Version May 2024
INTRODUCTION — Cardiac glycosides (digitalis preparations including digoxin and digitoxin) are used clinically in two situations: heart failure due to systolic dysfunction, and in certain supraventricular tachyarrhythmias [1]:
●The ability to enhance cardiac contractility and modulate neurohumoral activation can lead to symptomatic improvement in systolic heart failure, although it is unclear if survival is prolonged even in carefully selected patients with low therapeutic serum levels. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.)
●Digoxin also slows conduction through the atrioventricular (AV) junction (node) by increasing cardiac vagal tone modulation. It may also have a sympathoinhibitory effect in therapeutic doses. As a result, it is sometimes used (usually adjunctively with beta blockers or calcium channel blockers) for controlling the ventricular response in atrial fibrillation and atrial flutter when there is excessively rapid transmission of stimuli from the atria to the ventricles through the AV junction. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Control of ventricular rate in atrial flutter".)
●Digoxin may also be effective in the treatment of certain types of reentrant paroxysmal supraventricular tachycardia involving the AV node.
Digoxin toxicity continues to be an important clinical problem which may be life-threatening [2]. The incidence of digoxin excess and toxicity, along with the potential associated arrhythmias, are presented here. The management of digoxin intoxication, including the treatment of cardiac arrhythmias associated with digoxin toxicity, is discussed separately. (See "Digitalis (cardiac glycoside) poisoning" and "Cardioversion for specific arrhythmias", section on 'Cardioversion in patients with digitalis toxicity'.)
INCIDENCE OF DIGOXIN TOXICITY — Technical advances and changes in practice patterns have lowered the incidence of digoxin overdose in patients receiving chronic therapy [3]. However, digoxin toxicity remains an important clinical syndrome in which potentially fatal cardiac arrhythmias can occur [4]. (See "Digitalis (cardiac glycoside) poisoning".)
In a large study of patients with congestive heart failure who were treated with digoxin, definite digoxin toxicity occurred in 0.8 percent and possible toxicity in another 4 percent [5]. Digoxin toxicity was also reported in 4 percent of patients in a 1998 study [6]. In spite of efforts to educate prescribers to use lower digoxin doses (in heart failure patients) with a goal of lower plasma digoxin levels, the frequency of emergency department visits related to digoxin toxicity has remained relatively unchanged [7].
PLASMA DIGOXIN LEVELS ASSOCIATED WITH TOXICITY — Life-threatening digoxin-induced arrhythmias and other toxic manifestations occur at substantially increasing frequency as the plasma digoxin concentration rises above 2.0 ng/mL (2.6 nmol/L). However, clinicians should be aware that signs of toxicity may occur at levels below 1.3 to 1.5 ng/mL (1.7 to 1.9 nmol/L), and such toxicity is more likely in the presence of one or more comorbid conditions (eg, hypokalemia, hypomagnesemia, hypercalcemia, myocardial ischemia). Hypokalemia is a particularly important risk factor that can promote digoxin-induced arrhythmias. Patients with heart failure who are older than 65 years are also at increased risk [8]. (See "Digitalis (cardiac glycoside) poisoning".)
Retrospective analysis of data from the large digitalis investigation group (the DIG trial) revealed that serum digoxin levels ranging from 1.2 to 2.0 ng/mL (1.5 to 2.6 nmol/L) were associated with an excess mortality versus placebo in women with heart failure [9]. Therefore, we recommend maintaining trough digoxin levels at the lower range (eg, between 0.5 and 0.8 ng/mL [0.6 to 1.0 nmol/L]) in both male and female patients to help minimize toxicity [10,11].
The safety and effectiveness of digoxin in patients with atrial fibrillation with and without chronic heart failure also continue to generate controversy and conflicting findings [12,13]. Until more definitive prospective clinical trial data are available [13], serum digoxin concentrations should be maintained within the low therapeutic range (0.5 to 0.8 ng/mL [0.6 to 1.0 nmol/L]), with careful monitoring of renal function and serum potassium concentrations.
Plasma digoxin levels should be measured at least 6 hours and preferably 12 or more hours after the last dose since this is the time required for attainment of the steady state due to gradual distribution through the extravascular space. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.)
