereby facilitated. Several studies have demonstrated the development of digitalis intoxication concomitantly with renal dialysis. This is due to the lowering of intracellular potassium which is not necessarily reflected by the serum potassium. Indeed, Lubash et al. (24) found it necessary to administer 30 Gm. of KC1 to the perfusion bath in order to convert a digitalis-lnduced arrhythmia during dialysis, after which no increase in the serum potassium was noted. Whenever possible, it is preferable to delay digitalization of these patients until dialysis is completed. Patients with severe heart disease and those with myocarditis of any cause may be somewhat sensitive to digitalis; therefore, digitalis should be used carefully. In the .former case, patients have been reported who were so acutely ill that therapy other than digitalis had to be instituted prior to the safe administration of the cardiac glycosides. Patients with thyrotoxicosis frequently have breatlflessness and excrtional fatigue. In the majority, this is related to their hyper57

metabolism and hypervolemia, and digitalization will have no beneficial effect unless atrial arrhythmias are a problem. If heart failure exists, usually due to the coexistence of organic heart disease, they may require larger digitalizing and maintenance doses "than usual. As they become euthyroid, a decrease in their maintenance doses may be necessary in order to prevent the onset of digitalis intoxication. After treatment of thyrotoxicosis, digitalis can often be stopped in these patients, even in some with organic heart disease. This is in contradistinction to other types of heart failure where the cardiac glycosides are usually required for life. Myxedematous patients with organic heart disease and heart failure are quite susceptible to digitalis intoxication, and only small doses may be tolerated. As they attain euthyroldism, additional doses may be necessary to control their heart failure. SUMMARY

Although the cardiac glycosides arc most useful drugs, morbidity and mortality may result from their presence within the body in excessive amounts; the s)Tnptoms and signs of digitalis excess are commonly referred to as digitalis intoxication. Its incidence seems to be increasing due, in part, to the greater awareness of physicians and to the increased longevity of the population in general and, in particular, of those with cardiovascular disease. Adequate data concerning its actual incidence, however, are lacking. The known predilection of older patients probably is due to the fact that heart disease causing congestive failure, for which these drugs are given, occurs primarily in older persons and is not due to any factor of age per se. Nearly all of the unwanted effects of digitalis are due to overdosage, either relative or absolute, and of these effects our major concern is the occurrence of cardiac arrhythmias. Ahhough S T - T and Q T interval changes usually appear in the electrocardiogram after digitalis administration, their presence cannot be used to determine where on the spectrum of digitalization an individual patient lies. For this purpose, careful observation of the patient and his electrocardiogram before and after a reduction or an increase in the dose of digitalis will usually provide the correct answer. When a more urgent need to know the state of 58

digitalization exists, one m a y employ various diagnostic tests, such as carotid sinus stimulation or tile acetyl strophanthidin tcst. When minor degrees of digitalis intoxication are prescnt, the problem can be handled satisfactorily by cessation of the drug or by correction of any predisposing factors. This diagnosis must, nevertheless, be m a d e promptly, since further administration of the drug m a y rcsult in the onset of serious and, indeed, potentially lethal arrhythmias. 'When such arrhythmias occur, they can usually be m a n a g e d quite effectively by potassium or procaine amide administration. T h e prevention of digitalis intoxication has been stressed particularly in elderly patients and in patients with severe myocardial disease. T h e use of tile various glycosides based on their individual time of onsct and m a x i m u m effectiveness, the avoidance of parenteral administration and the appreciation of the limitations of these drugs are all important in the prevention of this disorder. O u r purpose has been to review the diagnosis, prevention, and m a n a g e m e n t of digitalis intoxication since an understanding of the potentially harmful effects of these drugs is crucial in order that digitalis m a y be given effectively and with confidence. Although intoxication m a y occur, digitalis, properly given, remains the most effective drug for the treatment of heart failure. These cases must be considered as the most hopeless and deplorable that exist; . . . so that upon the whole, the instanccs I am going to adduce may truly be considered as cases lost to the common run of practice, and only snatched from destruction, by the efficacy of the digitalis; and this in so remarkable a manner that, if the properties of that plant had not been discovered, by far the greatest part of these patients must have died (1). Supported in part by grants from the U. S. Public IIealth Service [H-5579 (CI)] and the Chicago Heart Association.

