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CASE PRESENTA 73-year-old Afcal problems wascope associatedand dyspnea on expalpitations, chest pain, or paroxysmal nocturnal dyspnea.

The patients comorbidities included obesity, hyperten-sio

hiscre

164.1diagnosed with nonischemic cardiomyopathy by cardiaccatheterization a decade prior, with normal coronary arte-

on of 10%-ocardiogramproved lefttherapy. He, alcohol, or

goxin 0.125m extended-, furosemideironolactone

25 mg daily, amlodipine 10 mg twice a day, calcium acetate667 mg with meals, isosorbide dinitrate 10 mg 3 times daily,

electrocardiograms. A corrected QT interval was increasedat 529 ms. Premature ventricular complexes also were noted(Figure 1).

scr

Division of Cardiology, Department of Medicine, University of Californiaat Los Angeles, 100 UCLA Medical Plaza, Suite 630, Los Angeles, CA90095.

E-mail address: Datsunian@gmail.com.

0002-9343/$ -see front matter 2012 Elsevier Inc. All rights reserved.doi:10.1016/j.amjmed.2011.09.019n, diabetes mellitus, and dyslipidemia. He also had a hydralazine 10 mg 3 times daily, and subcutaneous insulin.He had been taking this regimen consistently for approxi-mately 2 years.

An electrocardiogram on admission demonstrated sinusrhythm, first-degree atrioventricular block with a PR inter-val of 236 ms, and a left bundle branch block pattern witha QRS width of 176 ms, which had been present on previous

Funding: None.Conflict of Interest: None.Authorship: All authors had a significant role in writing the manu-

ipt.Requests for reprints should be addressed to Eric H. Yang, MD,shed utilization, but not abandonment ofncidence of toxicity has subsequently de-the level of suspicion of more recentlys.

ATIONrican-American male with multiple medi-

admitted for recurrent episodes of syn-with coughing, and increasing weaknessertion at 10 feet. He denied any history of

riography and a left ventricular ejection fracti15% on ventriculography. A transthoracic echa year before admission demonstrated an imventricular ejection fraction of 50% on medicalhad no known allergies, and denied any tobaccoillicit drug use.

His outpatient regimen had consisted of dimg daily, carvedilol 25 mg twice a day, diltiazerelease 120 mg daily, simvastatin 20 mg daily40 mg twice a day, valsartan 160 mg daily, spigitalis Toxicity: A Fading bRecognize

c H. Yang, MD,a Sonia Shah, MD,b John M. Criley, MDb

ivision of Cardiology, Department of Medicine, University of Caldicine, Harbor-UCLA Medical Center, Torrance, Calif.

ABSTRACT

Digoxin usage has decreased in the treatment of conof its inferiority to beta-adrenergic inhibitors and agactivated renin-angiotensin-aldosterone system. Astoxicity has become an uncommon occurrence butfemale sex, low lean body mass, and renal insufficirisk for toxicity. Arrhythmias suggesting digoxin tox 2012 Elsevier Inc. All rights reserved. The AmKEYWORDS: Arrhythmia; Digitalis; Digoxin; Heart fail

rdiac glycosides have been used for the treatment ofngestive heart failure for over 2 centuries, and in theatment of arrhythmias for over 100 years, and were forny years a leading agent responsible for iatrogenicCrucial Complication

at Los Angeles; bDivision of Cardiology, Department of

e heart failure and atrial fibrillation as a resultat interfere with the deleterious effects of the

t of reduction of usage and dosage, glycosidee overlooked when it does occur. Older age,

ontribute to higher serum levels and enhanceded to its recognition in the case presented here.

