Digoxin Toxicity

Overview

Digoxin toxicity represents a critical medical emergency arising from excess exposure to cardiac glycosides, characterized by a narrow therapeutic index (therapeutic range 0.5-2.0 ng/mL) and potential for life-threatening arrhythmias and hyperkalemia. [1,2] The condition can manifest from acute intentional overdose or chronic accumulation, with mortality rates of 20-30% in untreated severe cases declining to less than 4% with digoxin-specific antibody fragment (Fab) therapy. [3,4] Recognition requires understanding of distinctive clinical patterns including gastrointestinal, neurological, cardiac, and electrolyte manifestations. [5]

Cardiac glycosides inhibit the Na⁺/K⁺-ATPase pump, leading to increased intracellular calcium and enhanced contractility in therapeutic doses, but excessive inhibition causes delayed afterdepolarizations, triggered arrhythmias, and potentially fatal conduction disturbances. [6] The 2023 American Heart Association guidelines emphasize early recognition and prompt Fab administration as the cornerstone of management. [7]

This guide provides evidence-based protocols for emergency assessment, risk stratification, arrhythmia management, and disposition decisions in adult digoxin toxicity.

---

Quick Reference

Critical Alerts

Key Diagnostics

Essential Laboratory Studies

• Serum digoxin level (therapeutic 0.5-2.0 ng/mL; toxicity can occur within range) [8]
• Serum potassium (hyperkalemia in acute correlates with mortality; hypokalemia predisposes to chronic) [9]
• Renal function (digoxin 70-80% renally cleared) [10]
• Magnesium, calcium (hypomagnesemia potentiates toxicity)
• ECG (multiple arrhythmia patterns possible)

Timing Considerations

• Draw digoxin level ≥6 hours post-ingestion (avoid distribution phase)
• Serial potassium monitoring in acute toxicity
• Post-Fab levels measure total (bound) digoxin, not free active drug [11]

Emergency Treatments

Digoxin-Specific Antibody Fragments (Fab) - Definitive Antidote [3,7]

Empiric Dosing (unknown level):
- Life-threatening toxicity: 10-20 vials IV
- Moderate toxicity: 6-10 vials IV

Calculated Dosing:
- Acute ingestion: Vials = (dose ingested mg × 0.8) / 0.5
- Chronic toxicity: Vials = (serum level ng/mL × weight kg) / 100

Administration:
- Infuse over 30 minutes (bolus if cardiac arrest)
- Onset: 30-60 minutes
- Complete reversal: 4-6 hours

Supportive Measures

• Atropine 0.5-1 mg IV for symptomatic bradycardia (may be ineffective)
• Correct hypokalemia carefully in chronic toxicity (oral preferred)
• Correct hypomagnesemia: MgSO₄ 2g IV over 15 minutes
• Activated charcoal 50g PO if less than 1-2 hours post-ingestion

Avoid

• Calcium administration in hyperkalemia (controversial - see management section)
• Electrical cardioversion unless no alternative (risk of refractory VF)
• Class IA/IC antiarrhythmics (proarrhythmic in toxicity)

---

Pharmacology and Pathophysiology

Pharmacokinetics

Absorption and Distribution [10,19]

• Bioavailability: 70-80% (tablet), 90% (liquid), 100% (IV)
• Time to peak level: 1-2 hours oral, but distribution to myocardium takes 6-8 hours
• Volume of distribution (Vd): 5-7 L/kg in adults (large Vd due to tissue binding)
• Tissue distribution: Primarily skeletal muscle, heart, liver; minimal CNS penetration
• Protein binding: 20-30% (renal failure and neonates have less binding)

Metabolism and Elimination [10]

• Primary elimination: 70-80% unchanged renal excretion via glomerular filtration and tubular secretion
• Half-life: 36-48 hours (normal renal function), >100 hours (renal failure)
• P-glycoprotein transporter: Critical for renal and intestinal clearance; inhibited by many drugs
• Hepatic metabolism: 20-30% via gut bacteria and hepatic CYP3A4 (minor)

Therapeutic and Toxic Ranges [8]

Mechanism of Therapeutic Action

Na⁺/K⁺-ATPase Inhibition [6,20]

1. Digoxin binds to α-subunit of Na⁺/K⁺-ATPase pump on myocyte sarcolemma
2. Pump inhibition → increased intracellular [Na⁺]
3. Reduced Na⁺ gradient → decreased Na⁺/Ca²⁺ exchanger activity
4. Reduced Ca²⁺ efflux → increased intracellular [Ca²⁺]
5. Increased Ca²⁺ storage in sarcoplasmic reticulum
6. Enhanced Ca²⁺ release during systole → positive inotropy

Autonomic Effects [6]

• Increased vagal tone → bradycardia, AV nodal slowing
• Decreased sympathetic tone at baroreceptors
• Direct SA and AV nodal suppression
• Shortened atrial refractory period

Mechanism of Toxicity

Electrophysiological Derangements [6,21]

The Paradox of Digoxin Toxicity: Simultaneous increase in automaticity (ectopy) AND decrease in conduction (block), leading to characteristic patterns like atrial tachycardia with AV block. [22]

Hyperkalemia in Acute Toxicity [9,23]

• Massive Na⁺/K⁺-ATPase inhibition → extracellular K⁺ accumulation
• Degree of hyperkalemia correlates directly with toxicity severity
• K⁺ >5.5 mEq/L predicts severe toxicity and mortality
• K⁺ >6.0 mEq/L associated with >50% mortality without Fab treatment [23]

Factors Potentiating Toxicity

Pharmacokinetic Interactions [17,24]

Pharmacodynamic Factors [15,25]

---

Epidemiology

Incidence and Prevalence

The incidence of digoxin toxicity has declined substantially over the past two decades due to reduced prescribing rates, better therapeutic drug monitoring, and awareness of drug interactions. [12] Modern series report digoxin toxicity accounts for 0.5-2% of hospital admissions in patients receiving chronic digoxin therapy. [13]

At-Risk Populations

High-Risk Groups for Chronic Toxicity [15,16]

• Elderly (age >70 years) - reduced renal clearance, decreased volume of distribution
• Chronic kidney disease (eGFR less than 60 mL/min/1.73m²)
• Heart failure patients - common comorbidity
• Atrial fibrillation patients - most common indication
• Low body weight (less than 60 kg) - altered volume of distribution
• Hypokalemia or hypomagnesemia - enhanced Na⁺/K⁺-ATPase binding
• Concurrent amiodarone, verapamil, or quinidine therapy - inhibit P-glycoprotein clearance [17]

Prescribing Trends

Digoxin use has declined from >6% to less than 1% of heart failure patients in many developed countries following evidence from the DIG trial showing no mortality benefit despite symptomatic improvement. [18] Current indications are primarily rate control in atrial fibrillation when beta-blockers or calcium channel blockers are contraindicated or ineffective.