MECHANISMS OF CARDIAC TOXICITY — The mechanism(s) by which digoxin toxicity promotes the development of arrhythmias remain incompletely understood. Two general categories have been described: enhanced ectopy with tachyarrhythmias, and bradyarrhythmias [14]. Digoxin can affect cardiac tissue in a number of ways which may result in toxicity:
●Digoxin directly inhibits the ATPase dependent sodium-potassium pump, increasing intracellular sodium. This, in turn, reduces the activity of a sodium-calcium exchanger that normally extrudes calcium from the cell [15]. The resulting increase in intracellular calcium is responsible for the positive inotropic action of digoxin. The fluxes in calcium can also have electrophysiologic effects.
●Cardiac glycosides activate ryanodine receptors, which could contribute to increased calcium release from the sarcoplasmic reticulum and could play a role in the inotropic action of glycosides in vivo [16].
●Digoxin increases vagal tone through central and peripheral effects; however, at excess levels, digoxin may augment cardiac sympathetic tone [17].
As a result of the effect on intracellular calcium concentrations and vagal tone, high levels of digoxin can have a variety of effects that facilitate the development of arrhythmias. They can enhance and depress automaticity, induce triggered membrane activity (especially delayed afterdepolarizations), increase or decrease excitability, slow conduction, and alter refractoriness, also producing conditions conducive to the development of reentrant arrhythmias.
DIGOXIN-INDUCED ARRHYTHMIAS — A wide range of arrhythmias occurring at almost any intracardiac location can be seen with digoxin toxicity, depending in part upon the age of the patient and the state of the myocardium. Accentuation of vagal effects and resulting bradyarrhythmias are more commonly seen in younger, healthier individuals. Conversely, patients with severe cardiac disease and concurrent digoxin toxicity are more susceptible to ventricular ectopy and tachyarrhythmias. (See "ECG tutorial: Miscellaneous diagnoses", section on 'Digitalis toxicity'.)
There are, however, some arrhythmias that are generally not directly induced by digoxin. Atrial flutter, atrial fibrillation, and Mobitz type II second degree AV block are the least likely of all the arrhythmias to be caused by digoxin toxicity. However, superimposed digoxin toxicity may occur in these settings, for example leading to an excessively slow or regularized ventricular response in atrial fibrillation, or increased ventricular ectopy.
The arrhythmias associated with digoxin toxicity will be discussed according to their myocardial site of origin, including the sinoatrial nodal tissue, atrial myocardium, atrioventricular nodal tissue, and ventricular myocardium.
Sinus bradycardia, tachycardia, block, and arrest — The effect of digoxin and digoxin toxicity on the sinoatrial (SA) node is often difficult to determine because of both indirect and direct actions. As an example, improved hemodynamics in heart failure usually results in a fall in heart rate due to alterations in autonomic balance. Alternatively, sinus bradycardia may also be one of the earliest signs of digoxin excess.
Cardiac glycosides have no direct effect on slowing automaticity in the isolated SA node or in the transplanted human heart [18,19]. However, the diseased SA node may be quite sensitive to cardiac glycosides, resulting in sinus bradycardia and SA nodal block [5,20-22]. Animal and human studies suggest that the slowing of the heart rate in this setting is due both to increased vagal tone (mediated by hypersensitization of carotid sinus baroreceptors, central stimulation, increased vagal traffic, and possible potentiation of the effect of acetylcholine on the SA node) and to sympatholytic activity.
While most commonly sinus bradycardia is seen, the sinus pacemaker may accelerate in the presence of excess digoxin. Both adrenergic stimulation [18,23-25] and direct stimulation of the SA node may contribute to this response [26-28].
Toxic levels of digoxin can also result in SA nodal block (waveform 1A-B) or even nodal arrest. (See "Sinoatrial nodal pause, arrest, and exit block".)
Ectopic atrial tachycardia with block — Therapeutic concentrations of digoxin have little effect on atrial tissue, but toxic levels may result in an ectopic atrial tachycardia, often with 2:1 AV block. Animal studies suggest that the atrial tachycardia is probably mediated by increased automaticity in the atrium and/or delayed afterpotentials, often occurring near and perhaps sometimes within the SA node [27,29,30]. The AV block probably results from the rapid atrial rate, as well as the vagotonic activity and a direct effect of digoxin on AV nodal conduction (see below).
