410 CHUNG - J-STAGE

Digitalis-Induced Cardiac Arrhythmias:

A Report of 180 Cases

Edward K. CHUNG, M.D., F.A.C.C.*

SUMMARY

Digitalis is an essential drug in the treatment of congestive heart failure and various supraventricular arrhythmias. However, digitalis may

produce or aggravate congestive heart failure and almost every known cardiac arrhythmia. A recognition of digitalis-induced arrhythmias is extremely important because cardiac arrhythmias may often indicate digitalis intoxication without any other signs.

One hundred and eighty patients with digitalis intoxication studied by this author were presented. The total incidence of digitalis-induced arrhythmias was 346 episodes. The overall incidence of ventricular ar-rhythmias was highest (104 patients) and, among these, ventricular pre-mature contractions predominated. The basic rhythm was atrial fibrillation in 87 patients and almost all of these patients showed either non-

paroxysmal A-V nodal tachycardia or A-V nodal escape rhythm. This information is extremely important since A-V nodal arrhythmia in the

presence of atrial fibrillation are frequently misinterpreted as uncom-plicated atrial fibrillation. Frequent occurrence of A-V dissociation with A-V nodal arrhythmias was emphasized. Nineteen patients had atrial tachycardia and A-V conduction disturbances were encountered in 64

patients.Sudden appearance of rapid or slow heart action during digitalization

should make one suspect digitalis toxicity rather than need for increased digitalis. Immediate recognition of digitalis toxicity particularly digitalis-induced arrhythmias and withdrawal of digitalis are essential to minimize the relatively high mortality.

Additional Indexing Words: Digitalis intoxication Cardiac arrhythmias Digitalis toxicity Digitalis poisoning

LTHOUGH digitalis is an indispensable drug in the treatment of con-

gestive heart failure and most supraventricular tachyarrhythmias, it may

cause or aggravate the congestive heart failure or various cardiac arrhythmias

if the patient develops digitalis intoxication.

From the Division of Cardiology, Department of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia.

Associate Professor of Medicine and Physician-in-Charge, Electrocadiographic Laboratory.Received for publication May 7, 1969.

409

410 CHUNG Jap. Heart J. September, 1969

The purpose of this paper is to review the previous literature concerning digitalis intoxication, with particular emphasis placed on the importance of early recognition of digitalis-induced arrhythmias especially A-V nodal tachy-cardia or escape rhythm in the presence of atrial fibrillation. One hundred and eighty cases of digitalis intoxication collected will be included for discus-sion.

MATERIALS AND METHODS

One hundred and eighty patients with digitalis intoxication diagnosed both clinically and electrocardiographically were studied in this series. Records were reviewed and some interesting and important electrocardiographic tracings were selected for illustration. Laboratory tests included chest roentgenogram, blood count and serum electrolyte determination. One hundred and two patients were men and 78 patients women. Ages ranged between 20 and 94 years. One hundred and thirty-five of the patients were more than 60 years old and almost all who were studied had received oral diuretics. Digoxin (Lanoxin) was being taken by practi-cally all. The signs and symptoms of congestive heart failure continued to progress in all subjects but in different degrees. Gastrointestinal symptoms were surprisingly not clearly evident, but I attribute this to a masking in many instances by both the severity of the underlying congestive heart failure and cerebral insufficiency.

RESULTS

One hundred and forty-one had evidence of coronary and/or hypertensive heart disease. Specifically, 4 had evidence of acute myocardial infarction and 12 patients had evidence of old myocardial infarction. Thirteen patients had chronic cor pulmonale. Rheumatic heart disease was found in 5 subjects, cardiomyopathy was diagnosed in 6 and luetic heart disease was encountered in 4 patients. An analysis of the underlying heart disease in 180 patients with digitalis intoxication is summarized in Table I. Thirty-eight patients died of intractable congestive heart failure and/or irreversible cardiac arrhythmias. In treating mild cases of digitalis intoxication, discontinuing the drug alone was satisfactorily effective. However, if intoxication was manifested by fre-

quent premature contractions or tachyarrhythmias, potassium or Dilantin (diphenylhydantoin) was administered in addition to omitting digitalis. Potas-sium was highly effective even in the presence of a normal serum potassium value. In urgent situations, an intravenous infusion of potassium or Dilantin was carried out. Potassium, by all means, was not given if there were con-traindications present such as hyperkalemia, significant renal insufficiency and/or second or third degree A-V block. Potassium and Dilantin were equally effective in treating digitalis-induced supraventricular tachyarrhythmias

