a test of metal…

• Post operative delirium
• Stroke
• Serotonin syndrome
• Lithium toxicity…

• Lithium level
• EUC (especially Na+)
• CT-Brain
• ECG

Chronic Lithium Toxicity…

A monovalent cation primarily used in the management of bipolar disorder.

• A metal salt (lithium carbonate) & mood-stabilising agent.
• Mechanism of action poorly understood.
  • Lithium ions substitute for sodium and potassium ions
  • Thought to modulate intracellular second messengers.
  • Increases serotonin release & receptor sensitivity. Also inhibits noradrenaline and dopamine release.

Pharmacokinetics;

• Complete oral absorption within 6 hours.
• Peak serum levels within 0.5-4 hours.
  • Absorption can be delayed in overdose (peak levels delayed up to 12 hours with slow-release preparations).
• Not bound to plasma proteins (therefore Vol.D similar to body water ~ 0.4L/kg)
• Slow redistribution from intravascular space to tissue compartment.
  • Brain lithium distribution may take up to 24 hours.
  • Neurological effects do not correlate with serum levels (often a 2-3 fold discrepancy between plasma & CSF levels).
• Elimination is entirely renal.
  • Elimination half-life is ~18-24 hours (double in elderly)
• Clearance is dependent upon GFR (freely filtered by glomerulus).
  • Reduced in water & sodium-depleted states.

Chronic Lithium Toxicity.

Occurs in a patient who takes lithium regularly has significant body stores & develops toxicity due to increased absorption or decreased lithium renal elimination. This occurs in up to 75-90% of patients on long-term lithium therapy.

• Elderly patients are more at risk of toxicity due to lower volumes of distribution, reduced renal clearance & associated medication use (esp. loop diuretics & ACEi).
• Chronic toxicity classically displays earlier & greater neurologic effects in association with lower serum levels.
• Associated with nephrogenic diabetes insipidus which can result in hyponatraemia & dehydration (hence increasing lithium levels).
• Lithium also inhibits the synthesis & release of thyroid hormone with hypothyroidism occurring in ~5% of patients on chronic lithium therapy.

Risk Assessment.

• Consider lithium intoxication in any patient on lithium therapy that presents with neurological signs or symptoms.
• Significant obtundation or seizure activity indicates severe toxicity & carries a risk of permanent neurological sequelae.
• Serum lithium concentrations correlate poorly with clinical features of toxicity.
• Toxicity can be precipitated by;
  • Renal failure
  • Volume depletion
  • Hyperthermia / NMS
  • Infection, DM, CCF, Cirrhosis.
  • Surgery.

Clinical Features.

• Principally neurological;
  • Grade 1 (Mild)
    • Tremor, hyperreflexia, agitation, muscle weakness, ataxia
  • Grade 2 (Moderate)
    • Stupor, rigidity, hypertonia, hypotension
  • Grade 3 (Severe)
    • Coma, convulsions, myoclonus.
• GI features are not prominent.
• There may be features of an underlying precipitating illness.
  • Eg. Impaired renal function, DI, sodium depletion, dehydration or drug interactions.
• Nephrogenic DI & hypothyroidism can co-exist.

Investigations.

• Serum lithium level.
  • Essential to confirm diagnosis
  • Note: serum levels do not correlate well with CSF levels and clinical severity
• EUC
• TFTs
• Others (ECG, paracetamol level etc).

Management.

• Resus, supportive care & monitoring.
  • Airway protection, ventilatory & haemodynamic support.
  • Resuscitation per se is generally not needed with the exception of extreme neurotoxicity (coma & seizures).
    • Treat seizures with benzos.
    • Phenytoin is not helpful (& likely decreases lithium excretion)
  • Correction of sodium & water deficits.
  • Restoration of renal function.
  • Cessation of lithium & interacting drugs
• Decontamination.
  • No role for activated charcoal or gastric lavage.
  • Whole-bowel irrigation remains controversial.
• Enhanced elimination.
  • Haemodialysis enhances elimination
    • Increases clearance from 15-20mL/min to 100mL/min.
    • Considered for patients with neurological symptoms and level > 2.5mmol/L (but no evidence based consensus established).
    • Likely to be useful in setting of established renal failure.
    • Sessions may need to be prolonged & repeated.
• Antedotes.
  • None.

Disposition.

• Patients with chronic lithium toxicity always require admission
• Resolution of neurological symptoms may be very slow & sometimes incomplete.
  • SILENT (Syndrome of Irreversible Lithium-Effectuated Neurotoxicity) when > 2 months duration.
    • Cerebellar dysfunction, persistent extrapyramidal symptoms, brainstem dysfunction & dementia.
    • Fever is a poor prognostic sign.

Other.

Lithium has also been implemented in neuroleptic malignant syndrome & serotonin syndrome.

• Avoid lithium in conjunction with serotonin agents (SSRIs, MAOi, St John’s Wort,  TCAs, amphetamines & some opiates [pethidine, tramadol, fentanyl, buprenorphine].

• Lithium was ceased.
• Likely toxicity secondary to prolonged pre-op fasting state and subsequent dehydration.

• CT-Brain showed old microvascular changes, but no acute pathology.
• Her symptoms gradually resolved over the next 8-10 days.

1. Murray L, Daly F, Little M & Cadogan M. Toxicology Handbook. 2nd Edition. Elsevier 2011.
2. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 7th Edition.
3. Rosenʼs Emergency Medicine. Concepts and Clinical Approach. 7th Edition