Overview

Digoxin Toxicity

Quick Reference

Critical Alerts

Any arrhythmia can occur in digoxin toxicity - maintain high suspicion
Hyperkalemia in acute toxicity correlates with severity and mortality
Digoxin-specific antibody fragments (Fab) are antidotal and life-saving
Avoid calcium in hyperkalemia with digoxin toxicity (classic teaching, though debated)
Electrical cardioversion carries risk of inducing refractory arrhythmias

Key Diagnostics

Serum digoxin level (therapeutic 0.5-2.0 ng/mL, but toxicity can occur within range)
Serum potassium (hyperkalemia in acute; hypokalemia predisposes to chronic)
ECG (multiple possible findings)
Renal function (clearance-dependent)
Magnesium, calcium levels

Emergency Treatments

Digoxin Immune Fab (Digibind/DigiFab): Definitive antidote
- Life-threatening arrhythmias: 10-20 vials empirically
- Known ingestion: Calculate based on body load
Atropine: For symptomatic bradycardia
Correct hypokalemia/hypomagnesemia: Predisposes to toxicity
Avoid: Calcium (debated), cardioversion if possible

Definition

Digoxin toxicity refers to the adverse effects that occur when digoxin levels exceed the therapeutic window or when factors enhance sensitivity to digoxin. It can occur from both acute overdose and chronic accumulation. Cardiac glycosides inhibit the sodium-potassium ATPase pump, leading to increased intracellular calcium and enhanced cardiac contractility, but in excess cause life-threatening arrhythmias.

Sources of Cardiac Glycosides

Source	Example
Prescription medications	Digoxin, digitoxin
Plants	Foxglove, oleander, lily of the valley
Animal	Bufo toad (bufotoxin)

Epidemiology

Incidence: Decreasing due to reduced prescribing
At-risk population: Elderly, renal insufficiency, heart failure, AF patients
Mortality without treatment: 20-30% in severe cases
Mortality with Fab treatment: <4%

Classification

Type	Timeframe	Potassium	Digoxin Level	Features
Acute	Hours	Elevated (marker of severity)	Very high (may be >0 ng/mL)	Intentional OD, massive GI and neuro symptoms
Chronic	Days to weeks	Low or normal	Mildly elevated (2-4 ng/mL)	Often subtle, elderly, drug interactions

Pathophysiology

Mechanism of Action

Therapeutic Effect

Digoxin inhibits Na+/K+-ATPase pump on myocyte membrane
Intracellular Na+ accumulates
Na+/Ca2+ exchanger reduces Ca2+ efflux
Increased intracellular Ca2+ → enhanced contractility (positive inotropy)

Toxic Effect

Excessive Na+/K+-ATPase inhibition
Delayed afterdepolarizations (DADs)
Triggered arrhythmias
Enhanced automaticity
AV nodal conduction slowing
Increased vagal tone (especially GI effects)

Electrophysiological Effects

Effect	Mechanism	Clinical Consequence
Increased automaticity	Phase 4 depolarization	Ectopic beats, tachyarrhythmias
Decreased conduction	AV nodal depression	Heart block
Shortened refractory period	Direct membrane effect	Re-entrant tachycardias
Vagotonic effect	CNS and direct	Bradycardia, AV block

Factors Potentiating Toxicity

Pharmacokinetic

Factor	Effect
Renal impairment	Decreased clearance
Decreased lean body mass	Reduced volume of distribution
Drug interactions (amiodarone, verapamil, quinidine)	Increased levels
Dehydration	Concentrated plasma

Pharmacodynamic

Factor	Effect
Hypokalemia	Increased binding to Na+/K+-ATPase
Hypomagnesemia	Potentiates toxicity
Hypercalcemia	Synergistic effect
Hypothyroidism	Reduced clearance and sensitivity
Hypoxia	Enhanced sensitivity

Clinical Presentation

Symptoms by System

Gastrointestinal (Most Common Early)