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DIGITALIS-INDUCED CARDIAC ARRHYTHMIAS 411

Table I. Underlying Heart Diseases in 180 Patients

whereas the latter was more effective in treating ventricular arrhythmias. In fact, 18 patients with ventricular arrhythmias and 5 patients with supraven-tricular arrhythmias responded well to Dilantin when potassium was ineffective initially. If the clinical situation was not urgent, oral potassium or Dilantin was administered. The dosage of these 2 drugs varied from patient to

patient depending both on the response of the arrhythmias and the therapy and associated modifying factors. Propranolol was not frequently used since it is contraindicated in the presence of congestive heart failure and/or significant

pulmonary disease. Xylocaine was administered to 6 patients for the treat-ment of ventricular arrhythmias with various success. Pronestyl, quinidine and sodium EDTA were not used in my study. Two patients required D.C. shock as a last resort for refractory ventricular fibrillation but all these patients died. A temporary catheter pacemaker was used with good results in 2 patients for complete A-V block. One woman suffering from myxedema heart disease received a permanent pacemaker implantation for the treatment of Adams-Stokes syndrome due to complete A-V block with frequent ventricular prema-ture contractions but she expired 8 days later from ventricular fibrillation. The presence of various modifying factors significantly increased the mortality of the patients in my study. Specifically, 13 patients had chronic lung disease, 11 renal insufficiency, 24 hypokalemia (serum level: lower than 3.0 mEq./L.), 4 acute myocardial infarction, 5 rheumatic heart disease, and one


Table II. Incidence of Digitalis-Induced Arrhythmias in 180 Patients

(346 Episodes of Arrhythmias)

Vol. 10 No. 5 DIGITALIS-INDUCED CARDIAC ARRHYTHMIAS 413

patient had subacute bacterial endocarditis. Myxedema heart disease was found in 2 subjects, and thyrotoxicosis was diagnosed in one.

As can be expected, every known type of cardiac arrhythmia and/or con-duction disturbance were encountered in this study (Table II). One hundred and twenty-seven patients had 2 or more different arrhythmias and among these 42 subjects showed 3 or more different arrhythmias and/or conduction disturbances. The total incidence of digitalis-induced arrhythmias was there-fore 346 episodes in 180 patients (Table II). The basic rhythm was atrial

Fig. 1. Leads II-a, b and c are continuous. The rhythm is atrial fibrilla-tion and intermittent A-V nodal tachycardia (ventricular rate: 83 per min.) with intermittent aberrant ventricular conduction (Marked N) producing in-complete A-V dissociation. Some of the A-V nodal beats are normally con-ducted to the ventricles (Marked X).

Fig. 2. Atrial fibrillation and A-V nodal tachycardia (rate: 83 per min.) with intermittent 2:1 exit block producing incomplete A-V dissociation. Numbers represent hundredths of a second. (Chung and Thomas: Geriatrics 20:1006, 1965, Lancet Publication, Inc., Minneapolis).


fibrillation in 87 patients and almost all these patients (83) showed either non-

paroxysmal A-V nodal tachycardia (Fig. 1 and 2) or A-V nodal escape rhythm (Fig. 3) induced by digitalis (Table II). Atrial fibrillation and flutter were each found in only 3 patients (Table II). Nineteen patients (10.6%) had atrial tachycardia but in the majority (12 patients) of these patients it was associated with A-V block (Fig. 4). One interesting observation in this study was a relatively high incidence (11 patients) of blocked (non-conducted) atrial

premature contractions (Fig. 5). Disturbances of sinus impulse formation and conduction were found only in 28 subjects (15.6%). A-V conduction disturb-ances in various degrees were encountered in 64 patients (35.6%). Second degree A-V block was the most common (36 patients) form noted. Only 6

patients had complete A-V block in the presence of the sinus mechanism whereas 35 patients showed complete or advanced A-V block (Fig. 3) in the presence of atrial fibrillation. First degree A-V block was seen in 22 subjects (12.2%).

Fig. 3. Leads II-a and b and leads V1-a and b are continuous in each

given lead. The rhythm is atrial fibrillation with A-V nodal escape rhythm (indicated by arrows) due to complete A-V block and ventricular bigeminy (marked X). (Chung: Drug-Induced Diseases, Third Edition, p. 74, Excerpta, Medica, The Netherlands, 1968).

