-
REVIEW
D uttoEriaD iforniaMe
gestivents th
a resulmay b
ency cicity lerican
ure; To
Caco
trema
morbidity and mortality. The development of more ef-fective
cardiac drugs in the last half of the 20th centuryhas led to
diminiglycosides. The icreased, as hastrained physician
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: [email protected].
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
Original text: givenname
Original text: surname
Original text: givenname
Original text: surname
Original text: givenname
Original text: surname
-
tusure
rac
a dwikindisfuringmo
Heotobasis
adtivpaco
spiniaaftdono
no
eleplewiesc
ve
10
an
tia
entsrhyth.
. Sinusdegreeer ind*upwa
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
see
CANC
thougpresthan
er drumaco
d byage oonducity oular c
ody a
-
an
chatrwhhe3).addepefromi
co
38terpa
co
int4),hotro
sitiverows).
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.
-
wa
fac
DIDi20Wtiesev
an
tatlevchHologimshoincinhtiaintowi
me
priClwilef
forintwi
ymorpf 90 bythm,e undeositionws the
PR igoxin
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
plaproputioincthodia
an
wicre
celsulspoditheeffcen
thecesdiac -receptors.11,14
-
wilarplaren
taksivdigthe
incne
diurum
tiothaactstalidstrinme
livme
uriglymo
tox
toxdigma
hayeno
70
co
ve
tioto19tioplebigjunve
trigfiblarree
slotacitycicbraals
atrpeen
pacan
esc
imburigpa
traDidigass
tolno
sur
tobe
TaThM
Ectbo
De
De
Ect
AVescpacTri
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
-
aldsuc
gava
cidthaitywa
am
witheco
haex
co
(95
or
preofFaiedthiren
pawidigmo
tas
beingofinsan
hoformine
2 m
D
*m
tio
Do
Afcan
ex
hig
plefecan
atrthethaad
cre
depro19thodiepodigsus
ratwo
a gshoho
ofco
ren
0.2chbecre
shoat30dacre
ofrar
faico
theran
Reno
intsig
ov
ser
an
lifme
tordigca
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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Digitalis Toxicity: A Fading but Crucial Complication to
RecognizeCase PresentationDiscussionReferences