Neurological

Cardiac

ECG Manifestations

"Any Arrhythmia" Can Occur - Classic Teaching

Characteristic ECG Findings

Finding	Description
Salvador Dalí moustache	Scooped ST depression ("reverse tick")
T wave changes	Flattened or inverted
Shortened QT interval	Hypercalcemia-like
Increased U waves	May be prominent

Arrhythmias Associated with Toxicity

Type	Examples
Increased automaticity	Accelerated junctional rhythm, atrial tachycardia, ventricular ectopy, VT
Conduction block	Sinus bradycardia, AV block (1°, 2°, 3°)
Combined	Atrial tachycardia with block (PATHOGNOMONIC), regularized AF, bidirectional VT

Classic Toxicity Patterns

Physical Examination

Finding	Significance
Bradycardia	AV nodal depression
Irregular pulse	PVCs, AF, variable block
Signs of poor perfusion	Severe toxicity
Altered mental status	CNS toxicity or hypoperfusion
Signs of dehydration	Contributes to toxicity, renal impairment

Anorexia (often first symptom)

Common presentation.

Nausea and vomiting

Common presentation.

Abdominal pain

Common presentation.

Diarrhea

Common presentation.

Red Flags (Life-Threatening)

Critical Findings

Red Flag	Concern	Immediate Action
Potassium >.0 mEq/L (acute OD)	Severe poisoning, high mortality	Digoxin Fab immediately
Hemodynamic instability	Life-threatening arrhythmia	Digoxin Fab, supportive care
Third-degree AV block	Bradyarrhythmia, asystole risk	Atropine, pacing, Fab
Ventricular tachycardia/fibrillation	Sudden death risk	Digoxin Fab, antiarrhythmics
Digoxin level > ng/mL	Severe acute toxicity	Calculate Fab dose
Bidirectional VT	Classic toxicity, deterioration risk	Digoxin Fab

Indicators for Digoxin Immune Fab

Definite Indications

Life-threatening arrhythmia (VT, VF, symptomatic bradycardia not responsive to atropine)
Potassium >5.5 mEq/L in setting of digoxin toxicity
Evidence of end-organ hypoperfusion
Ingestion >10 mg in adults (or >4 mg in children)
Serum digoxin >10 ng/mL at steady state

Relative Indications

Progressive bradycardia
Second-degree AV block
Significant GI symptoms with elevated digoxin and renal impairment

Differential Diagnosis

Conditions Mimicking Digoxin Toxicity

Condition	Distinguishing Features
Other cardiac glycoside poisoning	History of plant/toad exposure, may not have positive assay
Hyperkalemia (cardiac effects)	Similar ECG changes; check electrolytes
Beta-blocker toxicity	Bradycardia; check drug history
Calcium channel blocker toxicity	Hypotension, bradycardia
Sick sinus syndrome	Preexisting arrhythmia
Myocardial ischemia/infarction	ST changes, troponin elevation
Hypothyroidism	May potentiate toxicity or cause similar symptoms

Causes of Elevated Digoxin Level Without Toxicity

Endogenous digoxin-like immunoreactive substances (DLIS)
Cross-reactivity on assay (pregnancy, renal failure, hepatic disease)
Post-Fab fragment interference (total level rises)

Diagnostic Approach

Initial Assessment

Key History

Digoxin prescription (current, dose, duration)
Recent changes in medications or renal function
Symptoms timeline (GI first, then cardiac)
Comorbidities (renal disease, heart failure, thyroid)
Intentional vs unintentional ingestion

Physical Examination Focus

Vital signs (bradycardia, hypotension)
Cardiac rhythm
Mental status
Signs of dehydration or volume overload

Laboratory Studies

Test	Purpose	Critical Values
Serum digoxin level	Diagnosis and dosing	Therapeutic: 0.5-2.0 ng/mL
Potassium	Predicts severity in acute	>.5 mEq/L = critical
Magnesium	Low potentiates toxicity	Replace if low
Calcium	Hyperkalemia management consideration
Creatinine/BUN	Clearance assessment
Troponin	If ischemia suspected

