A myriad of electrocardiographic findings associated with digoxin use

CASE 1

CLINICAL PRESENTATION

A 77-year-old woman with known ischaemic cardiomyopathy was admitted for an episode of acute decompensated heart failure (HF) precipitated by non-compliance to medications. She was on digoxin 125 mcg once daily as part of HF treatment. What does her admission electrocardiogram (ECG) show (Fig. 1)?

Fig. 1

The patient’s 12-lead ECG on admission.

ECG INTERPRETATION

The ECG in Fig. 1 shows a baseline sinus rhythm with a heart rate of 60 beats per minute (bpm). There is evidence of digoxin-induced ECG change (reverse-tick ST segment) that is most easily appreciated in leads V2–V5. This is more accurately described as a biphasic T wave with an initial negative and terminal positive deflection, and is most commonly seen in leads with a dominant R wave (V4–V6). There is evidence of PR prolongation (first-degree atrioventricular [AV] block) due to the effect of digoxin in increasing vagal tone.

CLINICAL COURSE

The patient’s presenting chest radiograph (Fig. 2) showed features consistent with congestive HF, such as alveolar oedema (bat’s wing opacities), Kerley B lines, cardiomegaly, dilated upper lobe pulmonary vessels and pleural effusion. She was treated with intravenous (IV) furosemide 40 mg twice daily and her symptoms improved remarkably.

Fig. 2

Chest radiograph of the patient on presentation shows the features of congestive heart failure: alveolar oedema (black arrows), interstitial or Kerley B lines (white arrow), cardiomegaly (black arrowhead), dilated upper lobe vessels (white arrowhead) and pleural effusion (dotted arrow).

It is important to determine the underlying cause of decompensation. Common causes include ischaemia (myocardial infarction), tachyarrhythmias (atrial fibrillation with rapid ventricular response, supraventricular or ventricular tachycardias), bradyarrhythmias (heart blocks), sepsis, and non-compliance to medications, fluid and dietary restrictions. In Case 1, the decompensation was due to poor compliance to medications and fluid restrictions. Every possible effort should be made to address the underlying cause to reduce future re-admissions.

CASE 2

CLINICAL PRESENTATION

A 68-year-old woman was flown into Singapore via emergency air ambulance for shortness of breath of two days’ duration. She had a history of pulmonary arterial hypertension secondary to congenital right pulmonary arteriovenous malformation, complicated by recurrent episodes of HF. The patient was diagnosed with cardiogenic shock and admitted into the coronary care unit (CCU). Her acute presentation was complicated by acute kidney injury secondary to cardiorenal syndrome and hyperkalaemia. Relevant cardiac medications included bosentan 62.5 mg twice daily, digoxin 62.5 mcg once daily, tadalafil 20 mg once daily and furosemide 40 mg twice daily.

During her stay in the CCU, she developed an acute episode of confusion. Continuous ECG monitoring showed multiple arrhythmias, as captured on 12-lead ECGs (Figs. 3a–c), although her electrolyte levels (potassium, calcium, magnesium) were within normal limits. What do the ECGs show (Figs. 3a–c)?

Fig. 3

12-lead ECG shows (a) atrial fibrillation at baseline; and (b) frequent ventricular ectopic beats with an initial bigeminy pattern during acute confusional state. (c) ECG during acute confusion shows further arrhythmia.

ECG INTERPRETATION

The ECG in Fig. 3a shows atrial fibrillation with an irregularly irregular R-R interval. There is no ‘p’ wave. Atrial fibrillation is the patient’s baseline ECG rhythm. Fig. 3b shows frequent ventricular ectopic beats with an initial bigeminy pattern. There is narrow complex QRS (black arrowhead) followed by wide complex QRS (white arrowhead). The third beat has a preceding ‘p’ wave (white arrow). Subsequent wide complex QRS with alternating beat-to-beat frontal plane axis (black arrows) is documented on lead II. This is a classic instance of bidirectional ventricular tachycardia, an arrhythmia associated with digoxin toxicity, but is also seen in familial catecholaminergic polymorphic tachycardia.