Also referred to as "paroxysmal" (ectopic) atrial tachycardia (PAT) with AV block, this arrhythmia is strongly suggestive of digoxin toxicity in patients taking this medication or in cases of suspected overdose. However, the arrhythmia is typically not paroxysmal when induced by digoxin; rather, it is a persistent arrhythmia until specific therapy is instituted or digoxin levels fall below the toxic range (see "Focal atrial tachycardia", section on 'Treatment'). It should be noted that most cases of ectopic atrial tachycardia with block are not due to digoxin excess in contemporary practice.
Clinically, up to one-half of patients with nonparoxysmal atrial tachycardia with AV nodal block have a P wave morphology similar to the sinus P wave (waveform 2). This observation supports the suggestion in animal studies that the ectopic site is often near, or is perhaps in, the SA node. The remaining cases arise at other sites and typically have an abnormal P wave axis as seen in the ectopic atrial tachycardias.
Atrial tachycardia with block may superficially resemble atrial flutter. There are two major distinguishing features between these arrhythmias:
●The atrial rate is faster (usually 250 to 350 beats/min) with atrial flutter.
●The baseline between P waves is isoelectric in atrial tachycardia with block, while there is a constantly undulating baseline between the flutter waves in atrial flutter.
It is important to distinguish between atrial flutter and atrial tachycardia due to digoxin excess since the administration of additional digoxin, which may be an appropriate therapy for atrial flutter, can accelerate the atrial rate in an atrial tachycardia, increasing the degree of AV block and potentially precipitating a more serious digoxin-toxic arrhythmia. (See "Electrocardiographic and electrophysiologic features of atrial flutter".)
Atrial fibrillation and flutter — Digoxin toxicity can occur in patients with atrial fibrillation or flutter, even though these arrhythmias are rarely caused by digoxin. A more important clinical problem is the effect of digoxin toxicity on transmission of atrial stimuli through the AV node in patients with preexisting atrial fibrillation. The electrocardiographic findings vary with increasing degrees of digoxin toxicity and with the possible presence of block above or below the pacemaker (waveform 3A-D) [31]. Casual evaluation of such a patient who might have severe digoxin toxicity may lead to the mistaken conclusion that the irregular rhythm is due to persistent AF and the digoxin may be inappropriately continued or the dose even increased.
Atrial flutter is rarely, if ever, the result of digoxin intoxication. However, the diagnosis of atrial flutter may be difficult to establish when, as commonly occurs during digoxin therapy, the atrial flutter has a slow ventricular response, with a rate that overlaps that seen in other supraventricular tachycardias, such as nonparoxysmal atrial tachycardia with a 2:1 AV response due to digoxin intoxication. (See 'Ectopic atrial tachycardia with block' above.)
Atrioventricular nodal block — Therapeutic concentrations of digoxin decrease the conduction velocity through the AV node and increase the refractoriness of the AV node; this affects the conduction of the normal as well as a premature impulse. These effects are mediated primarily by an increase in vagal tone and, to a lesser degree, a reduction in sympathetic activity [5,20,21,26,32-35]. As a result of this dependence on autonomic balance, digoxin is of little value in controlling the ventricular response in patients who have undergone cardiac transplantation due to the denervated nature of the transplanted heart [34,35].
AV conduction may be blocked partially or completely by digoxin excess.
●First degree block (AV conduction delay) – Some degree of PR lengthening may be expected with digoxin therapy (waveform 4). More marked widening of the PR interval to above 0.2 sec suggests early digoxin toxicity.
●Second degree AV block – With higher levels of digoxin, first degree AV block may progress to second degree block of the Mobitz type I (Wenckebach) variety (waveform 5). By contrast, Mobitz type II second degree AV block is rarely, if ever, induced by digoxin alone. (See "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)".)
●Third degree AV block – Third-degree (complete) heart block and other types of AV dissociation may also occur with digoxin toxicity (waveform 6). (See "Third-degree (complete) atrioventricular block".)
AV block with digoxin is more likely to occur in the presence of atrial fibrillation, an ectopic atrial rhythm, or atrial flutter than during normal sinus rhythm. The reason is that more atrial impulses are present to reach the AV node during these atrial tachyarrhythmias than during slower rates. In atrial fibrillation, a high degree of AV block may occur, resulting in the ventricles being controlled intermittently by a lower junctional or ventricular pacemaker.