Journal of Medicine (2012) 125, 337-343xicity

tory of chronic renal insufficiency with an admissionatinine of 3.78 mg/dL, or glomerular filtration rate of.8 mL/min/1.73 m2; the serum level ranged from 2.7 to

mg/dL for the past 2 years before admission. He was

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338 The American Journal of Medicine, Vol 125, No 4, April 2012The patient subsequently developed altered mental sta-, associated with hypercarbic hypoxemic respiratory fail-that required endotracheal intubation. A repeat transtho-

ic echocardiogram performed on hospital day #3 showedepressed left ventricular ejection fraction of 25%-30%,

th global left ventricular hypo-esis, but no significant valvarease. His clinical state wasther complicated by worsen-renal failure, necessitating he-

dialysis on hospital day #18.also required emergent trache-my due to traumatic self-extu-

tion, causing vocal cord paraly-and tracheal trauma.During this time, digoxin was

ministered along with his conges-e heart failure medications. Thetient had a prolonged hospitalurse due to renal failure and re-ratory issues, including pneumo-. On hospital day #32, 2 hourser receiving his daily digoxinse, the patient was noted to benresponsive, and bradycardia wasted on the telemetry monitor. Anctrocardiogram revealed com-te atrioventricular heart blockth a sinus rhythm of 90 beats per minute, and a fascicularape rhythm of 50 beats per minute with multiple premature

ntricular complexes (Figure 2). A repeat electrocardiogramminutes later demonstrated resolution of complete atrioven-

CLINICAL SIGNIFI

Digoxin toxicity, aloccurrence, may betients (women moreinsufficiency or othwith glycoside phar

Arrhythmias causesides include blockatrioventricular chanced automatictional, and ventric

Anti-digoxin antibindicated for patilife-threatening ardynamic instability

Figure 1 Electrocardiogram on admission3 ventricular premature complexes (*), first-236 ms), and left bundle branch block. Laddtion and premature ventricular complexes (

pauses.ular block with return of the left bundle branch blockttern and a prolonged PR interval of 276 ms. When seen by

cardiology consultation service, the patient was restingmfortably and denied any nausea, vomiting, vision changes,ing green or yellow, chest pain, or palpitations. On exam-

ination the patient was afebrile, witha heart rate of 83 beats per minute,blood pressure of 115/59 mm Hg,respiratory rate of 20 breaths perminute, and oxygen saturation of100% on tracheostomy collar. Hisjugular venous pressure was esti-mated at 10 cm H20. Auscultationrevealed regular rhythm with no mur-murs, rubs, or gallops. He had de-creased breath sounds in his posteriorlung bases. No peripheral edema waspresent.

Serum potassium was 3.9mmol/L, bicarbonate 24 mmol/L,and a digoxin level was 1.6 ng/mL,previously obtained approximately30 hours before the patients pre-sentation of heart block. Digoxinlevels were obtained 2 hours beforethe daily administration of digoxin.

Because of a high clinical suspi-cion for digoxin toxicity, digoxin

d atrioventricular nodal blocking agents (carvedilol and dil-zem) were discontinued.Approximately 3 hours after the return of sinus rhythm,

patient developed bradycardia, became unresponsive,

E

h an infrequentent in older pa-men) with renalgs that interferekinetics.

digitalis glyco-f sinoatrial andtion and en-f atrial, junc-ells.

dministration iswith refractory,mias and hemo-

rhythm rate 73 beats per minute, withatrioventricular block (PR interval of

icates delayed atrioventricular conduc-rd arrows) followed by compensatorythetricpatheco

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339Yang et al Digitalis Toxicityd progressed to pulseless electrical activity. Precordialest compressions were initiated while epinephrine andopine were administered. Ventricular fibrillation ensued,ich required 3 200-joules countershocks to convert to a

modynamically stable wide complex tachycardia (FigureIntravenous amiodarone and sodium bicarbonate were

ministered, but the patient was noted to develop third-gree atrioventricular block with sinus rhythm of 64 beatsr minute, and an escape rhythm suggestive of an originm the left posterior fascicle with a rate of 47 beats pernute. Because of mounting suspicion of digoxin toxicity,

Figure 2 Complete heart block. Sinus rhy50 beats per minute, with 3 premature ventrcomplexes exhibit a superior axis and are poin the left posterior fascicle (downward arfascicular pacemaker.