Fig. 4. Leads V1-a, b and c are continuous. Arrows indicate P waves in lead V1-a. The rhythm is atrial tachycardia (atrial rate: 210 per min.), with

varying A-V block (ventricular rate: 145-160 per min.).


The overall incidence of ventricular arrhythmias was highest (104 patients: 57.8) in my study and among these arrhythmias, ventricular premature con-tractions predominated (85 patients: 47.3%). The incidence of ventricular bigeminy (28 patients) and multifocal ventricular premature contractions (30

patients) was almost equal. Ventricular tachycardia was found in 16 patients

Fig. 5. Leads II-a, b, c and d are continuous. Arrows indicate ectopic P waves. The tracing exhibits sinus rhythm with frequent atrial premature contractions. Some of atrial premature contractions are not conducted to the ventricles (second beat of lead II-b; 6th beat of lead II-C)- some of them are interpolated (first and fifth beats of lead II-a) and some of them are more aberrantly conducted to the ventricles (marked X). Note that P-R intervals

(0.26 sec.) of atrial premature contractions are markedly prolonged.

Fig. 6. Leads II-a and b and leads V1-a and b are continuous in each

given lead. Arrows indicate atrial activities (rate: 200 per min.) which represent atrial tachycardia. Some areas where atrial activities are not dis-cernible probably represent intermittent exit block from atrial ectopic focus. It is interesting to note that there is bidirectional ventricular tachycardia with a rate of 150 per min. Short and long R-R intervals appear alternatively throughout the tracing. Atrial and ventricular activities are independent so that complete A-V dissociation exists. (Chung: Drug-Induced Diseases, Third Edition, p. 69, Excerpta Medica, The Netherlands, 1968).


(8.9%) and 2 of them had bidirectional ventricular tachycardia (Fig. 6). The mortality rate (60%) of this group was highest among all other arrhythmias. Two patients had ventricular fibrillation and both expired.

Seven patients showed very interesting multiple rhythm or tachycardia

(Fig. 6). The incidence of digitalis-induced arrhythmias in 180 patients is summarized in Table II and an analysis and comparison with other similar studies is shown in Table III. A precise comparison between my study and that of others is unfortunately impossible since most authors failed to describe various arrhythmias.

DISCUSSION

General Consideration

Although such gastrointestinal symptoms as anorexia, nausea and vomit-ing had been said to be the most common early symptoms, cardiac arrhythmias may often indicate digitalis toxicity without such signs. The occurrence of cardiac arrhythmias is particularly common when using the purified glycosides. In fact, the occurrence of various cardiac arrhythmias in digitalis intoxication has been a common manifestation than gastrointestinal symptoms when the

purified glycosides have been used.1)-5) Cardiac arrhythmias are frequently the only signs of digitalis intoxication when using such preparations. It is also known that hypokalemia induced by frequent use of potent diuretics predisposes to the development of digitalis-induced arrhythmias.

An early recognition of cardiac arrhythmias induced by digitalis is quite important because gastrointestinal symptoms are often difficult or even im-

possible to evaluate in elderly patients and younger children. Furthermore, since the most serious and life threatening manifestations of digitalis intoxica-tion are cardiac arrhythmias, these arrhythmias must be immediately treated, for pre-existing congestive heart failure becomes rapidly worse under super-imposed arrhythmias.

It is well known fact that digitalis may produce every known type of arrhythmias via an alteration of impulse formation, conduction or both. It is commonly observed that patients with digitalis intoxication demonstrate various combination of arrhythmias. Arrhythmias may change from one to an-other in the same electrocardiographic tracing. Digitalis-induced arrhythmias appear to develop more frequently when parenteral digitalization is used.1)-5) In general, cardiac arrhythmias occur in 80 to 90 per cent of patients presenting with digitalis intoxication.


