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Digoxin toxicity with normal digoxin and serum potassium levels: beware of magnesium, the hidden malefactor

The Journal of Emergency Medicine, Vol. 45, No. 2, pp. e31–e34, 2013 Copyright Ó 2013 Elsevier Inc.
Printed in the USA. All rights reserved 0736-4679/$ - see front matter DIGOXIN TOXICITY WITH NORMAL DIGOXIN AND SERUM POTASSIUM LEVELS: BEWARE OF MAGNESIUM, THE HIDDEN MALEFACTOR Mamatha Punjee Raja Rao, MBBSPrashanth Panduranga, MRCP,† Kadhim Sulaiman, FRCPI,† and Mahmood Al-Jufaili, FRCPC *Department of Emergency Medicine and †Department of Cardiology, Royal Hospital, Muscat, Oman Reprint Address: Mamatha Punjee Raja Rao, MBBS, Department of Emergency Medicine, Royal Hospital, Post Box 1331, Muscat-111, Sultanate of Oman , Abstract—Background: In recent years, digoxin use has the Digitalis Investigation Group trial, the overall inci- been on the decline, with decreased incidence of digoxin tox- dence of digoxin toxicity was 2% over a 3-year period icity. Hence, digoxin toxicity, when it occurs, remains an elu- . Recently, the incidence of digoxin toxicity has been sive diagnosis to emergency physicians. Objective: To present decreasing due to less use of digoxin in heart failure pa- a case of digoxin toxicity with normal levels of digoxin and tients, and it remains an elusive diagnosis to emergency serum potassium, but with severe hypomagnesemia. Case physicians . We present a case of digoxin toxicity pre- Report: A 66-year-old woman presented with junctional senting with junctional tachycardia and ectopic atrial tachycardia and ectopic atrial tachycardia. She was knownto have congestive cardiac failure on diuretic therapy. Her se- tachycardia in an elderly patient with congestive cardiac rum digoxin level was within the normal range (2.4 nmol/L [normal = 1.9–2.6]) along with a normal serum potassiumlevel (3.9 mmol/L [normal = 3.5–5]). However, there was se- vere hypomagnesemia (0.39 mmol/L [normal = 0.65–1.25])precipitating A 66-year-old woman was referred from a health center sponded well to intravenous magnesium therapy. Conclusion: to the Emergency Department (ED) with a 1-day history This case reiterates that digoxin toxicity can occur in patients of abdominal discomfort, nausea, vomiting, and intermit- with normal digoxin and potassium levels, and in such pa- tent palpitations. Her past history was significant for tients, magnesium needs to be checked and treated to prevent diabetes, hypertension, severe left ventricular systolic potentially life-threatening dysrhythmias.
dysfunction, and congestive cardiac failure. She was be- ing treated for the last 6 months with anti-failure medica- , Keywords—digoxin toxicity; hypomagnesemia; hypoka- tions, and her current medications included furosemide lemia; dysrhythmia 40 mg twice daily, spironolactone 25 mg once daily, di-goxin 0.125 mg once daily, carvedilol 6.25 mg twicedaily, and lisinopril 10 mg once daily, along with metfor-min and calcium supplement.
At presentation, the patient was conscious and ori- ented with a blood pressure of 145/70 mm Hg, pulse Digoxin toxicity can be acute, due to overdose, or rate of 110 beats/min with no gallop, and a clear chest.
chronic, when taken for a prolonged period of time. In Her initial electrocardiogram (ECG) done in the referral RECEIVED: 22 January 2012; FINAL SUBMISSION RECEIVED: 17 September 2012;ACCEPTED: 22 November 2012

M. P. Raja Rao et al.
Figure 1. Twelve-lead electrocardiogram demonstrating a narrow QRS tachycardia with a heart rate of 130 beats/min with in-verted P waves falling on T waves (arrow), and upright P in aVR suggestive of a junctional tachycardia.
health center demonstrated narrow QRS tachycardia with = 1.9–2.6] using Abbott AxSYM analyzer; Abbott Labo- a heart rate of 130 beats/min with inverted P waves falling ratories, Abbott Park, IL). Her troponin T was negative, on T waves and upright P in aVR , arrowheads), serum potassium was 3.9 mmol/L (normal = 3.5–5), cre- suggestive of junctional tachycardia. An ECG done in our atinine was 91 mmol/L (normal = 45–90), calculated glo- ED demonstrated a narrow QRS tachycardia, peaked P merular filtration rate (GFR) was 54 mL/min/1.73 m2, waves with prolonged PR interval at 110 beats/min heart and brain natriuretic peptide was 2017 pg/mL (normal rate, and typical ECG signs of the ‘‘digoxin effect'' in the = 20–285). These results initially ruled out digoxin toxic- form of a scooped appearance of the asymmetric down- ity and suggested that the dysrhythmia may be due to un- sloping ST depression (‘‘reversed tick'' sign) ).
derlying cardiomyopathy. However, in view of the ECG This ECG was suspicious for an ectopic atrial tachycardia changes being highly suspicious for digoxin toxicity, with 1:1 conduction. In view of the patient taking digoxin, her magnesium and calcium levels were requested. The she was suspected to have digoxin toxicity, and her blood calcium level was normal, but the serum magnesium level was sent for routine blood tests along with digoxin levels.
was low at 0.39 mmol/L (normal = 0.65–1.25). She was All of the patient's blood investigations were reported as diagnosed to have digoxin toxicity precipitated by hypo- normal, including free digoxin level (2.4 nmol/L [normal Figure 2. Twelve-lead electrocardiogram (ECG) illustrating a narrow QRS tachycardia, peaked P waves with prolonged PR inter-val at 110 beats/min heart rate, and typical ECG signs of the ‘‘digoxin effect'' in the form of a scooped appearance of the asym-metric down-sloping ST depression (‘‘reversed tick'' sign; arrow). This ECG is suggestive of an ectopic atrial tachycardia with 1:1conduction.