The ECG in Fig. 3c shows a regular broad complex rhythm at a rate of 60 bpm. The QRS morphology is consistent with that of left bundle branch block. Accelerated idioventricular rhythm with capture beat (arrowhead) and fusion beat (arrow) is seen.

CLINICAL COURSE

The patient underwent an episode of cardiorenal syndrome secondary to acute decompensated HF, with serum creatinine rising from 63 µmol/L to 242 µmol/L. Her symptoms and ECG changes in the presence of worsening renal function were suggestive of digoxin toxicity. A serum digoxin level of 3.6 µg/L confirmed the diagnosis of digoxin toxicity. Digoxin-specific antibody fragments were administered as a reversal agent. There was resolution of arrhythmias, with a corresponding normalised serum digoxin level of 1.3 µg/L.

DISCUSSION

Digoxin is a drug used in treatment of HF as well as for heart rate control in atrial fibrillation. The results of the Digitalis Investigation Group (DIG)(1) trial, published in 1997, were central in establishing the place of digoxin in the treatment of HF relative to other established pharmacological therapies. In this trial, patients with left ventricular ejection fraction ≤ 45% and in normal sinus rhythm were randomised to receive either digoxin or a placebo, with a background of concomitant treatment using angiotensin-converting enzyme (ACE) inhibitors and diuretics. 80% of the patients had New York Heart Association Class II–III HF. The results showed that digoxin has no effect on the primary outcome of all-cause mortality. However, the rate of hospitalisation was reduced for the group of patients treated with digoxin, compared to those treated with placebo.

Under the 2016 European Society of Cardiology Guidelines(2) for the diagnosis and treatment of acute and chronic HF, digoxin is currently the fourth-line drug in the management of HF to reduce the risk of both HF-related and all-cause hospitalisation. Similarly, the 2013 American College of Cardiology Guidelines(3) for the management of HF mentions that digoxin may be beneficial for symptomatic improvement of HF patients on top of neurohormonal treatment such as ACE inhibitors. These statements establish digoxin’s place as adjunctive pharmacological therapy in the management of HF, largely due to its narrow therapeutic index, and its lack of mortality benefit for HF patients.(4,5)

Serum digoxin levels and mortality

The overall incidence of digoxin toxicity was 2% over three years in the DIG trial.(5) Serum digoxin levels of > 2.0 ng/mL are usually considered toxic. However, a post-hoc analysis of the DIG trial done by Rathore et al(9) and Lopes et al(10) demonstrate that serum digoxin concentrations (SDCs) of ≥ 1.2 ng/mL are associated with increased mortality. Rathore’s study(9) shows that an SDC of 0.5–0.8 ng/mL is the likely optimal therapeutic range for HF with left ventricular dysfunction. The importance of monitoring SDC is recognised by the National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand,(11) which recommended that SDC be kept at < 1.2 ng/mL.

Digoxin toxicity can occur in both acute (e.g. overdose) and chronic settings. With reference to Case 2, digoxin toxicity may occur in patients taking recommended doses (0.125–0.25 mg once daily) when there is an additional precipitating factor such as hypokalaemia, hypomagnesaemia, hypothyroidism, acute kidney injury and chronic kidney disease.(7) Conditions that predispose a patient to digoxin toxicity are listed in Box 1. Besides cardiac manifestations, symptoms of digoxin toxicity may manifest in other organ systems as confusion, gastrointestinal disturbance, visual blurring and altered coloured vision (Box 2).(4) Electrolyte abnormalities can also result in ECG changes that may occur concomitantly with digoxin-related ECG changes.(12)

Box 1

Predisposing conditions for digoxin toxicity:(4,13,14)

Box 2

Signs and symptoms of digoxin toxicity in each system:(4)

Besides concomitant disease states, drug-drug interactions may increase SDCs that risk toxicity. Digoxin is a substrate for p-glycoprotein, and inhibition by several known drugs (amiodarone, verapamil, clarithromycin, erythromycin and quinidine) has been implicated in resultant increases in SDCs, as they increase gastrointestinal absorption and reduce renal clearance.(13,14)