Figure 3 Rhythm after successful counterThere is a wide complex irregular tachycardi

not evident. The varying QRS morphology suggestsnfirmed by a 4.3-ng/mL serum digoxin level, 7 vials of-mg digoxin-specific antibody fragments were adminis-ed as an intravenous bolus. A temporary transvenouscemaker electrode was placed in the right ventricle.The patient gradually regained atrioventricular nodenduction with first-degree atrioventricular block (PRerval of 350 ms) with left bundle branch block (Figurewhich he maintained throughout the remainder of his

spitalization. The right ventricular pacemaker elec-de was removed 2 days later. The patient remainedurologically intact, with no further cardiac events and

te 87 beats per minute, ventricular rateomplexes (PVCs). The prevalent QRS

in lead V1, suggesting an escape focusThe PVCs (upward arrows) reset the

and return of spontaneous circulation.124 beats per minute. Atrial activity isne

shocka, ratethm, raicular ca polymorphic ventricular tachycardia.

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340 The American Journal of Medicine, Vol 125, No 4, April 2012s eventually discharged to a ventilator managementility.

SCUSSIONgitalis glycosides have been used extensively for over0 years, since British physician and botanist Williamithering first reported on the foxgloves medical proper-s in treating ascites, anasarca, and dropsy.1 Over the pasteral decades, digitalis administration has evolved fromantiquated practice of titrating doses until toxic manifes-ions arose, to a lower dosing regimen guided by serumels. Digoxin continues to play a role in treatment of

ronic systolic/diastolic heart failure and atrial fibrillation.wever, due to several landmark studies showing physio-ic and symptomatic improvement2-5 but no demonstrablepact on overall survival in heart failure,2 other agentswn to have significant morbidity and mortality benefits,luding beta-blockers, angiotensin-converting enzyme-Iibitors, and aldosterone antagonists, have been preferen-

lly employed. Estimates of digoxin usage in heart failurethe past decade have decreased from approximately 80%30%, with only 8% of patients being started on digoxinth symptoms of heart failure before discharge.6,7By current guidelines, digoxin is indicated for the treat-nt of Stage C heart failure (structural heart disease withor/current symptoms of heart failure). It currently holds aass IIa indication for pharmacologic treatment for patientsth current or prior symptoms of heart failure and reduced

Figure 4 Rhythm after resolution of polwide complex rhythm is seen with a rate oappears to be an accelerated ventricular rhallows a sinus beat to manifest showing thinterval of approximately 350 ms. Superimpon another QRS complex (blue box) shodownsloping of the T wave. The prolongedventricular complexes are consistent with dit ventricular ejection fraction to decrease hospitalizations carheart failure.8 Digoxin holds a Class I indication forravenous and oral use to control the heart rate in patientsth atrial fibrillation and heart failure. It also holds a Classindication to be used in conjunction with either a beta-cker or nondihydropyridine calcium channel antagonistcontrol the heart rate at rest and during exercise in atrialrillation.9Derived from Digitalis lanata, a species of the foxglovent, digoxin is an inhibitor of the intrinsic membranetein sodium-potassium adenosine triphosphate-ase

mp, resulting in elevated intracellular sodium concentra-n, a reduction in cytoplasmic potassium, and a resultantrease in calcium available to the contractile elementsught to be responsible for a modest increase in myocar-l contractility.At therapeutic levels, digitalis decreases automaticity

d increases the cellular membrane potential. However,th toxic concentrations, arrhythmias originate from in-ased cell excitability secondary to a decreased restinglular membrane potential. Increased automaticity can re-t from afterdepolarizations and aftercontractions due tontaneous cycles of Ca2 release and reuptake.10 In ad-