ECG Interpretation

Step-by-Step Approach

Identify rate and rhythm
Look for AV conduction abnormalities
Check for ectopy (atrial and ventricular)
Assess for scooped ST changes (therapeutic effect, not toxicity)
Look for specific toxicity patterns

Toxicity Indicators on ECG

New or worsening arrhythmia in patient on digoxin
Atrial tachycardia with block
Regularized ventricular response in AF
Bidirectional VT
Frequent PVCs progressing to bigeminy/trigeminy

Digoxin Level Interpretation

Level (ng/mL)	Interpretation
<0.5	Subtherapeutic
0.5-2.0	Therapeutic range
2.0-4.0	Elevated but toxicity depends on clinical context
>.0	High risk for serious toxicity
>0.0 (acute)	Severe; consider empiric Fab

Important Notes

Toxicity can occur at "therapeutic" levels (especially with hypokalemia, drug interactions)
Level drawn <6 hours post-dose may not reflect true tissue distribution
Post-Fab, total level rises (bound to Fab), free level falls

Treatment

Immediate Management

Stabilization

1. ABCs - protect airway if altered mental status
2. IV access
3. Continuous cardiac monitoring
4. 12-lead ECG
5. Labs: Digoxin level, electrolytes, renal function
6. Prepare Digoxin Immune Fab

Digoxin-Specific Antibody Fragments (Fab)

Preparations

Digibind (38mg/vial, binds ~0.5 mg digoxin)
DigiFab (40mg/vial, binds ~0.5 mg digoxin)

Dosing Strategies

Scenario	Calculation
Empiric (unknown level/dose)	10-20 vials IV for life-threatening toxicity
Known acute ingestion	Vials = (ingested dose in mg × 0.8) / 0.5
Known serum level (chronic)	Vials = (serum level ng/mL × weight kg) / 100

Administration

Reconstitute in sterile water
Infuse over 30 minutes (may give faster if critical)
Can give as bolus in cardiac arrest
Onset of effect: 30-60 minutes
Complete reversal in 4-6 hours

Post-Fab Monitoring

Total digoxin level will rise dramatically (digoxin-Fab complex measured)
FREE digoxin level if needed (special assay)
Clinical improvement is the marker of success
Fab is eliminated renally - watch for rebound in renal failure

Arrhythmia Management

Bradycardia

First-line: Atropine 0.5-1 mg IV (may not be effective)
Second-line: Digoxin Immune Fab
Third-line: Transcutaneous pacing (keep current low to avoid inducing VF)

Ventricular Tachyarrhythmias

First-line: Digoxin Immune Fab
Second-line: Lidocaine 1-1.5 mg/kg IV (safer than other agents)
           Phenytoin 15-20 mg/kg IV slowly
Third-line: Magnesium 2g IV (stabilizes membrane)

AVOID:
- Cardioversion if possible (risk of refractory VF)
- Class IA antiarrhythmics (procainamide, quinidine)
- Class III antiarrhythmics (amiodarone) - limited data in toxicity

If Cardioversion Needed

Start at lowest effective energy
Maximize antidote therapy first
Have defibrillator ready for VF

Electrolyte Management

Hyperkalemia (Acute Toxicity)

Mild (5.0-5.9 mEq/L):
- Digoxin Fab (treats both toxicity and K+)
- Sodium bicarbonate 50-100 mEq IV
- Insulin 10 units + D50W 50 mL
- Albuterol nebulizer

Severe (≥6.0 mEq/L):
- Emergent Digoxin Fab
- Above measures
- Calcium - CONTROVERSIAL
  - Classic teaching: Avoid (stone heart theory)
  - Current evidence: May be safe but generally avoid if possible
  - If using: Give slowly (calcium gluconate 1g over 10 min)

Hypokalemia (Chronic Toxicity Contributor)

Gentle repletion (too rapid may worsen toxicity)
Oral KCl if mild
IV KCl 10-20 mEq/hour max via peripheral

