Digoxin poisoning

Acute digoxin poisoning manifests with vomiting, hyperkalaemia and brady-tachyarrhythmias potentially leading to death, whereas chronic digoxin toxicity is far more insidious, still with gastrointestinal symptoms but in addition bradycardia and automaticity on the ECG.

Toxic Mechanism:

Digoxin inhibits the membrane Na-K-ATPase pump, this results in an increase in intracellular sodium which in turn cause an increase in intracellular calcium (via the sodium and calcium exchanger) and an increase in extracellular potassium. As a result of the increased intracellular calcium there is enhanced automaticity and a positive inotropic effect. Digoxin also enhances the vagal tone leading to decreased sinoatrial and atrioventricular node conduction velocities. Digoxin can cause any number of arrhythmias either tachy or brady-arrhythmias, although the classic description is of automaticity.

Toxicokinetics: 

• Good oral absorption, bioavailability of 60-80% (important fact when we calculate the antidote)
• Peak levels at 6 hours
• Large volume of distribution 5-10L/kg – thus haemodialysis is not useful for removing the digoxin.
• Hepatic metabolism
• Predominant renal excretion.
• Elimination half-life is approximately 30-40 hours but can be prolonged in renal impairment.

Resuscitation:

• Cardiac arrest:
  • In imminent cardiac arrest, it is justified to give 5+5 vials of digoxin immune Fab. Otherwise, based on pharmacokinetic modelling and case series, it is recommended to give 80 mg bolus of digoxin immune Fab, repeated as required according to clinical parameters (ECG & HR) because the onset of clinical response is usually rapid.
  • Resuscitation attempts should continue for at least 30 minutes after the digoxin immune Fab is given and seek toxicology advice.
• Cardiac dysrhythmias:
  • If digoxin immune Fab is not immediately available:
    • Atrioventricular block: Given atropine 0.6mg IV bolus. Repeat to a maximum of 1.8 mg (20 micrograms/kg in children). Adrenaline can aggravate cardiac instability, pacing may work.
    • Ventricular tachydysrhythmias: Administer lignocaine 1 mg/kg (max 100 mg) IV over 2 minutes (unproven), cardioversion is often refractory.
• Hyperkalaemia:
  • Consider sodium bicarbonate 100 mEq IV bolus 1 mEq/kg in children)
  • Insulin (actrapid/novorapid) 10 units and 50ml 50% dextrose as an IV bolus (0.1 units/kg insulin and 2mL/kg 10% dextrose in children).
  • Salbutamol may aggravate cardiac instability.
  • A potassium >5.5 mmol/L in acute overdose predicts 100% mortality without digoxin immune Fab.

Calcium and the stone heart:

• The classic teaching is that if you give calcium to a patient with digoxin toxicity (because of the hyperkalaemia), you will kill them. The extra dose of calcium will cause the heart contract and then due to the super levels of calcium it will not relax, causing the stone heart.
• So where does this stem from……..there are five human case reports showing a temporal relationship between calcium administration and death in digoxin toxicity. These reports are from the 1930s and 1950s, the symptoms of digoxin toxicity are not reported and no digoxin levels were measured.
• But its okay, there were several animal models that also seemed to show an increase in mortality and morbidity after administration of calcium in digoxin toxicity. Well, not really, the animals were made severely hypercalcemic before they received digoxin (not what we see in digoxin toxic patients). Subsequent animal models failed to demonstrate adverse effects.
• Levine, M et al 2011 did a retrospective chart review including 161 patients. They looked for potentially fatal dysrhythmias within an hour of IV calcium administration. 22% of patients died who received calcium and 20% died who did not receive calcium. However, almost all of these patients had chronic digoxin toxicity.
• There is little evidence on acute digoxin toxic patients.
• Bottom Line: Patients with digoxin toxicity will often be hyperkalemic. The ECG will look scary and you will want to give calcium. In the undifferentiated hyperkalaemic patient giving calcium is required (you are not going to wait 1 hour to get the digoxin level back). However, if you know the patient has taken an acute overdose and this is the reason for the hyperkalaemia, giving more calcium is unnecessary as they are already intracellularly loaded with calcium, the treatment is digoxin immune Fab.
• See CCC stone heart and the poison review for a detailed discussion.

