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Management of digoxin toxicity

Matthew Pincus
Cardiologist SUMMARY
The Prince Charles Hospital
Brisbane Digoxin toxicity can emerge during long-term therapy as well as after an overdose. It can occur
even when the serum digoxin concentration is within the therapeutic range.
Key words Toxicity causes anorexia, nausea, vomiting and neurological symptoms. It can also trigger fatal
arrhythmia, digoxin, arrhythmias. There is a range of indications for using digoxin-specific antibody fragments. The
digoxin-specific antibody
fragments
amount ingested and serum digoxin concentration help to determine the dose required, but are
not essential.

Aust Prescr 2016;39:18–20 Digoxin-specific antibody fragments are safe and effective in severe toxicity. Monitoring should
http://dx.doi.org/10.18773/ continue after treatment because of the small risk of rebound toxicity.
austprescr.2016.006 Restarting therapy should take into account the indication for digoxin and any reasons why the
concentration became toxic.

Introduction digoxin concentration is inaccurate unless taken

Digoxin can be used to treat heart failure when at least six hours after the last dose. Only a post-
symptoms remain despite the use of other drugs. It is distribution measurement reflects the severity
also used for atrial fibrillation to reduce the ventricular of intoxication and this is the measurement that
rate.1 For heart failure, the recommended range for can help when calculating the dose of digoxin-
the serum digoxin concentration has been reduced specific antibody.9 This applies in both acute and
over the past decade from 0.8–2.0 nanogram/mL to chronic poisoning.
0.5–0.9 nanogram/mL.2 This is because of evidence
The elimination of digoxin is mainly by renal clearance
of better outcomes at lower concentrations.3 Whether
and is prolonged in patients with renal impairment.
this range should also apply to patients with atrial
Transport by P-glycoprotein also contributes to
fibrillation without heart failure is unknown.
elimination.8 Consequently, a higher serum digoxin
Incidence of toxicity concentration for a given dose occurs in patients
with renal impairment, lower body weight and in
Digoxin use has declined since the 1990s.4 While the
those taking amiodarone, verapamil, macrolides,
overall incidence of toxicity per population has also
azole antifungals and cyclosporin, which inhibit
declined, the incidence per treated patient may have
P-glycoprotein transport.10
remained unchanged.4,5 The Australian Institute of
Health and Welfare records cardiac glycoside toxicity Although the serum digoxin concentration does
as the diagnosis on hospital discharge in 280, 233 predict the likelihood of toxicity,8,11 several conditions
and 139 patients in 1993–94, 2003–04 and 2011–12 increase sensitivity to digoxin. They at least partly
respectively.6 Chronic toxicity is far more common account for patients who develop toxicity when
than acute intoxication.7 their serum digoxin concentration is within the
therapeutic range.11 These conditions include
Digoxin pharmacology hypokalaemia, hypomagnesaemia, hypercalcaemia,
Digoxin increases intracellular calcium in myocardial myocardial ischaemia, hypoxaemia and acid–base
cells indirectly, by inhibiting the sodium–potassium disturbances.10
pump in the cell membrane. Increased intracellular
calcium increases cardiac contractility, but also the Clinical features
risk of tachyarrhythmias.8 Inhibition of this pump The clinical features of toxicity are often non-
causes the hyperkalaemia commonly seen in toxicity. specific. They commonly include lethargy, confusion
Digoxin also causes an increase in vagal activity, and gastrointestinal symptoms (anorexia, nausea,
reducing activity in the sinus node and prolonging vomiting, diarrhoea and abdominal pain).10 Visual
conduction in the atrioventricular node. effects (blurred vision, colour disturbances, haloes
After a dose of digoxin, distribution to the tissues and scotomas) are rarer in contemporary practice.8
takes several hours. This means that the serum Cardiac arrhythmias account for most deaths.9