Digitalis-Induced Cardiac Arrhythmias

1) Disturbances of sinus impulse formation and conduction: In digitalis intoxication, the mechanism responsible for the disturbance

in sinus impulse formation and conduction is rather complicated. Minor toxic effects of digitalis may induce sinus arrhythmia and/or sinus bradycardia but these arrhythmias may lead to more serious arrhythmias such as sinus arrest and sinoatrial block when digitalization continues. A sudden reduction of the heart rate below 50 per min. should raise the possible diagnosis of diagitalis toxi-city in all adult patients during digitalis therapy. A slow pulse rate below 100

per min. in infancy has the same clinical significance.6) Marked sinus arrhy-thmia is much more common in infancy or young children than in the adult

population.6) Sinoatrial block with or without the Wenckebach phenomenon is not uncommon in digitalis intoxication, particularly in children.7)-10) In fact, digitalis may be the most common cause of S-A block.9) In this arrhy-thmia, the sinus pacemaker itself produces the cardiac impulse as usual but the impulse is unable to activate the atria due to a block at the sinoatrial junctional tissue. The P-P intervals which include the dropped P waves are multiples of the sinus cycles. Although the occurrence of sinus tachycardia was reported in digitalis intoxication by several investigators,3),4),11) it is difficult to under-stand the fundamental mechanism responsible for this arrhythmia. It is logical to assume that some patients with congestive heart failure may have persisting sinus tachycardia even after full digitalization when the congestive heart failure is associated with other diseases such as chronic lung disease, hyperthyroidism and anemia, etc.

2) Atrial Arrhythmias: Although digitalis is the drug of choice in the treatment of most atrial

tachyarrhythmias, the drug is also capable of producing various atrial arrhy-thmias. Atrial tachycardia with A-V block was described by Sir Thomas Lewis in 1906 and was attributed to digitalis by Sir James MacKenzie in 1911.12),13) Hermann and his associates have studied 44 cases of digitalis in-toxication and 20 cases of paroxysmal atrial tachycardia with A-V block (PAT with block) which were thought to be induced by digitalis.14) The frequent occurrence of digitalis-induced PAT with block was repeatedly emphasized by Lown and Levine.15),17) The same authors16) reported that digitalis-induced PAT with block was found in 73 per cent of 88 patients with the arrhythmia due to various causes. The importance of PAT with block induced by digitalis was emphasized because the arrhythmia was often found in serious underlying heart disease with a high mortality rate.15),18) Although the frequent occur-rence of digitalis-induced PAT with block is emphasized by some investiga-


tors,14),17) its average incidence by different authors is only 10 per cent of

the total digitalis-induced cardiac arrhythmias.1),3)-5),11),14),18)-21) In fact,

many different series demonstrated a much lower incidence of this ar-

rhythmia.1),3),4),19)-24)

This author found only one instance of PAT with block among 17 patients

with digitalis intoxication in a previous study.19) Present study revealed 12

instances of atrial tachycardia with A-V block (Fig. 4) and 7 instances without

A-V block among 180 cases. A case of an unusual double atrial tachycardia

induced by digitalis was reported previously. This is probably the first re-

ported case of this arrhythmia.25) A few cases of double supraventricular

tachycardia consisting of simultaneous atrial tachycardia and A-V nodal tachy-

cardia resulting in A-V dissociation has been reported.10),19),26)-28) This author

reported a very unusual triple tachycardia consisting of atrial tachycardia, A-V

nodal tachycardia and ventricular parasystolic tachycardia which was found

in a patient with digitalis intoxication.29) From the above observations, the

occurrence of so-called •gPAT with block•h is not so common as some authors

have stated. In addition, PAT is not always associated with A-V block. The

term •gPAT•h may be inappropriate because digitalis-induced atrial tachy-

cardia often does not show the characteristic feature of paroxysm. This ar-

rhythmia actually commonly persists unless the digitalis intoxication is treated

promptly. Thus, the term •gPAT with block•h should not be used at random

and it should be called simply atrial tachycardia unless it has a paroxysmal

nature. The presence of A-V block is another feature of digitalis intoxication.

In digitalis-induced atrial tachycardia, the P-P cycles on the electrocardiogram

may be precisely regular, sometimes slightly or grossly irregular. Irregular

P-P cycles in atrial tachycardia are often due to multifocal foci and this form of

atrial tachycardia occasionally changes to atrial fibrillation with its more grave

prognosis.

The differential diagnosis between atrial tachycardia and atrial flutter

is very important since the former is frequently digitalis-induced, whereas the

latter almost always require more digitalis. Some investigators observed that

carotid sinus stimulation frequently halfs PAT with block not due to digitalis

toxicity and is ineffective when digitalis is the etiologic factor.30) However, I

would like to emphasize the danger of applying carotid sinus stimulation to

patients with suspected digitalis intoxication although this procedure is fre-

quently used in the differential diagnosis or treatment of various arrhythmias.