Hypomagnesemia

Magnesium sulfate 2g IV over 15 min
Continuation infusion 1-2g/hour
Stabilizes membrane, reduces arrhythmias

Decontamination

Activated Charcoal

Effective if given within 1-2 hours of ingestion
May benefit even later due to enterohepatic circulation
Dose: 1 g/kg (max 50g)
Multiple doses may enhance elimination

Gastric Lavage: Generally not recommended

Disposition

ICU Admission Criteria

Life-threatening arrhythmia
Hemodynamic instability
Requirement for Digoxin Fab
Potassium >5.5 mEq/L
Altered mental status
Post-Fab observation (especially with renal impairment)

Monitored Bed (Telemetry)

Elevated digoxin level without life-threatening features
Symptomatic but stable
New arrhythmia requiring monitoring
Chronic toxicity with mild symptoms

Observation Considerations

Mild toxicity with GI symptoms only
Level mildly elevated in setting of acute kidney injury
New drug interaction identified, medication held

Discharge Criteria

Asymptomatic with therapeutic or low digoxin level
Precipitant identified and corrected
No arrhythmia on monitoring
Medication reconciliation completed
Follow-up arranged

Patient Education

Understanding Digoxin

Digoxin helps the heart pump more effectively
It has a narrow safety margin - small changes can cause problems
Many medications and conditions can affect digoxin levels
Regular blood tests are important

Preventing Future Toxicity

Medication Safety

Take exactly as prescribed
Do not double doses if missed
Inform all healthcare providers you take digoxin
New medications should be verified for interactions

Warning Signs

Nausea, vomiting, loss of appetite
Visual changes (halos around lights)
Feeling your heart is slow or irregular
Unusual fatigue or weakness
Confusion

Important Interactions to Avoid

Do not start new medications without checking
Avoid excessive potassium supplements without guidance
Limit licorice (can lower potassium)
Some antibiotics and heart medications interact

Follow-up

Regular digoxin level monitoring
Kidney function tests
Electrolyte monitoring
Cardiology follow-up

Special Populations

Elderly Patients

Higher risk due to reduced renal function
Smaller volume of distribution
More drug interactions
May present atypically (confusion, falls)
Start with lower doses

Renal Impairment

Digoxin cleared renally
Dose must be adjusted to CrCl
Monitor levels closely during acute illness
Consider level even at "normal" steady state

Pediatric Considerations

Poisoning from plant ingestion (foxglove, oleander)
Fab dosing based on weight or estimated ingestion
Higher toxicity threshold traditionally quoted (but treat aggressively)

Pregnancy

Digoxin crosses placenta
Used for fetal arrhythmias
Fab is Category C (use if benefit outweighs risk)
Monitor fetal heart rate in overdose

Plant and Animal Exposures

Foxglove (Digitalis purpurea)

Contains digitoxin and digoxin glycosides
Fab effective
Digoxin assay may not detect all glycosides

Oleander (Nerium oleander)

Oleandrin - potent cardiac glycoside
Cross-reacts partially with digoxin assay
Fab is effective

Bufo Toad (Bufotoxin)

Licked or ingested by dogs (commonly) or humans
Digoxin assay does not detect
Fab is effective

Quality Metrics

Performance Indicators

Metric	Target
ECG within 10 min of arrival	>5%
Digoxin and potassium level ordered	100%
Fab administered within 1 hour for critical toxicity	>0%
Continuous monitoring initiated	100%
Drug interaction review performed	100%
Poison control notification	Consider for all intentional

Documentation Requirements

Digoxin indication and dose
Time of last dose
Symptoms timeline
Electrolyte results
ECG interpretation
Fab dose calculation and rationale
Response to treatment
Disposition plan and follow-up

Key Clinical Pearls

Diagnostic Pearls

Potassium is prognostic in acute overdose - >5.5 = severe
Any arrhythmia can occur - have high suspicion
Atrial tachycardia with block is virtually pathognomonic
Bidirectional VT is classic but rare
GI symptoms often precede cardiac in chronic toxicity

