Cardiovasc Toxicol (2012) 12:363–368
DOI 10.1007/s12012-012-9171-1
Recrudescent Digoxin Toxicity Treated with Plasma Exchange:
A Case Report and Review of Literature
Saurabh Rajpal • Jagan Beedupalli •
Pratap Reddy
Published online: 23 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A 53-year-old woman presented with digitalis
toxicity caused by acute overdose that manifested as atrial
tachycardia with block, sinus pauses, and competing AV
junctional rhythm with atrial fibrillation. Patient admitted to
overdosing with digoxin 15–20 h before presentation with
intent to commit suicide. Serum digoxin level was 35.6 ng/ml
and renal function was normal. Patient was treated with
1,040 mg of digoxin-specific antibody Fab fragment with
prompt resolution of arrhythmias and restoration of sinus
rhythm. Four hours after digoxin antibody administration,
serum digoxin level declined to 0.2 ng/ml. Eighteen hours
after treatment with Fab fragment, patient developed pre-
mature ventricular complexes, atrial tachycardia with and
without atrioventricular block, and non-sustained ventricular
tachycardia followed by ventricular fibrillation from which
she was successfully resuscitated. Electrocardiogram showed
no evidence of acute myocardial infarction, and emergent
coronary angiogram did not reveal significant coronary artery
disease. Repeat digoxin level was 20.4 ng/ml. A diagnosis of
recrudescent digoxin toxicity was made and the patient was
treated with one session of plasma exchange with resolution
of arrhythmias. Immediately after plasma exchange, digoxin
level decreased to 10.4 ng/ml, and after 10 h, the level further
decreased to 6.6 ng/ml. The following day, digoxin level had
decreased to 2.9 ng/ml. Our experience with this case would
suggest that plasma exchange should be considered as a
treatment modality for recrudescent digoxin toxicity.
S. Rajpal (&)
Department of Medicine, Louisiana State University Health
Sciences Center, 1501 Kings Hwy, Shreveport, LA 71105, USA
e-mail: rajpalsrbh@gmail.com
J. Beedupalli
P. Reddy
Division of Cardiology, Louisiana State University Health
Sciences Center, Shreveport, LA 71103, USA
Keywords Recrudescent digoxin toxicity