Several investigators31),34) have shown that 4 patients expired from ventricular

fibrillation during or after carotid sinus stimulation. All of them had been

critically ill and had received cardiac glycosides. Based on these observations,

carotid sinus stimulation should be avoided as much as possible on patients who


interval (Fig. 5). I believe that frequent occurrence of non-conducted atrial

premature contractions is an almost pathognomonic sign of digitalis intoxication during digitalis therapy.

3) A-V Nodal Arrhythmias: It is well documented that digitalis frequently induced various A-V nodal

arrhythmias either due to passive impulse formation resulting in A-V nodal escape rhythm as a physiologic mechanism or enhancement of A-V nodal im-

pulse formation resulting in A-V nodal tachycardia.1),19),20),27),24) The in-cidence of digitalis-induced A-V nodal arrhythmias has increased markedly in recent years probably because of a better understanding regarding the arrhyth-mia itself and a common association of atrial fibrillation as an underlying cardiac rhythm. Digitalis-induced A-V nodal arrhythmias are very common in the

presence of atrial fibrillation particularly in elderly individuals.1),19),20) In my study, 87 patients had atrial fibrillation as the underlying rhythm and almost all of them (73 cases) had either A-V nodal tachycardia or A-V nodal escape rhythm as a manifestation of digitalis intoxication. This information is ex-tremely important since A-V nodal arrhythmias in the presence of atrial fibrilla-tion are frequently misinterpreted as either uncomplicated atrial fibrillation or sinus rhythm or even sinus tachycardia. Continued administration of digitalis, needless to say, would lead to irreversible congestive heart failure or even death under these circumstances. The importance of recognizing A-V dissociation in the presence of A-V nodal arrhythmias is well known because A-V nodal arrhythmias almost always are associated with A-V dissociation. A detailed description regarding A-V dissociation is outlined elsewhere by this author.43),44)

In a rare form of A-V dissociation, the atria and ventricles may be con-trolled by 2 different pacemakers at the A-V junction. In this circumstance the atria are activated in retrograde fashion. Each pacemaker at the A-V

junction may produce an A-V nodal escape rhythm or non-paroxysmal A-V nodal tachycardia. In a previous study of double A-V nodal rhythms,1) 4 out of 5 cases had unequivocal digitalis intoxication so that the presence of this rare arrhythmia is almost a pathognomonic sign of digitalis toxicity during digitalis therapy.

If there is further progression of the digitalis intoxication, exit block of various degrees may develop below the ectopic pacemaker so that ventricular action may become slower or irregular (Fig. 2). When the exit block is Wencke-bach type, the cardiac rhythm will show regular irregularity.27),42) On the other hand, digitalis may induce further acceleration of A-V nodal impulse formation resulting in bidirectional A-V nodal tachycardia. The incidence of digitalis-induced A-V nodal arrhythmias is probably as high as ventricular

premature contractions. Digitalis-induced A-V nodal premature contractions


are taking even small amounts of digitalis. If carotid sinus stimulation is de-finitely indicated, it should never exceed 5 sec. in duration.

The fundamental mechanism responsible for the production of atrial tachyarrhythmias, digitalis' indirect vagal stimulating action, results in a mark-edly shortened refractory period of the atrial musculature. Thus, increased conductivity within the atrial muscle can produce various rapid atrial ar-rhythmias. A combination of the depressive effect on the A-V conduction and the shortening effect on the refractory period results in rapid arrhythmias with varying degrees of A-V block.

Besides atrial tachycardia, transient or permanent atrial fibrillation may be induced by digitalis.10),24),35)-27) This should be suspected when atrial fibrillation develops suddenly in the digitalized patient who previously had sinus rhythm or when a paradoxical acceleration of ventricular response occurs in the patient with pre-existing atrial fibrillation.36),38),39) However, a para-doxical acceleration of the ventricular rate in atrial fibrillation, atrial flutter or atrial tachycardia may occur in Wolff-Parkinson-White syndrome without evidence of digitalis toxicity if these atrial tachyarrhythmias are treated with digitalis or quinidine alone. The reason for this is that digitalis blocks the normal A-V pathway whereas quinidine (or pronestyl) predominantly blocks the anomalous (accessory) pathway so that a rapid conduction of atrial im-

