Lithium toxicity

Background

• Mechanism of action is poorly understood.
• Despite availability of newer drugs, Lithium remains most effective treatment for bipolar disorder, and it is still in use
• Lithium initially distributes in extracellular fluid, then gradually redistributes to other areas including the brain (takes up to 24 hours after absorption)
• 95% renal excretion
  • NSAIDs, diuretics, ACE-inhibitors → ↑ Lithium serum concentration by ↓ lithium excretion
• Lithium toxicity rarely fatal (only 11 deaths out of 6815 reported toxic exposures in 2012)

Common Precipitants

• Overdose
• Renal failure
• Volume depletion
  • Diuretic use, vomiting, diarrhea, diaphoresis, decreased oral intake
• Hyperthermia
• Infection
• CHF
• Surgery
• Cirrhosis

Clinical Features

Three recognized patterns of Lithium toxicity - "Acute", "Acute-on-chronic", and "Chronic".

Acute

Occurs in patients not previously receiving lithium (i.e. with no current body stores)

Serum concentrations can fall rapidly as lithium redistributes to tissues, and serum level does not correlate with degree of toxicity. GI symptoms predominate.

• GI - nausea/vomiting, diarrhea, abdominal pain
  • Earliest and most common symptoms
• Cardiac effects - bradycardia, QT prolongation, T-wave flattening or inversion
  • Can also cause Brugada-like ECG pattern
• CNS Depression - late finding (takes time for lithium to distribute to CNS), indicates progression of toxicity

Acute-on-Chronic

Also called "Acute-on-therapeutic", occurs in patients currently taking lithium due to acute ingestion of supra-therapeutic doses.

• Symptoms are a mix of both acute and chronic - includes both GI and CNS effects

Chronic

Occurs insidiously in patients on chronic lithium therapy. Toxicity is secondary to increased absorption or decreased elimination. CNS symptoms predominate.

Chronic lithium therapy is associated with nephrogenic diabetes insipidus, which → hypernatremia, fluid loss → ↑ lithium levels (can precipitate toxicity)

• Neurotoxicity is major finding, and is generally more profound than that seen in acute toxicity
  • Mild symptoms include tremor, drowsiness
  • Progressive symptoms include hyperreflexia, confusion, ataxia, seizures, extrapyramidal symptoms, coma
• Hypothyroidism (lithium inhibits thyroid hormone release)

Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT)

• Persistent sequelae of lithium toxicity
• Defined as neurologic dysfunction persisting > 2 months after cessation of lithium therapy
• Exact mechanism unknown (possibly related to CNS demyelination).
• Symptoms
  • Cerebellar dysfunction (dysarthria, ataxia, tremor, gait instability)
  • Peripheral neuropathy
  • Extrapyramidal symptoms
• Brainstem dysfunction
• Dementia

Differential Diagnosis

Heavy metal toxicity

• Aluminum toxicity
• Antimony toxicity
• Arsenic toxicity
• Barium toxicity
• Bismuth toxicity
• Cadmium toxicity
• Chromium toxicity
• Cobalt toxicity
• Copper toxicity
• Gold toxicity
• Iron toxicity
• Lead toxicity
• Lithium toxicity
• Manganese toxicity
• Mercury toxicity
• Nickel toxicity
• Phosphorus toxicity
• Platinum toxicity
• Selenium toxicity
• Silver toxicity
• Thallium toxicity
• Tin toxicity
• Zinc toxicity

Evaluation

• Lithium level
  • Therapeutic level = 0.6-1.2 meq/L
  • Serum level may be falsely elevated if placed in a green top tube due to the heparin lithium interaction
  • Serum levels do not predict CNS levels and only roughly correlate with clinical symptoms
• Metabolic Panel
• TSH
• ECG
• Acetaminophen and Salicylate Levels (possible coingestants)

Management

GI decontamination

• Whole bowel irrigation (only for extended release tablets)
• Gastric lavage and activated charcoal not effective and potentially harmful

Fluid resuscitation

• Average patient has Na/volume deficit; giving fluid helps reestablish normal renal Lithium excretion
• Give 2L NS bolus, then start 200mL/hr or 2x maintenance rate

Hemodialysis

Most effective method of removal. Must follow serial lithium levels - levels will likely rise after HD due to redistribution from tissues; additional HD may be required. Indications:

• Kidney function is impaired and the [Li+] >4.0 mEq/L (1D recommendation)
• Clinical deterioration
• In the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of [Li+] (1D)
• [Li+].>5.0 mEq/L (2D suggestion)
• If the expected time to obtain a [Li+]<1.0 mEq/L with optimal management is >36 h (2D suggestion)
• Baseline renal failure
• Contraindication to aggressive fluid resuscitation (CHF, etc)
• Make final decision after consulting toxicologist and/or nephrologist since it's a complex decision

Disposition

• Consider discharge for patients who are asymptomatic after 4-6hr obs, 2 downtrending lithium levels, and no worsening of renal function
• Admit all patients with Li level >1.5
• Admit all patients with ingestion of sustained-release preparation (regardless of Li level)

See Also

• Toxicology (Main)
• Lithium
• Heavy metals