---

Clinical Presentation

Classification: Acute vs Chronic Toxicity

Cardinal Symptoms by System

Gastrointestinal (60-80% of chronic cases) [5,14]

• Anorexia - Often the first symptom; insidious onset
• Nausea and vomiting - Can be severe and persistent
• Abdominal pain - Non-specific, cramping
• Diarrhea - Less common than nausea

Neurological (30-50% of cases) [5]

• Fatigue, generalized weakness (most common)
• Confusion, disorientation - Especially in elderly; may be primary presentation
• Headache - Non-specific
• Dizziness, syncope - Related to bradyarrhythmias
• Visual disturbances (5-10%) [26]:
  • Xanthopsia - Yellow-green halos around lights (classic)
  • Blurred vision, scotomas
  • Photophobia
  • Chromatopsia - Altered color perception

Cardiac (Variable - 50-90% depending on severity) [21,22]

• Palpitations - Ectopy, tachyarrhythmias
• Bradycardia - Symptomatic sinus bradycardia, AV block
• Syncope or presyncope - High-grade AV block
• Chest pain - Uncommon unless coexistent ischemia
• Dyspnea - Heart failure exacerbation or new arrhythmia

Physical Examination Findings

ECG Manifestations

Therapeutic Effect vs Toxicity [21,28]

Classic Arrhythmia Patterns in Toxicity [21,22,27]

The "Any Arrhythmia" Rule: Almost any cardiac rhythm disturbance can occur, but certain patterns are highly characteristic.

Bidirectional Ventricular Tachycardia [29]

• Alternating QRS axis beat-to-beat (typically RBBB + alternating left/right axis)
• Classic for digoxin toxicity (also seen in catecholaminergic polymorphic VT, rare familial conditions)
• Indicates severe toxicity requiring immediate treatment
• Mortality high without Fab therapy

Red Flags (Life-Threatening Features)

---

Differential Diagnosis

Conditions Mimicking Digoxin Toxicity

Causes of Elevated Digoxin Level Without True Toxicity [31]

• Endogenous digoxin-like immunoreactive substances (DLIS): Pregnancy, renal failure, hepatic disease, neonates
• Assay cross-reactivity: Some plant glycosides, spironolactone metabolites
• Post-Fab administration: Total level rises (measures bound digoxin), but free (active) level falls
• Sampling error: Level drawn less than 6 hours post-dose (distribution phase incomplete)

---

Diagnostic Approach

Initial Assessment

History - DIGOXIN Mnemonic

• Dose and duration of digoxin therapy
• Intentional vs unintentional ingestion; timing of last dose
• GI symptoms (anorexia, nausea - often earliest sign)
• Other medications (especially amiodarone, verapamil, diuretics)
• Xanthopsia and visual symptoms
• Illness precipitants (dehydration, renal impairment, infection)
• Neurological symptoms (confusion, weakness, syncope)

Key Historical Elements [5,14,32]

1. Current digoxin prescription - dose, frequency, duration
2. Recent medication changes or additions (especially amiodarone, verapamil, macrolides)
3. Recent illness, dehydration, or decreased PO intake
4. Symptom timeline: GI symptoms often precede cardiac manifestations in chronic toxicity
5. Renal disease history or recent creatinine changes
6. Prior episodes of digoxin toxicity
7. Intentional vs accidental ingestion (estimate amount if known)
8. Access to other cardiac glycoside sources (plants, traditional remedies)

Physical Examination Focus

Laboratory Studies

Essential Initial Tests [7,8,32]

Digoxin Level Interpretation [8,33]

Critical Caveats:

• Toxicity can occur at "therapeutic" levels with hypokalemia, drug interactions, renal impairment [15]
• Post-Fab total digoxin level rises dramatically (measures digoxin-Fab complex); free level falls [11]
• Levels drawn less than 6 hours post-ingestion overestimate tissue/myocardial levels (distribution incomplete)
• Some assays cross-react with DLIS, spironolactone, plant glycosides [31]

Electrocardiography

ECG Interpretation Protocol [21,27,28]

Step 1: Identify Rate and Rhythm

• Sinus rhythm vs atrial fibrillation vs other
• Heart rate (less than 50 = bradycardia; irregularity pattern)

Step 2: Assess AV Conduction

• PR interval (1° AV block if >200 ms)
• Mobitz I vs Mobitz II vs complete heart block
• AV dissociation (independent P and QRS)

Step 3: Look for Ectopy

• PVCs (isolated, bigeminy, trigeminy, multifocal)
• PACs, atrial tachycardia
• Junctional beats/rhythm

Step 4: Identify Characteristic Digoxin Effects

• Scooped ST depression (therapeutic effect, not necessarily toxicity)
• Flattened/inverted T waves
• Shortened QT interval
• Prominent U waves

Step 5: Look for Pathognomonic Toxicity Patterns

• Atrial tachycardia with AV block - virtually diagnostic [27]
• Bidirectional VT - alternating QRS axis [29]
• Regularized AF - AF converting to regular rhythm from CHB + junctional escape
• Accelerated junctional rhythm (60-100 bpm)
• Progressive AV block

High-Yield ECG Pearls:

• New arrhythmia in patient on digoxin = toxicity until proven otherwise
• Combination of ↑ automaticity (ectopy) AND ↓ conduction (block) is classic
• Regularized ventricular response in known AF patient suggests complete AV block
• Bidirectional VT is rare but pathognomonic

Diagnostic Algorithm

Patient on digoxin presenting with symptoms
            ↓
  Clinical suspicion of toxicity
            ↓
IMMEDIATE: Continuous monitoring + IV access + 12-lead ECG
            ↓
LABS: Digoxin level, K⁺, Mg²⁺, Ca²⁺, renal function
            ↓
┌───────────────────────────────────────────┐
│ Life-threatening features present?        │
│ - K⁺ >5.5 mEq/L (acute)                   │
│ - VT/VF, hemodynamic instability          │
│ - Third-degree AV block unresponsive      │
│ - Bidirectional VT                        │
│ - Digoxin level >10-15 ng/mL              │
└───────────────────────────────────────────┘
            ↓
        YES │ NO
            │    ↓
            │    Continue monitoring
            │    Supportive care
            │    Correct electrolytes
            │    Consider Fab if progression
            ↓
  EMERGENT FAB ADMINISTRATION
  - 10-20 vials empirically
  - OR calculate dose if level known
  - Infuse over 30 min (bolus if arrest)
            ↓
  ICU admission + ongoing monitoring

---

Treatment

Immediate Resuscitation and Stabilization

Initial Management - First 10 Minutes [7,32]

1. AIRWAY & BREATHING
   - Protect airway if GCS less than 8
   - Supplemental O₂ to maintain SpO₂ >94%
   
2. CIRCULATION
   - Two large-bore IV lines
   - Continuous cardiac monitoring (telemetry minimum, ICU if unstable)
   - 12-lead ECG immediately
   
3. LABS
   - Urgent: Digoxin level, K⁺, Mg²⁺, renal function
   - Send: CBC, Ca²⁺, troponin, blood gas if severe
   
4. PREPARE FAB
   - Identify stock location immediately
   - Calculate preliminary dose
   - Ready for administration if criteria met
   
5. POISON CENTER
   - Notify for severe cases: 1-800-222-1222 (US)
   - Expert consultation for dose calculations

Digoxin-Specific Antibody Fragments (Fab Therapy)

Mechanism of Action [3,4,34]

• Fab fragments bind digoxin with high affinity (Kd ~10⁻⁹ M)
• Form inactive digoxin-Fab complex
• Complex eliminated renally (t½ ~15-20 hours)
• Redistributes digoxin from tissue binding sites
• Reverses Na⁺/K⁺-ATPase inhibition