pulses may traverse the unblocked pathway.40) If other digitalis-induced arrhythmias particularly ventricular bigeminy or trigeminy are associated with atrial fibrillation, the diagnosis of digitalis intoxication is almost certain.37),39) Brest et al. have reported the conversion of atrial fibrillation to atrial flutter using digitalis.41) In my study, atrial fibrillation and flutter were each found in only 3 patients. It is quite interesting to note that atrial fibrillation and flutter which are both rare digitalis-induced arrhythmias1),19),20) have been reported by different investigators as relatively common arrhythmias3),4),11),14),23) in digitalis toxicity (Table III). This is usually due to misinterpreting A-V nodal arrhythmias in the presence of atrial fibrillation or flutter. The exact reason why digitalis-induced atrial fibrillation or flutter is so rare compared with atrial tachycardia is uncertain.

Although atrial premature contractions are not as common as ventricular ones, if the former occur, the ectopic atrial beats are frequently not conducted to the ventricles (non-conducted or blocked atrial premature contractions). Sometimes, a prolonged P-R interval may be observed in the atrial premature beats even in the presence of a normal P-R interval of the basic rhythm. The combination of impaired A-V conduction in the atrial ectopic beats plus the increased excitability in the atrial results in frequent non-conducted atrial

premature contractions or atrial premature contractions with prolonged P-R


Table III. Incidence of Digitalis-Induced Arrhythmias

(9 Different Studies)

Key to the Table:

A.P.C.: Atrial Premature ContractionW.A.P.: Wandering Atrial Pacemaker

N.E.R.: Nodal Escape Rhythm

N.P.C.: Nodal Premature Contraction

V.P.C.: Ventricular Premature Contraction

Vent.: VentricularIdiovent. R.: Idioventricular Rhythm

are occasionally observed but much less common than A-V dissociation.4) Ventricular Arrhythmias: Ventricular premature contractions are the most common and often

the earliest manifestation of digitalis intoxication in the adult popula-tion.9),35),36),46)-51) Various investigators have reported that its incidence is ap-

proximately 50 per cent of all digitalis-induced arrhythmias.1),3)-5),11),14),19)-21)


It has been known for many years that ventricular bigeminy (Fig. 3) is a specific arrhythmia in diagnosing digitalis intoxication during digitalis therapy. Occasionally, ventricular premature contractions may appear after only 1 or 2 doses of digitalis.52) In children and normal adults, supraventricular arrhy-thmias and A-V conduction disturbances are a more common occurrence than ventricular premature contractions.6),9),49),51) Therefore, it is stated that ven-tricular bigeminy, trigeminy or quadrigeminy induced by digitalis frequently occurs in the presence of a diseased myocardium particularly in the aged. In the experience of this author1),2),19),20) and others, 3)-5),11),14),18),21) ventricular

premature contractions occurred considerably more often than atrial or A-V nodal premature contractions whereas atrial or A-V nodal tachyarrhythmias were far more common than ventricular tachyarrhythmias in digitalis intoxica-tion. The overall incidence of ventricular arrhythmias by this author was highest (104 patients: 57.8%) in my study and among these arrhythmias, ven-tricular premature contractions predominated (85 patients: 47.3%).

The ventricular premature contractions may be originating from a single focus or multifocal foci. Multifocal ventricular premature contractions are more pathognomonic for digitalis intoxication than unifocal ventricular pre-mature contractions. Bidirectional ones are quite suggestive of digitalis toxi-city. Ventricular premature contractions may appear as group beats or may lead to short runs of ventricular tachycardia. It has been repeatedly stressed that ventricular premature contractions particularly multifocal or bidirectional ones associated with digitalis-induced supraventricular arrhythmias are a patho-

gnomonic feature of digitalis intoxication.36),37) Furthermore, Schwartz and Schwartz have pointed out that even a single ventricular premature contractions associated with atrial fibrillation was found in over 90 per cent of patients with digitalis intoxication. If ventricular bigeminy (Fig. 3) is present in atrial fibrillation, the possibility of digitalis toxicity was 100 per cent.