Magnesium and Digoxin Toxicity The patient was admitted and was treated with intrave- Hypokalemia or hypomagnesemia sensitize the myo- nous magnesium sulfate 2 g in 100 mL saline over 60 cardium to digoxin even when digoxin levels are within min. The digoxin was discontinued. After 1 h of infusion, the normal range (Lanoxin product information; Aspen her rhythm changed to sinus with a heart rate of 70 beats/ Pharma, St. Leonards, NSW, Australia). Digoxin directly min and a prolonged PR interval ). The P wave inhibits sodium-potassium ATPase pump in the mem- morphology was different between the second ECG and brane of cardiac myocyte, causing an increase in intra- third ECG, suggesting that her second ECG showed ec- cellular sodium and calcium (through a sodium and topic atrial tachycardia. A further magnesium sulfate in- calcium exchanger) with subsequent increase in myocar- fusion of 5 g (approximately 40 mEq) in 500 mL saline dial contractility Hypokalemia increases digoxin was given for 24 h. Repeat serum magnesium at 6 h cardiac sensitivity because potassium and digoxin com- was 0.67 mmol/L. Her thyroid-stimulating hormone level pete for the same ATPase-binding site . This leads was normal. The patient was discharged after 72 h of ob- to a decrease in atrioventricular (AV) node conduction, servation, with no recurrence of any dysrhythmia. At dis- and an increase in automaticity (increased intracellular charge, digoxin level was 1.4 nmol/L and magnesium calcium) and ectopic pacemaker activity. In addition, level was 1.1 mmol/L.
there is an increase in vagal tone (inhibits sodium-potassium ATPase pump in vagal afferent fibers), caus- ing bradycardia and AV blocks. Magnesium is a cofactorof the sodium-potassium ATPase pump . Hypomagne- In a relatively recent study, digoxin toxicity was identi- semia increases myocardial digoxin uptake, further in- fied in 0.04% of all admissions . The incidence rate hibiting sodium-potassium ATPase pump activity for digoxin toxicity-related admissions was 48 per Hypomagnesemia is associated with hypokalemia in 100,000 prescriptions, which corresponds to 1.94 admis- 40–60% and hypocalcemia in 40% of toxicity cases sions for toxicity per 1000 treatment-years. Women had However, hypomagnesemia can produce intracellu- a 1.4-fold higher risk of intoxication than men. In patients lar potassium depletion in the presence of normal serum taking digoxin in recommended doses (0.125 to 0.25 mg potassium levels . It is known that long-term digoxin once daily), digoxin toxicity can occur when they are ex- users often have hypokalemia or hypomagnesemia, pre- posed to precipitating factors such as hypokalemia, hypo- sumably due to diuretic usage in patients with congestive magnesemia, or hypothyroidism, even though the serum heart failure .
digoxin level is within normal limits . In addition, Even though this patient had several risk factors for di- drug-to-drug interactions can increase digoxin level goxin toxicity, including elderly age, female gender, and (e.g., quinidine, verapamil, spironolactone, flecainide, a moderately reduced GFR, it was the diuretic-induced amiodarone, erythromycin, clarithromycin) and cause di- hypomagnesemia that precipitated digoxin-induced junc- goxin toxicity Furthermore, elderly age, female gen- tional and atrial tachycardia. This patient did not manifest der, low muscle mass, and reduced GFR can predispose to serum hypokalemia due to the co-administration of digoxin toxicity in patients taking a normal recommen- a potassium-sparing diuretic and angiotensin-converting enzyme inhibitor. However, it is possible that the Figure 3. Twelve-lead ECG post-magnesium sulfate infusion for digoxin-induced dysrhythmia demonstrating sinus rhythm witha heart rate of 70 beats/min and prolonged PR interval with ST depression suggestive of digoxin effect.
M. P. Raja Rao et al.
hypomagnesemia was associated with intracellular potas- sium depletion, leading to digoxin-related dysrhythmiasEnhanced automaticity and impaired conduction This case reiterates that digoxin toxicity can occur in pa- are the hallmarks of digitalis toxicity Digoxin can tients with normal digoxin and potassium levels, and in cause any type of dysrhythmia, but especially the follow- such patients, magnesium must be monitored and treated ing: frequent premature ventricular complexes; atrial fi- to prevent potentially life-threatening dysrhythmias.
brillation with slow, regular ventricular rate or completeAV block; non-paroxysmal junctional tachycardia; atrial tachycardia with block; and bidirectional ventriculartachycardia .
Normal levels of serum digoxin and the absence of hy- pokalemia (the most common precipitant of digoxin- induced dysrhythmias) initially led to the conclusion that the dysrhythmias may be due to underlying cardiomy- opathy. However, magnesium was found to be very low and magnesium replacement resulted in conversion to si- nus rhythm without the need for any anti-dysrhythmic agents. Management of digoxin toxicity involves with- drawal of the medication as well as administration of digoxin-specific Fab antibodies for life-threatening car- diovascular compromise . In addition, it is necessary to treat precipitating conditions such as replacement of electrolyte deficiencies. In the patient presented here, treatment of hypomagnesemia resulted in conversion of atrial tachycardia to sinus rhythm without the need for Fab antibodies. Magnesium therapy 9. Mercader MA, Bader Y. Internet diagnosis of digitalis toxicity. BMJ requires monitoring of serum levels and is contra- Case Rep 2009;pii: bcr09.2008.0918, doi: 10.1136/bcr.09.2008.
0918. Epub 2009 Apr 7.
indicated in patients with bradycardia or AV block, or severe renal failure.

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