ion, digitalis has significant neurohormonal effects inart failure; it exerts sympatholytic activity by inhibitingerent sympathetic nerve activity, resulting in lower con-trations of epinephrine and renin.11-13 It also normalizesblunted baroreflex response that is responsible for ex-

sive sympathetic nerve activation and downregulation of

hic ventricular tachycardia. A regulareats per minute. Initially, the rhythmbut a premature ventricular complexrlying rhythm to be sinus, with a PRof the visible P and QRS morphologyconcealment of the P wave in the

nterval and the presence of prematuretoxicity.IIablotofib

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341Yang et al Digitalis ToxicityThe bioavailability of digoxin is approximately 66%,th a plasma half-life ranging from 20-50 hours. It has age volume of distribution of approximately 6 L/kg, withsma protein binding around 20%. In patients with normalal function, steady-state plateau concentrations usuallye 7-10 days (length of 4-5 half-lives). The drug is exten-ely distributed into fat, making dialysis ineffective initalis toxicity. In patients with end-stage renal disease,half life can be as long as 4-6 days.15,16

Concomitant metabolic disorders or medications also canrease digoxin concentrations. Hypokalemia, hypomag-

semia, and hypercalcemiawhich can be induced byretic usecan exacerbate digoxin toxicity at lower se-

levels by promoting sodium pump inhibition. In addi-n, multiple drug interactions can occur with digoxin uset can reduce its clearance in the renal system.7,9,10 Inter-ing drugs that are used in a variety of cardiac diseasetes, including amiodarone, verapamil, quinidine, macro-es, itraconazole, and cyclosporine, have been demon-ated in in vitro studies to inhibit P-glycoprotein transportrenal tubular cells.17-21 P-glycoprotein is a 170-kDambrane efflux transport protein that is located in theer, pancreas, kidney, colon, and jejunum. Its theoreticalchanism involves active transport of digoxin into thene, which leads to decreased clearance in the presence ofcoprotein inhibitors. If such drugs must be used, closenitoring and digoxin dosing should be reduced to avoidicity.Both cardiac and extra-cardiac symptoms of digoxinicity have been extensively described over the history ofoxin use. The more prominent features of extra-cardiacnifestations have involved visual disturbances, including

zy or blurring vision, flashing lights, halos, and green orllow patterns. Anorexia and nausea, vomiting, and othernspecific gastrointestinal symptoms can occur in 30%-% of patients with suspected digoxin toxicity.16Multiple arrhythmias have been documented due to the

mplex pharmacologic effects of digitalis toxicity, withntricular extrasystoles being a common manifesta-n.22,23 A mechanistic classification of arrhythmias relateddigitalis toxicity was devised by Fisch and Knoebel in8523 (Table). The most common arrhythmic manifesta-n of digoxin toxicity are premature ventricular com-xes, which can present multifocally or as ventriculareminy.24 Arrhythmias such as junctional tachycardia,ctional escape rhythm, parasystole, and bidirectional

ntricular tachycardia are more likely due to automatic focigered by digoxin. On the other hand, atrial flutter, atrial

rillation, premature ventricular complexes, and ventricu-tachycardia/flutter/fibrillation are most likely caused by antry mechanism (ie, macroreentry circuit conduction,w-fast pathway interactions). Bidirectional ventricularhycardia, a pathognomonic arrhythmia of digoxin toxic-, is characterized by alternating QRS complexes of fas-ular origin at regular intervals through the left bundlench fibers.25 Finally, sinus arrest and sinoatrial exit block

o have been reported. bloDigitalis is thought to have multifactorial effects on theioventricular node, by prolonging its effective refractoryriod and through partial vagal and antiadrenergic influ-ce.24 In many situations, both ectopy and depression ofcemakers and conduction, respectively, can overlap. This

