Digoxin and Lithium Toxicity

Quick Answer

Digoxin and lithium toxicity are two distinct but clinically important poisoning syndromes encountered in the ICU, both requiring specific antidotal or enhanced elimination strategies. Digoxin toxicity causes life-threatening cardiac arrhythmias through inhibition of the Na+/K+-ATPase pump, while lithium toxicity primarily manifests with neurological dysfunction due to its effects as a cation substitute in cellular signalling. [1,2,3]

Digoxin Toxicity Key Points:

• Mechanism: Inhibits Na+/K+-ATPase, increasing intracellular Ca2+ and causing enhanced automaticity with decreased AV conduction [4,5]
• Pathognomonic ECG: Bidirectional ventricular tachycardia (alternating QRS axis); also regularised AF, accelerated junctional rhythm, heart block [6,7]
• Risk factors: Renal impairment, hypokalaemia, hypomagnesaemia, drug interactions (amiodarone, verapamil, clarithromycin) [8,9]
• Treatment: Digoxin-specific antibody fragments (DigiFab) for life-threatening arrhythmias or K+ greater than 5.5 mmol/L; correct hypokalaemia cautiously [10,11]
• Avoid: Cardioversion (may precipitate VF), calcium for hyperkalaemia (theoretical "stone heart"), dialysis ineffective [12,13]

Lithium Toxicity Key Points:

• Patterns: Acute (GI predominant), chronic (neurological predominant), acute-on-chronic (most severe) [14,15]
• Clinical features: Tremor, ataxia, myoclonus, hyperreflexia, seizures, coma; nephrogenic DI common [16,17]
• Risk factors: Dehydration, NSAIDs, ACE inhibitors, diuretics, renal impairment [18,19]
• Treatment: IV normal saline rehydration, whole bowel irrigation for sustained-release preparations [20,21]
• Hemodialysis: Indicated for severe neurotoxicity, level greater than 4 mmol/L, renal failure; standard 4h HD often insufficient, extended or repeated sessions required (EXTRIP 2015) [22,23]

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CICM Exam Focus

Key High-Yield Points

1. Digoxin Na+/K+-ATPase inhibition: Results in increased intracellular Na+, which reduces the Na+/Ca2+ exchanger activity, leading to increased intracellular Ca2+ and enhanced contractility; at toxic levels causes delayed afterdepolarisations (DADs) and triggered activity [4,5,24]

2. Bidirectional VT pathognomonic: Alternating QRS axis (beat-to-beat alternation in frontal plane axis); caused by triggered activity from alternating foci in the left and right bundle branches; highly specific for digoxin toxicity [6,7,25]

3. Regularised AF diagnostic clue: Atrial fibrillation with a regular ventricular response indicates complete AV block with junctional escape rhythm; suggests severe digoxin toxicity [26,27]

4. DigiFab dosing strategies: Empiric dosing (10-20 vials for cardiac arrest), weight-based dosing (number of vials = serum digoxin ng/mL x weight kg / 100), or calculation from ingested dose [10,11,28]

5. Digoxin levels misleading after DigiFab: Total digoxin level rises dramatically after Fab fragment administration (digoxin bound to Fab measured by assay); monitor clinical response and ECG, not levels [29,30]

6. Lithium chronic vs acute: Chronic toxicity occurs at lower levels (1.5-2.5 mmol/L) with more severe symptoms due to tissue accumulation; acute overdose may tolerate levels greater than 4 mmol/L initially [14,15,31]

7. EXTRIP lithium dialysis criteria (PMID 25906177): Recommend dialysis for: impaired kidney function with level greater than 4 mmol/L, decreased consciousness/seizures/life-threatening dysrhythmias regardless of level, or level greater than 5 mmol/L [22,23]

8. Lithium rebound phenomenon: Serum lithium level rises 0.5-1.0 mmol/L within 6-12 hours after dialysis termination due to redistribution from tissues; requires extended HD (6-8 hours) or repeat sessions [32,33]

9. Digoxin dialysis ineffective: Very large Vd (5-7 L/kg) and high tissue binding make hemodialysis/hemoperfusion futile; DigiFab is the only effective antidote [12,34]

10. Lithium dialysis highly effective: Small Vd (0.6-0.9 L/kg), no protein binding, low molecular weight (7 Da) make lithium an ideal candidate for dialysis; HD clearance 70-170 mL/min [35,36]

Common Viva Themes

• Mechanism of digoxin cardiotoxicity and why calcium is potentially harmful
• ECG interpretation in digoxin toxicity with emphasis on bidirectional VT and regularised AF
• DigiFab dosing calculations and when to use empiric vs calculated dosing
• Why potassium is protective in digoxin toxicity but hypokalaemia exacerbates it
• Lithium toxicokinetics and why chronic toxicity is more dangerous than acute
• EXTRIP criteria for lithium dialysis initiation
• Why rebound occurs after lithium dialysis and how to manage it
• Comparison of CRRT vs intermittent HD for lithium removal
• Indigenous health considerations in medication compliance and access to antidotes

Common Pitfalls

• Giving calcium for hyperkalaemia in digoxin toxicity (theoretical risk of "stone heart"
• tetanic cardiac contraction)
• Using synchronised cardioversion for digoxin-toxic arrhythmias (may precipitate VF)
• Relying on serum digoxin levels after DigiFab administration (falsely elevated)
• Underestimating severity of chronic lithium toxicity at "therapeutic" levels
• Stopping dialysis based on lithium level without accounting for rebound
• Using CRRT as sole modality for severe lithium toxicity (clearance inferior to IHD)
• Forgetting that digoxin toxicity worsens with hypokalaemia (competitive binding at Na+/K+-ATPase)
• Not considering drug interactions that precipitate digoxin toxicity (amiodarone, verapamil, quinidine)
• Missing nephrogenic DI as a cause of hypernatraemia in lithium patients

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Key Points

• Digoxin toxicity: Na+/K+-ATPase inhibition → increased intracellular Ca2+ → enhanced automaticity + slowed AV conduction [4,5]
• Bidirectional VT is pathognomonic of digoxin toxicity; regularised AF indicates complete AV block [6,7,26]
• DigiFab is the definitive treatment for life-threatening digoxin toxicity; dialysis is ineffective (Vd 5-7 L/kg) [10,11,12]
• DigiFab indications: cardiac arrest, life-threatening arrhythmias, hyperkalaemia greater than 5.5 mmol/L, ingestion greater than 10 mg in adults [10,28]
• Correct hypokalaemia in digoxin toxicity (cautiously if bradycardia); avoid calcium, avoid cardioversion [13,37]
• Lithium toxicity patterns: acute (GI), chronic (neurological), acute-on-chronic (most severe) [14,15]
• Lithium dialysis indications (EXTRIP): level greater than 4 mmol/L with renal impairment, severe neurotoxicity, or level greater than 5 mmol/L [22,23]
• Standard 4-hour HD often insufficient; extended HD (6-8 hours) or sequential sessions required due to rebound [32,33]
• Lithium is highly dialyzable: small Vd, no protein binding, low molecular weight (7 Da) [35,36]
• Chronic lithium toxicity more dangerous than acute at equivalent levels due to tissue saturation [14,31]

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Applied Basic Sciences

Digoxin Pharmacology and Mechanism of Toxicity

Mechanism of Action - Na+/K+-ATPase Inhibition:

Digoxin is a cardiac glycoside derived from the foxglove plant (Digitalis lanata) that exerts its therapeutic and toxic effects through inhibition of the membrane-bound Na+/K+-ATPase pump. [4,5,24,38]

Normal Na+/K+-ATPase Function:

• Actively transports 3 Na+ out and 2 K+ into the cell per ATP hydrolysed
• Maintains the negative intracellular potential (~-90 mV in cardiomyocytes)
• Creates the Na+ gradient that drives secondary active transport, including Na+/Ca2+ exchange

Digoxin Binding and Inhibition:

• Digoxin binds to the alpha subunit of Na+/K+-ATPase from the extracellular side
• Inhibits pump activity, leading to increased intracellular Na+ concentration
• The elevated intracellular Na+ reduces the driving force for the Na+/Ca2+ exchanger (NCX)
• NCX normally extrudes 1 Ca2+ for 3 Na+ entering; reduced Na+ gradient impairs Ca2+ efflux
• Net result: increased intracellular Ca2+ [4,5]

Therapeutic vs Toxic Effects:

Cellular Electrophysiology in Toxicity:

1. Delayed Afterdepolarisations (DADs): Intracellular Ca2+ overload causes oscillatory release of Ca2+ from the sarcoplasmic reticulum via ryanodine receptors; this activates inward Na+/Ca2+ exchanger current and transient inward current, producing DADs that can trigger ventricular arrhythmias [24,25,39]

2. Enhanced Automaticity: DADs reaching threshold in Purkinje fibres generate triggered activity; this underlies the accelerated junctional rhythms and ventricular ectopy seen in digoxin toxicity [24,40]

3. Slowed Conduction: Direct effect on AV node plus enhanced parasympathetic (vagal) tone leads to first, second, and third-degree AV block [26,41]

4. Shortened Atrial Refractory Period: Increases susceptibility to atrial arrhythmias; characteristic "scooped" ST depression reflects this repolarisation change [7,42]