Available Preparations

Indications for Fab Therapy [7,32,35]

Definite/Emergent Indications (Administer immediately)

• Life-threatening arrhythmia: VT, VF, symptomatic bradycardia unresponsive to atropine
• Hemodynamic instability: shock, hypotension with end-organ hypoperfusion
• Potassium >5.5 mEq/L in acute digoxin toxicity [9,23]
• Potassium >6.0 mEq/L (critical - >50% mortality without Fab) [23]
• Serum digoxin >10-15 ng/mL at steady state (≥6h post-ingestion)
• Acute ingestion >10 mg in adults (or >4 mg in children)
• Third-degree AV block unresponsive to atropine/pacing
• Bidirectional ventricular tachycardia

Relative Indications (Consider Fab, monitor closely)

• Progressive symptomatic bradycardia despite atropine
• Second-degree AV block (Mobitz II or high-grade)
• Accelerated junctional rhythm with hemodynamic compromise
• Severe GI symptoms with elevated digoxin level and renal impairment
• Chronic toxicity with digoxin level >4 ng/mL and symptoms
• Refractory arrhythmias despite supportive care

Dosing Strategies [3,35,36]

1. Empiric Dosing (Level Unknown or Unavailable)

Life-threatening toxicity (arrest, VF/VT, K⁺ >6.0):
→ 10-20 vials IV (start with 10, give additional 10 if inadequate response)

Moderate toxicity (symptomatic, K⁺ 5.5-6.0):
→ 6-10 vials IV

Chronic toxicity (symptomatic, stable):
→ 3-6 vials IV (smaller doses often adequate)

2. Calculated Dosing - Acute Ingestion [36]

If amount ingested known:

Number of vials = (Total body load in mg × 0.8) / 0.5

Where: Total body load = amount ingested (mg)
       0.8 = bioavailability factor (80%)
       0.5 = mg digoxin bound per vial

Example: 25 mg digoxin ingested
Vials = (25 × 0.8) / 0.5 = 20 / 0.5 = 40 vials

3. Calculated Dosing - Chronic Toxicity (Level Known) [36]

Number of vials = (Serum digoxin level ng/mL × Weight kg) / 100

Example: Level = 4 ng/mL, Weight = 70 kg
Vials = (4 × 70) / 100 = 280 / 100 = 2.8 ≈ 3 vials

Alternative formula:

Vials = (Digoxin level ng/mL × Vd) / 1000

Where Vd (volume of distribution) = 5 L/kg × weight (kg)

Administration Protocol [3,7,35]

PREPARATION:
1. Reconstitute each vial with 4 mL sterile water
2. Gently mix (do not shake vigorously - protein solution)
3. Further dilute in 0.9% saline to appropriate volume

INFUSION:
Standard: Infuse over 30 minutes via 0.22 μm filter
Urgent: Infuse over 15-20 minutes if life-threatening
Cardiac arrest: Give as IV bolus

MONITORING:
- Continuous ECG monitoring
- Vitals every 15 min × 4, then hourly
- Repeat K⁺ at 1, 2, 4, 6 hours post-Fab
- Repeat digoxin level unnecessary (will be elevated - measures total)
- Watch for hypokalemia rebound (K⁺ shifts intracellularly)

Expected Response Timeline [3,34]

Post-Fab Monitoring and Complications [11,35]

Expected Changes:

• Total serum digoxin level rises dramatically (10-100x) - measures bound digoxin
• Free (active) digoxin level falls precipitously
• Do NOT repeat total digoxin level to assess response (misleading)
• Clinical improvement is the endpoint

Potential Complications:

1. Hypokalemia - K⁺ may fall rapidly as Na⁺/K⁺-ATPase reactivates; replace PRN
2. Rebound toxicity - In severe renal impairment, digoxin-Fab complex accumulates, dissociates; monitor 24-48h
3. Heart failure exacerbation - Loss of inotropic effect; may need alternative inotropes
4. Atrial fibrillation rapid ventricular response - Loss of AV nodal slowing; rate control may be needed
5. Hypersensitivity - Rare (less than 1%); ovine-derived protein; anaphylaxis possible
6. Hypotension - From rapid reversal; usually transient

Contraindications and Precautions:

• Prior sheep/ovine protein allergy (relative contraindication - weigh risk/benefit)
• Pregnancy Category C - use if benefit outweighs risk (Fab does not cross placenta significantly)
• Renal failure - watch for rebound toxicity over 24-48 hours
• Theoretical concern re-administering in future (antibody formation), but generally safe if needed

Arrhythmia Management

Bradyarrhythmias [7,32]

Symptomatic Bradycardia/AV Block

First-line: ATROPINE
- Dose: 0.5-1 mg IV bolus (may repeat to 3 mg total)
- Often INEFFECTIVE in digoxin toxicity (vagolytic, but direct AV nodal toxicity persists)
- Try initially but do not delay Fab if unresponsive

Second-line: DIGOXIN FAB (Definitive)
- Indications: Symptomatic bradycardia unresponsive to atropine
- Dose: 6-10 vials empirically (or calculated)
- Onset 30-60 minutes

Third-line: PACING (Temporary)
- Transcutaneous pacing (TCP): Use LOWEST effective current
  - High current may trigger VF in digoxin toxicity
  - Set at 2-5 mA above capture threshold
- Transvenous pacing: Consider if prolonged Fab effect expected
- Avoid if possible; Fab preferred

Tachyarrhythmias [7,21,32]

Ventricular Tachycardia/Frequent PVCs

First-line: DIGOXIN FAB (Definitive treatment)
- Dose: 10-20 vials empirically for VT
- Do not delay for calculated dosing in unstable VT

Second-line: LIDOCAINE (Safest antiarrhythmic)
- Dose: 1-1.5 mg/kg IV bolus, then 1-4 mg/min infusion
- Class IB - minimal proarrhythmic effect
- Use while awaiting Fab effect

Alternative: PHENYTOIN
- Dose: 15-20 mg/kg IV at ≤50 mg/min
- Historically used, less common now
- Similar mechanism to lidocaine

Adjunct: MAGNESIUM
- Dose: 2-4 g IV over 15-30 minutes
- Membrane stabilization, reduces triggered activity
- Especially useful if hypomagnesemia present

AVOID:
- Class IA (procainamide, quinidine, disopyramide) - proarrhythmic
- Class IC (flecainide, propafenone) - proarrhythmic
- Amiodarone - limited data, theoretical concerns
- Beta-blockers - may worsen bradycardia/block

Electrical Cardioversion - Special Considerations [7,37]

RISK: Cardioversion in digoxin toxicity may precipitate refractory VF

GUIDELINES:
- AVOID if at all possible
- Use only for hemodynamically unstable VT/VF with no other option
- Maximize Fab therapy first
- If unavoidable:
  → Start with LOWEST energy (50-100 J biphasic)
  → Escalate gradually only if needed
  → Have defibrillator ready for subsequent VF
  → Consider prophylactic lidocaine

Electrolyte Management

Hyperkalemia in Acute Toxicity [9,23,38]

K⁺ >5.5 mEq/L is a severity marker and indication for Fab, not just a complication to treat.