The ECG findings vary with atrial fibrillation, due to a number of factors, including the possible presence of exit block below the pacemaker. The following additional arrhythmias can be seen with increasing degrees of digoxin toxicity in the presence of atrial fibrillation (waveform 3A-D) [31,36]:
●A high but not complete degree of AV block in atrial fibrillation will initially lead to single junctional, subjunctional, or ventricular escape beats with a cycle length characteristic of that of the underlying pacemaker. These escape beats recur episodically during a rhythm strip; they can be diagnosed by the demonstration that the recurring longest R-R intervals have a constant cycle length.
●A higher degree of AV or third degree block results in so few atrial impulses being conducted that a lower pacemaker takes over, leading to an escape junctional, subjunctional, or ventricular rhythm with a slow regular R-R interval for two or more cycles.
●The presence of an accelerated lower pacemaker (due, eg, to triggered activity causing an accelerated junctional rhythm) with regularization of the R-R intervals, in contrast to the irregularly irregular intervals in atrial fibrillation, strongly suggests digoxin toxicity. Simply palpating the peripheral pulse in this setting may lead to the erroneous assumption that the patient has converted to sinus rhythm; however, the ECG will continue to show fibrillatory waves [31].
●More rarely, the lower pacemaker may be regular but there is a Wenckebach type of exit block, resulting in decreasing R-R intervals with group beating characteristic of the Wenckebach phenomenon. Casual evaluation of such a patient who might have severe digoxin toxicity may lead to the mistaken conclusion that the irregular rhythm is due to persistent atrial fibrillation and the digoxin may be continued or the dose increased. (See "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)".)
●Even less commonly, impulses from the lower pacemaker travel alternately down the right and left bundle branches, resulting in a bidirectional ventricular tachycardia (waveform 7). (See 'Bidirectional ventricular tachycardia' below.)
Junctional rhythm, tachycardia, and bradycardia — AV junctional rhythms are sometimes a sign of digoxin toxicity. Digoxin toxicity can result in varying degrees of AV block that may allow the appearance of junctional escape beats and escape junctional (or atrioventricular nodal) rhythms. The junctional rate may be normal (40 to 60 beats/min), accelerated (60 to 120 beats/min, due to direct effects or adrenergic influences), or depressed (less than 40 beats/min, due to enhanced vagal tone, dysfunctional pacemakers in organic heart disease, or to hyperkalemia caused by the digoxin toxicity) [5,20,21,37].
The QRS complex is usually narrow with junctional rhythms, since the pacemaker is typically above the bifurcation of the bundle branches. However, the QRS may be wide if there is a conduction disturbance distal to the pacemaker, a dominant subjunctional pacemaker, or a dominant ventricular pacemaker.
Ventricular arrhythmias — A variety of ventricular arrhythmias may result from digoxin toxicity, including premature ventricular complexes (PVCs), ventricular tachycardia, and ventricular fibrillation.
Premature ventricular complexes — PVCs, often the first sign of digoxin toxicity, are also the most common arrhythmia due to digoxin toxicity. While isolated PVCs may be seen, the PVCs often appear in a bigeminal pattern (waveform 8). Although ventricular bigeminy can result from organic heart disease, it should raise the suspicion of digoxin intoxication in relevant contexts.
Ventricular tachycardia — Due to reentry or possibly to triggered membrane activity (delayed afterdepolarizations), ventricular tachycardia (VT) can be induced by digoxin excess [30]. With triggered membrane activity, VT may be resistant to interruption by ventricular pacing since the faster rate of pacing may in itself increase the transient inward current and worsen the arrhythmia. The axis and width of the QRS complex on the ECG are determined by the site of origin of the VT, which may be in the specialized fascicles.
Ventricular fibrillation — Ventricular fibrillation (VF) can occur with digoxin toxicity, but is usually a late rhythm. VF can, however, be induced by the use of electric cardioversion in patients with an atrial tachyarrhythmia associated with excess digoxin [38].
Bidirectional ventricular tachycardia — An unusual arrhythmia is the so-called "bidirectional" ventricular tachycardia in which the rhythm is regular but every other beat has a different axis as it travels alternately down different conduction pathways (waveform 7). In most cases, the rhythm has a right bundle branch block morphology with an alternating left and right axis [39]. However, alternating right and left bundle branch patterns may be seen. Bidirectional ventricular tachycardia may be confused with ventricular bigeminy. In true bigeminy, the ventricular beat in the bigeminal pattern is premature. By comparison, the R-R interval is regular with a bidirectional tachycardia, since all of the beats arise from a single focus.