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Arrhythmias can occur even if the patient has no used. However, economic arguments have been made
symptoms. Almost any arrhythmia can occur, with for their use in non-life-threatening toxicity, as the
the exception of atrial tachyarrhythmias with a duration of hospitalisation may be reduced.17
rapid ventricular response,8 because these usually
Dose and administration
require intact conduction in the atrioventricular
node. Characteristic arrhythmias are those in which Only one formulation is available in Australia. Each
a tachyarrhythmia occurs simultaneously with sinus ampoule contains 40 mg of powdered digoxin-
or atrioventricular node suppression, such as atrial specific antibody and is reconstituted with 4 mL of
and junctional tachycardia with atrioventricular water. This can be given as a slow push in cardiac
block. However, sinus bradycardia, atrioventricular arrest, but otherwise the total dose is diluted further
block and ventricular ectopy are more common.12 with normal saline and infused over 30 minutes.
With severe toxicity, ventricular tachycardia (which The response begins about 20 minutes
may be bidirectional) and ventricular fibrillation can (range 0–60 min) after administration. A complete
occur. ‘Reverse tick’ T-wave inversion is not a sign response occurs in 90 minutes (range 30–360 min).14
of toxicity. Conventional dosing protocols aim to neutralise total
body digoxin completely. The total dose is usually
Treatment
expressed in vials. It depends on whether the post-
There are no evidence-based guidelines for the
distribution serum digoxin concentration is known, the
management of mild to moderate toxicity so there is a
amount ingested is known, or neither is known.15
wide variation in treatment.13 Severe toxicity requires
hospital admission and consideration of the need Known digoxin concentration
for digoxin-specific antibody fragments. Although If the post-distribution concentration is known
digoxin-specific antibody fragments are safe and (in either acute or chronic ingestion), knowing the
effective, randomised trials have not been performed. amount ingested is unnecessary. The dose is:
The antibody fragments form complexes with the number of vials = post-distribution serum digoxin
digoxin molecules. These complexes are then excreted concentration (nanogram/mL) x weight (kg)/100
in the urine. (multiply by 0.78 if SI units are used for post-
distribution serum digoxin concentration).
Indications for digoxin-specific antibody
fragments Known amount ingested
The indications for digoxin-specific antibody If the quantity of digoxin ingested is known, but
fragments are inconsistent. Four contemporary the post-distribution serum digoxin concentration is
sources1,9,14,15 recommend administration for strongly unknown, the dose is:
suspected or known digoxin toxicity with:
number of vials = amount ingested (mg) x 2 x 0.7
•• life-threatening arrhythmia (0.7 is the bioavailability of digoxin tablets supplied
•• cardiac arrest in Australia).
•• potassium >5.0 mmol/L (significant hyperkalaemia
Unknown data
is a strong indication for treatment because of
When neither the post-distribution serum digoxin
its association with a poor prognosis if digoxin-
concentration nor the amount ingested is known, use
specific antibody fragments are not given16).
empiric dosing. Repeat in 30 minutes if the response
However, the same sources vary in their
is inadequate. The dose is:
recommendations for administration when there is:
for adults and children greater than 20 kg
•• acute ingestion of >10 mg in adults or >4 mg
in children
•• five vials if haemodynamically stable

•• evidence of end-organ dysfunction

•• 10 vials if unstable
for children less than 20 kg
•• moderate to severe gastrointestinal symptoms
•• serum digoxin concentration >12 nanogram/mL
•• one vial.