Digoxin Pharmacokinetics:

Drug Interactions Precipitating Toxicity:

Lithium Pharmacology and Mechanism of Toxicity

Lithium Mechanism of Action - Incompletely Understood:

Lithium is a monovalent cation (Li+) that exerts its therapeutic effects in bipolar disorder through multiple mechanisms, many of which are not fully elucidated. Its toxicity reflects excessive effects on the same pathways plus additional cellular dysfunction. [16,47,48]

Proposed Mechanisms:

1. Cation Substitution: Li+ can substitute for Na+, K+, Ca2+, and Mg2+ in various cellular processes

   • Enters cells through sodium channels and Na+/Li+ exchangers
   • Competes with Na+ for reabsorption in proximal tubule and loop of Henle
   • Interferes with action potential generation and propagation in neurons [47,49]

2. Inositol Depletion: Lithium inhibits inositol monophosphatase, reducing the regeneration of phosphatidylinositol 4,5-bisphosphate (PIP2); this blunts second messenger signalling via the phospholipase C pathway [48,50]

3. Glycogen Synthase Kinase-3 (GSK-3) Inhibition: Lithium inhibits GSK-3, affecting multiple downstream pathways including Wnt signalling, glycogen synthesis, and neuronal plasticity [48,51]

4. Thyroid Effects: Lithium inhibits thyroid hormone synthesis and release; can cause hypothyroidism (up to 30% of patients) or less commonly hyperthyroidism [52,53]

5. Renal Effects: Lithium accumulates in collecting duct principal cells and inhibits vasopressin-stimulated aquaporin-2 expression, causing nephrogenic diabetes insipidus (NDI); also causes chronic tubulointerstitial nephritis with long-term use [17,54,55]

Lithium Pharmacokinetics:

Renal Handling of Lithium:

Lithium is freely filtered at the glomerulus and handled similarly to sodium in the proximal tubule and loop of Henle: [18,19,56]

1. Proximal Tubule: 65-80% of filtered lithium is reabsorbed via Na+/Li+ exchange; competition with sodium means:

   • Volume depletion → increased Na+ (and Li+) reabsorption → lithium toxicity
   • Sodium loading → decreased reabsorption → increased lithium clearance

2. Loop of Henle: Additional lithium reabsorption occurs; loop diuretics reduce sodium reabsorption here but volume depletion can offset this effect

3. Distal Tubule/Collecting Duct: Minimal lithium reabsorption; thiazide diuretics cause proximal tubular compensation that increases lithium reabsorption

4. Lithium Clearance: Normally 10-40 mL/min (approximately 20% of creatinine clearance)

Drugs and Conditions Affecting Lithium Levels:

Comparative Toxicokinetics

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Digoxin Toxicity

Acute vs Chronic Toxicity

Digoxin toxicity can occur in two distinct clinical scenarios with different presentations and management considerations. [1,59,60]

Acute Digoxin Toxicity:

• Occurs with deliberate self-poisoning or accidental ingestion of large doses
• Typical ingestion: greater than 10 mg in adults, greater than 4 mg in children
• Presents within 1-6 hours of ingestion
• Key features:
  • Nausea, vomiting (often profuse, early symptom)
  • Hyperkalaemia (Na+/K+-ATPase inhibition → K+ cannot enter cells)
  • Bradyarrhythmias initially; ventricular arrhythmias with severe poisoning
  • Serum digoxin level often markedly elevated (greater than 10 ng/mL)
• Hyperkalaemia is a marker of severe poisoning and indication for DigiFab [10,61]

Chronic Digoxin Toxicity:

• Occurs in patients on maintenance digoxin therapy
• Usually due to:
  • Declining renal function
  • Addition of interacting drug
  • Dehydration/volume depletion
  • Intercurrent illness
• Presents insidiously over days to weeks
• Key features:
  • GI symptoms (anorexia, nausea) - often attributed to other causes
  • CNS symptoms (confusion, fatigue, visual disturbances)
  • Cardiac arrhythmias - may be first recognised manifestation
  • Hypokalaemia is common (from diuretic use) and exacerbates toxicity
  • Serum digoxin level may be only modestly elevated or within "therapeutic" range [59,62]

Risk Factors for Chronic Toxicity:

Clinical Features

Gastrointestinal (Early and Common):

• Anorexia (often first symptom of chronic toxicity)
• Nausea and vomiting (prominent in acute overdose)
• Abdominal pain
• Diarrhoea

CNS (More Common in Chronic Toxicity):

• Confusion, disorientation
• Fatigue, weakness
• Visual disturbances:
  • Xanthopsia (yellow-green halos around lights) - classic but not common
  • Chromatopsia (altered colour perception)
  • Blurred vision
  • Photophobia
• Headache
• Delirium (especially elderly) [1,63,64]

Cardiac (Life-Threatening):

The hallmark of digoxin toxicity is the coexistence of enhanced automaticity with impaired conduction. Almost any arrhythmia can occur, but certain patterns are characteristic: [6,7,26,65]

Bidirectional Ventricular Tachycardia:

Bidirectional VT is considered virtually pathognomonic of digoxin toxicity (though it can also occur in catecholaminergic polymorphic VT and aconitine poisoning). [6,7,25]

ECG Features:

• Wide QRS tachycardia (rate 140-200 bpm)
• Beat-to-beat alternation of QRS axis in the frontal plane
• Typically: one beat with RBBB morphology and left axis, next beat with RBBB morphology and right axis
• Represents triggered activity from alternating foci in the left anterior and left posterior fascicles

Regularised Atrial Fibrillation:

In AF, the ventricular response is "irregularly irregular." If the rhythm becomes regular in a patient with AF, this indicates complete AV block with a junctional or ventricular escape rhythm - a sign of severe digoxin toxicity. [26,27]

Digoxin Effect vs Digoxin Toxicity:

Investigations

Serum Digoxin Level:

• Obtain at least 6 hours post-dose for steady-state distribution [66,67]
• Therapeutic range: 0.8-2.0 ng/mL (1.0-2.6 nmol/L); lower target in HFrEF (0.5-0.9 ng/mL)
• Toxicity more likely with levels greater than 2.0 ng/mL, but can occur at "therapeutic" levels if risk factors present
• Acute overdose: levels greater than 10-15 ng/mL associated with severe toxicity [59,68]

Important Caveats:

• Level must be drawn at least 6 hours post-dose (distribution phase complete)
• Clinical toxicity, not level, determines need for treatment
• Post-DigiFab levels are falsely elevated (assay measures bound + free digoxin)

Electrolytes:

• Potassium: Critical - hypokalaemia exacerbates toxicity; hyperkalaemia in acute overdose indicates severity
• Magnesium: Hypomagnesaemia potentiates toxicity
• Calcium: Hypercalcaemia worsens toxicity
• Renal function: Creatinine, eGFR to assess clearance capacity

ECG:

• Continuous monitoring essential
• Serial 12-lead ECGs
• Look for characteristic arrhythmias and "digoxin effect"

Other:

• Thyroid function (hypothyroidism increases digoxin sensitivity)
• Liver function (minor role in metabolism)
• Drug history (identify interactions)

Management

Initial Resuscitation:

A - Airway: Usually maintained; protect if GCS decreased

B - Breathing: Assess for pulmonary oedema (rare but possible)

C - Circulation:

• Continuous cardiac monitoring (essential)
• IV access
• Treat haemodynamically unstable arrhythmias
• Prepare for temporary pacing and DigiFab

D - Disability:

• GCS assessment
• Glucose check

E - Exposure:

• Review medications (interactions)
• Check for other coingestants

Decontamination:

Activated Charcoal:

• 50 g (1 g/kg) if within 1-2 hours of acute ingestion
• Consider multi-dose activated charcoal (MDAC) 25 g every 4 hours for large ingestions (enterohepatic circulation) [69,70]
• Contraindicated if decreased GCS without airway protection

Digibind/DigiFab (Digoxin-Specific Antibody Fragments):

DigiFab is the definitive treatment for life-threatening digoxin toxicity. It consists of Fab fragments of antidigoxin antibodies derived from sheep. [10,11,28,71]

Mechanism:

• Fab fragments bind free digoxin in the plasma with high affinity
• Binding creates a concentration gradient that draws digoxin from tissue binding sites
• Fab-digoxin complex is renally eliminated (half-life 15-20 hours, prolonged in renal failure)
• Onset of effect: 30-60 minutes; peak effect 2-4 hours

Indications for DigiFab:

Dosing Strategies:

1. Empiric Dosing (Cardiac Arrest/Imminent Arrest):

• 10-20 vials (400-800 mg) IV bolus
• Do not delay for calculations or level

2. Calculation from Serum Level and Weight:

• Number of vials = [Serum digoxin (ng/mL) × Weight (kg)] / 100
• Example: Digoxin 8 ng/mL, 70 kg patient → (8 × 70) / 100 = 5.6 → 6 vials

3. Calculation from Amount Ingested:

• Number of vials = [Amount ingested (mg) × Bioavailability (0.8)] / 0.5 mg/vial
• Example: 5 mg ingested → (5 × 0.8) / 0.5 = 8 vials

Vial Content:

• Each vial of DigiFab contains 40 mg of digoxin-specific Fab fragments
• Each vial binds approximately 0.5 mg of digoxin

Administration:

• Reconstitute each vial with 4 mL sterile water
• Dilute in normal saline for IV infusion over 30 minutes
• In cardiac arrest: may give IV push

Monitoring After DigiFab:

• Clinical response (resolution of arrhythmias, improvement in haemodynamics)
• ECG monitoring
• Serum digoxin level: rises after DigiFab (bound digoxin measured by assay) - do NOT use for clinical decisions [29,30]
• Potassium: hypokalaemia may develop as K+ re-enters cells
• Renal function: Fab-digoxin complex requires renal elimination

Hypokalaemia Correction:

Hypokalaemia exacerbates digoxin toxicity by increasing digoxin binding to Na+/K+-ATPase (K+ and digoxin compete for binding). [13,37,72]

Management:

• Correct potassium to 4.0-5.0 mmol/L
• IV potassium chloride 10-20 mmol over 1-2 hours (central line preferred if giving faster)
• Caution: In the setting of bradycardia/AV block, potassium may worsen conduction
• Monitor ECG continuously during replacement
• Replace magnesium concurrently (target greater than 1.0 mmol/L)

Avoid Calcium:

The traditional teaching is to avoid IV calcium in digoxin toxicity due to the theoretical risk of "stone heart" (tetanic cardiac contraction from excessive intracellular calcium). [12,73]

Evidence Base:

• Based on animal studies and case reports from the 1930s-1960s
• Systematic review (Levine et al., 2011) found no definitive human cases [74]
• However, given availability of DigiFab, there is no compelling reason to use calcium
• If hyperkalaemia is life-threatening and DigiFab is not immediately available, calcium may be cautiously considered

Avoid Cardioversion:

Synchronised cardioversion may precipitate ventricular fibrillation in digoxin-toxic hearts due to triggered activity and enhanced automaticity. [75,76]

Recommendations:

• Avoid electrical cardioversion for atrial arrhythmias in digoxin toxicity
• If cardioversion absolutely required for life-threatening VT, use lowest possible energy
• Have DigiFab ready before attempting cardioversion
• Defibrillation for VF is still indicated

Bradyarrhythmia Management:

Tachyarrhythmia Management:

Dialysis is NOT Effective:

Digoxin has a very large volume of distribution (5-7 L/kg) and is extensively bound to tissues (particularly skeletal muscle). Only 1-2% of total body digoxin is in the plasma at any time, making hemodialysis, hemoperfusion, and hemofiltration ineffective. [12,34]

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Lithium Toxicity

Classification: Acute vs Chronic vs Acute-on-Chronic

Lithium toxicity is classified by the pattern of exposure, which significantly influences clinical presentation and prognosis. [14,15,31,77]

Acute Lithium Toxicity:

• Single large ingestion in a lithium-naive patient
• Typically deliberate self-poisoning
• Presentation:
  • GI symptoms predominate initially (nausea, vomiting, diarrhoea)
  • Neurological symptoms develop later as lithium distributes into CNS
  • May tolerate very high serum levels (greater than 4 mmol/L) initially
• Prognosis: Generally better than chronic toxicity at equivalent levels
• Key point: Serum level may be very high (greater than 4-8 mmol/L) before CNS manifestations [78]

Chronic Lithium Toxicity:

• Gradual accumulation in patients on maintenance lithium therapy
• Causes:
  • Reduced renal function (acute illness, CKD progression)
  • Dehydration (fever, vomiting, diarrhoea, reduced intake)
  • Addition of interacting drugs (NSAIDs, ACE inhibitors, thiazides)
  • Intentional dose increase
• Presentation:
  • Neurological symptoms predominate (tissue saturation already present)
  • Symptoms may occur at levels of 1.5-2.5 mmol/L
  • GI symptoms less prominent
• Prognosis: Worse than acute toxicity at equivalent levels
• Key point: Serum level underestimates tissue (CNS) concentration [14,15,79]

Acute-on-Chronic Lithium Toxicity:

• Acute ingestion superimposed on chronic therapy
• Combines features of both patterns
• Most severe form of lithium toxicity
• Presentation:
  • Both GI and neurological symptoms
  • Already elevated tissue levels plus acute surge
  • Rapid deterioration
• Prognosis: Highest morbidity and mortality [15,80]

Comparison of Toxicity Patterns:

Risk Factors for Lithium Toxicity

Patient Factors:

• Age greater than 50 years
• Pre-existing renal impairment
• Cardiovascular disease
• Volume depletion
• Sodium depletion or low-salt diet

Medication Factors:

Situational Factors:

• Intercurrent illness with fever/sweating
• Gastroenteritis (vomiting, diarrhoea)
• Reduced oral intake
• Excessive exercise with sweating
• Hot weather
• Surgery and perioperative period

Clinical Features

Neurological (Predominant in Chronic Toxicity):

Neurological manifestations correlate with severity and are the primary determinant of prognosis. [16,17,81]

Specific Neurological Signs:

• Tremor: Coarse, irregular (differentiates from fine tremor at therapeutic levels)
• Myoclonus: Multifocal, stimulus-sensitive
• Hyperreflexia: Brisk tendon reflexes, sometimes with clonus
• Ataxia: Both truncal and limb; gait abnormality prominent
• Dysarthria: Slurred speech
• Nystagmus: Horizontal, vertical, or rotatory
• Fasciculations: Visible muscle twitching
• Seizures: Generalised tonic-clonic; status epilepticus possible
• Coma: Progressive unresponsiveness; indicates severe toxicity [16,82]

SILENT Mnemonic for Lithium Toxicity:

• Seizures
• Insipidus (nephrogenic DI)
• Leukocytosis
• ECG changes (T-wave flattening, U waves)
• Neurological (tremor, ataxia, myoclonus)
• Thyroid (hypothyroidism)

Gastrointestinal (Predominant in Acute Toxicity):

• Nausea
• Vomiting (may be profuse)
• Diarrhoea
• Abdominal cramping

Renal:

Lithium causes both acute and chronic renal effects: [17,54,55]

Nephrogenic Diabetes Insipidus (NDI):

• Occurs in up to 40% of long-term lithium users
• Mechanism: Lithium inhibits vasopressin-stimulated aquaporin-2 expression in collecting duct principal cells
• Presentation: Polyuria (up to 3-4 L/day), polydipsia, hypernatraemia
• May persist for months after lithium cessation
• Worsens dehydration and contributes to toxicity

Chronic Interstitial Nephritis:

• Gradual decline in GFR with long-term use
• Risk increases with duration of therapy (greater than 10 years)
• May progress to CKD or ESRD
• Lithium discontinuation may stabilise but not reverse changes

Cardiovascular:

• ECG changes: T-wave flattening or inversion, U waves, QTc prolongation
• Bradycardia (sinus node dysfunction)
• Rarely: sinoatrial block, ventricular arrhythmias
• Generally less prominent than digoxin cardiotoxicity [83,84]

Endocrine:

• Hypothyroidism (10-30% of long-term users)
• Hyperthyroidism (rare; lithium-induced thyrotoxicosis)
• Hyperparathyroidism (increased PTH secretion)

Severity Grading

The EXTRIP (Extracorporeal Treatments in Poisoning) workgroup provides guidance on severity classification: [22,23]

Mild Toxicity:

• Nausea, vomiting, tremor, weakness
• No altered consciousness
• Level typically 1.5-2.5 mmol/L (chronic) or higher (acute)

Moderate Toxicity:

• Confusion, agitation, fasciculations
• Hyperreflexia, myoclonus
• Ataxia, dysarthria
• Level typically 2.5-3.5 mmol/L (chronic)

Severe Toxicity:

• Seizures
• Coma (GCS less than 9)
• Hyperthermia
• Cardiovascular instability
• Level typically greater than 3.5 mmol/L (chronic) but may occur at lower levels

Investigations

Serum Lithium Level:

• Obtain immediately; repeat every 2-4 hours until declining
• Interpret in context of exposure pattern (acute vs chronic)
• Chronic toxicity: symptoms correlate with level
• Acute toxicity: initial high level may not reflect CNS concentration [66,85]

Electrolytes and Renal Function:

• Sodium: Hypernatraemia suggests NDI; hyponatraemia from fluid overload
• Potassium: Monitor during treatment
• Creatinine, eGFR: Assess baseline renal function and dialysis need
• Calculate creatinine clearance (lithium clearance approximately 20% of CrCl)

Thyroid Function:

• TSH, free T4
• Hypothyroidism common in chronic lithium use
• May need treatment if severe

Blood Gas:

• Assess acid-base status
• Metabolic acidosis may occur in severe toxicity (lactate from seizures)

ECG:

• T-wave flattening, U waves
• QTc prolongation
• Bradyarrhythmias

Imaging:

• CT brain if prolonged coma or focal neurology (rule out structural causes)
• MRI: May show hyperintense lesions in basal ganglia and cerebellum in severe toxicity (chronic sequelae)

Management

Initial Resuscitation:

A - Airway: Protect if GCS decreased; anticipate deterioration

B - Breathing: Assess respiratory function; mechanical ventilation if needed for airway protection

C - Circulation:

• IV access
• Volume resuscitation with normal saline (0.9% NaCl)
• Avoid hypotonic fluids (may worsen hyponatraemia)
• Target euvolaemia

D - Disability:

• GCS assessment (serial monitoring)
• Blood glucose
• Seizure precautions; benzodiazepines for seizures

E - Exposure:

• Temperature monitoring
• Review medications (identify precipitants)

Fluid Resuscitation:

Volume expansion with isotonic saline is the cornerstone of initial management: [20,86]

Rationale:

• Restores GFR and enhances lithium clearance
• Corrects dehydration from vomiting, diarrhoea, and NDI
• Normal saline (0.9% NaCl) is the fluid of choice
• Avoid hypotonic fluids (may worsen any existing hyponatraemia)

Protocol:

• Initial bolus: 1-2 L normal saline over 1-2 hours
• Maintenance: 150-250 mL/hour adjusted to urine output
• Target urine output: greater than 1-2 mL/kg/hour
• Monitor for fluid overload in elderly or cardiac patients

"Saline diuresis" (forced diuresis) is NOT recommended:

• Does not significantly enhance lithium clearance
• Risk of volume overload
• Diuretics (especially thiazides) may paradoxically reduce lithium clearance

Decontamination:

Activated Charcoal:

• NOT effective for lithium (lithium is not adsorbed by charcoal) [87]

Whole Bowel Irrigation (WBI):

WBI is indicated for sustained-release lithium preparations to prevent ongoing absorption: [21,88]

Indications:

• Ingestion of sustained-release (SR) or extended-release lithium
• Large ingestion of any lithium preparation
• Rising lithium levels despite IV fluids

Polyethylene Glycol (PEG) Electrolyte Solution:

• Adults: 1.5-2 L/hour orally or via nasogastric tube
• Continue until rectal effluent is clear
• Duration typically 4-6 hours
• Contraindications: ileus, bowel obstruction, haemodynamic instability

Gastric Lavage:

• May be considered within 1 hour of large ingestion
• Limited evidence; lithium tablets may be too large to pass through lavage tube
• Generally not recommended

Enhanced Elimination - Hemodialysis:

Lithium is an ideal candidate for hemodialysis due to its pharmacokinetic properties: [35,36,89]

EXTRIP Recommendations for Lithium Dialysis (2015): [22,23]

Dialysis Recommended:

• Impaired kidney function AND serum lithium greater than 4 mmol/L
• Decreased level of consciousness, seizures, or life-threatening dysrhythmias (regardless of level)
• Serum lithium greater than 5 mmol/L (in acute toxicity)

Dialysis Suggested:

• Confusion regardless of lithium level
• Expected long time to achieve lithium less than 1 mmol/L with conservative therapy

Dialysis Modality:

Intermittent Hemodialysis (IHD):

• Preferred modality for severe toxicity
• Clearance: 70-170 mL/min
• Can reduce lithium level by 1 mmol/L per hour
• Duration: 4 hours standard, but often insufficient

Extended or Repeated Dialysis:

• Standard 4-hour HD often insufficient due to rebound
• Extended HD (6-8 hours) reduces rebound
• Sequential sessions (repeat HD after 6-8 hour break) may be needed
• Continue until lithium less than 1 mmol/L at least 6 hours after last session [32,33]

Continuous Renal Replacement Therapy (CRRT):

• Clearance: 20-60 mL/min (inferior to IHD)
• Role: Haemodynamically unstable patients unable to tolerate IHD
• Can follow initial IHD session to prevent rebound
• CRRT alone is NOT adequate for severe lithium toxicity [90,91]

Rebound Phenomenon:

After dialysis, serum lithium levels rise 0.5-1.0 mmol/L within 6-12 hours due to redistribution from intracellular and tissue compartments: [32,33]

Management:

• Check lithium level 6 hours post-dialysis
• Repeat dialysis if level rises above 1 mmol/L with symptoms
• Consider extended HD sessions (6-8 hours) initially
• Alternative: IHD followed by CRRT to prevent rebound
• End point: Lithium less than 1 mmol/L sustained at least 6 hours post-dialysis

Seizure Management:

• Benzodiazepines first-line (diazepam 5-10 mg IV, midazolam 5-10 mg IV/IM)
• Levetiracetam or phenobarbital for refractory seizures
• Avoid phenytoin (limited evidence for non-epileptic seizures)
• If status epilepticus: standard protocol with escalation to general anaesthesia

Nephrogenic Diabetes Insipidus:

• Identify (polyuria, hypernatraemia)
• Free water replacement for hypernatraemia
• Amiloride 5-10 mg BD may help (blocks ENaC, reduces lithium uptake into principal cells)
• May persist for weeks to months after lithium cessation [54]

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ICU Considerations

Monitoring Requirements

Digoxin Toxicity:

• Continuous cardiac monitoring (essential; arrhythmias can occur suddenly)
• Transcutaneous pacing pads in place
• Transvenous pacing equipment available
• Serial ECGs (every 1-2 hours during active toxicity)
• Electrolyte monitoring (K+, Mg2+, Ca2+) every 4-6 hours
• Serum digoxin level (note: falsely elevated post-DigiFab)
• Renal function monitoring

Lithium Toxicity:

• Continuous cardiac monitoring
• Neurological observations (GCS, pupil response) hourly
• Seizure precautions
• Serial lithium levels every 2-4 hours until declining
• Electrolytes (Na+, K+) every 4-6 hours
• Renal function monitoring
• Fluid balance (input/output chart)
• Temperature monitoring

Equipment Preparation

Digoxin Toxicity:

• DigiFab (check availability; may need to source from pharmacy stores or blood bank)
• Transcutaneous pacing equipment
• Transvenous pacing kit (may be needed if transcutaneous fails)
• Magnesium sulfate
• Lignocaine
• Activated charcoal (if recent ingestion)

Lithium Toxicity:

• Dialysis catheter insertion kit (femoral or internal jugular)
• Hemodialysis machine and consumables
• CRRT machine as backup
• Polyethylene glycol solution (for WBI)
• Benzodiazepines
• Intubation equipment (for airway protection if GCS declining)

RRT Access and Timing

Lithium:

• Early consultation with nephrology/renal service
• Insert dialysis catheter early if dialysis likely
• Do not delay dialysis while waiting for "final" lithium level
• Dialysis decision should be based on clinical severity, not just level
• In Australian rural/remote settings: arrange retrieval to tertiary centre with dialysis capability early

Digoxin:

• Dialysis is NOT effective
• Focus on DigiFab and supportive care

Retrieval Medicine Considerations (Australian Context)

Remote and Rural Settings:

• DigiFab availability: May not be stocked in small rural hospitals; check with state poisons information centre
• Lithium dialysis: Requires transfer to centre with hemodialysis capability
• Early retrieval consultation: Contact state retrieval service (e.g., RFDS, AV PIPER, NSW Aeromedical)
• Temporising measures while awaiting retrieval:
  • "Digoxin: IV fluids, atropine, transcutaneous pacing, magnesium"
  • "Lithium: IV normal saline, WBI for SR preparations, benzodiazepines for seizures"

Telemedicine Support:

• State poisons information centre: 13 11 26 (Australia)
• Specialist toxicology consultation available
• Can guide DigiFab dosing and dialysis decisions remotely

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Australian/NZ Context

ANZICS-CORE and CICM Guidelines

While there are no specific ANZICS-CORE statements on digoxin or lithium toxicity, management aligns with international toxicology guidelines and the EXTRIP (Extracorporeal Treatments in Poisoning) workgroup recommendations. [22,23]

Key Australian Resources:

• Australian Toxicology Online (AusTox): Evidence-based toxicology information
• Poisons Information Centre: 13 11 26 (24/7 specialist advice)
• Therapeutic Guidelines (eTG Complete): General principles of poisoning management
• PBS/TGA: DigiFab is PBS-listed for digoxin toxicity (Section 100)

Antidote Availability

DigiFab:

• Available in Australia as Digibind (GlaxoSmithKline) or DigiFab
• Stocked in major hospital pharmacies and emergency departments
• PBS Section 100 (restricted benefit)
• Cost: Approximately $800-1000 per vial; total cost for treatment can be $5,000-20,000
• Small hospitals may need to access via state health department antidote programs
• RFDS carries limited stock on some aircraft

State-Based Antidote Programs:

• NSW: Statewide Antidote Network (access via Clinical Toxicology Service)
• Victoria: Victorian Poisons Information Centre coordinates supply
• Queensland: Queensland Poisons Information Centre
• Other states: Contact local poisons centre

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Peoples:

Higher rates of cardiovascular disease, renal disease, and mental health conditions contribute to increased exposure to both digoxin and lithium: [92,93]

Risk Factors for Toxicity:

• Higher rates of rheumatic heart disease requiring digoxin for AF rate control
• Higher rates of CKD affecting drug clearance
• Geographic isolation affecting medication supply and monitoring
• Limited access to specialist services and monitoring
• Potential for medication adherence challenges due to cultural, social, and economic factors

Management Considerations:

• Cultural safety: Involve Aboriginal Health Workers (AHWs) and Aboriginal Liaison Officers (ALOs) early
• Language: Use interpreter services; ensure understanding of diagnosis and treatment
• Family involvement: Extended family may be involved in healthcare decisions
• Discharge planning: Consider access to medications, monitoring, and follow-up in remote communities
• Health literacy: Provide culturally appropriate information about avoiding future toxicity

Māori Health (New Zealand):

• Higher rates of cardiovascular disease and bipolar disorder
• Whānau (family) involvement in healthcare decisions is important
• Engage Māori Health Workers where available
• Consider tikanga (cultural protocols) in care delivery
• Ensure culturally safe communication about medications and monitoring

Medication Compliance and Monitoring

Challenges in Rural/Remote Australia:

• Limited access to pathology for therapeutic drug monitoring
• Tyranny of distance for specialist follow-up
• Medication supply issues (transport, storage)
• Shared care models may have communication gaps

Strategies:

• Point-of-care lithium testing where available
• Telehealth follow-up with specialists
• Clear communication between primary care, mental health services, and specialists
• Medication education for patients and families
• Aboriginal Community Controlled Health Services can provide culturally appropriate care

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Prognosis and Outcomes

Digoxin Toxicity

With DigiFab Treatment:

• Excellent prognosis; mortality less than 5% [10,94]
• Complete response in 80-90% of patients
• Onset of improvement within 30-60 minutes
• Full resolution typically within 24-48 hours
• Recurrence rare if adequate dosing

Without DigiFab:

• Mortality historically 15-30% [95]
• Worse outcomes with:
  • Hyperkalaemia greater than 6.5 mmol/L
  • Haemodynamically unstable arrhythmias
  • Advanced age
  • Underlying cardiac disease

Post-Recovery Considerations:

• Evaluate need for ongoing digoxin therapy
• Review for drug interactions
• Renal function monitoring
• Consider lower maintenance dose or alternative rate control agents

Lithium Toxicity

Mortality:

• Overall mortality: 9-25% depending on severity [96,97]
• Chronic toxicity: Higher mortality than acute at equivalent levels
• Prompt dialysis improves outcomes

Neurological Sequelae - SILENT Syndrome (Syndrome of Irreversible Lithium-Effectuated Neurotoxicity):

Persistent neurological deficits may occur after severe lithium toxicity, even with appropriate treatment: [98,99]

Features:

• Cerebellar dysfunction (ataxia, dysarthria, nystagmus)
• Extrapyramidal symptoms (rigidity, bradykinesia)
• Cognitive impairment (memory, executive function)
• Downbeat nystagmus (characteristic)
• Dementia

Risk Factors for Permanent Neurological Damage:

• Duration of toxicity before treatment
• Chronic toxicity pattern
• Hyperthermia
• Age greater than 50 years
• Concurrent neuroleptic use (NMS-like syndrome)
• Delays in dialysis initiation

Prognosis of Neurological Sequelae:

• Complete recovery: 50-60%
• Partial recovery: 25-35%
• Permanent deficits: 10-15%
• Recovery may continue for months after acute episode

Renal Outcomes:

• Acute kidney injury usually reversible
• Chronic interstitial nephritis may progress
• Monitor renal function long-term
• Nephrogenic DI may persist

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Progressive Difficulty Assessments

Basic Level (Foundation Knowledge)

Question 1: Definition

Q: What is the mechanism of digoxin toxicity at the cellular level?

A: Digoxin inhibits the Na+/K+-ATPase pump, which normally transports 3 Na+ out and 2 K+ into the cell. This leads to:

1. Increased intracellular Na+
2. Reduced activity of the Na+/Ca2+ exchanger (which relies on Na+ gradient)
3. Increased intracellular Ca2+
4. Enhanced contractility (therapeutic effect)
5. At toxic levels: Delayed afterdepolarisations and triggered activity (arrhythmias)

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Question 2: Risk Factors

Q: List 5 risk factors for chronic digoxin toxicity.

A:

1. Renal impairment (reduced elimination)
2. Hypokalaemia (increased digoxin binding to Na+/K+-ATPase)
3. Drug interactions (amiodarone, verapamil)
4. Advanced age (reduced renal function)
5. Hypomagnesaemia (depletes intracellular K+)

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Question 3: Lithium Dialysis

Q: Why is lithium an ideal candidate for hemodialysis?

A:

1. Low molecular weight (7 Da) - freely crosses membrane
2. Zero protein binding - all drug available for removal
3. Small volume of distribution (0.6-0.9 L/kg)
4. No active metabolites
5. Dialysis clearance (70-170 mL/min) far exceeds endogenous clearance (10-40 mL/min)

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Question 4: ECG Recognition

Q: Describe the ECG features of bidirectional ventricular tachycardia.

A:

1. Wide QRS complex tachycardia (rate 140-200 bpm)
2. Beat-to-beat alternation of QRS axis in frontal plane
3. Alternating morphology: typically RBBB with left axis then RBBB with right axis
4. Caused by triggered activity from alternating foci in left anterior and left posterior fascicles
5. Pathognomonic of digoxin toxicity (also seen in CPVT and aconitine poisoning)

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Intermediate Level (Applied Knowledge)

Question 1: Case-Based - Digoxin

Stem: A 78-year-old woman on digoxin for AF and heart failure presents with nausea, confusion, and an irregular pulse. She recently started clarithromycin for bronchitis.

HR 45 bpm, BP 95/60 mmHg

ECG: Complete heart block with junctional escape rhythm at 45 bpm

Labs: K+ 5.8 mmol/L, Creatinine 180 umol/L (baseline 95), Digoxin 4.2 ng/mL

Q1: Explain the mechanism of toxicity in this patient. (4 marks)

A1:

• Clarithromycin inhibits P-glycoprotein, reducing digoxin clearance (1 mark)
• This increases serum digoxin levels (1 mark)
• Additionally, acute renal impairment (creatinine risen from 95 to 180) further reduces elimination (1 mark)
• Digoxin toxicity causes enhanced vagal tone and direct AV nodal depression, leading to complete heart block (1 mark)

Q2: What treatment should be initiated? (4 marks)

A2:

• DigiFab (digoxin-specific antibody fragments) is indicated for:
  • Life-threatening arrhythmia (complete heart block with bradycardia) (1 mark)
  • Hyperkalaemia greater than 5.5 mmol/L (K+ 5.8) (1 mark)
• Dosing: Using formula: vials = [4.2 × 75] / 100 = 3.15 → 4 vials (1 mark)
• Atropine 0.6-1.2 mg IV as temporising measure; prepare transcutaneous pacing (1 mark)

Q3: Why should calcium not be given for the hyperkalaemia? (2 marks)

A3:

• Theoretical risk of "stone heart" (tetanic cardiac contraction) from combined effect of digoxin-induced intracellular Ca2+ overload plus exogenous calcium (1 mark)
• DigiFab is the appropriate treatment for digoxin-induced hyperkalaemia (1 mark)

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Question 2: Case-Based - Lithium

Stem: A 55-year-old man on lithium 900 mg daily for bipolar disorder presents after a gastroenteritis illness with 3 days of vomiting and diarrhoea. He is confused and has coarse tremor.

HR 65 bpm, BP 110/70 mmHg, Temp 37.2C

Labs: Na+ 148 mmol/L, K+ 3.1 mmol/L, Creatinine 220 umol/L (baseline 90), Lithium 3.2 mmol/L

Q1: What type of lithium toxicity is this, and why is it important? (3 marks)

A1:

• This is chronic lithium toxicity (patient on maintenance therapy, gradual accumulation) (1 mark)
• Precipitated by dehydration from gastroenteritis and acute kidney injury (1 mark)
• Important because chronic toxicity causes more severe symptoms at lower levels due to tissue (CNS) saturation, compared to acute overdose (1 mark)

Q2: Outline your initial management. (4 marks)

A2:

• IV normal saline resuscitation: 1-2 L bolus then 150-250 mL/hour (1 mark)
• Withhold lithium (1 mark)
• Correct hypokalaemia: IV KCl (1 mark)
• Nephrology consultation for consideration of hemodialysis (confusion = moderate toxicity; may meet EXTRIP criteria) (1 mark)

Q3: What phenomenon may occur after hemodialysis, and how would you manage it? (3 marks)

A3:

• Rebound: Lithium level may rise 0.5-1.0 mmol/L within 6-12 hours after dialysis due to redistribution from tissues (1 mark)
• Check lithium level 6 hours post-dialysis (1 mark)
• Options: extended HD sessions (6-8 hours), repeated HD sessions, or IHD followed by CRRT to prevent rebound (1 mark)

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Exam Level (CICM Second Part Standard)

See SAQ Practice section below.

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SAQ Practice

SAQ 1: Digoxin Toxicity with Bidirectional VT

Time Allocation: 10 minutes Total Marks: 20

Stem:

A 72-year-old woman is brought to the Emergency Department after being found unresponsive at home. She has a history of permanent atrial fibrillation and heart failure with reduced ejection fraction, for which she takes digoxin 125 mcg daily, furosemide 40 mg daily, and ramipril 5 mg daily. Her neighbour reports she has had gastroenteritis for 3 days.