Treatment Pearls

Fab is antidotal - don't hesitate if criteria met
Empiric 10-20 vials for life-threatening toxicity
Lidocaine is safest antiarrhythmic after Fab
Avoid cardioversion if at all possible
Watch for Fab rebound in renal failure

Disposition Pearls

All symptomatic patients warrant admission
Post-Fab observation is essential - rebound possible
Medication reconciliation before discharge
Schedule digoxin level check as outpatient
Clear return precautions for symptoms

References

Hauptman PJ, Kelly RA. Digitalis. Circulation. 1999;99(9):1265-1270.
Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicol Rev. 2004;23(3):135-143.
Bismuth C, et al. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol. 1973;6(2):153-162.
Levine M, et al. The effects of intravenous calcium in patients with digoxin toxicity. J Emerg Med. 2011;40(1):41-46.
Lapostolle F, et al. Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning. Crit Care Med. 2008;36(11):3014-3018.
Proudfoot AT, et al. Position Paper on urine alkalinization and multiple-dose activated charcoal. Clin Toxicol. 2004.

Version History

Version	Date	Changes
1.0	2025-01-15	Initial comprehensive version with 14-section template

Source

Example

Prescription medications

Digoxin, digitoxin

Plants

Foxglove, oleander, lily of the valley

Animal

Bufo toad (bufotoxin)

Type

Timeframe

Potassium

Digoxin Level

Features

Acute

Hours

Elevated (marker of severity)

Very high (may be >0 ng/mL)

Intentional OD, massive GI and neuro symptoms

Chronic

Days to weeks

Low or normal

Mildly elevated (2-4 ng/mL)

Often subtle, elderly, drug interactions

Effect

Mechanism

Clinical Consequence

Increased automaticity

Phase 4 depolarization

Ectopic beats, tachyarrhythmias

Decreased conduction

AV nodal depression

Heart block

Shortened refractory period

Direct membrane effect

Re-entrant tachycardias

Vagotonic effect

CNS and direct

Bradycardia, AV block

Factor

Effect

Renal impairment

Decreased clearance

Decreased lean body mass

Reduced volume of distribution

Drug interactions (amiodarone, verapamil, quinidine)

Increased levels

Dehydration

Concentrated plasma

Factor

Effect

Hypokalemia

Increased binding to Na+/K+-ATPase

Hypomagnesemia

Potentiates toxicity

Hypercalcemia

Synergistic effect

Hypothyroidism

Reduced clearance and sensitivity

Hypoxia

Enhanced sensitivity

Finding

Description

Salvador Dalí moustache

Scooped ST depression ("reverse tick")

T wave changes

Flattened or inverted

Shortened QT interval

Hypercalcemia-like

Increased U waves

May be prominent

Type

Examples

Increased automaticity

Accelerated junctional rhythm, atrial tachycardia, ventricular ectopy, VT

Conduction block

Sinus bradycardia, AV block (1°, 2°, 3°)

Combined

Atrial tachycardia with block (PATHOGNOMONIC), regularized AF, bidirectional VT

Finding

Significance

Bradycardia

AV nodal depression

Irregular pulse

PVCs, AF, variable block

Signs of poor perfusion

Severe toxicity

Altered mental status

CNS toxicity or hypoperfusion

Signs of dehydration

Contributes to toxicity, renal impairment

Red Flag

Concern

Immediate Action

Potassium >.0 mEq/L (acute OD)

Severe poisoning, high mortality

Digoxin Fab immediately

Hemodynamic instability

Life-threatening arrhythmia

Digoxin Fab, supportive care

Third-degree AV block

Bradyarrhythmia, asystole risk

Atropine, pacing, Fab

Ventricular tachycardia/fibrillation

Sudden death risk

Digoxin Fab, antiarrhythmics

Digoxin level > ng/mL

Severe acute toxicity

Calculate Fab dose

Bidirectional VT

Classic toxicity, deterioration risk

Digoxin Fab

Condition

Distinguishing Features

Other cardiac glycoside poisoning

History of plant/toad exposure, may not have positive assay

Hyperkalemia (cardiac effects)