Plasma exchange
Digoxin antibody
Arrythmias
Background
Digitalis toxicity is reported to occur in 1.1 % of outpa-
tients and 10–18 % of nursing home patients on digoxin
therapy with a reported mortality rate ranging from 3 to
50 % depending on the severity of overdose [1]. Digoxin-
specific antibody Fab fragments have long been the
definitive treatment for severe digitalis toxicity [2–5].
Recrudescence of digitalis toxicity after digoxin-specific
antibody administration is known to occur and is a feared
complication in patients with very high digoxin levels
[6, 7]. Plasma exchange has been proposed for treatment of
recurrent digitalis toxicity [8–10]. However, plasma
exchange is not considered standard of care because of lack
of large studies that demonstrate its effectiveness. To our
knowledge, there are only three reported cases in the lit-
erature of recrudescence of digoxin toxicity that were
treated with plasma exchange [8–10]. In all three cases,
renal failure was present and was felt to be the reason for
recrudescence of toxicity. In this report, we present a case
with normal renal function and digoxin toxicity treated
with digoxin antibody Fab fragment that was complicated
by recrudescence and subsequently treated successfully
with plasma exchange.
Case Report
A 53-year-old African-American woman with hyperten-
sion, seizure disorder, tobacco and alcohol abuse, chronic
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obstructive pulmonary disease, and paroxysmal atrial
fibrillation presented with complaints of worsening short-
ness of breath, chest tightness, and diffuse abdominal pain
with nausea and occasional vomiting of 3 days duration.
She gave a history of consuming 6 beers along with nearly
a pint of whiskey the day prior to presentation. Her home
medications list included sustained release nifedipine
60 mg a day, digoxin 0.25 mg a day, propafenone 150 mg
3 times a day, hydrochlorthiazide 25 mg a day, rosuvast-
atin 20 mg a day, phenytoin 100 mg 3 times a day, and
albuterol inhaler on a PRN basis.
On physical examination, the patient was drowsy and
smelled of alcohol. BP was 138/60, HR was 50/min, and
oxygen saturation was 94 % on 2 l of O2. Cardiac exami-
nation revealed an apical impulse that was displaced laterally
with normal first and second heart sounds and no S3 or S4.
There was a 2/6 holosystolic murmur at the apex radiating to
axilla. Examination of lungs revealed decreased air entry
over the right base with mild diffuse expiratory wheezes.
Abdominal and extremities examination was unremarkable.
Neurological examination revealed decreased mental status
with no focal neurologic deficit.
Electrocardiogram (ECG) at presentation revealed atrial
tachycardia with 2:1 AV conduction and marked ST
depression (Fig. 1). Also noted were sinus pauses of up to
3.8 s in duration. Two hours later, a repeat ECG showed
atrial fibrillation with competing junctional rhythm
(Fig. 2). An echocardiogram showed normal left
Fig. 1 Atrial tachycardia with diminutive P waves (arrows) at a rate of 114 beats/min with 2:1 atrioventricular conduction for the most part.
Also, ST depression typical of digitalis effect is seen
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Cardiovasc Toxicol (2012) 12:363–368
ventricular wall motion with an ejection fraction of 60 %,
mild mitral and tricuspid regurgitation and normal right
ventricular function. Her laboratory data (see Table 1)
revealed a blood alcohol level of 187 mg/dl, serum sodium
of 138 mmol/l, potassium of 5.1 mmol/l, and magnesium
of 3.0 mmol/l, BUN of 12 mg/dl, and creatinine of 0.4 mg/
dl. She had a WBC count of 7.04 thousands. Troponin level
was 1.6 ng/ml. Urine drug screen was positive for benzo-
diazepines. Arterial blood gas showed compensated respi-
ratory acidosis with normal PO2. Chest X-ray revealed a
right lower lobe infiltrate. Serum digoxin level measured
between 21 and 26 h after the ingestion of overdose was
35.6 ng/ml. She was admitted to the medical intensive care
unit (MICU). Cardiac monitoring showed AV junctional
tachycardia and runs of non-sustained ventricular tachy-
cardia. Eight hours after patients’ presentation to the
emergency room, she was given 26 vials (1,040 mg) of
digoxin-specific antibody Fab fragment. The dose of Fab
fragment was calculated on the basis of serum concentra-
tion of digoxin [11]. The arrhythmias were promptly
reversed with restoration of normal sinus rhythm with
occasional ventricular and supraventricular premature
complexes. Four hours after digoxin antibody administra-
tion, serum digoxin level declined to 0.2 ng/ml. Eighteen
hours after digoxin Fab administration, the patient started
having arrhythmias again. Telemetry monitor showed atrial
tachycardia with aberrant conduction and intermittent 2:1
AV conduction (Fig. 3). There also were runs of non-
Cardiovasc Toxicol (2012) 12:363–368 365

Fig. 2 Atrial fibrillation with

competing AV junctional
rhythm. ST depression typical
of digitalis effect is also seen

Table 1 Laboratory Data

Lab value At After digoxin After digoxin After
presentation Fab fragment Fab fragment plasmapheresis
administration (2 h) administration (18 h) (48 h)

Sodium (mmol/l) 138 136 139 140

Potassium (mmol/l) 5.1 4.9 3.5 3.9
Calcium (corrected) 8.5 9.0 8.5 8.4
(mg/dl)
Creatinine (mg/dl) 0.9 1.0 1.1 1.0
Magnesium 3.0 3.5 2.6 2.9
Digoxin level (ng/ml) 35.6 0.2 20.4 2.9
Blood alcohol (mg/dl) 187

