Digoxin toxicity
Background
- Cardioactive glycoside, a subset of cardioactive steroids, that comes from the foxglove plant, Digitalis lanata
Mechanism of Action
- Inhibits Na+/K+ ATPase in the myocardium[1]
- Causes increase in intracellular sodium levels
- Results in reversal of sodium-calcium exchanger
- Normally imports three extracellular sodium ions into the cardiac myocyte in exchange for one intracellular calcium being exported
- Sodium accumulates intracellularly and is exchanged for Calcium.
- Causes an increase in the intracellular calcium concentration increasing contractility
- Also a lengthening of phase 4 and phase 0 of the cardiac action potential which ultimately decreases heart rate
- Summary
- Inhibits NaK pump
- Positive inotropy
- Negative chronotropy/dromotropy
- Indirect vagal stimulator
- Inhibits NaK pump
Adverse Effects
- Increases vagal tone
- At toxic levels, digoxin can block the SA node's intrinsic impulses along with blocking AV nodal conductions
- Can lead to bradyarrhythmias (esp in young)
- Increases automaticity
- Digoxin acts on the Purkinje fibers by decreasing the resting potential, shortening the action potential duration, and causing enhanced automaticity leading to ventricular dysrhythmias (esp in elderly)
Risk Factors
- Recent dose increase
- Electrolyte Imbalance
- Hypovolemia
- Renal insufficiency
- Digoxin is renally cleared thus any injury to the kidney can lead to accumulation
- Cardiac Ischemia
- Hypothyroidism
- Meds
Environmental Exposures
- Plants that contain cardiac glycosides:
- Oleander
- Foxglove
- Lily of the valley
- Milkweed
Acute vs. Chronic
Category | Acute | Chronic |
Mortality | Lower | Higher |
Arrythmias | Bradycardia / AV block more common | Ventricular dysrhythmias more common |
Age | Younger | Older |
Therapy | Often do not need Fab | Often need Fab therapy |
Clinical Features
Cardiac
- Syncope
- Dysrhythmias
- PVCs (most common)
- Bradycardia
- SVT with AV block
- Junctional escape
- Increased Automaticity: atrial tachycardia, regularized atrial fibrillation
- Regularized AF is atrial fibrillation with 3rd degree AV block and a junctional escape rhythm
- Atrial fibrillation with an underlying regular ventricular rate is suspicious (but not pathognomonic) for Digoxin toxicity
- Ventricular dysrhythmias, including bidirectional V-tach (esp in chronic toxicity)
- Bidirectional vtach is pathognomonic for digoxin toxicity
- Digitalis Effect (seen with therapeutic levels; not indicative of toxicity)
- T wave changes (flattening or inversion)
- QT interval shortening
- Scooped ST segments with depression in lateral leads
- Sometimes referred to as the 'Salvador Dali mustache'
- Increased U-wave amplitude
GI
- Often the earliest manifestation of toxicity
Neuro
- Confusion
- Weakness
- Visual disturbances
- Yellow halos
- Scotomas
- Delirium
Metabolic
- Hyperkalemia (acute poisoning)
- Hypokalemia
- Hypomagnesemia
- Worsens toxicity
Differential Diagnosis
Symptomatic bradycardia
- Cardiac
- Inferior MI (involving RCA)
- Sick sinus syndrome
- Neurocardiogenic/reflex-mediated
- Increased ICP
- Vasovagal reflex
- Hypersensitive carotid sinus syndrome
- Intra-abdominal hemorrhage (i.e. ruptured ectopic)
- Metabolic/endocrine/environmental
- Hyperkalemia
- Hypothermia (Osborn waves on ECG)
- Hypothyroidism
- Hypoglycemia (neonates)
- Toxicologic
- Infectious/Postinfectious
- Other
Wide-complex tachycardia
Assume any wide-complex tachycardia is ventricular tachycardia until proven otherwise (it is safer to incorrectly assume a ventricular dysrhythmia than supraventricular tachycardia with abberancy)
- Regular
- Monomorphic ventricular tachycardia
- PSVT with aberrant conduction:
- PSVT with bundle branch block^
- PSVT with accessory pathway
- Atrial flutter with bundle branch block^
- Sinus tachycardia with bundle branch block^
- Accelerated idioventricular rhythm (consider if less than or ~120 bpm)
- Metabolic
- Irregular
- Atrial fibrillation/atrial flutter with variable AV conduction AND bundle branch block^
- Atrial fibrillation/atrial flutter with variable AV conduction AND accessory pathway (e.g. WPW)
- Atrial fibrillation + hyperkalemia
- Polymorphic ventricular tachycardia
^Fixed or rate-related
Evaluation
Work-Up
- Digoxin level
- Only useful prior to administration of Fab (otherwise becomes falsely elevated)
- Chemistry
- Urine output
- ECG (serial)
- PVCs most common arrhythmia
- May see "regularized AF" on ECG where junctional escape rhythm takes over secondary to complete AV block
- Atach/Aflutter with slow conduction
Evaluation
- Must use H&P and labs in combination; no single element excludes or confirms the diagnosis
- Digoxin level
- Normal = 0.5-2 ng/mL (ideal = 0.7-1.1)