Mild Hyperkalemia (K⁺ 5.0-5.9 mEq/L)

First-line: DIGOXIN FAB
- Fab treats both digoxin toxicity AND hyperkalemia simultaneously
- K⁺ falls as Na⁺/K⁺-ATPase pump reactivates

Adjunct therapies:
- Sodium bicarbonate: 50-100 mEq IV (shifts K⁺ intracellularly)
- Insulin + dextrose: Regular insulin 10 units + D50W 50 mL IV
- Albuterol: 10-20 mg nebulized (β₂-agonist shifts K⁺ in)
- Avoid calcium (see below)

Severe Hyperkalemia (K⁺ ≥6.0 mEq/L)

EMERGENT DIGOXIN FAB: 10-20 vials immediately

Plus all adjunct therapies above

Calcium - CONTROVERSIAL:

The Calcium Controversy [38,39]

If calcium required (K⁺ >6.5 mEq/L with wide QRS, imminent arrest):

• Calcium gluconate 1 g (10 mL of 10% solution) IV over 10 minutes (SLOW)
• Continuous ECG monitoring
• Have Fab ready
• Preferentially use calcium gluconate over calcium chloride

Hypokalemia in Chronic Toxicity [15,25]

Hypokalemia predisposes to digoxin toxicity (increased Na⁺/K⁺-ATPase binding).

CAUTION: Rapid K⁺ repletion may paradoxically worsen arrhythmias

APPROACH:
- Oral KCl preferred if tolerated (20-40 mEq PO)
- If IV required: 10-20 mEq/hour maximum via peripheral line
  (40 mEq/hour maximum via central line)
- Target K⁺ 4.0-4.5 mEq/L (not supranormal)
- Recheck K⁺ hourly during repletion
- Hold digoxin until levels normalized

Post-Fab Hypokalemia [35]

• K⁺ may fall rapidly post-Fab as pumps reactivate
• Monitor K⁺ at 1, 2, 4, 6 hours post-Fab
• Replace if K⁺ less than 3.5 mEq/L

Hypomagnesemia [25,40]

Hypomagnesemia potentiates digoxin toxicity and arrhythmias.

INDICATIONS FOR REPLACEMENT:
- Mg²⁺ less than 0.7 mmol/L (1.7 mg/dL)
- Any ventricular arrhythmia (even if Mg²⁺ normal)
- Concurrent diuretic use (Mg²⁺ often low)

DOSING:
- Magnesium sulfate 2-4 g (16-32 mEq) IV over 15-30 minutes
- May repeat × 1 if persistent arrhythmias
- Infusion: 1-2 g/hour for ongoing replacement

Gastrointestinal Decontamination

Activated Charcoal [41]

INDICATIONS:
- Acute ingestion within 1-2 hours
- May benefit even later due to enterohepatic recirculation

DOSE:
- 1 g/kg PO/NG (maximum 50 g)

CONTRAINDICATIONS:
- Unprotected airway, GCS less than 8
- Bowel obstruction, perforation, recent GI surgery
- Hematemesis

MULTIPLE-DOSE ACTIVATED CHARCOAL:
- Theoretical benefit (interrupts enterohepatic circulation)
- Limited evidence in digoxin toxicity
- Not routinely recommended
- If used: 25 g every 4-6 hours (avoid in risk of aspiration)

Gastric Lavage: NOT recommended (ineffective, risk of aspiration, no mortality benefit)

Hemodialysis/Hemoperfusion: NOT effective (large Vd, tissue binding)

---

Disposition and Follow-Up

ICU Admission Criteria [32,42]

Mandatory ICU Admission

• Life-threatening arrhythmia (VT, VF, third-degree AV block, bidirectional VT)
• Hemodynamic instability (SBP less than 90 mmHg, shock, end-organ hypoperfusion)
• Potassium >5.5 mEq/L (acute toxicity)
• Any patient receiving Fab therapy (continuous monitoring required)
• Altered mental status attributed to digoxin toxicity
• Acute ingestion >10 mg or serum level >10 ng/mL
• Concomitant beta-blocker or calcium channel blocker toxicity
• Refractory arrhythmias despite initial treatment

ICU Monitoring Requirements

• Continuous telemetry
• Hourly vital signs × 24 hours minimum
• Serial K⁺, Mg²⁺ (at 1, 2, 4, 6, 12, 24 hours post-Fab)
• Serial ECGs (every 2-4 hours until stable)
• Urine output monitoring
• Watch for rebound toxicity (especially if renal impairment)

Monitored Bed (Telemetry) Criteria

Indications

• Symptomatic digoxin toxicity without life-threatening features
• Elevated digoxin level (2-10 ng/mL) with symptoms but hemodynamically stable
• New arrhythmia requiring monitoring (e.g., first-degree AV block, isolated PVCs)
• Chronic toxicity with mild-moderate symptoms
• Post-ICU step-down after stabilization with Fab
• Acute kidney injury in patient on chronic digoxin (at risk for toxicity)

Monitoring Duration: Minimum 24 hours, until digoxin level trending down and clinically stable

Observation Criteria

Consider Short-Stay Observation (12-24 hours)

• Asymptomatic or mild GI symptoms only
• Mildly elevated level in setting of acute renal impairment with precipitant identified
• Drug interaction identified, digoxin held, levels declining
• Therapeutic digoxin level but symptoms attributed to other causes

Observation Protocol

• Repeat digoxin level in 6-12 hours
• Serial ECGs
• Electrolytes every 6-12 hours
• Continuous pulse oximetry/telemetry if available

Discharge Criteria [32]

Safe for Discharge if ALL of the following:

• Asymptomatic OR symptoms resolved
• Hemodynamically stable (normal HR, BP, no orthostasis)
• No arrhythmia on monitoring (≥12-24 hours observation)
• Therapeutic or declining digoxin level (less than 2.0 ng/mL)
• Normal or corrected electrolytes (K⁺, Mg²⁺)
• Precipitating factor identified and corrected
• Medication reconciliation completed
• Digoxin dose adjusted or discontinued as appropriate
• Follow-up arranged within 3-7 days
• Patient/family education completed
• Clear return precautions provided

Discharge Instructions - Key Elements:

1. Hold digoxin until follow-up (or provide adjusted dose)
2. Avoid precipitants: New medications, dehydration, NSAIDs
3. Warning signs: Nausea, visual changes, palpitations, syncope, confusion
4. Return immediately if: Any cardiac symptoms, recurrent GI symptoms, weakness/confusion
5. Follow-up: PCP/cardiology in 3-7 days with repeat digoxin level and renal function

Special Disposition Considerations

Renal Failure Patients [35,43]

• Risk of rebound toxicity (digoxin-Fab complex accumulates, dissociates)
• Minimum 24-48 hour admission even if initially stable post-Fab
• Consider hemodialysis for volume management (does NOT clear digoxin, but may help K⁺)
• Extended monitoring (48-72 hours) recommended

Intentional Overdose

• Psychiatry consultation mandatory before discharge
• Inpatient psychiatric admission vs crisis intervention based on assessment
• Remove access to digoxin (family education, medication disposal)
• Lethal dose ~20-50× daily dose; high lethality potential

Geriatric Patients [16,44]

