Lithium Toxicity

Lithium has a narrow therapeutic index (serum level 0.6 to 1.2 mmol/L) and is cleared almost entirely by the kidney. It is reabsorbed with sodium in the proximal tubule, so sodium depletion and renal impairment raise levels.

Patterns

• Acute overdose in a naive patient: high level but relatively mild neurological toxicity at first, with gastrointestinal symptoms and delayed central nervous system entry
• Acute-on-chronic overdose: severe
• Chronic toxicity: the commonest, caused by dehydration, intercurrent illness, acute kidney injury, or interacting drugs. It produces severe neurological toxicity at modest levels (1.5 to 2.5 mmol/L) because of brain accumulation.

Interacting drugs: non-steroidal anti-inflammatory drugs, ACE inhibitors, angiotensin receptor blockers, thiazide diuretics, loop diuretics (less), and metronidazole. Complications: coarse tremor, ataxia, seizures, coma, nephrogenic diabetes insipidus, arrhythmia, and the syndrome of irreversible lithium-effectuated neurotoxicity (persistent cerebellar deficits).

• Mild (1.5 to 2.5 mmol/L): coarse tremor, nausea, vomiting, diarrhea, polyuria, thirst, drowsiness, muscle weakness
• Moderate (2.5 to 3.5 mmol/L): confusion, ataxia, dysarthria, nystagmus, myoclonus, hyperreflexia, fasciculation
• Severe (over 3.5 mmol/L): seizures, coma, hypotension, QT prolongation, bradyarrhythmia, renal failure
• Nephrogenic diabetes insipidus with polyuria and hypernatremia
• Red flags: seizures, falling consciousness, severe dehydration and acute kidney injury

1. Serum lithium level: use a plain or EDTA tube, never a lithium heparin tube (it gives a false rise). Repeat every 4 to 6 hours until falling on 2 occasions (a delayed peak occurs with sustained-release preparations). Clinical severity matters more than the level in chronic toxicity.
2. Urea, creatinine, electrolytes (sodium), calcium, glucose, osmolality, thyroid function and ECG.
3. Urine output and urine osmolality for diabetes insipidus.
4. Paracetamol and salicylate levels in deliberate overdose.

Differentials: sepsis-associated encephalopathy, serotonin syndrome, neuroleptic malignant syndrome, anticholinergic toxicity, cerebellar stroke, hypercalcemia.

1. Stop lithium and interacting drugs.
2. Fluids: IV 0.9% saline 1 to 2 L over 1 to 2 hours, then 150 to 200 mL/h, adjusted to urine output over 1 mL/kg/h. Use 0.45% saline or 5% dextrose if hypernatremia develops. Monitor sodium every 6 hours.
3. Activated charcoal does not bind lithium. Use whole bowel irrigation (polyethylene glycol solution 1 to 2 L/h orally or by tube until the effluent is clear) for large sustained-release overdoses in alert patients with an intact airway.
4. Haemodialysis (the extracorporeal treatment of choice):
   • Indications: lithium over 4.0 mmol/L with impaired kidney function, a level over 5.0 mmol/L regardless of function, a reduced level of consciousness, seizures or life-threatening arrhythmia irrespective of the level, or a level over 1.0 mmol/L when the expected time to reach below 1.0 with optimal management exceeds 36 hours.
   • Continue until the level is under 1.0 mmol/L, or for at least 6 hours, and check a level 6 hours after stopping since rebound is common (repeat dialysis if the level rises over 1.0 mmol/L).
   • Continuous venovenous haemodiafiltration is used if the patient is haemodynamically unstable.
5. Nephrogenic diabetes insipidus: amiloride 5 to 10 mg orally once daily, with adequate hydration.
6. Seizures: lorazepam 4 mg IV (children 0.1 mg/kg, maximum 4 mg).
7. Avoid diuretics, which worsen lithium retention.
8. Hypotension: crystalloid 20 mL/kg and norepinephrine 0.05 to 0.5 micrograms/kg/min.

Prevention: check levels 12 hours after the last dose, at 5 to 7 days after any dose change, then every 3 to 6 months with renal and thyroid function. Counsel patients to hold lithium during vomiting, diarrhea or dehydration and avoid non-steroidal anti-inflammatory drugs. Lithium is teratogenic (cardiac malformations), so plan pregnancy with a specialist.