When ventricular premature contractions become frequent particularly multifocal or bidirectional ones, a brief period of ventricular tachycardia may develop producing unidirectional or bidirectional tachycardia or even ven-tricular fibrillation.36) Ventricular tachycardia induced by digitalis has not been rare in recent years in spite of early recognition and treatment. The average incidence of ventricular tachycardia is approximately 10 per cent of all digitalis-induced arrhythmias. Ventricular tachycardia may appear as the initial sign of digitalis toxicity without preceding ventricular premature con-tractions,36) but often it may be a terminal digitalis-induced arrhythmia. Ven-tricular tachycardia may be transient or permanent depending upon the degree of digitalis toxicity, the underlying heart disease and the effectiveness of treat-ment. If ventricular tachycardia persists, there is always the possibility of the


development of ventricular fibrillation and sudden death. The mortality of

patients with digitalis-induced ventricular tachycardia is extremely high (68 to 100%).1),2),18) Bidirectional ventricular tachycardia (Fig. 6) is considered to be a more pathognomonic feature of digitalis toxicity than the unidirectional entity.9),11),36),46),53) Often bidirectional tachycardia is initiated by ventricular bigeminy or trigeminy particularly multifocal ones. This arrhythmia is more common in advanced heart disease and frequently the basic atrial mechanism is atrial fibrillation, flutter or tachycardia.1),2) Bidirectional ventricular tachy-cardia may be originating from one focus or from 2 or more foci. R-R inter-vals on the electrocardiogram are precisely regular if the tachycardia originates from a single focus whereas multifocal ventricular tachycardia produces alter-nating short and long R-R intervals. Often it is difficult or at times impossible to distinguish between bidirectional ventricular tachycardia and A-V nodal tachycardia with aberrant ventricular conduction producing a form of electrical alternans.54) The clinical significance of these 2 arrhythmias in digitalis in-toxication is almost the same and needs immediate treatment. Therefore, dif-ferential diagnosis may not be too important. In ventricular tachycardia, either unidirectional or bidirectional, the average heart rate is between 150 and 180 per min., the latter often having a faster rate. It should be emphasized that bidirectional tachycardia, either ventricular or A-V nodal in origin, is a very serious manifestation of digitalis toxicity and frequently may lead to ven-tricular fibrillation and death. In fact, any patient in digitalis toxicity, with ventricular premature contractions particularly multifocal and ventricular tachycardia may develop ventricular fibrillations at any time when the condi-tion is not recognized early. Transient or permanent ventricular fibrillation has been induced in patients who have been taking digitalis (either small or toxic doses) by carotid sinus stimulation. All of these patients expired during or after the procedure.31),34) When ventricular fibrillation develops in digitalis intoxication, these patients almost always expire regardless of treatment. Von Capeller et al. reported that only one among 11 proven cases with ventricular fibrillation induced by digitalis had survived.11) Ventricular fibrillation in digitalis toxicity is apt to develop after the intravenous administration of glyco-sides.11) Cohen pointed out that digitalis-induced ventricular fibrillation waves may be slower, more regular and more uniform than those due to other causes.52)

Except for idioventricular rhythm, the mechanism of ventricular tachy-cardia or fibrillation is most likely similar to that responsible for ventricular

premature contractions. These arrhythmias are either due to increased ir-ritability of the myocardium or a re-entry mechanism due to myocardial depres-sion leading to increased automaticity.55),59) Among these 2 mechanisms, the theory of increased irritability in digitalis toxicity has become an erroneous


concept.59) Thus, enhancement of automaticity is probably responsible for digitalis-induced ventricular arrhythmias.47),59)

Whenever an impulse from the sinus node or atria is unable to conduct to the ventricles, due to S-A block, sinus arrest or complete A-V block, idioven-tricular rhythm may appear particularly when the A-V node is unable to pro-duce A-V nodal escape rhythm. Idioventricular rhythm is usually slow (30-40 per min.) with bizarre QRS complexes. Terminally, the idioventricular rhythm gradually slows and finally ventricular standstill ensues.

5) A-V Conduction Disturbances: Digitalis may produce various degrees of A-V conduction disturbances

due to both the direct and indirect actions of the drug. These actions are very important for the drug's therapeutic effect on various supraventricular tachy-arrhythmias particularly atrial fibrillation. The degree of A-V block in digi-talis intoxication depends on the dose of the drug, underlying heart disease, pre-existing A-V conduction disturbances and the possible presence of electrolyte imbalance. It is shown that patients with ischemic heart disease, myocarditis

particularly rheumatic in origin and acute diaphragmatic myocardial infarction are prone to develop varying degrees of A-V block as a manifestation of digitalis toxicity. Although first degree A-V block is probably one of the commonest and earliest manifestations of digitalis toxicity,10),30) except in children or in-fants, some investigators14), 18),22),24) do not include it as a toxic manifestation of the drug. Thus, the true incidence of first degree A-V block is probably much higher than the reported incidence (12 per cent).1),5),11),18)-21) Further-more, an early manifestation of digitalis toxicity may be a slightly prolonged P-R interval compared to the pre-digitalizing electrocardiogram although the P-R interval may still be entirely within normal limits. These patients should be observed closely for the possible development of A-V block induced by digitalis.