Observations on arrival:

• HR: 170 bpm
• BP: 75/50 mmHg
• RR: 22/min
• SpO2: 94% on room air
• GCS: 9 (E2V3M4)

ECG (provided): Wide complex tachycardia at 170 bpm with beat-to-beat alternation of QRS axis

Investigations:

• pH: 7.28
• K+: 6.2 mmol/L
• Creatinine: 380 umol/L (baseline 120 umol/L)
• Digoxin: 5.8 ng/mL (therapeutic range 0.5-2.0)

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Question 1.1 (8 marks)

Identify the ECG abnormality and explain its mechanism in this clinical context.

Question 1.2 (6 marks)

Outline your immediate management priorities in the first 30 minutes.

Question 1.3 (6 marks)

Discuss the role and dosing of digoxin-specific antibody fragments (DigiFab) in this patient.

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Model Answer

Question 1.1 (8 marks)

ECG Interpretation (4 marks):

• The ECG shows bidirectional ventricular tachycardia (1 mark)
• Characterised by wide complex tachycardia with beat-to-beat alternation of QRS axis in the frontal plane (1 mark)
• Typically alternates between RBBB with left axis and RBBB with right axis (1 mark)
• This is virtually pathognomonic of digoxin toxicity (also seen in CPVT and aconitine poisoning) (1 mark)

Mechanism (4 marks):

• Digoxin inhibits Na+/K+-ATPase, leading to increased intracellular Na+ and subsequently increased intracellular Ca2+ (1 mark)
• Intracellular calcium overload causes oscillatory release from sarcoplasmic reticulum via ryanodine receptors (1 mark)
• This triggers delayed afterdepolarisations (DADs) and triggered activity in Purkinje fibres (1 mark)
• Bidirectional VT results from triggered activity alternating between left anterior fascicle and left posterior fascicle (1 mark)

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Question 1.2 (6 marks)

Airway and Breathing (1 mark):

• Protect airway given GCS 9; consider intubation if deteriorating
• High-flow oxygen

Circulation (3 marks):

• Do NOT attempt cardioversion - may precipitate VF in digoxin toxicity (1 mark)
• Large bore IV access; cautious fluid resuscitation (dehydration but cardiac failure) (1 mark)
• Prepare for DigiFab administration (definitive treatment); this is a cardiac arrest situation if deteriorates (1 mark)

Hyperkalaemia Management (1 mark):

• Do NOT give calcium (theoretical "stone heart" risk)
• Insulin 10 units + 50 mL 50% dextrose IV (shifts K+ intracellularly)
• DigiFab will also address hyperkalaemia by restoring Na+/K+-ATPase function

Specific Treatment (1 mark):

• Magnesium sulfate 2 g IV (suppresses triggered activity)
• Avoid anti-arrhythmics that may worsen conduction (amiodarone, class Ia/Ic agents)

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Question 1.3 (6 marks)

Indications in This Patient (2 marks):

• Life-threatening arrhythmia (bidirectional VT with haemodynamic instability) (1 mark)
• Hyperkalaemia greater than 5.5 mmol/L (K+ 6.2 mmol/L) (1 mark)

Mechanism (1 mark):

• Fab fragments bind free digoxin with high affinity, creating concentration gradient that draws digoxin from tissue binding sites; Fab-digoxin complex is renally eliminated

Dosing (2 marks):

• Empiric dosing appropriate for unstable/arresting patient: 10-20 vials IV bolus (1 mark)
• Alternatively, calculation based on level:
  • Number of vials = [Digoxin (ng/mL) × Weight (kg)] / 100
  • "Assuming 70 kg: [5.8 × 70] / 100 = 4.06 → 5 vials minimum (1 mark)"
• Given severity, empiric 10 vials would be appropriate

Monitoring (1 mark):

• Monitor clinical response (resolution of arrhythmia, improved haemodynamics)
• Post-DigiFab digoxin levels are falsely elevated (bound digoxin measured) - do not use for clinical decisions
• Monitor for hypokalaemia as K+ re-enters cells

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Examiner Comments:

• Strong candidates recognised bidirectional VT immediately and understood its pathognomonic significance
• Common errors: suggesting cardioversion, giving calcium for hyperkalaemia, incorrect DigiFab dosing
• Excellent candidates discussed why calcium and cardioversion are contraindicated

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SAQ 2: Lithium Toxicity Requiring Dialysis

Time Allocation: 10 minutes Total Marks: 20

Stem:

A 48-year-old man with bipolar disorder is transferred to ICU from the psychiatric ward. He has been on lithium carbonate 1200 mg daily (sustained-release) for 10 years. Three days ago he was commenced on naproxen for back pain. He presented today with progressive confusion, tremor, and ataxia.

Observations on arrival to ICU:

• HR: 88 bpm
• BP: 125/80 mmHg
• RR: 16/min
• SpO2: 98% on room air
• Temperature: 37.8C
• GCS: 11 (E3V3M5)

Investigations:

• Na+: 152 mmol/L
• K+: 3.4 mmol/L
• Creatinine: 165 umol/L (baseline 80 umol/L)
• Lithium: 3.6 mmol/L (therapeutic range 0.6-1.2)
• TSH: 8.5 mIU/L (normal 0.5-4.0)

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Question 2.1 (6 marks)

Classify this type of lithium toxicity and explain the factors that contributed to its development.

Question 2.2 (8 marks)

Outline your approach to managing this patient, including the role of hemodialysis.

Question 2.3 (6 marks)

Discuss the phenomenon of post-dialysis rebound and how you would manage it.

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Model Answer

Question 2.1 (6 marks)

Classification (2 marks):

• This is chronic lithium toxicity (1 mark)
• Patient on long-term maintenance therapy with gradual accumulation rather than acute ingestion (1 mark)

Contributing Factors (4 marks):

• NSAID (naproxen): Inhibits renal prostaglandin synthesis, reducing renal blood flow and GFR, and enhancing proximal tubular lithium reabsorption; increases lithium level by 15-30% (1 mark)
• Acute kidney injury: Creatinine doubled from 80 to 165 umol/L, reducing lithium clearance (likely NSAID-induced or contributed by volume depletion) (1 mark)
• Hypernatraemia (152 mmol/L): Suggests nephrogenic diabetes insipidus (common with chronic lithium use) with free water deficit; volume depletion enhances lithium reabsorption (1 mark)
• Chronic lithium use (10 years): Pre-existing tissue/CNS saturation means neurological symptoms occur at relatively lower serum levels compared to acute overdose (1 mark)

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Question 2.2 (8 marks)

Immediate Management (2 marks):

• Cease lithium immediately (1 mark)
• Cease naproxen and any other NSAIDs/ACE inhibitors/ARBs (1 mark)

Fluid Resuscitation (2 marks):

• IV normal saline bolus 1 L over 1 hour, then 150-250 mL/hour (1 mark)
• Aim to correct free water deficit for hypernatraemia (Na+ 152) - calculate deficit and correct slowly over 48-72 hours (1 mark)

Hemodialysis Indication (2 marks):

• This patient meets EXTRIP criteria for hemodialysis:
  • Lithium greater than 4 mmol/L with impaired kidney function (close at 3.6 mmol/L with creatinine 165) (0.5 mark)
  • Decreased level of consciousness (GCS 11, confusion) (0.5 mark)
• Recommend dialysis as confusion represents moderate-severe neurotoxicity (1 mark)

Dialysis Modality (2 marks):

• Intermittent hemodialysis preferred (clearance 70-170 mL/min vs 20-60 mL/min for CRRT) (1 mark)
• Extended session (6-8 hours) rather than standard 4-hour session to minimise rebound (1 mark)

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Question 2.3 (6 marks)

Rebound Phenomenon Explanation (3 marks):

• After hemodialysis, serum lithium level rises 0.5-1.0 mmol/L within 6-12 hours (1 mark)
• Caused by redistribution of lithium from intracellular and tissue compartments (especially brain) into plasma (1 mark)
• This is a particular problem in chronic toxicity where tissue stores are saturated (1 mark)

Management Strategy (3 marks):

• Monitor lithium level 6 hours post-dialysis (1 mark)
• Repeat dialysis if level rises above 1.0 mmol/L with ongoing symptoms (1 mark)
• Options to reduce rebound:
  • Extended HD sessions (6-8 hours initially)
  • Sequential HD sessions (repeat after 6-8 hour break)
  • IHD followed by CRRT to prevent rebound
  • "End point: Lithium less than 1 mmol/L sustained at least 6 hours after last dialysis (1 mark)"

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Examiner Comments:

• Strong candidates clearly distinguished chronic from acute lithium toxicity
• Excellent answers identified NSAIDs as precipitant and explained the mechanism
• Common errors: Recommending CRRT as sole modality (inferior clearance), not addressing rebound, incorrect dialysis thresholds
• Top candidates knew EXTRIP criteria and could discuss rebound management strategies

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Viva Scenarios

Viva Scenario 1: Chronic Digoxin Toxicity

Stem: "You are called to the ward to review a 75-year-old man with atrial fibrillation and heart failure. He has become confused over 3 days and the nurses have noted an irregular slow pulse. His usual medications include digoxin 250 mcg daily, furosemide 80 mg daily, and he was recently started on amiodarone 200 mg daily by his cardiologist."

Duration: 12 minutes (2 min reading + 10 min discussion)

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Opening Question (Examiner): "What are your immediate concerns about this patient?"

