Lithium Toxicity

Aka: Lithium Toxicity, Lithium Poisoning, Lithium Intoxication

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II. Epidemiology

  1. Incidence of Lithium Intoxication: 7000 cases/year U.S.
    1. Most patients on chronic Lithium will experience at least one episode of toxicity
  2. Mortality
    1. Current: <1%
    2. Historical: 9 to 25%

III. Mechanism

  1. Lithium has a narrow therapeutic range
  2. Lithium concentrates most in CNS and renal tissue

IV. Pharmacokinetics

  1. See Lithium

V. Risk Factors: Toxicity

  1. Renal dysfunction (Low Glomerular Filtration Rate)
  2. Sodium Retention states (associated with greater Lithium reabsorption)
    1. Volume depletion (Vomiting or Diarrhea, Diuretics)
    2. Acute Heart Failure
    3. Cirrhosis
  3. Medications
    1. Thiazide Diuretics (e.g. Hydrochlorothiazide, Chlorthalidone)
    2. Spironolactone
    3. ACE Inhibitors
    4. NSAIDS
    5. Calcium Channel Blockers
  4. Socioeconomic Factors
    1. Poor health care access
    2. Poor living conditions

VI. Findings: General Based on Timing of Presentation

  1. Acute Lithium Toxicity
    1. Early Findings: Gastrointestinal symptoms
    2. Late Findings: Neurologic symptoms
  2. Acute on Chronic Toxicity
    1. Early Findings: Gastrointestinal symptoms (more severe than in acute toxicity alone)
    2. Late Findings: Neurologic symptoms (may appear sooner than in acute toxicity alone)
  3. Chronic Toxicity
    1. Neurologic findings
      1. No delay in neurologic findings as Lithium distribution in the CNS has already occurred

VII. Findings: Gastrointestinal

  1. Nausea or Vomiting
    1. Lithium may cause Nausea as an adverse effect, but Vomiting is a red flag for toxicity
    2. Gastrointestinal losses and Dehydration (with decreased GFR) may worsen toxicity
  2. Diarrhea
  3. Abdominal Pain

VIII. Findings: Neurologic (late sign in acute toxicity, common in chronic toxicity)

  1. Listless or sluggish
  2. Ataxia
  3. Confusion
  4. Agitation
  5. Tremors or Myoclonic Jerks
    1. LithiumTremor
      1. May be seen in patients on chronic Lithium WITHOUT toxicity
      2. Symmetric, upper extremity fine motor Tremor
    2. Lithium Toxicity Tremor
      1. Course, more severe Tremor that may affect all extremities
  6. Seizures and encephalopathy (severe cases)
    1. See below for Syndrome of Irreversible Lithium Effectuated Neurotoxicity (SILENT)

IX. Labs: General

  1. Complete Blood Count (CBC)
    1. White Blood Cell Count is commonly increased with Lithium Toxicity
  2. Serum chemistry (chem8)
    1. Nephrotoxicity (especially associated with chronic Lithium Toxicity)
      1. Increased Serum Creatinine, Blood Urea Nitrogen
    2. Nephrogenic Diabetes Insipidus (typically with chronic Lithium Toxicity)
      1. Hyponatremia
    3. Lithium is not typically associated with acid base disorders
      1. See Unknown Ingestion
      2. Consider coingestion (e.g. Toxic Alcohols)
  3. Urine Pregnancy Test
  4. Urinalysis
    1. Very low Urine Specific Gravity in Nephrogenic Diabetes Insipidus
  5. Thyroid Stimulating Hormone (TSH)
    1. Hypothyroidism or Hyperthyroidism
  6. Unknown Ingestion and Altered Level of Consciousness testing
    1. Venous Blood Gas
    2. Acetaminophen Level
    3. Salicylate Level
    4. Urine Drug Screen
    5. Serum Glucose

X. Labs: Lithium Level

  1. Precautions
    1. Peak levels may not be reached for >12 hours after Overdose of sustained release Lithium
    2. For a given level, symptoms may be more mild in acute toxicity than in chronic toxicity
    3. Obtain levels every 4 hours to trend absorption and distribution until the level peaks
      1. Lithium levels may be initially needed every 4 to 6 hours for >24 hours
  2. Therapeutic Level: 0.8 to 1.2 mEq/L
  3. Mild Toxicity: 1.5 to 2.5 mEq/L (Hansen and Amdisen Grade 1)
    1. Tremor
    2. Slurred Speech
    3. Listlessness
    4. Ataxia
    5. Nausea or Vomiting
  4. Moderate Toxicity: 2.5 to 3.5 mEq/L (Hansen and Amdisen Grade 2)
    1. Stupor
    2. Rigidity and hypertonia
    3. Hypotension
  5. Severe Toxicity: >3.5 mEq/L (Hansen and Amdisen Grade 3)
    1. Encephalopathy or coma
    2. Seizures
    3. Myoclonus