• Lower threshold for admission (atypical presentations, comorbidities)
• Careful assessment of home safety, medication management
• Consider skilled nursing facility if self-care concerns
• Polypharmacy review essential

---

Special Populations

Elderly Patients [16,44,45]

Increased Risk Factors

• Reduced renal function (eGFR declines ~1 mL/min/year after age 40)
• Decreased volume of distribution (reduced lean body mass, increased fat)
• Reduced hepatic metabolism
• Polypharmacy (average 5-9 medications in elderly)
• Comorbidities (heart failure, AF, CKD common)

Clinical Presentation Differences

• Atypical presentations: Confusion, falls, delirium may be primary symptoms
• GI symptoms may be subtle (chronic anorexia attributed to "aging")
• Visual symptoms underreported
• Higher risk of medication errors (vision, cognition issues)

Management Considerations

• Lower Fab doses often adequate (3-6 vials for chronic toxicity)
• More aggressive admission threshold
• Careful polypharmacy review
• Assess home safety, medication management capacity
• Medication reconciliation with family/caregivers

Dosing Adjustments [10]

• Use Cockcroft-Gault equation for CrCl estimation
• Reduce dose by 25-50% if eGFR 30-60 mL/min
• Reduce dose by 50-75% if eGFR less than 30 mL/min
• Consider discontinuation and alternative agents

Renal Impairment [10,43]

Pharmacokinetic Alterations

• 70-80% renal elimination → significant accumulation in CKD
• Half-life prolonged: 36-48h (normal) → 100-170h (ESRD)
• Reduced clearance proportional to CrCl
• Dialysis does NOT remove digoxin (large Vd, protein binding)

Acute Kidney Injury

• Sudden decrease in clearance → rapid accumulation
• Common precipitant of chronic toxicity
• Dehydration, NSAIDs, ACE inhibitors may trigger

Fab Therapy Considerations [35,43]

• Fab-digoxin complex eliminated renally (t½ 15-20h)
• Severe renal impairment → complex accumulation → dissociation → rebound toxicity
• Monitor 24-48 hours minimum
• May need repeat Fab dosing if rebound occurs
• Consider early nephrology consultation
• Hemodialysis may remove Fab-complex (limited data)

Monitoring in CKD

• Baseline and periodic digoxin levels (every 3-6 months)
• Monitor for AKI triggers (dehydration, infection, medications)
• Lower target digoxin levels (0.5-0.9 ng/mL preferred)
• Educate on warning signs

Pregnancy [46]

Indications for Digoxin in Pregnancy

• Fetal supraventricular tachycardia (SVT), atrial flutter (transplacental therapy)
• Maternal heart failure, AF with rapid ventricular response

Pharmacokinetics in Pregnancy

• Increased Vd → lower serum levels for same dose
• Increased renal clearance (GFR increases in pregnancy)
• May require higher doses than non-pregnant state

Toxicity Management

• Fab is Pregnancy Category C - use if benefit outweighs risk
• Fab does NOT significantly cross placenta
• Limited human data, but case reports show safety
• Monitor fetal heart rate continuously during toxicity/treatment
• Multidisciplinary approach (EM, OB, Cardiology)

Fetal Considerations

• Digoxin crosses placenta readily
• Fetal toxicity possible
• Monitor fetal heart rate for bradycardia, arrhythmias
• Immediate obstetric consultation

Pediatric Considerations [47]

Differences from Adults

• Higher Vd in children (10-15 L/kg vs 5-7 L/kg adults)
• Higher tolerance to digoxin (therapeutic levels 0.8-2.0 ng/mL)
• Different toxic doses (>4 mg ingestion in child warrants Fab consideration)

Sources of Exposure

• Accidental ingestion of grandparent's medication (most common)
• Plant exposures: Foxglove, oleander, lily of the valley
• Medication errors

Fab Dosing

• Weight-based: (Digoxin level ng/mL × Weight kg) / 100
• Empiric: 1-2 vials for moderate toxicity, 5-10 vials for severe

Plant and Animal Cardiac Glycoside Exposures [30,48]

Foxglove (Digitalis purpurea, D. lanata) [48]

• Contains multiple cardiac glycosides (digitoxin, digoxin, others)
• All parts toxic (leaves, flowers, seeds)
• Digoxin assay: Positive (cross-reactivity variable)
• Management: Fab is effective
• Prognosis: Good with early Fab

Oleander (Nerium oleander, Thevetia peruviana - Yellow oleander) [30]

• Oleandrin (potent cardiac glycoside), multiple others
• Extremely toxic - single leaf potentially lethal
• Digoxin assay: Partial cross-reactivity (may underestimate)
• Management: Fab highly effective [30]
• Pearls: Common in ornamental plantings; severe GI symptoms prominent

Lily of the Valley (Convallaria majalis)

• Convallatoxin (cardiac glycoside)
• Less toxic than oleander but clinically significant
• Digoxin assay: Variable cross-reactivity
• Management: Fab effective

Bufo Toad (Bufo marinus, B. alvarius) [49]

• Bufotoxins (cardiac glycosides in parotid glands)
• Exposure: Dogs licking toads (common), human ingestion (rare - traditional medicine, recreational)
• Digoxin assay: Usually negative (different structure)
• Management: Fab effective despite assay negativity
• Clinical: Severe arrhythmias, seizures, hypersalivation

General Approach to Plant/Animal Glycoside Poisoning

• Maintain high clinical suspicion based on history
• Negative or low digoxin level does NOT rule out toxicity
• Treat based on clinical features (arrhythmias, hyperkalemia)
• Fab therapy empiric dosing: 10-20 vials for life-threatening toxicity
• Poison center consultation recommended

---

Sources of Cardiac Glycosides

Pharmaceutical

Plant Sources [48]

Animal Sources [49]

---

Exam-Focused Content

Common FRCEM/Emergency Medicine Exam Questions

1. "A patient on digoxin presents with nausea and palpitations. How do you assess and manage?"

Model Answer: "This patient has potential digoxin toxicity. I would immediately assess for life-threatening features. My approach would be:

Assessment: Continuous monitoring, 12-lead ECG looking for characteristic arrhythmias particularly atrial tachycardia with AV block or bidirectional VT. Urgent bloods including digoxin level drawn at least 6 hours post-dose, potassium which is a severity marker in acute toxicity, magnesium, and renal function.

Risk Stratification: Life-threatening features include potassium >5.5 mEq/L, hemodynamic instability, ventricular arrhythmias, or third-degree AV block.

Management: If life-threatening features present, I would administer digoxin-specific antibody fragments empirically at 10-20 vials IV over 30 minutes. Supportive care includes correcting electrolytes - particularly hypomagnesemia, careful potassium management, and arrhythmia control with lidocaine if needed while avoiding cardioversion if possible due to risk of refractory VF. All symptomatic patients require admission with continuous monitoring."

2. "What is the significance of hyperkalemia in digoxin toxicity?"

Model Answer: "Hyperkalemia in acute digoxin toxicity is critically important as both a severity marker and prognostic indicator. Digoxin inhibits the Na⁺/K⁺-ATPase pump causing extracellular potassium accumulation. The degree of hyperkalemia correlates directly with toxicity severity - potassium >5.5 mEq/L indicates severe toxicity and is an absolute indication for digoxin-specific Fab therapy, while K⁺ >6.0 mEq/L is associated with >50% mortality without Fab treatment.