cause inhibition at one level while triggering accelerated orape pacemaker rhythms at another level. Digoxin has min-al effect on conduction velocity in the atrium, ventricle, Hisndle, or bundle branches; thus, left bundle branch block,ht bundle branch block, or intraventricular conduction delaytterns are rarely due to digoxin toxicity.23The recommended target level of serum digoxin concen-tion of 1.0 ng/m is based on post hoc analyses of thegitalis Investigation Group (DIG) study, which found thatoxin at a serum concentration of 0.5-0.9 ng/mL wasociated with less mortality and rehospitalization in sys-ic and diastolic heart failure patients.26 It is important tote that the serum digoxin concentration should be mea-ed at least 6 hours after the last dose of digoxin in orderavoid overestimation of serum digoxin concentrations,

cause the drug will be in its distributive phase from the

ble Classification by Fisch and Knoebel23 of Arrhythmiasat Can Be Induced by Digitalis Toxicity, Categorized byechanism

opic rhythms due to reentry or enhanced automaticity, orthAtrial tachycardia with blockAtrial fibrillationAtrial flutterNonparoxysmal junctional tachycardiaVPCsVentricular tachycardiaVentricular flutter and fibrillationBidirectional ventricular tachycardiaParasystolic ventricular tachycardiaEctopic rhythms from multiple sites of specializedconducting tissuepression of pacemakerSinoatrial arrestpression of conductionSinoatrial blockAV blockExit blockopic rhythms with simultaneous depression of conductionAtrial tachycardia with high degree AV blockdissociation due to suppression of dominant pacemaker withape of subsidiary pacemaker or acceleration of a loweremaker, or dissociation with AV junctional rhythmggered automaticityAccelerated junctional impulses after premature ectopicimpulsesVentricular arrhythmias triggered by supraventriculartachycardiaJunctional tachycardia triggered by ventricular tachycardia

AV atrioventricular; VPC ventricular premature complex.od to extravascular tissues.16 Of note, drugs such as

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342 The American Journal of Medicine, Vol 125, No 4, April 2012osterone, potassium canrenoate, and herbal medicationsh as Chan Su, Siberian ginseng, Asian ginseng, ashwa-

ndha, and danshen have been documented to falsely ele-te serum digoxin levels.27Excluding toxicity due to intentional overdose from sui-al gestures, multiple studies have looked for risk factorst predispose patients towards developing digitalis toxic-. A subgroup post hoc study of the DIG study that digoxins associated with a significantly higher risk of deathong women (adjusted hazard ratio of 1.23) comparedth placebo.28 In a retrospective study of the DIG trial of

relationship of serum digoxin concentration and out-mes with women in heart failure, a level of 0.5-0.9 ng/mLd a beneficial effect of digoxin on morbidity and nocess in mortality. However, women with serum digoxinncentrations of 1.2 had a hazard ratio for death of 1.33% confidence interval, 1.001-1.76, P .049).29Elderly patients, or those with chronic renal insufficiencyend-stage renal disease, also are at increased risk, asviously discussed. An observational surveillance studypatients who received treatment with Digoxin Immuneb therapy noted that more than 60% of the patients stud-were men or women above the age of 70 years, with two

rds of these patients having moderate to severe impairedal function.30 A retrospective cohort of hemodialysis

tients on digoxin showed that digoxin use was associatedth a 28% increased risk for death. Increasing serumoxin concentrations were significantly associated withrtality, especially in patients with predialysis serum po-sium levels of 4.3 mEq/L.31The development of digoxin antibody Fab fragments has

en shown to be highly effective in treating life-threaten-signs of digoxin toxicity,30,32 especially in the presencerefractory, life-threatening arrhythmias, hemodynamictability, and hyperkalemia. The volume of distribution oftidigoxin Fab is 0.4 L/kg, with a half-life of about 12-20urs in patients with normal renal function. It is indicateddigoxin toxicity presenting with life-threatening arrhyth-

as or hyperkalemia. The amount of antidigoxin Fabeded in acute ingestion of digoxin can be determined by