- May have toxicity even with "therapeutic" levels (especially with chronic toxicity)
- Measure at least 6hr after acute ingestion (if stable); immediately for chronic ingestion
- Steady state level (6-8 hours after ingestion) and not peak level is used to guide therapy
- If measure before this may be falsely elevated due to incomplete drug distribution
- Not practical to wait 6-8 hours for intervention so clinical picture should guide decision making
- Normal = 0.5-2 ng/mL (ideal = 0.7-1.1)
- Potassium level
- Acute toxicity: Degree of Hyperkalemia correlates with degree of toxicity
- Historical studies show K+ >5.5 mEq/L 100% mortality; K+ < 5 mEq/L 100% Survival [2]
- Chronic toxicity: K+ may be normal/low (concomitant diuretic use), or high (renal failure)
- Hypokalemia sensitizes myocardium to digoxin [3]
- Acute toxicity: Degree of Hyperkalemia correlates with degree of toxicity
- Magnesium level
- hypomagnesemia can enhance digoxin's effects
Management
See Stone Heart for controversy regarding administration of calcium in digoxin toxicity
- Digoxin Immune Fab
- Indications
- Ventricular dysrhythmias: PVCs most common, Bidirectional VTach is rare (but pathognomonic for digoxin toxicity)
- Symptomatic bradycardias unresponsive to atropine
- Hyperkalemia >5.0 mEq/L secondary to digitalis intoxication
- Coingestions of cardiotoxic drugs (beta-blockers, cyclic antidepressants)
- Acute digoxin ingestion of greater than 10 mg in adults or greater than 4 mg in children
- Acute digoxin ingestion with post distribution digoxin >10 ng/mL (by 6 hours post ingestion)
- Chronic digoxin ingestion leading to steady state serum digoxin concentrations of >4 ng/ml
- Indications
- Activated Charcoal
- Questionable efficacy
- Only an adjunctive treatment; NOT an alternative to fab fragment therapy
- Consider only if present within 1 hr of ingestion
- 1 g/kg (max 50 g)
- Digoxin has high volume of distribution so not readily removed by dialysis
Dysrhythmias
- Digoxin Immune Fab is the agent of choice for all dysrhythmias!
- Cardioversion should only be used as a last resort (may precipitate V-Fib)
- Consider lower energy settings (25-50J)
- Bradyarrhythmias (symptomatic)
- Ventricular dysrhythmias
- Phenytoin
- Enhances AV conduction
- Phenytoin: 15-20 mg/kg at 50 mg/min
- Fosphenytoin: 15-20 mg PE/kg at 100-150 mg/min
- Lidocaine
- Decreases ventricular automaticity
- 1-3 mg/kg over several minutes; follow by 1-4 mg/min
- Magnesium
- Many patients have Hypomagnesemia and labs can be unreliable
- 2-4 g IV over 20-60 mins
- Phenytoin
Hyperkalemia
- The most important predictor of outcome in the setting of digoxin toxicity
- Treat with Fab, not with usual meds
- Once Fab is given hyperkalemia will rapidly correct
- If Fab unavailable and hyperkalemia is life-threatening then treat with:
- Dextrose-insulin
- Sodium bicarb
- Kayexylate
- Dialysis
- Calcium (controversial: some say dangerous, others say not)
- Theoretical concern for inducing "stone heart"; Ca channels open and may lead to cardiac muscle tetany
- Chronic digoxin toxic patients likely have hyperkalemia from renal failure, and calcium administration is likely safe in these patients[4]
- Acutely toxic patients will not benefit from calcium, and priority must be placed on administering DigiFab
Hypokalemia
- Chronic intoxication
- Raise level to 3.5-4
- Acute intoxication
- Do not treat (likely that potassium level is rapidly rising)
Hypomagnesemia
- Treat with 1-2g over 10-20 min
- Monitor for respiratory depression
- Avoid in patients with:
- Renal failure
- Bradydysrhythmias/conduction blocks
Disposition
- Admit for signs of toxicity or history of large ingested dose; admit to ICU if Fab given
- Discharge after 12hr observation if asymptomatic after accidental overdose
- Of note[5]:
- No routine role for hemodialysis
- Rechecking digoxin levels after Digifab is given is clinically useless, as both free and bound levels are measured
See Also
External Links
References
- ↑ Gheorghiade M. et al. Digoxin in the Management of Cardiovascular Disorders. Circulation. 2004; 109: 2959-2964
- ↑ Bismuth C et al. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol. 1973; 6(2): 153–62.
- ↑ Shapiro W. Correlative studies of serum digitalis levels and the arrhythmias of digitalis intoxication. Am J Cardiol. 1978; 41(5):852-9.
- ↑ Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in patients with digoxin toxicity. J Emerg Med. 2011 Jan;40(1):41-6. doi: 10.1016/j.jemermed.2008.09.027. Epub 2009 Feb 6.
- ↑ Pharmacy Times. Feb 2016. Digoxin Overdose: Still No Role for Dialysis. https://www.pharmacytimes.com/contributor/craig-cocchio-pharmd/2016/02/digoxin-overdose-still-no-role-for-dialysis.