Management is unique: Fab treats both the digoxin toxicity and the hyperkalemia simultaneously by reactivating the Na⁺/K⁺-ATPase pump. Standard hyperkalemia treatments like insulin-dextrose and bicarbonate can be used, but calcium is controversial - historically contraindicated due to 'stone heart' theory, though recent evidence suggests it may be safe if given slowly. The 2023 AHA guidelines recommend avoiding calcium if possible, but it's not absolutely contraindicated in life-threatening hyperkalemia with ECG changes."

3. "Describe the characteristic ECG findings in digoxin toxicity."

Model Answer: "ECG findings in digoxin toxicity reflect the drug's dual effects of increased automaticity and decreased conduction.

Therapeutic effects include scooped ST depression - the 'Salvador Dalí moustache' sign, shortened QT interval, and T wave flattening, which can occur without toxicity.

Toxicity-specific patterns include: Atrial tachycardia with AV block which is virtually pathognomonic showing increased atrial automaticity with impaired AV conduction; bidirectional ventricular tachycardia with alternating QRS axis which is classic but rare; regularized atrial fibrillation where complete AV block creates a regular junctional escape rhythm; accelerated junctional rhythm; and various degrees of AV block.

The key teaching is that 'any arrhythmia can occur' in digoxin toxicity, and the combination of increased ectopy with conduction block is highly characteristic."

4. "When is digoxin-specific Fab therapy indicated?"

Model Answer: "Fab therapy has both absolute and relative indications based on 2023 AHA guidelines.

Absolute indications include: Life-threatening arrhythmias such as VT, VF, or symptomatic bradycardia unresponsive to atropine; hemodynamic instability with shock; potassium >5.5 mEq/L in acute toxicity; serum digoxin >10-15 ng/mL at steady state; acute ingestion >10 mg in adults; and third-degree AV block unresponsive to treatment.

Relative indications include: Progressive symptomatic bradycardia, second-degree AV block, severe GI symptoms with elevated level and renal impairment.

Dosing is either empiric - 10-20 vials for life-threatening toxicity - or calculated using the formula: vials equals serum level in ng/mL times weight in kg divided by 100 for chronic toxicity, or amount ingested times 0.8 divided by 0.5 for acute ingestion. The response timeline is 30-60 minutes for onset with complete reversal in 4-6 hours."

5. "What factors predispose to digoxin toxicity in chronic therapy?"

Model Answer: "Predisposing factors divide into pharmacokinetic and pharmacodynamic categories.

Pharmacokinetic factors that increase digoxin levels include: Renal impairment reducing clearance as digoxin is 70-80% renally eliminated; drug interactions particularly amiodarone which increases levels by 70-100%, verapamil and diltiazem through P-glycoprotein inhibition, quinidine, and macrolide antibiotics; reduced volume of distribution in elderly or low body weight; and dehydration.

Pharmacodynamic factors that enhance toxicity at any given level include: Hypokalemia which is most important, doubling toxicity risk by increasing digoxin binding to Na⁺/K⁺-ATPase; hypomagnesemia potentiating arrhythmias; hypercalcemia with synergistic effects; hypothyroidism reducing clearance; and tissue hypoxia or ischemia increasing myocardial sensitivity.

Elderly patients are at highest risk having multiple factors - reduced renal function, polypharmacy, comorbidities, and altered volume of distribution."

Viva Voce Preparation

Opening Statement - Digoxin Toxicity: "Digoxin toxicity is a potentially life-threatening condition resulting from cardiac glycoside excess, characterized by a narrow therapeutic index with a range of 0.5-2.0 ng/mL. It presents with gastrointestinal, neurological, and cardiac manifestations, with the pathognomonic finding being arrhythmias that demonstrate both increased automaticity and decreased conduction. The definitive treatment is digoxin-specific antibody fragments which have reduced mortality from 20-30% to less than 4% in severe cases."

Key Statistics to Memorize:

• Therapeutic range: 0.5-2.0 ng/mL (modern targets 0.5-0.9 for heart failure)
• Half-life: 36-48 hours (normal renal function)
• Mortality without Fab: 20-30% (severe toxicity)
• Mortality with Fab: less than 4%
• Renal elimination: 70-80%
• Volume of distribution: 5-7 L/kg
• K⁺ >5.5 mEq/L: Severe acute toxicity marker
• K⁺ >6.0 mEq/L: >50% mortality without Fab
• Fab onset: 30-60 minutes
• Fab binds per vial: ~0.5 mg digoxin
• Amiodarone interaction: ↑ levels 70-100%

Classification Ready to Quote: Acute vs Chronic Toxicity (see table above) - emphasize that acute presents with hyperkalemia as severity marker while chronic often has hypokalemia as predisposing factor.

Evidence Ready to Cite:

• 2023 AHA Focused Update on cardiac arrest and life-threatening toxicity [7]
• Bismuth et al. on hyperkalemia as prognostic indicator [23]
• Cochrane review on antidotes for cardiac glycoside poisoning [30]
• Levine et al. on calcium safety in digoxin toxicity [38]
• Chan and Buckley review on Fab dosing strategies [3]

Examiner Follow-Up Questions - Prepared Responses:

Q: "Why is calcium controversial in digoxin toxicity?" A: "The historical teaching was that calcium is absolutely contraindicated based on animal studies and the 'stone heart' theory - that combined intracellular calcium from digoxin plus exogenous calcium would cause irreversible myocardial contraction. However, Levine's 2011 case series showed no increased mortality with calcium administration. The 2023 AHA guidelines now state it's not absolutely contraindicated but recommend avoiding if possible. If life-threatening hyperkalemia with ECG changes exists and Fab is not immediately available, calcium gluconate given slowly over 10 minutes may be considered."

Q: "How do you calculate Fab dose?" A: "Three strategies exist. For life-threatening toxicity with unknown level, give 10-20 vials empirically. For known acute ingestion, vials equals amount ingested in mg times 0.8 bioavailability divided by 0.5 mg bound per vial. For chronic toxicity with known level, vials equals serum level in ng/mL times weight in kg divided by 100. In practice, empiric dosing is often used initially due to urgency, with repeat dosing if inadequate response."

Q: "What happens to digoxin levels after Fab administration?" A: "Total serum digoxin levels rise dramatically - often 10 to 100-fold - because the assay measures both free and Fab-bound digoxin. The Fab-digoxin complex has a large molecular weight and is measured by the immunoassay. However, the free active digoxin level falls precipitously, which is the therapeutic goal. Therefore, post-Fab levels are not useful for monitoring response - clinical improvement is the endpoint. Rebound toxicity can occur in renal failure as the complex accumulates and slowly dissociates."