•• significant clinical features of digoxin toxicity with Other regimens

serum digoxin concentration >1.6 nanogram/mL. Some authors have argued for modification of the
Such disagreements over when to use digoxin- calculated doses to be given as an initial half dose
specific antibody fragments arise from cost–benefit, followed by either further doses as required18 or an
not harm–benefit, considerations. The cost is roughly infusion.19 These suggestions follow from the view
$1000 per ampoule and several ampoules may be that full dosing is unnecessary to achieve tolerable

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 VOLUME 39 : NUMBER 1 : FEBRUARY 2016

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concentrations of digoxin and may be undesirable Lignocaine8 can be used for ventricular
in patients who need digoxin.18,20 There are also tachyarrhythmias and atropine15 for bradyarrhythmias.
concerns that significant amounts of digoxin-specific Cardioversion, which can result in ventricular
antibody fragments may be eliminated before full fibrillation, should be avoided.
removal of digoxin from tissue stores.19 Furthermore, In cardiac arrest, resuscitation efforts should be
in practice many hospitals will not stock sufficient continued for at least 30 minutes after giving digoxin-
ampoules for the full calculated dose. In this case specific antibody fragments.
specialist toxicological advice should be sought on the
adequacy of modified dosing. Restarting digoxin
When considering restarting digoxin, first determine
Precautions and adverse effects
whether the patient’s indication for use and target
Hypomagnesaemia and, more importantly, serum digoxin concentration were consistent with
hypokalaemia (common with diuretic use) should be current guidelines, as these have changed markedly
corrected before or during administration because over the past couple of decades. Digoxin can be
digoxin-specific antibody fragments will further resumed after adjusting the dose for changes in
lower potassium.14 Hypokalaemia occurs as a result of target serum digoxin concentration, renal function
treatment in about 4% of patients.21 Serum potassium and weight if necessary. This should be delayed until
should be frequently monitored.14 all the digoxin-specific antibody fragments have been
‘Rebound’ toxicity14 is the reappearance of toxicity cleared, which will take up to a week, but far longer in
after an initial response to digoxin-specific antibody the presence of renal dysfunction.18,22
fragments. This occurs in about 2% of patients given
a full neutralising dose.21 It can develop 12–24 hours Conclusion
after treatment, but up to 10 days later in patients
with renal failure.14 Serum digoxin concentration is of
Digoxin toxicity has declined, possibly as a result
no use in diagnosis, because it measures the digoxin
of a decreasing use and a reduced recommended
in the complexes with antibody fragments as well as
therapeutic range. It can occur when serum digoxin
unbound digoxin. The concentration therefore rises
concentration is within the therapeutic range and, as
many fold after digoxin-specific antibody fragments
the presenting features are usually non-specific, the
are given even in the absence of rebound toxicity.22
diagnosis can be difficult.
Heart failure or atrial fibrillation with rapid ventricular
Digoxin-specific antibody fragments are used when
response (presumed re-emergent due to removal
there is a risk of a life-threatening arrhythmia. The
of digoxin effect) occurs in up to 3% of patients.14
decision to use digoxin-specific antibody fragments
Allergic reactions occur in about 1% of infusions.21
is not dependent on knowledge of the serum digoxin
SELF-TEST Other treatments concentration or the amount of digoxin ingested, but
QUESTIONS when either of these is known they should be used
Other treatments for severe toxicity should be seen
True or false? to calculate the dose. Further research is needed into
as temporising or adjunct measures, rather than
5. Digoxin toxicity can optimal dosing protocols and whether digoxin-specific
alternatives to digoxin-specific antibody fragments.
occur when the serum antibody fragments can be cost-effectively used for
digoxin concentration Activated charcoal23 can be used in patients who
non-life-threatening toxicity.
is within the reference present within two hours of acute ingestion.
range. Dr Pincus has been an investigator in trials sponsored
Hyperkalaemia will improve with giving digoxin-
6. Concentrations of by Bristol-Myers Squibb, GlaxoSmithKline, AstraZeneca,
specific antibody fragments, and conventional
serum digoxin should Sanofi, Servier, Amgen and Janssen. He received financial
be measured within six treatments such as calcium will generally be
assistance for conference attendance from Eli Lilly, Bayer,
hours of a dose. unnecessary or harmful.15 If the patient has severe Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer.
Answers on page 27 hypokalaemia and digoxin toxicity, it is important to Digoxin and the only available digoxin-specific Fab
correct the serum potassium. (DigiFab) are not supplied by these companies.

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