Lithium toxicity

Background

• Lithium remains the most effective treatment for bipolar disorder despite availability of newer agents
• Mechanism of action poorly understood; modulates neurotransmitter signaling
• Narrow therapeutic index (therapeutic level: 0.6-1.2 mEq/L)
• Pharmacokinetics:
  • Rapidly absorbed (peak 1-2h for immediate release; 4-12h for sustained release)
  • Initially distributes in extracellular fluid → gradually redistributes to CNS (up to 24 hours)
  • 95% renally excreted; handled like sodium by proximal tubule
• Lithium toxicity rarely fatal (only 11 deaths out of 6815 reported toxic exposures in 2012)

Common Precipitants

• Volume depletion: vomiting, diarrhea, diaphoresis, decreased PO intake
• Medications that decrease lithium excretion:
  • NSAIDs, ACE inhibitors/ARBs, thiazide diuretics
• Acute kidney injury or chronic kidney disease
• Intentional overdose
• Hyperthermia, CHF, sepsis
• Nephrogenic diabetes insipidus (caused by chronic lithium use) → dehydration → ↑ lithium levels

Clinical Features

Three recognized patterns of toxicity:

Acute Ingestion

• Patient not previously on lithium (no body stores)
• GI symptoms predominate: nausea, vomiting, diarrhea, abdominal pain (earliest/most common)
• Cardiac: bradycardia, QT prolongation, T-wave flattening/inversion, Brugada-like pattern
• CNS depression is a late finding (takes time for lithium to redistribute to brain)
• Serum levels may be very high but do not correlate with clinical toxicity

Acute-on-Chronic

• Patient on chronic lithium who takes supra-therapeutic dose
• Mixed GI and CNS symptoms

Chronic Toxicity

• Insidious onset in patients on chronic therapy
• Due to increased absorption or decreased elimination
• CNS symptoms predominate (generally more severe than acute):
  • Mild: fine tremor, drowsiness, muscle weakness
  • Moderate: hyperreflexia, confusion, coarse tremor, ataxia, slurred speech
  • Severe: seizures, myoclonus, coma, extrapyramidal symptoms
• Hypothyroidism (lithium inhibits thyroid hormone release)

SILENT Syndrome

• Syndrome of Irreversible Lithium-Effectuated Neurotoxicity
• Neurologic dysfunction persisting >2 months after cessation of lithium
• Cerebellar dysfunction (dysarthria, ataxia, gait instability), peripheral neuropathy, dementia

Differential Diagnosis

• Serotonin syndrome
• Neuroleptic malignant syndrome
• Thyroid storm / hypothyroidism
• Alcohol or sedative-hypnotic intoxication
• Structural CNS lesion
• Other heavy metals toxicity
• Uremia

Evaluation

• Lithium level:
  • Therapeutic: 0.6-1.2 mEq/L
  • Levels >1.5 mEq/L may be associated with toxicity (chronic > acute for same level)
  • Do NOT use green top (lithium heparin) tube — falsely elevates level
  • Serum levels do not predict CNS levels and only roughly correlate with clinical symptoms
  • Serial levels every 2-4 hours (especially after overdose or post-HD)
• BMP: creatinine, sodium (often hyponatremic or hypernatremic), calcium
• TSH (chronic use → hypothyroidism)
• ECG: QT prolongation, T-wave changes, bradycardia, Brugada pattern
• Acetaminophen and salicylate levels (possible coingestants)
• Urinalysis (urine specific gravity to evaluate concentrating ability)

Management

GI Decontamination

• Whole bowel irrigation (WBI): only for sustained-release tablet ingestion
  • PEG solution via NG at 1-2 L/hr (adults)
• Activated charcoal is NOT effective (lithium is not adsorbed)
• Gastric lavage generally not effective and potentially harmful

Fluid Resuscitation

• Most important initial intervention — most patients have volume/sodium deficit
• NS is preferred (restores sodium, promotes renal lithium excretion)
• Give 2L NS bolus, then 200 mL/hr (or 2× maintenance)
• Target UOP 1-2 mL/kg/hr
• Avoid forced diuresis with loop diuretics (may worsen lithium toxicity)

Hemodialysis

• Most effective method of lithium removal
• Must follow serial lithium levels post-HD — levels will rebound due to tissue redistribution
• May require multiple sessions
• EXTRIP Workgroup Indications:
  • Recommended (1D): impaired kidney function AND Li >4.0 mEq/L
  • Recommended (1D): clinical deterioration (decreased LOC, seizures, life-threatening dysrhythmias) regardless of level
  • Suggested (2D): Li >5.0 mEq/L
  • Suggested (2D): expected time to Li <1.0 mEq/L with optimal management >36 hours
• Contraindication to aggressive fluids (CHF) lowers threshold for HD
• Consult toxicology and nephrology — complex decision

Endpoint of Dialysis

• Continue HD until lithium level <1.0 mEq/L
• Recheck level 6-8 hours post-HD for rebound

Disposition

• Discharge considerations (acute ingestion):
  • Asymptomatic after 4-6 hours observation
  • Two downtrending lithium levels
  • No worsening renal function
• Admit:
  • All patients with Li level >1.5 mEq/L
  • All sustained-release preparation ingestions (regardless of Li level)
  • Any patient with neurologic symptoms
  • Any patient requiring hemodialysis
• Poison control: 1-800-222-1222

See Also

• Toxicology
• Heavy metals
• Bipolar disorder
• Serotonin syndrome
• Neuroleptic malignant syndrome

References

• Baird-Gunning J, et al. Lithium poisoning. J Intensive Care Med. 2017;32(4):249-263. PMID 27055773
• Ott M, et al. Lithium intoxication: incidence, clinical course and renal function — a population-based retrospective cohort study. J Psychopharmacol. 2016;30(10):1008-1019. PMID 27530173