sustained ventricular tachycardia followed by ventricular Discussion

fibrillation from which she was successfully resuscitated.
Digoxin level at this time was 20.4 ng/ml.
The patient was started on lidocaine drip. She underwent
emergent coronary angiography which showed normal
coronaries except for a 40 % lesion in distal LAD coronary
artery. Recrudescent digoxin toxicity was diagnosed, and it
was decided to give her one 4-h session of plasma exchange
which was initiated 3 h after cardiac arrest episode. At the
end of plasma exchange session, patient’s digoxin level
decreased from 20.4 to 10.5 ng/ml, and after 10 h, the level
further decreased to 6.6 ng/ml. The following day, the level
had dropped to 2.9 ng/ml followed by its normalization
within 48 h of plasma exchange. During this time, her
ECGs showed sinus rhythm with first-degree AV block and
isolated PVCs. She was subsequently extubated and trans-
ferred from the intensive care unit to telemetry unit. The
patient later confessed to overdosing herself with digoxin
15–20 h before her presentation to the hospital with suicidal
intent. Patient said she took ‘‘all the pills left in her digoxin
pill bottle’’. One month before presentation to the hospital,
she had the digoxin prescription filled for a 3-month supply.
Assuming she was taking only the prescribed dose of
0.25 mg (one table) a day as she claimed, there would have
been 60 tablets (15 mg) left in the bottle. The patient was
discharged home in a stable condition after a 2-week
inpatient psychiatric counseling and treatment.
The case described here is an acute overdose in a patient
who was on chronic therapy and unique in that digoxin
level quickly declined after digoxin antibody Fab fragment
administration with prompt resolution of arrhythmias fol-
lowed by rebounding of digoxin level. Rebound in digoxin
level was simultaneous with occurrence of atrial and ven-
tricular tachycardia and ventricular fibrillation which
responded well to treatment with plasma exchange.
After the administration of Fab fragment, the patient’s
arrhythmias resolved within minutes with restoration of
sinus rhythm. This dramatic effect is due to Fab fragment’s
high affinity for digoxin, quickly removing the drug from
its pharmacologically active binding sites within the tissue
and sequestering it in the extracellular fluid [1–4]. How-
ever, our patient had a recrudescence of digoxin toxicity
manifested as high serum level and arrhythmias typical of
digoxin toxicity 18 h after treatment. This was due to the
bimodal elimination pharmacokinetics of digoxin which
decreases rapidly after Fab fragment administration due to
sequestration and then increases or rebounds. The rebound
in free digoxin peaks approximately 3–24 h after digoxin
antibody administration in patients with normal renal
function (may occur after as long as several days in patients
with renal failure) and then declines more slowly depend-
ing on the rate of elimination of Fab fragment by renal and