Similar ECG changes; check electrolytes

Beta-blocker toxicity

Bradycardia; check drug history

Calcium channel blocker toxicity

Hypotension, bradycardia

Sick sinus syndrome

Preexisting arrhythmia

Myocardial ischemia/infarction

ST changes, troponin elevation

Hypothyroidism

May potentiate toxicity or cause similar symptoms

Test

Purpose

Critical Values

Serum digoxin level

Diagnosis and dosing

Therapeutic: 0.5-2.0 ng/mL

Potassium

Predicts severity in acute

>.5 mEq/L = critical

Magnesium

Low potentiates toxicity

Replace if low

Calcium

Hyperkalemia management consideration

Creatinine/BUN

Clearance assessment

Troponin

If ischemia suspected

Level (ng/mL)

Interpretation

<0.5

Subtherapeutic

0.5-2.0

Therapeutic range

2.0-4.0

Elevated but toxicity depends on clinical context

>.0

High risk for serious toxicity

>0.0 (acute)

Severe; consider empiric Fab

Scenario

Calculation

Empiric (unknown level/dose)

10-20 vials IV for life-threatening toxicity

Known acute ingestion

Vials = (ingested dose in mg × 0.8) / 0.5

Known serum level (chronic)

Vials = (serum level ng/mL × weight kg) / 100

First-line: Digoxin Immune Fab Second-line: Lidocaine 1-1.5 mg/kg IV (safer than other agents) Phenytoin 15-20 mg/kg IV slowly Third-line: Magnesium 2g IV (stabilizes membrane) AVOID: - Cardioversion if possible (risk of refractory VF) - Class IA antiarrhythmics (procainamide, quinidine) - Class III antiarrhythmics (amiodarone) - limited data in toxicity

Mild (5.0-5.9 mEq/L): - Digoxin Fab (treats both toxicity and K+) - Sodium bicarbonate 50-100 mEq IV - Insulin 10 units + D50W 50 mL - Albuterol nebulizer Severe (≥6.0 mEq/L): - Emergent Digoxin Fab - Above measures - Calcium - CONTROVERSIAL - Classic teaching: Avoid (stone heart theory) - Current evidence: May be safe but generally avoid if possible - If using: Give slowly (calcium gluconate 1g over 10 min)

Elderly Patients

Higher risk due to reduced renal function
Smaller volume of distribution
More drug interactions
May present atypically (confusion, falls)
Start with lower doses

Renal Impairment

Digoxin cleared renally
Dose must be adjusted to CrCl
Monitor levels closely during acute illness
Consider level even at "normal" steady state

Pediatric Considerations

Poisoning from plant ingestion (foxglove, oleander)
Fab dosing based on weight or estimated ingestion
Higher toxicity threshold traditionally quoted (but treat aggressively)

Pregnancy

Digoxin crosses placenta
Used for fetal arrhythmias
Fab is Category C (use if benefit outweighs risk)
Monitor fetal heart rate in overdose

Plant and Animal Exposures

Foxglove (Digitalis purpurea)

Contains digitoxin and digoxin glycosides
Fab effective
Digoxin assay may not detect all glycosides

Oleander (Nerium oleander)

Oleandrin - potent cardiac glycoside
Cross-reacts partially with digoxin assay
Fab is effective

Bufo Toad (Bufotoxin)

Licked or ingested by dogs (commonly) or humans
Digoxin assay does not detect
Fab is effective

Metric

Target

ECG within 10 min of arrival

>5%

Digoxin and potassium level ordered

100%

Fab administered within 1 hour for critical toxicity

>0%

Continuous monitoring initiated

100%

Drug interaction review performed

100%

Poison control notification

Consider for all intentional

Version

Date

Changes

1.0

2025-01-15

Initial comprehensive version with 14-section template