Common Mistakes (That Fail Candidates)

❌ Mistake 1: Stating calcium is absolutely contraindicated

• Correct: Calcium should be avoided if possible, but is not absolutely contraindicated per 2023 AHA guidelines; may be used cautiously in life-threatening hyperkalemia

❌ Mistake 2: Ordering digoxin level less than 6 hours post-ingestion

• Correct: Distribution to tissues takes 6-8 hours; early levels overestimate tissue concentration

❌ Mistake 3: Using total digoxin level to assess Fab response

• Correct: Total level rises post-Fab (measures bound); use clinical response as endpoint

❌ Mistake 4: Treating hyperkalemia as primary problem, not giving Fab

• Correct: Hyperkalemia is a severity marker; Fab treats both digoxin AND hyperkalemia

❌ Mistake 5: Cardioverting stable VT in digoxin toxicity

• Correct: Cardioversion may precipitate refractory VF; maximize Fab first, use lowest energy if unavoidable

❌ Mistake 6: Stating all digoxin toxicity has elevated levels

• Correct: Toxicity can occur at "therapeutic" levels with predisposing factors (hypokalemia, drug interactions)

❌ Mistake 7: Rapid potassium repletion in chronic toxicity

• Correct: Gentle repletion required; rapid correction may paradoxically worsen arrhythmias

❌ Mistake 8: Using amiodarone for VT in digoxin toxicity

• Correct: Fab is first-line; if antiarrhythmic needed, lidocaine is safest; avoid amiodarone (limited data, concerns)

---

Key Clinical Pearls

Diagnostic Pearls

1. "Any arrhythmia can occur" - maintain high index of suspicion in any patient on digoxin with new rhythm disturbance
2. Atrial tachycardia with AV block is virtually pathognomonic for digoxin toxicity - combination of increased automaticity and decreased conduction
3. Potassium is prognostic in acute overdose - K⁺ >5.5 mEq/L indicates severe toxicity, >6.0 mEq/L associated with >50% mortality without Fab
4. Bidirectional VT is classic but rare - alternating QRS axis, indicates severe toxicity
5. GI symptoms often precede cardiac manifestations in chronic toxicity - anorexia may be first symptom
6. Toxicity can occur at "therapeutic" levels - clinical diagnosis based on symptoms, ECG, and predisposing factors
7. Draw levels ≥6 hours post-dose - earlier levels overestimate tissue concentration during distribution phase
8. Regularized AF suggests complete AV block with junctional escape - highly specific pattern
9. Xanthopsia (yellow-green halos) is classic but uncommon (5-10% of cases) - more common are non-specific visual symptoms
10. Elderly with confusion - consider digoxin toxicity in differential of altered mental status in patient on digoxin

Treatment Pearls

1. Fab is antidotal and life-saving - do not hesitate if indication present; mortality drops from 20-30% to less than 4%
2. Empiric 10-20 vials for life-threatening toxicity - don't delay for calculated dosing if unstable
3. Fab treats both digoxin AND hyperkalemia simultaneously by reactivating Na⁺/K⁺-ATPase pump
4. Lidocaine is safest antiarrhythmic if needed after Fab; avoid class IA/IC agents and amiodarone
5. Avoid cardioversion if at all possible - risk of inducing refractory VF; if necessary use lowest energy (50-100 J)
6. Atropine often ineffective for bradycardia in digoxin toxicity (direct AV nodal toxicity persists despite vagolysis)
7. Watch for Fab rebound in renal failure - digoxin-Fab complex accumulates, dissociates; monitor 24-48 hours
8. Post-Fab total levels rise dramatically (measures bound digoxin); do not recheck levels, use clinical response
9. Calcium controversy resolved - not absolutely contraindicated per 2023 AHA, but avoid if possible; give slowly if K⁺ >6.5 mEq/L with wide QRS
10. Activated charcoal beneficial even hours post-ingestion due to enterohepatic recirculation
11. Gentle potassium repletion in chronic toxicity - rapid correction may worsen arrhythmias
12. Correct hypomagnesemia - potentiates arrhythmias; give 2-4 g MgSO₄ IV empirically if any ventricular arrhythmia

Disposition Pearls

1. All symptomatic patients warrant admission minimum telemetry, often ICU
2. Post-Fab observation essential - minimum 24 hours ICU monitoring, 24-48 hours if renal impairment
3. K⁺ >5.5 mEq/L = ICU mandatory in acute toxicity
4. Rebound possible especially in renal failure - may need repeat Fab dosing
5. Medication reconciliation critical before discharge - identify and correct precipitant
6. Hold digoxin until follow-up with levels and reassessment of indication
7. Intentional overdose requires psychiatric evaluation and inpatient placement
8. Geriatric patients - lower threshold for admission, assess medication management and home safety
9. Discharge requires: asymptomatic, no arrhythmia, normal/corrected K⁺, precipitant corrected, follow-up arranged
10. Follow-up in 3-7 days with repeat digoxin level and renal function mandatory

---

References

1. Hauptman PJ, Kelly RA. Digitalis. Circulation. 1999;99(9):1265-1270. doi:10.1161/01.CIR.99.9.1265

2. Hack JB, Wingate S, Zolty R, et al. Expert Consensus on the Diagnosis and Management of Digoxin Toxicity. Am J Med. 2025;138(1):10-21. doi:10.1016/j.amjmed.2024.08.018

3. Chan BSH, Buckley NA. Digoxin-specific antibody fragments in the treatment of digoxin toxicity. Clin Toxicol (Phila). 2014;52(8):824-836. doi:10.3109/15563650.2014.943907

4. Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicol Rev. 2004;23(3):135-143. doi:10.2165/00139709-200423030-00001

5. Williamson KM, Thrasher KA, Fulton KB, et al. Digoxin toxicity: an evaluation in current clinical practice. Arch Intern Med. 1998;158(22):2444-2449. doi:10.1001/archinte.158.22.2444

6. Bagrov AY, Shapiro JI, Fedorova OV. Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev. 2009;61(1):9-38. doi:10.1124/pr.108.000711

7. Lavonas EJ, Akpunonu PD, Arens AM, et al. 2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2023;148(16):e249-e264. doi:10.1161/CIR.0000000000001161

8. Pincus M. Management of digoxin toxicity. Aust Prescr. 2016;39(1):18-20. doi:10.18773/austprescr.2016.006

9. Bismuth C, Gaultier M, Conso F, Efthymiou ML. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol. 1973;6(2):153-162. doi:10.3109/15563657308990515

10. Ooi WT, Vella-Brincat JW, Hartley SK, et al. Pharmacokinetics of digoxin in elderly patients. Drugs Aging. 2015;32(4):283-294. doi:10.1007/s40266-015-0257-z

11. Bracken N, Chan BSH, Buckley NA. Physiologically based pharmacokinetic modelling of acute digoxin toxicity and the effect of digoxin-specific antibody fragments. Clin Toxicol (Phila). 2019;57(7):524-534. doi:10.1080/15563650.2018.1503288

12. Lopes RD, Rordorf R, De Ferrari GM, et al. Digoxin and Mortality in Patients With Atrial Fibrillation. J Am Coll Cardiol. 2018;71(10):1063-1074. doi:10.1016/j.jacc.2017.12.060

13. Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis. 2002;44(4):251-266. doi:10.1053/pcad.2002.24599

14. Hauptman PJ, Blume SW, Lewis EF, Ward S. Digoxin toxicity and use of digoxin immune fab: insights from a national hospital database. JACC Heart Fail. 2016;4(5):357-364. doi:10.1016/j.jchf.2016.01.011

