- both acute and chronic digoxin toxicity are potentially life-threatening # Pharmacology ### Pharmacokinetics - moderately well absorbed following oral administration - bioavailability 50-80% - initial Vd - small -> redistributed to skeletal muscle -> large Vd 7L/kg - narrow therapeutic index - excreted unchanged by kidney - half-life 36 hours - drug interaction - level increased by - amiodarone - flecainide - verapamil - quinidine - spironolactone - erythromycin - tetracycline ### Pathophysiology - inhibits Na-K ATPase -> intracellular K falls, Na rises - high intracellular Na -> low gradient for Na/Ca exchanger -> accumulation of intracellular Ca - this leads to - weak +ive inotropy - increased vagal tone - AVN blockade (increased refractoriness) - decreased conduction velocity - increased myocardial automaticity (mainly Purkinje fibres) # Clinical features - virtually all types of arrhythmia have been reported in the context of digoxin toxicity ### Acute toxicity - usually intentional - non-cardiac manifestation - nausea, vomiting (early; can be the presenting complaint) - hyperkalaemia - cardiac manifestation - sinus bradycardia - SA node dysfunction - increased ventricular ectopy - varying degree of heart blocks (1st, 2nd, 3rd) - VT/VF - the progressive worsening of conduction usually occurs over a period of hours ### Chronic toxicity - commonly seen in elderly - maybe precipitated by therapeutic errors, intercurrent illness causing impaired renal function or by drug interactions (quinidine, CCBs, amiodarone, ==indomethacin==) - non-cardiac manifestation - nausea, vomiting (can be the presenting complaint)' - neurological manifestations (characteristic of chronic toxicity) - visual disturbances - yellow vision (Van Gogh) - weakness and fatigue - serum potassium - ==hyperkalaemia seldom occurs in chronic toxicity unless in acute renal failure== - instead these patients can be hypokalaemic and myomagnesemic due to concurrent diuretics usage - both of these can worsen digoxin toxicity - cardiac manifestation - sinus bradycardia - AF with slowed ventricular response - junctional escape rhythm - atrial tachycardia with block - VT/VF - death usually caused by pump failure, renal failure, severe cardiac conduction impairment or ventricular arrhythmia that is caused by underlying cardiac disease rather than from chronic digoxin toxicity # Management ### R — Resuscitation - Usual A, B, C - In a cardiac arrest situation, conventional ALS measures are futile - ALS is initiated until 20 vials of DigiFab are administered - CPR should commence for at least 30 mins following administration - In chronic toxicity with cardiac arrest — use 5 vials - If no DigiFab available, then temporising measures such as treatment of hyperkalaemia should be commenced - Hyperkalaemia - Sodium bicarbonate 100 mEq IV bolus (1 mEq/kg in children) - Actrapid10 units in 50 ml 50% glucose as a bolus (0.1 unit/kg insulin and 2 ml/kg 10% glucose in children) - NB: calcium previously taught as contraindicated — this has been disproven; **give calcium for hyperkalaemia** (updated on eTG) - AV block - Atropine 0.6 mg IV bolus, repeat until desired effect, max 1.8 mg (20 mcg/kg/dose in children) - Ventricular tachydysrhythmias - Lignocaine 1 mg/kg (max 100 mg) IV over 2 mins ### R — Risk assessment - Acute ingestion >10× daily dose - Potentially lethal dose (indication for Fab) - ==\>10 mg (adult), 4 mg (child)== - ==Serum digoxin level >15 nmol/L (12 ng/mL) at any time== - Serum potassium >5.5 mmol/L - NB: potentially lethal natural cardiac glycoside intoxication can occur following ingestion of certain plants/plant parts/toad-skins - Children: ingestion up to 75 mcg/kg is safe and does not require observation or treatment unless symptomatic - Chronic digoxin toxicity has a mortality rate of 15–30% within 7 days if not treated ### S — Supportive care - IV fluids / correct hypovolaemia - Treatment of hyperkalaemia, hypokalaemia, or hypomagnesaemia - Observation may be the only treatment required - Treatment of underlying cause in chronic toxicity ### I — Investigations - Serial ECGs / cardiac monitoring - [Digoxin effect](https://litfl.com/digoxin-effect-ecg-library/) - Downsloping ST depression with a characteristic "reverse tick" or "Salvador Dali sagging" appearance - Flattened, inverted, or biphasic T waves - Shortened QT interval - [Digoxin toxicity](https://litfl.com/digoxin-toxicity-ecg-library/) - Supraventricular tachycardia (due to increased automaticity) - Slow ventricular response (due to decreased AV conduction) - Serum electrolytes - Renal function - Serum digoxin level (4 hours, then 2-hourly until definitive treatment or levels improving) - therapeutic (0.6-1.0 nmol/L) - early concentrations greater than 15 nmol/L -> serious poisoning - unreliable once digibind given - Paracetamol level ### D — Decontamination - Oral activated charcoal 1 g/kg up to 50 g in the first hour if cooperative and not an airway threat - Not indicated in chronic toxicity ### E — Enhanced elimination - Not clinically useful ### A — Antidotes - DigiFab — dose depends on severity - Acute, cardiac arrest: 20 vials - Chronic, cardiac arrest: 5 vials - Chronic ingestion where indicated: 1–2 vials usually enough to reverse all features within 12 hours - DigiFab indications - Cardiac arrest - Life-threatening cardiac dysrhythmia - Ingested dose >10 mg (adult) / >4 mg (child) - Serum digoxin level >15 nmol/L (12 ng/mL) - Serum potassium >5.5 mmol/L - Dose 1–2 vials in 24–48 hours (previously given as a comparative dose to ingested dose); if cardiac arrest, give 20 vials or as many as available - Binds digoxin on a mole-for-mole basis -> complexes are excreted in urine - Cinical response within 20-30 min of administration - Less effective in chronic toxicity since the clinical effects can be multifactorial ### D — Disposition - At 6 hours, if no GI symptoms, falling digoxin level, normal K and renal function, and no arrhythmia — can be discharged - Children: ingestion up to 75 mcg/kg is safe and does not require observation or treatment unless they develop symptoms - If given DigiFab, observe for 24–48 hours and monitor for ==refractory hypokalaemia== --- ## DigiFab dose calculations (per tox handbook) ### Acute toxicity - Known digoxin dose - Number of ampoules = ingested dose (mg) × 0.8 (bioavailability) × 2 - Unknown digoxin dose - Commence empirically with 5 ampoules - If HD unstable, consider 10 ampoules ### Chronic toxicity - Number of ampoules = [serum digoxin (ng/mL) × body weight (kg)] / 100 - Alternatively, commence empirically with 2 ampoules and observe; can repeat in 30 mins ## Indications for Fab administration following acute OD - Hyperkalaemia (K >5.5 mmol/L) associated with toxicity - History of ingestion >10 mg (adults), 4 mg (children) - Haemodynamically unstable cardiac arrhythmia - Cardiac arrest from digoxin toxicity - Serum digoxin level >15 nmol/L