XI. Diagnostics

  1. Electrocardiogram (EKG changes are uncommon)
    1. QTc Prolongation (increased risk with higher Lithium levels)
    2. T Wave Flattening
    3. Sinus Bradycardia
    4. Heart Block
    5. Ventricular tachyarrhythmias

XII. Differential Diagnosis

  1. See Altered Level of Consciousness
  2. See Unknown Ingestion
  3. Serotonin Syndrome
  4. Neuroleptic Malignant Syndrome
  5. Alcohol Withdrawal
  6. Benzodiazepine Withdrawal
  7. Closed Head Injury
  8. Cerebrovascular Accident
  9. Thyroid Disease (e.g. Thyrotoxicosis, Myxedema Coma)
  10. Hypoglycemia

XIII. Management: General

  1. See ABC Management
  2. Gastric Decontamination (acute toxicity only)
    1. AVOID Activated Charcoal (no benefit)
      1. Lithium is not absorbed by Activated Charcoal
    2. Whole Bowel Irrigation
      1. Consider in awake asymptomatic patients
        1. Extended release acute ingestions (e.g. Lithium SR) within first 2-4 hours
        2. Immediate release acute large ingestions within first hour
      2. Give 500 to 2000 ml Polyethylene Glycol via Nasogastric Tube until rectal output clear
  3. Fluid Resuscitation
    1. First-line management of Lithium Toxicity
    2. Isotonic crystalloid (NS or LR)
      1. Administer initial 2 Liter bolus of crystalloid, followed by 200 ml/hour (2x maintenance)
      2. Rate of replacement should be decreased if Hyponatremia (prevent Central Pontine Myelinolysis)
      3. Avoid Diuretics (may worsen toxicity and fluid status)
        1. If Diuretics are needed, monitor closely volume status and intake and output (e.g. ICU)
  4. Altered Mental Status
    1. See Altered Level of Consciousness
    2. See Unknown Ingestion
    3. Bedside Serum Glucose (and treat Hypoglycemia)
    4. Consider Naloxone
    5. Consider Thiamine
  5. Seizures
    1. See Status Epilepticus
    2. Benzodiazepines
  6. Disposition
    1. Evaluate for Suicidality in possible intentional Overdose
    2. Admit Lithium Toxicity to medical ward (severe toxicity to ICU)
      1. May discharge when patient is asymptomatic and serum Lithium <1.5 mEq/L
    3. Asymptomatic patient Emergency Department Indications for home discharge
      1. Multiple downward trending Lithium levels (including a final Lithium level <1.0 mEq/L) AND
      2. Normal Renal Function AND
      3. Unremarkable 4 to 6 hour observation

XIV. Management: Hemodialysis Indications

  1. Serum Lithium Level >5 mEq/L
  2. Serum Lithium Level >4 mEq/L AND concurrent Serum Creatinine >2.0 mg/dl)
  3. Serum Lithium Level >2.5 mEq/L AND
    1. Neurologic symptoms (Seizures, decreased mental status) OR
    2. Conditions in which flud Resuscitation is limited (e.g. Congestive Heart Failure) OR
    3. Conditions limiting Lithium excretion (e.g. Renal Failure)
  4. Serum Lithium Level >1.5 mEq/L AND
    1. Life threatening complications attributed to Lithium Toxicity
    2. Increasing serum Lithium levels despite maximal medical therapy with fluid Resuscitation

XV. Complications: Chronic Lithium Toxicity

  1. Syndrome of Irreversible Lithium Effectuated Neurotoxicity (SILENT)
    1. Higher risk with acute Lithium Toxicity
    2. Persistent neurologic and psychiatric effects despite Lithium discontinuation
    3. Effects may include Extrapyramidal Effects, Dementia, Ataxia, visual changes, Brainstem or cerebellar dysfunction
  2. Nephrogenic Diabetes Insipidus
  3. Thyroid Dysfunction

XVI. References

  1. Perrone and Chatterjee (2018) UpToDate, accessed 8/20/2018
  2. Micromedex, accessed 8/20/2018
  3. Mike Avila, MD (2018), email communication, received 8/15/2018
  4. Clark, Pang and Al Jalbout (2025) Crit Dec Emerg Med 39(4): 29-37 [PubMed]

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