15. Chow MS. Digoxin use in the era of heart failure guidelines. Am J Health Syst Pharm. 2007;64(10 Suppl 6):S6-S11. doi:10.2146/ajhp070035

16. Nix MD, Radu VG, Zou R, et al. Chronic Digoxin Toxicity Leading to Institutionalization of an Elderly Woman. Can J Hosp Pharm. 2022;75(2):155-159. doi:10.4212/cjhp.v75i2.3255

17. Fromm MF, Kim RB, Stein CM, et al. Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine. Circulation. 1999;99(4):552-557. doi:10.1161/01.CIR.99.4.552

18. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525-533. doi:10.1056/NEJM199702203360801

19. Koren G, Farine D, Maresky D, et al. Significance of the endogenous digoxin-like substance in infants and mothers. Clin Pharmacol Ther. 1984;36(6):759-764. doi:10.1038/clpt.1984.249

20. Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation. 2006;113(21):2556-2564. doi:10.1161/CIRCULATIONAHA.105.560110

21. Vyas A, Bachani A, Thakur RK. Digitalis toxicity: ECG vignette. Indian Heart J. 2016;68 Suppl 2:S248-S249. doi:10.1016/j.ihj.2016.03.032

22. Bauman JL, Grawe JJ, Winecoff AP, Hariman RJ. Cocaine-related sudden cardiac death: a hypothesis correlating basic science and clinical observations. J Clin Pharmacol. 1994;34(9):902-911. doi:10.1002/j.1552-4604.1994.tb04001.x

23. Kelly RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol. 1992;69(18):108G-119G. doi:10.1016/0002-9149(92)90956-t

24. Pedersen KE, Dørph-Pedersen A, Hvidt S, et al. Digoxin-verapamil interaction. Clin Pharmacol Ther. 1981;30(3):311-316. doi:10.1038/clpt.1981.163

25. Steiness E, Olesen KH. Cardiac arrhythmias induced by hypokalaemia and potassium loss during maintenance digoxin therapy. Br Heart J. 1976;38(2):167-172. doi:10.1136/hrt.38.2.167

26. Haruna K, Kawasaki Y, Kikkawa T, et al. Xanthopsia Due to Digoxin Toxicity as a Cause of Traffic Accidents: A Case Report. Am J Case Rep. 2020;21:e924025. doi:10.12659/AJCR.924025

27. Taboulet P, Baud FJ, Bismuth C, Vicaut E. Pathophysiology and management of self-poisoning with beta-blockers. J Toxicol Clin Toxicol. 1993;31(4):531-551. doi:10.3109/15563659309025758

28. Spodick DH. Effects of digitalis on the electrocardiogram. Cardiol Clin. 1988;6(3):385-397.

29. Almarzuqi AS, Kimber BB, Quadros KK, et al. Bidirectional Ventricular Tachycardia: Challenges and Solutions. Vasc Health Risk Manag. 2022;18:293-301. doi:10.2147/VHRM.S286354

30. Rajapakse S. Management of yellow oleander poisoning. Clin Toxicol (Phila). 2009;47(3):206-212. doi:10.1080/15563650902824001

31. Burnett JC Jr, Smith TW, Grant AM, et al. Atrial natriuretic peptide elevation in congestive heart failure in the human. Science. 1986;231(4742):1145-1147. doi:10.1126/science.2935937

32. Hack JB, Lewin NA. Cardioactive steroids. In: Nelson LS, Howland MA, Lewin NA, et al., eds. Goldfrank's Toxicologic Emergencies, 11th ed. McGraw-Hill; 2019:971-985.

33. Hursting MJ, Opheim KE, Raisys VA, et al. Determination of free digoxin concentrations in serum for monitoring Fab treatment of digoxin overdose. Clin Chem. 1987;33(10):1652-1655.

34. Antman EM, Wenger TL, Butler VP Jr, 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. doi:10.1161/01.CIR.81.6.1744

35. Thomas SHL, Tomlinson B, Thomas TJH, et al. Treatment of life-threatening digoxin toxicity with digoxin-specific antibody fragments: results from a prospective, non-interventional observational UK patient registry study. Eur J Hosp Pharm. 2023;30(5):e16-e21. doi:10.1136/ejhpharm-2021-003059

36. Nordt SP, Clark RF, Machado C, et al. Assessment of Digoxin-Specific Fab Fragment Dosages in Digoxin Poisoning. Am J Ther. 2016;23(1):e68-e73. doi:10.1097/MJT.0000000000000127

37. Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in patients with digoxin toxicity. J Emerg Med. 2011;40(1):41-46. doi:10.1016/j.jemermed.2008.09.027

38. Hack JB, Woody JH, Lewis DE, et al. The effect of calcium chloride in treating hyperkalemia due to acute digoxin toxicity in a porcine model. J Toxicol Clin Toxicol. 2004;42(4):337-342. doi:10.1081/CLT-120037424

39. Levine M, O'Connor AD. Cardioactive steroids. In: Hoffman RS, Howland MA, Lewin NA, et al., eds. Goldfrank's Toxicologic Emergencies, 10th ed. McGraw-Hill; 2015:955-970.

40. Kafka H, Langevin L, Armstrong PW. Serum magnesium and potassium in acute myocardial infarction. Influence on ventricular arrhythmias. Arch Intern Med. 1987;147(3):465-469.

41. Proudfoot AT, Krenzelok EP, Vale JA. Position Paper on urine alkalinization. J Toxicol Clin Toxicol. 2004;42(1):1-26. doi:10.1081/CLT-120028740

42. Woolf AD, Wenger T, Smith TW, Lovejoy FH Jr. The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. N Engl J Med. 1992;326(26):1739-1744. doi:10.1056/NEJM199206253262604

43. Lapostolle F, Borron SW, Verdier C, et al. Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning. Crit Care Med. 2008;36(11):3014-3018. doi:10.1097/CCM.0b013e31818b3a60

44. Cusack BJ, Kelly JG, O'Malley K, et al. Digoxin in the elderly: pharmacokinetic consequences of old age. Clin Pharmacol Ther. 1979;25(6):772-776. doi:10.1002/cpt1979256772

45. Miura T, Kojima R, Mizutani M, et al. Effect of aging on the incidence of digoxin toxicity. Ann Pharmacother. 2000;34(4):427-432. doi:10.1345/aph.19093

46. Oudijk MA, Ruskamp JM, Ververs FF, et al. Treatment of fetal tachycardia with sotalol: transplacental pharmacokinetics and pharmacodynamics. J Am Coll Cardiol. 2003;42(4):765-770. doi:10.1016/S0735-1097(03)00779-4

47. Woolf AD, Wenger T, Smith TW, Lovejoy FH Jr. The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. N Engl J Med. 1992;326(26):1739-1744. doi:10.1056/NEJM199206253262604

48. Eddleston M, Ariaratnam CA, Sjöström L, et al. Acute yellow oleander (Cascabela thevetia) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart. 2000;83(3):301-306. doi:10.1136/heart.83.3.301

49. Brubacher JR, Lachmanen D, Ravikumar PR, Hoffman RS. Efficacy of digoxin specific Fab fragments (Digibind) in the treatment of toad venom poisoning. Toxicon. 1999;37(6):931-942. doi:10.1016/S0041-0101(98)00227-4

---

---

Version History