Model Response: My immediate concerns are:

1. Digoxin toxicity - highly likely given:

   • Confusion (CNS manifestation of chronic toxicity)
   • Slow irregular pulse (possible heart block or junctional rhythm)
   • Drug interaction: Amiodarone increases digoxin levels by 50-100% by inhibiting P-glycoprotein
   • High-dose furosemide may have caused hypokalaemia, which potentiates digoxin toxicity

2. Cardiac arrhythmia - the "irregular slow pulse" could represent:

   • Complete heart block with irregular escape rhythm
   • Regularised AF (AF with complete AV block - junctional escape)
   • Atrial tachycardia with variable AV block
   • Any of these could be life-threatening

3. Alternative diagnoses to consider: Sepsis, stroke, electrolyte disturbance, medication toxicity (other than digoxin)

Follow-up (Examiner): "His ECG shows atrial fibrillation with a regular ventricular response at 48 bpm. What does this indicate?"

Model Response: A regular ventricular response in a patient with atrial fibrillation indicates complete AV block with a junctional escape rhythm. This is highly specific for digoxin toxicity.

Normally in AF, the ventricular response is "irregularly irregular" due to random conduction of atrial impulses through the AV node. When the ventricular response becomes regular, it means no atrial impulses are conducting - complete AV block - and a subsidiary pacemaker (junctional or ventricular) has taken over.

This finding, combined with the clinical picture and drug interaction, confirms severe digoxin toxicity requiring:

• Immediate DigiFab administration
• Continuous cardiac monitoring
• Transcutaneous pacing capability

Follow-up (Examiner): "Explain how amiodarone causes digoxin toxicity."

Model Response: Amiodarone increases digoxin levels through multiple mechanisms:

1. P-glycoprotein inhibition: P-glycoprotein (ABCB1) is an efflux transporter that pumps digoxin out of intestinal cells (reducing absorption) and renal tubular cells (enhancing secretion). Amiodarone inhibits P-gp, resulting in:

   • Increased intestinal absorption
   • Reduced renal tubular secretion

2. Reduced renal clearance: Amiodarone reduces both glomerular filtration and tubular secretion of digoxin

3. Reduced non-renal clearance: Amiodarone inhibits hepatic metabolism of digoxin

The net effect is a 50-100% increase in serum digoxin concentration within 1-4 weeks of starting amiodarone. Guidelines recommend halving the digoxin dose when amiodarone is initiated.

Other drugs with similar interactions include verapamil, quinidine, and clarithromycin.

Follow-up (Examiner): "How does hypokalaemia exacerbate digoxin toxicity?"

Model Response: Hypokalaemia increases digoxin toxicity through competitive binding at the Na+/K+-ATPase:

1. Competitive binding: Both digoxin and potassium bind to the extracellular alpha subunit of Na+/K+-ATPase. When extracellular K+ is low, digoxin has less competition and binds more avidly to the pump.

2. Increased pump inhibition: At any given digoxin concentration, hypokalaemia results in greater inhibition of the pump and more intracellular calcium accumulation.

3. Arrhythmia facilitation: Hypokalaemia also independently increases the risk of arrhythmias through:

   • Prolonged repolarisation (QT prolongation)
   • Increased automaticity
   • This compounds the arrhythmogenic effects of digoxin toxicity

This is why potassium should be replaced to 4.0-5.0 mmol/L in digoxin toxicity. However, caution is needed if significant bradycardia is present, as potassium can worsen AV conduction.

Follow-up (Examiner): "His potassium returns at 2.8 mmol/L and digoxin level is 3.5 ng/mL. He is haemodynamically stable with HR 42 bpm. How would you manage the hypokalaemia?"

Model Response: This is a challenging situation - the patient needs potassium replacement (hypokalaemia exacerbates toxicity) but also has significant bradycardia (potassium may worsen this).

My approach:

1. Give DigiFab first - this is the priority. Once DigiFab binds digoxin, the toxic effects on the heart will be reversed, and potassium replacement will be safer.

2. Calculate DigiFab dose: Vials = [3.5 × 70] / 100 = 2.45 → 3 vials (assuming 70 kg) Given symptomatic toxicity, I would give 3-5 vials

3. Cautious potassium replacement after DigiFab initiated:

   • IV potassium chloride 20 mmol in 100 mL over 1 hour
   • Continuous cardiac monitoring
   • Target K+ 4.0-4.5 mmol/L

4. Also replace magnesium if low - hypomagnesaemia depletes intracellular potassium

5. Monitoring: Serial K+ every 2-4 hours, continuous ECG

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Viva Scenario 2: Acute Lithium Overdose

Stem: "A 28-year-old woman is brought to the Emergency Department by ambulance 4 hours after intentionally ingesting 60 tablets of lithium carbonate 250 mg (sustained-release preparation) in a suicide attempt. She has no psychiatric history and was not previously taking lithium."

Duration: 12 minutes (2 min reading + 10 min discussion)

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Opening Question (Examiner): "How would you classify this type of lithium toxicity and what does this mean for your clinical approach?"

Model Response: This is acute lithium toxicity in a lithium-naive patient.

Key implications:

1. Large dose ingested: 60 × 250 mg = 15 g of lithium carbonate. This is a massive overdose (therapeutic dose is 900-1200 mg/day).

2. GI symptoms will predominate initially: In acute overdose, nausea, vomiting, and diarrhoea are early symptoms. Neurological symptoms are delayed because:

   • Lithium distribution into the CNS takes time (hours to days)
   • Tissue and CNS are not yet saturated

3. Serum level may be very high without severe symptoms initially: Unlike chronic toxicity, patients may tolerate levels greater than 4-6 mmol/L initially before neurological deterioration.

4. Sustained-release preparation is concerning: Absorption will be prolonged over 12-24 hours. The level may continue to rise despite initial treatment. This is an indication for whole bowel irrigation.

5. Prognosis generally better than chronic toxicity: Because tissue stores are not yet saturated, prompt treatment including dialysis usually results in good outcomes.

Follow-up (Examiner): "Her initial lithium level at 4 hours post-ingestion is 2.8 mmol/L. She has nausea and mild tremor but GCS is 15. Would you dialyse her?"

Model Response: Not immediately, but I would prepare for dialysis and repeat the lithium level.

Current situation:

• Lithium 2.8 mmol/L at 4 hours post-ingestion
• GCS 15, no significant neurological toxicity
• GI symptoms only

However, critical concerns:

1. This is a sustained-release preparation - absorption continues for 12-24 hours
2. The level will rise - 2.8 mmol/L at 4 hours is likely to peak much higher
3. Total dose ingested (15 g) is massive

My approach:

1. Whole bowel irrigation (WBI): Start immediately with PEG solution 1.5-2 L/hour via NGT. This is specifically indicated for sustained-release lithium to prevent ongoing absorption.

2. IV normal saline: 1-2 L bolus then maintenance to achieve good urine output

3. Serial lithium levels: Every 2 hours until declining

4. Nephrology consultation: Early involvement as dialysis will likely be needed

5. Dialysis catheter insertion: Prepare for dialysis by inserting dialysis catheter now

I would dialyse if:

• Level rises above 4-5 mmol/L (EXTRIP recommends dialysis for level greater than 5 mmol/L in acute overdose)
• Any decline in GCS or neurological symptoms develop
• Level fails to decline with conservative measures

Follow-up (Examiner): "She has whole bowel irrigation started. Six hours later her lithium level is 4.8 mmol/L. GCS is now 13 (E3V4M6). How do you proceed?"

Model Response: This patient now meets criteria for hemodialysis based on EXTRIP guidelines:

• Lithium level approaching greater than 5 mmol/L (currently 4.8 and likely still rising)
• Declining level of consciousness (GCS 15 → 13)
• Massive ingestion with ongoing absorption despite WBI

Immediate actions:

1. Commence hemodialysis - intermittent HD is preferred over CRRT for severe lithium toxicity

   • High-flux dialyser
   • Blood flow 300-400 mL/min
   • Extended session (6-8 hours) rather than standard 4 hours

2. Continue WBI - there may still be lithium in the GI tract

3. Neuroprotective measures:

   • Airway protection if GCS declines further
   • Seizure precautions
   • Benzodiazepines available

4. Monitoring during dialysis:

   • Lithium level hourly during dialysis
   • Electrolytes (K+, Ca2+, Mg2+)
   • Vital signs, neurological observations

5. Post-dialysis management:

   • Check lithium 6 hours post-dialysis for rebound
   • May need repeat dialysis session

Follow-up (Examiner): "Why is intermittent hemodialysis preferred over CRRT for lithium toxicity?"

Model Response: Intermittent hemodialysis is preferred because of superior lithium clearance:

Clearance comparison:

• IHD: 70-170 mL/min lithium clearance
• CRRT (CVVHDF): 20-60 mL/min lithium clearance

Rate of removal:

• IHD can reduce lithium level by approximately 1 mmol/L per hour
• CRRT removes lithium more slowly

In severe toxicity (as here): Rapid removal of lithium is essential to prevent permanent neurological damage. The speed of IHD is crucial.

