Digoxin Toxicity

Reviewed and revised 11 July 2014

OVERVIEW

• Digoxin toxicity is characterised by gastrointestinal distress, hyperkalemia and life-threatening dysryhthmias, including increased automaticity and AV nodal blockade
• Digoxin has a narrow therapeutic index and chronic toxicity is more likely in the elderly and those with renal impairment
• Chronic digoxin toxicity varies in severity but is associated with a mortality at one week of 15-30% (!)
• Digoxin-specific Fab fragments (digibind) is the definitive treatment, toxicity is refractory standard dysrhythmia treatments
• there is often a reluctance to give the digibind antidote due to cost and underestimating the mortality associated with digoxin toxicity, however  it is prudent to administer digibind based on a considered risk assessment and before the life-threatening manifestations of digoxin toxicity develop
• digoxin levels cannot be accurately measured for about 3 weeks after administration of digibind, as they will be artefactually high given that most serum digoxin assays measure both free and digibind-bound digoxin in the circulation (some laboratories may be able to measure free digoxin levels specifically)
• supplies of digibind should be available on site in the emergency department, and in severe toxicities early steps to source more may be necessary

MECHANISM OF ACTION

Direct and indirect effects resulting in:

• increased inotropy (mild effect)
• increased automaticity
• negative dromotropy (slowing of AV conduction)
• increased vagal tone

DIRECT:
inhibition of Na/K ATPase on the cell surface
-> increased intracellular Na+ and increased extracellular K+
-> increased intracellular Ca2+ due to Na+/Ca2+ antiporter
-> calcium-mediated  inotropy and increased automaticity, as well as negative dromotropy due to decreased intracellular K+

INDIRECT EFFECT:
increased vagal tone (vagomimetic effect)

TOXICOKINETICS

• Absorption – good oral absorption with oral bioavailability of 80% and peak levels at 6 hours
• Distribution – 30% protein bound, Vd 10L/kg (higher in the elderly and obese)
• Metabolism – minimal hepatic metabolism
• Elimination – 60% renal, t ½ of 30-40 h, longer in renal failure

RISK ASSESSMENT

Acute toxicity is potentially lethal and digibind is indicated when:

•  cardiac arrest
• life-threatening dysrhythmia
• K >5mM
• >10mg ingested (adult), >4mg ingested (child)
• >15 nM level (>12ng/mL)

Chronic digoxin toxicity is diagnosed probabilistically on the basis of the serum digoxin level, the renal function and clinical features, as shown below:

CLINICAL FEATURES

Acute digoxin toxicity

• Time course: initial toxic effects of nausea and vomiting occur at 2-4 hours, peak serum levels at 6 hours and life-threatening cardiovascular complications  at 8-12h
• GI: anorexia, nausea, vomiting, diarrhoea, abdominal pain
• METABOLIC: hyperkalaemia (early sign of significant toxicity)
• CVS: enhanced automaticity (atrial tachycardia (e.g. flutter, AF) with AV block, VF, VT, ventricular ectopic beats), bradyarrhythmias (Conduction delays / blocks, slow or regularised AF), hypotension, shock
• CNS: lethargy, confusion

Chronic digoxin toxicity

• typically occurs  in the context of intercurrent illness, especially with impaired renal function
• clinical features are a combination of toxicity and the intercurrent illness
• symptoms may have an insidious onset over days to weeks
• features include those of acute digoxin toxicity as well as visual disturbances (e.g. reduced acuity, yellow halos (xanthopsia) and altered color perception (chromatopsia))

INVESTIGATIONS

Acute digoxin toxicity

• VBG for urgent K level
• UEC, glucose (especially renal function)
• Screening paracetamol level
• immediate digoxin level to confirm toxicity and guide therapy (repeat at 4-6 hours post-ingestion and q2h until digibind given or toxicity improves)
• ECG

Chronic digoxin toxicity

• Serum digoxin level –  a steady state level 6 or more hours after the last dose; levels can be misleading as levels near the therapeutic range (0.6-1.3 nmol/L) correlate poorly with severity of intoxication
• UEC, glucose
• ECG
• Investigations as indicated to assess for intercurrent illness

MANAGEMENT OF ACUTE DIGOXIN TOXICITY

Resuscitation

• Attend to life-threats resulting from dysrhythmias and hyperkalaemia
• Digoxin-induced cardiotoxicity is refractory to standard measures
• Bradyarrhythmias
  • digibind is the definitive treatment
  • atropine
  • adrenaline (but may aggravate cardiac irritability)
  • pacing (rarely effective)
• Tachyarrhythmias
  • digibind is the definitive treatment
  • MgSO₄ as an adjunctive measure
  • Lignocaine (unproven)
  • often refractory to cardioversion
• Hyperkalemia
  • Insulin and glucose, bicarbonate (salbutamol may aggravate automaticity)
  • Calcium is traditionally contra-indicated due to the risk of precipitating a ‘stone heart’ (this is a myth, see Calcium, Digoxin Toxicity and ‘Stone Heart’ Theory)

Supportive care and monitoring

• Cardiac monitoring must continue until reversal of toxicity

Decontamination

• Activated charcoal if presents <1h post-ingestion and not vomiting (unlikely to prevent severe toxicity in large ingestions)

Antidote

• Digibind is the definitive treatment (see here for indications)

MANAGEMENT OF CHRONIC DIGOXIN TOXICITY

Resuscitation

• as for acute digoxin toxicity

Supportive care and monitoring

• cardiac monitoring should be in place as for acute overdoses whilst the patient is being treated with digoxin immune fragments

Decontamination

• not indicated

Enhanced elimination

• renal replacement therapy may be indicated in the context of renal failure and hyperkalemia

Antidote

• note that the some of the indications for digibind differ (see here for indications)

Seek and treat underlying cause/ inter-current illness

DISPOSITION

Medical clearance at 6h if:

• Falling serial serum digoxin levels
• Normal serum K
• No GI symptoms
• No evidence of cardiotoxicity

or if digoxin-specific Fab given:

• Patients normal serum K
• no significant cardiac arrhythmia
• remains clinically well over the next 6h

Psychiatry assessment for suicide attempts

References and Links

LITFL CCC

• CCC – Digoxin
• ECG library – Digoxin Effect
• ECG library – Digoxin Toxicity

Journal articles and textbooks

• Antman EM, Wenger TL, Butler VP Jr, Haber E, Smith TW. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation. 1990 Jun;81(6):1744-52. PMID: 2188752. [Free Full Text]
• Ip D, Syed H, Cohen M. Digoxin specific antibody fragments (Digibind) in digoxin toxicity. BMJ. 2009 Sep 3;339:b2884. doi: 10.1136/bmj.b2884. PMID: 19729422. [Free Full Text]