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Fig. 3 Record from 18 h after treatment with digitalis antibody.
Recurrence of atrial tachycardia at the same rate (114 bpm) as before,
now with intermittent aberrant conduction (beginning of the record),
non-renal routes [6, 7]. This is due to the different elimi-
nation half-lives of digoxin and digoxin antibody which are
30 and 20 h, respectively [6, 7]. Our patient had normal
renal function and digoxin levels rebounded 18 h after the
administration of digoxin antibody.
Treatment of digitalis toxicity with digoxin antibody is
generally well tolerated and effective. However, 10–20 %
of patients do not respond to treatment, and recrudescent
toxicity is reported to occur in 3 % of patients [2, 6, 12]. In
an observational study by Hickey et al. [12], the single
most important factor associated with recrudescent toxicity
was treatment with an inadequate dose of digoxin antibody.
The reasons for development of recrudescent digoxin
toxicity in our patient are unclear. Possible explanations
include continued overdosing of digoxin after admission to
the hospital, delayed and continued absorption of any
digoxin left in the stomach after treatment with Fab frag-
ment, and inadequate dose of Fab fragment in the presence of
high digoxin levels. The first explanation is very unlikely
because the patient was in the MICU under close observation
and strict, monitored visiting hours. Also, the patient had no
medicines with her. The second explanation, though possible
since gastric lavage was not performed, is unlikely because
of the long interval between ingestion of drug and appear-
ance of recrudescent toxicity. The third possibility is also
unlikely because the administered dose of digoxin Fab
fragment calculated on the basis of serum drug level or the
total dose ingested should have been adequate [12]. A more
likely explanation is that much of digoxin antibody may have
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Cardiovasc Toxicol (2012) 12:363–368
2:1 AV conduction (arrows) and 1:1 AV conduction with normal
intraventricular conduction
cleared before all or enough of digoxin had rediffused from
the tissue for binding raising free digoxin level [13–15].
Reappearance of free digoxin is known to occur within 12 h
of administration of Fab therapy [6, 7, 15]. This explanation
is, however, speculative in the absence of free digoxin level.
It is generally accepted that measurement of total
digoxin level after treatment with digoxin antibody pro-
vides a falsely elevated value and that free digoxin levels
are essential in monitoring the progress of therapy [16, 17].
There is, however, at least one study using chemilumi-
nescent assay that reported falsely lowered concentration
of total digoxin level after administration of digoxin anti-
body [18]. We did not measure free digoxin levels in our
patient because at our institution it takes 5 business days to
get the results by which time it was unlikely to be of any
clinical relevance. We recognize the limitation of total
digoxin level in diagnosing recrudescent toxicity and that
free digoxin level measurement would have strengthened
our report. However, in our view, occurrence of arrhyth-
mias typical of digoxin toxicity simultaneous with a very
significant rebound in total digoxin level was unmistakable
and convincing evidence for recrudescent toxicity.
Because recrudescent digoxin toxicity is rare following
treatment with Fab fragment and often occurs in patients
with renal failure, a standard treatment has not been
developed. In cases where recrudescence was thought to be
due to inadequate dosing of Fab fragment, it was treated
with readministration of Fab fragment [13–15]. Eyer et al.
[15] proposed a modified dosing schedule with a smaller
Cardiovasc Toxicol (2012) 12:363–368
initial dose followed by continuous infusion of Fab frag-
ment over several hours to prevent recrudescence that may
be caused by rediffusion of digoxin from the tissues for
binding after much of Fab fragment had cleared. A third
modality proposed for treatment of recrudescence digoxin
toxicity is the use of extracorporeal techniques such as
plasma exchange, plasmapheresis and hemofiltration.
In one case reported by Robetoy et al. [8], a patient with
myeloma kidney disease and digoxin toxicity was success-
fully treated with administration of Fab fragment and two
treatments of plasmapheresis exchange that were given 17 h
apart starting 42 h after Fab fragment administration.
Additional treatments of plasmapheresis were given over the
following week with a decline in digoxin level to 0.5 ng/ml.
A second case report of digoxin toxicity with complete heart
block and a serum digoxin level of 21 ng/ml was success-
fully treated with digoxin antibody and plasma exchange that
was initiated 26 h after Fab fragment administration [9]. The
patient responded with resolution of complete heart block. In
the third case report, a patient with digoxin toxicity and acute
renal failure was successfully treated with plasma exchange
in combination with digoxin antibody [10]. Though often
used interchangeably, plasmapheresis and plasma exchange
differ significantly. Plasmapheresis is a two-step process in
which blood is initially separated into cells and plasma using
centrifugation pump and the separated plasma is then
allowed to flow along columns containing different adsor-
bents for the selective removal of certain molecules. The
processed plasma is reinfused back to the patient. In contrast,
plasma exchange is a single-step process in which blood is
similarly separated into plasma and cells and the cells are
returned back to the patient while the plasma is replaced with
either donor plasma or albumin [9, 19, 20]. Hemofiltration on
the other hand uses a semipermeable membrane and a
pressure gradient to remove low- and middle-molecular
weight substances [9, 19, 20].
Plasma exchange and plasmapheresis though effective
as adjunctive treatments only remove a small amount of
digoxin. However, even the small amount that is removed
can be significant because it represents the amount of drug
that is in reversible binding with the cellular receptor and
hence responsible for signs and symptoms of toxicity. The
continuous reduction in free digoxin concentration by
plasma exchange results in progressive removal of drug
from receptor sites as the drug–receptor equilibrium is
displaced in the direction of dissociation.
Conclusion
Recrudescent digoxin toxicity should be anticipated in
patients presenting with very high serum digoxin levels
even in patients with normal renal function. Repeat dosing
367
of Fab fragment or use of extracorporeal techniques such as
plasma exchange or both should be considered for
treatment.
Although the case reported here showed the usefulness
of plasma exchange in treating recrudescent digitalis tox-
icity, use of this modality for routine treatment will have to
await future large-scale clinical trials demonstrating the
effectiveness of plasma exchange. Recent advances in
extracorporeal techniques such as internal hemodiafiltra-
tion, double high flux hemodiafiltration, convection tech-
nology, high flux, high-efficiency membranes, and albumin
dialysis using the molecular adsorbent recirculating sys-
tems (MARS) leading to better removal of protein bound
molecules make a good case for such a large-scale study
[19, 21, 22].
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