When CRRT has a role:

1. Haemodynamically unstable patients who cannot tolerate IHD
2. After initial IHD session - CRRT can be used as a "bridge" to prevent rebound while tissues equilibrate
3. Sequential approach: IHD for rapid removal, then CRRT to maintain low levels and prevent rebound

For this patient (young, haemodynamically stable, severe toxicity), IHD is clearly preferred. I would do an extended 6-8 hour session, then reassess with a lithium level 6 hours later to check for rebound.

Follow-up (Examiner): "Discuss Indigenous health considerations relevant to lithium toxicity in Australia."

Model Response: Several Indigenous health considerations are relevant:

Access and Distance:

• Remote communities may have limited access to lithium monitoring and dialysis facilities
• Delayed presentation due to travel distances and limited healthcare access
• Early retrieval to tertiary centre with dialysis is essential

Medication Adherence:

• Complex social situations, housing instability, and competing priorities may affect adherence
• Lithium requires regular blood monitoring - this may be difficult in remote areas
• Alternative medications with less monitoring burden may be considered for some patients

Mental Health Context:

• Aboriginal and Torres Strait Islander peoples experience higher rates of mental health conditions
• But may have lower rates of lithium use due to monitoring requirements
• Culturally safe mental health services are essential

Acute Management:

• Involve Aboriginal Health Workers (AHWs) and Aboriginal Liaison Officers (ALOs)
• Family/community involvement in decision-making
• Ensure culturally appropriate communication about diagnosis and treatment
• Consider language services if needed

Discharge Planning:

• Ensure follow-up is feasible (telehealth, community nursing, Aboriginal Community Controlled Health Services)
• Clear communication with primary care and mental health services
• Medication counselling appropriate to health literacy level
• Consider whether lithium is the best choice long-term given monitoring requirements

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References

Guidelines and Consensus Statements

1. EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup. Recommendations for lithium poisoning. Clin J Am Soc Nephrol. 2015. PMID: 25906177 [22,23]

2. EXTRIP Workgroup. Recommendations for digoxin poisoning. Clin J Am Soc Nephrol. 2016. PMID: 27436578 [12]

3. Therapeutic Guidelines - Toxicology and Wilderness. Therapeutic Guidelines Limited, Melbourne. 2019.

4. Australian Resuscitation Council (ARC). Guideline 9.3.1 - Drug-induced arrhythmias. 2022.

Landmark Studies and Major Reviews

5. Smith TW, et al. Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. N Engl J Med. 1982. PMID: 6281585 [10,71]

6. Antman EM, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Circulation. 1990. PMID: 2404631 [11,94]

7. Wenger TL, et al. Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments. J Am Coll Cardiol. 1985. PMID: 2984357 [28]

8. Timmer RT, Sands JM. Lithium intoxication. J Am Soc Nephrol. 1999. PMID: 10073594 [14,31]

9. Baird-Gunning J, et al. Lithium poisoning. J Intensive Care Med. 2017. PMID: 27207012 [15,77]

10. Oakley PW, et al. Lithium toxicity: an iatrogenic problem in susceptible individuals. Aust N Z J Psychiatry. 2001. PMID: 11437805 [79,96]

Mechanism and Pharmacology Studies

11. Hauptman PJ, Kelly RA. Digitalis. Circulation. 1999. PMID: 10217697 [4,38]

12. Gheorghiade M, et al. Digoxin in the management of cardiovascular disorders. Circulation. 2004. PMID: 15520333 [5,24]

13. Bauman JL, et al. Effect of serum potassium on the digoxin-myocardial Purkinje fiber interaction. Am J Cardiol. 1984. PMID: 6320651 [37,72]

14. Greiner AC, Berry K. Skin pigmentation and corneal and lens opacities with prolonged chlorpromazine therapy. Can Med Assoc J. 1964. PMID: 14184988 [48]

15. Malhi GS, et al. Lithium therapy and its interactions. Aust Prescr. 2012. PMID: 24800085 [47,51]

ECG and Arrhythmia Studies

16. Wellens HJ, et al. Bidirectional tachycardia: a manifestation of simultaneous junctional and ventricular tachycardia. Am J Cardiol. 1985. PMID: 4003295 [6,25]

17. Ma G, et al. Electrocardiographic manifestations: digitalis toxicity. J Emerg Med. 2001. PMID: 11399187 [7,42]

18. Fisch C, et al. Digitalis cardiotoxicity. J Am Coll Cardiol. 1985. PMID: 3888803 [26,65]

19. Lely AH, Van Enter CH. Large-scale digitoxin intoxication. Br Med J. 1970. PMID: 5420610 [63]

Drug Interaction Studies

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21. Nademanee K, et al. Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications. J Am Coll Cardiol. 1984. PMID: 6707335 [43]

22. Klein HO, et al. Verapamil-digoxin interaction. N Engl J Med. 1980. PMID: 7421954 [44]

23. Finch CK, et al. Rifampin and rifabutin drug interactions: an update. Arch Intern Med. 2002. PMID: 12379058 [46]

24. Phelan KM, et al. Lithium interaction with the cyclooxygenase-2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry. 2003. PMID: 14658946 [18]

25. Finley PR, et al. Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol. 1996. PMID: 8926732 [19,57]

Dialysis and Extracorporeal Treatment Studies

26. Bailey B, McGuigan M. Comparison of patients hemodialyzed for lithium poisoning and those for whom dialysis was recommended by PCC but not done. Clin Toxicol. 2000. PMID: 10901668 [35]

27. Leblanc M, et al. Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis. 1996. PMID: 8960041 [36,89]

28. Jaeger A, et al. Kinetics of lithium elimination in lithium poisoning treated with hemodialysis. Clin Toxicol. 1993. PMID: 8360891 [32]

29. Chua HC, et al. Rebound lithium toxicity after dialysis for lithium intoxication. Intern Med J. 2002. PMID: 12534863 [33]

30. Waring WS, et al. Acute lithium intoxication: influence of lithium formulation on the kinetics of elimination. Ther Drug Monit. 2007. PMID: 17700429 [88]

Digoxin-Specific Fab Fragment Studies

31. Ujhelyi MR, et al. Disposition of digoxin immune Fab in patients with kidney failure. Clin Pharmacol Ther. 1993. PMID: 8458120 [29]

32. Sinclair AJ, et al. The measurement of serum digoxin in the presence of Fab fragments of antidigoxin antibodies. Ther Drug Monit. 1989. PMID: 2727386 [30]

33. Flanagan RJ, Jones AL. Fab antibody fragments: some applications in clinical toxicology. Drug Saf. 2004. PMID: 15471515 [71]

Clinical Toxicology Reviews

34. Proudfoot AT. Acute poisoning due to cardiac glycosides. Adverse Drug React Acute Poisoning Rev. 1983. PMID: 6364831 [59]

35. Antman EM. Digitalis toxicity. In: Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 19th ed. 2015. [60,62]

36. Hoffman RS, et al. Goldfrank's Toxicologic Emergencies. 11th ed. McGraw-Hill. 2019. [1,68]

37. Isbister GK. Lithium toxicity. Med J Aust. 2011. PMID: 21513999 [16,81]

Nephrogenic Diabetes Insipidus and Renal Effects

38. Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. 2009. PMID: 19190680 [17,54]

39. Presne C, et al. Lithium-induced nephropathy: rate of progression and prognostic factors. Kidney Int. 2003. PMID: 12675862 [55]

40. Bedford JJ, et al. Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. Clin J Am Soc Nephrol. 2008. PMID: 18596120 [54]

Neurological Sequelae

41. Adityanjee, et al. The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). Clin Neuropharmacol. 2005. PMID: 16062098 [98]

42. Mowry JB, et al. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System. Clin Toxicol. 2015. PMID: 26624241 [97]

43. Chen KT, et al. Permanent cerebellar ataxia following acute lithium intoxication. J Neurol. 2013. PMID: 24005731 [99]

Australian-Specific References

44. ANZICS CORE Annual Report 2023. Australian and New Zealand Intensive Care Society. [Available online]

45. Marley J, et al. Australian medicines handbook. Adelaide: Australian Medicines Handbook Pty Ltd. 2024.

46. Gray SL, et al. Aboriginal and Torres Strait Islander health and wellbeing. Med J Aust. 2020. PMID: 32488906 [92,93]

47. Poisons Information Centre Australia. National guidelines for poisoning management. [13 11 26]

48. RFDS (Royal Flying Doctor Service). Clinical guidelines for retrieval. 2023.

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Related Topics

Prerequisites

• [[Cardiac Electrophysiology]]
• [[Renal Replacement Therapy]]
• [[Antiarrhythmic Pharmacology]]
• [[Acid-Base Disorders]]

Related Conditions

• [[Beta-Blocker and Calcium Channel Blocker Overdose]]
• [[Hyperkalaemia]]
• [[Cardiac Arrhythmias]]
• [[Acute Kidney Injury]]

Complications

• [[Status Epilepticus]]
• [[Cardiogenic Shock]]
• [[Nephrogenic Diabetes Insipidus]]

Procedures

• [[Transcutaneous and Transvenous Pacing]]
• [[Hemodialysis in the ICU]]

Pharmacology

• [[Digoxin Pharmacology]]
• [[Lithium Pharmacology]]
• [[DigiFab (Digoxin-Specific Antibody Fragments)]]