However, there is no doubt that the further administration of digitalis frequently leads to higher degrees of A-V block and other digitalis-induced arrhythmias. Therefore, first degree A-V block during digitalization definitely should be considered as a manifestation of digitalis intoxication. Schwartz and Schwartz observed that some patients with first degree A-V block exhibit further

prolongation of P-R interval with the development of atrial fibrillation.37) It may be assumed that first degree A-V block predisposes to the displacement of the sinus pacemaker to a lower level in the atria resulting in the initiation of atrial fibrillation.37) Various studies indicate that the average incidence of second degree A-V block is 11 per cent.1)-5),11)-14),18)-21) Among second de-

gree A-V block, Wenckebach type is more common than the constant type such as 2:1, 3:1 or 4:1 A-V block; and the former was found in approximately

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No. 5 DIGITALIS-INDUCED CARDIAC ARRHYTHMIAS 425

two-thirds of all second degree A-V blocks (24 out of 36 cases). Wenckebach

phenomenon may be observed in the presence of underlying atrial fibrillation.

Digitalis-induced constant A-V block occurs less frequently than Wenckebach

A-V block. This is in contrast to the periodic A-V block (an occasional ap-

pearance of non-conducted P waves while all conducted P-R intervals remain

normal and constant such as 3:2, 4:3 A-V block) which has not been reported

as a manifestation of digitalis toxicity.60) It should be noted that the term

•g high degree or advanced A-V block•h has the same meaning as •galmost com-

plete A-V block.•h Thus, high degree A-V block is characterized by the ap-

pearance of occasionally conducted sinus or atrial beats (ventricular captured

beats) and otherwise complete A-V block causing incomplete A-V dissociation.

High degree A-V block is very common in digitalis intoxication when the under-

lying cardiac rhythm is atrial fibrillation.1),2),19),20) If any form of second or

high degree A-V block progresses, it results in complete A-V block. Digitalis-

induced high degree and complete A-V block in the presence of atrial fibrilla-

tion were encountered in 35 out of 180 cases in my study. It is reported that

digitalis intoxication is the second most common cause of complete A-V block.

It is also shown that the idioventricular rate in digitalis-induced complete A-V

block tends to be faster than that in complete A-V block due to other dis-

eases.7),10) Therefore, the Adams-Stokes syndrome in digitalis-induced com-

plete A-V block is not commonly observed.37),61) However, if the underlying

rhythm is atrial fibrillation, the incidence of Adams-Stokes seizures increases in

the course of high degree or complete A-V block.37),39) During digitalis therapy

in patients with pre-existing complete A-V block, the drug may produce a

slower or faster idioventricular rate.37),61) Schwartz and Schwartz emphasized

that the acceleration of idioventricular rate in complete A-V block is definitely

a toxic manifestation of digitalis37) and requires immediate withdrawal of the

drug. Digitalis-induced transient ventricular fibrillation or standstill has been

reported in the presence of normal sinus rhythm, 2:1 A-V block and complete

A-V block.10),37) Since there is a considerable difference of opinion regarding

the use of digitalis for congestive heart failure with pre-existing complete A-V

block, the drug should be cautiously administered. Digitalis is effective in

patients with congestive heart failure even in the pre-existing complete A-V

block because the drug increases the cardiac output through its inotropic action

on the heart muscle independent of its effect upon the ventricular rate.37)

6) Rare Electrocardiographic Manifestations:

Rare manifestations of digitalis intoxication include reciprocal beats,1),2),7)

concealed conduction,7) electrical alternans,19) multifocal tachycardia, and in-

traventricular conduction defects. An interesting arrhythmia •gparasystole•h

was thought to be induced by digitalis in some cases,7) but I was unable to find


any single case with parasystole due to digitalis intoxication.1),2),29),55),62)-65)

ACKNOWLEDGMENT

I wish to thank Mrs. Carol Johnson for her valuable technical assistance in the preparation of this manuscript.

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