Risk Assessment

Other:

• Children: <75 microgram/kg is considered safe unless symptoms develop.
• Natural Sources: foxglove, lily of the valley, oleander, rhododendron. In these cases toxicity may occur sooner due to the preparations ingested and higher doses of digoxin immune Fab have been required. Seek toxicology advice.

Supportive Care

• IV fluids to replace gastrointestinal losses
• For chronic toxicity, patients are frequently taking calcium channel blockers and beta-blockers as well as digoxin. It can be difficult to know which drug is the culprit for the bradyarrhythmia therefore it is worth ceasing these medications and re-introducing as tolerated.
• If the patient has developed an acute kidney injury then the underlying cause requires investigation and treatment.
• In chronic toxicity, correct hypokalemia if present and discontinue digoxin.

Investigations

• Screening: 12 lead ECG (note a ‘Salvador Dali’ ST segment does not indicate toxicity), BSL, Paracetamol level
• Specific:
  • Digoxin levels, confirm poisoning and provide treatment levels. Acute: perform at 4 hours post-ingestion and then every 4 hours until definitive treatment or toxicity has resolved. Chronic: perform levels 6+ hours post last dose to monitor steady state level. If digoxin immune Fab is given, subsequent blood tests will show a higher total digoxin concentration (free and bound) due to re-distribution of digoxin from the tissue.
  • EUC, to asses hyperkalaemia and renal function
  • ECG monitoring to asses for cardiotoxicity

Decontamination:

• 50 g of activated charcoal can be given within 2 hours of overdose if the patient is cooperative and not vomiting. It is worth adding an antiemetic to assist the administration of activated charcoal
• Paediatric dose 1g/kg.

Enhanced Elimination

• Not clinically useful.
• The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup reviewed the literature and found no evidence than extracorporeal treatments would improve clinical outcome regardless of the availability of digoxin immune Fab.

Antidote

• Digoxin immune Fab

Disposition

• Patients with falling serial serum digoxin levels, normal serum potassium and renal function, no gastrointestinal symptoms and no evidence of cardiotoxicity at 6 hours are medically cleared.
• Patients given digoxin immune Fab, have normal serum potassium and stable renal function, no gastrointestinal symptoms, no cardiotoxicity and remain well over 24 hours are medically cleared.
• Those patients with chronic toxicity usually require hospital admission for their intercurrent illness.

References and Additional Resources:

Additional Resources:

• CCC – Digoxin Toxicity
• ECG Library – Digoxin effect ECG
• ECG Library – Digoxin toxicity ECGs

References:

• Abad-Santos F, Carca AJ, Ibanez C et al. Digoxin level and clinical manifestations as determinants in the diagnosis of digoxin toxicity. Therapeutic Drug Monitoring 2000; 22(2):163-168.
• Antman EM, Wenger TL, Butler VP et al.  Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: final report of a multicenter study.  Circulation 1990; 81(6):1744-1752.
• Bateman DN.  Digoxin-specific antibody fragments: how much and when?  Toxicological Reviews 2004: 23(3):135-143.
• De Silva HA, Fonseka MM, Pathmeswaran A, et al.  Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial.  Lancet 2003; 361:1935-1938.
• DiDomenico RJ, Walton SM, Sanoski CA et al. Analysis of the use of digoxin immune fab for the treatment of non-life-threatening digoxin toxicity. Journal of Cardiovascular Pharmacology and Therapeutics 2000; 5(2):77-85.
• Eddleston M, Rajapakse S, Rajakanthan et al.  Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial.  Lancet 2000;355(9208):967-972.
• Lapostelle F, Borron SW, Verdier C et al.  Digoxin-specifc Fab fragments in single first-line therapy in digitalis poisoning.  Critical Care Medicine 2008; 36:3014-3018.
• Marik PE, Fromm L. A case series of hospitalised patients with elevated digoxin levels. American Journal of Medicine 1998; 105(2):110-115.
• Mowry JB et al. Extracorporeal treatment for digoxin poisoning: systematic review and recommendations from the EXTRIP Workgroup. 2016; 54(2):103-114
• Murray L et al. Toxicology Handbook 3rd Edition. Elsevier Australia 2015. ISBN 9780729542241
• Woolf AD, Wenger T, Smith TW et al.  The use of digoxin-specific Fab fragments for severe digitalis intoxication in children.  New England Journal of Medicine 1992; 326:1739-1744.