a test of metal…

The case.

64 year old female who is day 1 post elective left total-knee replacement. She has a past medical history of osteoarthritis, bipolar disorder and depression for which she takes quetiapine, lithium and paracetamol. You are asked to see her on the ward for optimization of her pain management with a concern that she “just isn’t quite right” with confusion & new onset of word finding difficulties.

Her current pain regime consists of

      • Paracetamol 1g q6h
      • Fentanyl PCA (10mcg q5min)
      • Ibuprofen 400mg q8h

She did receive two doses of tramadol the day before….

On examination she has an altered mental state with disorientation to time and place. At times she speaks in absolute gibberish. Of concern is her symmetrical hyperreflexia and inducible lower limb clonus ….

[DDET What are your concerns ?]

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


[DDET What investigations are you going to order ??]

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


[DDET The results…]


Lithium Level & TFTs]


[DDET The diagnosis…?]

Chronic Lithium Toxicity…


[DDET More about Lithium…]

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.


    • 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.


[DDET How are you going to manage this lady…]

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.


      • 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).


      • 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.


      • 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.


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].


[DDET Progress & Follow-up…]

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

Lithium Progress

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


[DDET References.]

  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


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