Bidirectional ventricular tachycardia is not specific for digoxin intoxication. It is a frequent finding in familial catecholaminergic polymorphic VT, a much less common disorder [40].
SUMMARY AND RECOMMENDATIONS
●Background – Arrhythmias resulting from digoxin toxicity are potentially life threatening; they are seen in up to 5 percent of patients receiving digoxin (or digitoxin). The incidence of digoxin toxicity has declined over time due to appropriate dose reductions in patients with renal dysfunction, more accurate methods for measuring plasma digoxin levels, and the availability of other medications for the treatment of chronic heart failure and tachyarrhythmias leading to a reduced reliance on digoxin. (See 'Introduction' above and 'Incidence of digoxin toxicity' above.)
●Digoxin levels
•Trough levels – Maintaining trough serum digoxin concentration levels at a lower therapeutic range (eg, between 0.5 and 0.8 ng/mL [0.6 to 1.0 nmol/L]) is recommended to help minimize toxicity.
•Life-threatening digoxin-induced arrhythmias occur at substantially increased frequency as the plasma digoxin concentration rises above 2.0 ng/mL (2.6 nmol/L). However, signs of toxicity may occur at much lower plasma levels, especially in the presence of comorbid conditions (eg, electrolyte abnormalities, myocardial ischemia, older age with heart failure).
•Hypokalemia is a particularly important risk factor that can promote digoxin-induced arrhythmias even if the digoxin concentration is thought to be within the "therapeutic" range. (See 'Incidence of digoxin toxicity' above and 'Plasma digoxin levels associated with toxicity' above.)
●Digoxin-induced arrhythmias – A wide range of arrhythmias occurring at almost any intracardiac location can be seen with digoxin toxicity, depending in part upon the age of the patient and the state of the myocardium. Accentuation of vagal effects and resulting bradyarrhythmias is more commonly seen in younger, healthier individuals. Conversely, patients with severe cardiac disease and concurrent digoxin toxicity are more susceptible to ventricular ectopy and tachyarrhythmias. (See 'Digoxin-induced arrhythmias' above.)
•Paroxysmal atrial tachycardia – This arrhythmia results from toxic levels of digoxin that cause ectopic atrial tachycardia, often with 2:1 atrioventricular (AV) block (waveform 2). This electrocardiographic (ECG) pattern is strongly suggestive of digoxin toxicity in patients on the drug. Contrary to its name, the arrhythmia is not typically paroxysmal when induced by digoxin; rather, it is a persistent arrhythmia until specific therapy is instituted or digoxin levels fall below the toxic range. (See 'Ectopic atrial tachycardia with block' above.)
•Atrial fibrillation or atrial flutter – Digoxin toxicity can occur in patients with atrial fibrillation or flutter, even though these arrhythmias are rarely caused by digoxin. The ECG findings vary with increasing degrees of digoxin toxicity and with the possible presence of block above or below the pacemaker (waveform 3A-D). (See 'Atrial fibrillation and flutter' above.)
•AV block and junctional rhythms – These are frequently a sign of digoxin toxicity. Digoxin toxicity can result in varying degrees of AV block (waveform 4 and waveform 5 and waveform 6). (See 'Atrioventricular nodal block' above.)
This AV block may allow the appearance of junctional escape beats and escape junctional (or AV nodal) rhythms. Depending on other factors such as adrenergic or vagal tone, the junctional rate may be normal (40 to 60 beats/min), accelerated (60 to 120 beats/min), or depressed (less than 40 beats/min). (See 'Junctional rhythm, tachycardia, and bradycardia' above.)
•Ventricular arrhythmias – A variety of ventricular arrhythmias may result from digoxin toxicity, including premature ventricular complexes (PVCs), ventricular tachycardia, and ventricular fibrillation. (See 'Ventricular arrhythmias' above.)
PVCs are often the first sign of digoxin toxicity and are the most common arrhythmia due to digoxin toxicity. PVCs can be isolated or occur in a bigeminal pattern (waveform 8). Although ventricular bigeminy can result from organic heart disease, it should raise the suspicion of digoxin intoxication. (See 'Premature ventricular complexes' above.).
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