ethods:16

ose (no. of vials) Total amount ingested (mg) 0.5*

g of digoxin bound per vial of FabThe second equation uses the serum digoxin concentra-n in determining the dose:

se (no. of vials)serum digoxin concentration (g/L) weight kg

100

ter administration, serum digoxin concentration levelsnot be used for accurate assessment due to the rapid

traction of digoxin from tissues into plasma. The resultant

h concentrations detected are from the Fab-digoxin com- anx. Because of the quick reversal of the physiologic ef-ts of digoxin, hypokalemia, exacerbation of heart failure,

d rapid ventricular response from previously controlledial fibrillation can occur. Hickey et al30 also reported thatrisk of rebound digoxin toxicity was 6-fold higher if lessn half of the calculated full neutralizing dose was

ministered.30The occurrence of digitalis toxicity has substantially de-ased over the past several decades, which is attributed to

creasing usage, decreased dose administration, and im-ved serum level monitoring. In a prospective study in

71, up to 23% of admitted patients on digoxin wereught to have toxic manifestations; 41% of these patientsd.33 The DIG trial, undertaken in the early 1990s, re-rted digoxin toxicity in 11.9% of patients receivingoxin, but also 7.9% of those receiving placebo by clinicalpicion; by factoring in the placebo rate as a false-positivee, the corrected actual incidence of digoxin toxicityuld be approximately 4%. More recently, an analysis ofroup of academic medical centers in the US in 1996wed an incidence of digoxin toxicity in 0.07% of all

spital admissions.34A suggested approach for administration and monitoringdigoxin in heart failure is to achieve a serum digoxin

ncentration of 0.7-1.1 ng/mL. In patients with normalal function (creatinine clearance 90), oral digoxin at5 mg daily can be started with a serum concentration

eck after 5 days (the serum digoxin concentration shouldchecked at least 6 hours after the last oral dose). With aatinine clearance of 60-89, daily oral digoxin 0.125 mguld be started with a serum digoxin concentration check5 days. Patients with a lower creatinine clearance of-59 should be started on digoxin 0.125 mg every othery, with a serum digoxin concentration check at 4 days. Aatinine clearance of30 should warrant extreme cautiondigoxin use.35 Intravenous administration of digoxin isely indicated and should never be used solely for heartlure treatment. Intravenous loading of digoxin can bensidered for ventricular rate control in atrial fibrillation in

absence of an accessory pathway,9 but caution is war-ted in the setting of a decreased glomerular filtration rate.peated measurements of serum digoxin concentration aret necessary unless the patients renal function changes, aneracting drug is started or discontinued, or if there arenificant weight changes.Although digoxin toxicity has significantly decreaseder the past several decades due to decreased usage,um monitoring, improved dose-determination methodsd drug interaction education and awareness, it is still ae-threatening condition that patients with the afore-ntioned risk factors can develop. Thus, careful moni-ing of digoxin administration, as well as recognition ofitalis-toxic arrhythmias and clinical manifestations,

n lead to effective treatment and decreases in morbidity

d mortality.

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Uses: with Practical Remarks on Dropsy and Other Diseases. London:CGJ and J Robinson, London; 1785.

2. The Digitalis Investigation Group. The effect of digoxin on mortalityand morbidity in patients with heart failure. N Engl J Med. 1997;336:525-533.

3. Uretsky BF, Young JB, Shahidi FE, et al. Randomized study assessingthe effect of digoxin withdrawal in patients with mild to moderatechronic congestive heart failure: results of the PROVED trial.PROVED Investigative Group. J Am Coll Cardiol. 1993;22(4):955-962.

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20. Wakasugi H, Yano I, Ito T, et al. Effect of clarithromycin on renalexcretion of digoxin: interaction with P-glycoprotein. Clin PharmacolTher. 1998;64:123-128.

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Digitalis Toxicity: A Fading but Crucial Complication to RecognizeCase PresentationDiscussionReferences