REFERENCES

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2. Enterline, P.: Personal communication. 3. Rodensky, P. L., and Wasserman, F.: Observations on digitalis intoxication, Arch. Int. Mcd. 108: 171, 1961. 4. Von Capeller, D., Copeland, G. D., and Stern, T. N.: Digitalis intoxication: A clinical report of 148 cases, Ann. Int. Med. 50:869, 1959. 5. Lown, B., and Lcvine, H. D.: Atrial Arrhythmlas, Digitalis and Potassium (New York: Landsberger Medical Books, Inc., 1958). 6. Lown, B., and Levine, S. A.: Current Concepts o[ Digitalis Therapy (Boston: Little, Brown & Company, 1954). 7. Kay, C. F.: The clinical use of digitalis preparations, Circulation 12: 116, 1955. 8. Goodman, L. S., and Gilman, A: The Pharmacological Basis o[ Therapeutics (2d ed.; New York: The Macmillan Company, 1955). 9. Wright, S. E.: The ~letabolism o[ Cardiac Glycosides (Springfield, Ill.: Charles G Thomas, Publisher, 1960). I0. Rosenheim, M. L., and Moulton, R. (eds.) : Sensitivity Reactions to Drugs: A Symposium (Springfield, Ill.: Charles C Thomas, Publisher, 1958). 11. Sherman, L.: Transplacental neonatal digitalis intoxication, Am. j. Cardiol. 6:854, 1960. 12. Softer, A.: The changing clinical picture of digitalis intoxication, Arch. Int. Med. 107:681, 1961. 13. Bliss, H. A., and Adolph, R. J.: Acetyl strophanthidin sensitivity in dogs with congestive heart failure, Am. Heart J. 57:886, 1959. 14. Gazes, P. C., et al.: Acute hemorrhage and necrosis of the intestines associated with digitalization, Circulation 23:358, 1961. 15. Pick, A., Langendorf, R., and Katz, L. N.: A-V nodal tachycardia with block, Circulation 24:12, 1961. 16. Lown, B., et al.: Effect of digitalis in patients receiving reserpine, Circulation 24:1185, 1961. 17. Lown, B.: In Digitalis, E. G. Dimond (ed.): (Springfield, IlL: Charles C Thomas, Publisher, 1957), pp. 226-230. 18. Gubner, R., and Kallman, H.: Treatment of digitalis toxicity by chelation of serum calcium, Am. J. M. Sc. 234: 136, 1957. 19. Cohen, B. D., et al.: Use of a calcium chelating agent (NaEDTA) in cardiac arrhythmias, Circulation 19:918, 1959. 20. Eliot, R. S., and Blount, S. G., Jr.: Calcium, chelates and digitalis: A clinical study, Am. Heart J. 62:7, 1961. 21. Nalbandian, R. M., Gordon, S., and Kaufman, J.: Calcium-digitalis tolerance test: A clinical report of the first 24 trials, Am. J. M. Sc. 2:34: 391, 1957. 22. Lown, B., Black, H., and Moore, F. D.: Digitalis, electrolytes and the surgical patient, Am. J. Cardiol. 6:309, 1960. 60

23. Harrison, D. C., Phinney, A. O., Jr., and Dexter. L.: The use of neostigmine to assess the state of dlgitalization, Proc. New England Cardiovas. Soc. 19:24, 1960-1961. 24. Lubash, (3. D., et al.: Electrocardiographic changes during hemodialysis with the artificial kidney: II. The treatment of digitalis intoxicatior~, Circulation 19:552, 1959.

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