- USES: Lithium carbonate is used therapeutically, primarily to treat bipolar disorder; it is less commonly used today due to the wide availability of other psychiatric medications with lesser side effects. It is available in oral formulations, both regular and extended release. Lithium orotate is a dietary supplement. Lithium is an important industrial material used to make batteries, alloys, and flux. PHARMACOLOGY: Lithium is a naturally occurring alkali metal and monovalent cation chemically similar to Na+ and K+. The exact mechanism by which it stabilizes mood is not known. It is thought to affect the CNS by altering nerve conduction, cortisol and monoamine metabolism, and increasing serotonin. TOXICOLOGY: In the kidney, lithium competes with Na+ and K+ in the renal tubules; conditions that increase renal sodium reabsorption (dehydration) decrease lithium elimination. Chronic toxicity is typically due to decreased clearance caused by dehydration, medication interactions, or renal impairment. EPIDEMIOLOGY: Acute poisoning is typically less severe than chronic toxicity. Chronic toxicity develops primarily in elderly patients, those with intercurrent illnesses, and those started on drugs that decrease lithium clearance. MILD TO MODERATE POISONING: Toxicity is categorized as acute or chronic. Acute overdose is typically less severe than chronic toxicity and results in gastrointestinal upset, while CNS manifestations are less common due to slow absorption into the brain. Chronic effects are usually less gastrointestinal and more neurological due to prior CNS saturation. Mild to moderate poisoning can cause nausea, vomiting, diarrhea, dehydration, nystagmus, and tremors. Hyperreflexia, cogwheel rigidity, ataxia, agitation, confusion, and lethargy are common. Bradycardia, T-wave abnormalities, hypoventilation may also occur. SEVERE POISONING: Severe effects in acute exposures are rare. Patients with chronic toxicity may manifest severe toxicity despite relatively modestly elevated serum lithium concentrations. Effects include photophobia, dehydration, electrolyte imbalances, thyroid dysfunction, hyperthermia, seizure, coma, rigidity, myoclonus, serotonin syndrome. ECG changes such as nonspecific T-wave abnormalities, QTc prolongation, bundle branch block, bradycardia, junctional rhythm, and hypotension may occur. Hypoventilation, respiratory failure, and ARDS may rarely develop. Bezoars may form in large ingestions. ADVERSE EFFECTS: At therapeutic doses, effects such as blurred vision, nystagmus, GI irritation, tremors, slowed mentation, cerebellar dysfunction may occur. Polyneuropathy and Parkinsonian syndrome have been described. ECG changes such as nonspecific ST/T changes, sinus node blocks may be present. Brugada Syndrome has been reported in several chronic lithium users. Nephrogenic Diabetes Insipidus, reduced glomerular filtration, and thyroid abnormalities, particularly hypothyroidism, may also occur. Lithium carbonate crosses the placenta and is also present in breast milk. Congenital malformations have been documented after exposure to lithium during pregnancy. DRUG INTERACTIONS: Lithium clearance is decreased by concomitant use of ACE inhibitors, angiotensin II antagonists, thiazide and loop diuretics, and nonsteroidal anti-inflammatory drugs.
Range of Toxicity:
- TOXICITY: Toxic dose is not well defined. In some patients on chronic lithium therapy, the serum concentrations associated with toxic effects are close to therapeutic levels.Therapeutic concentration is 0.6 to 1.2 mEq/L. CHRONIC VS ACUTE: Acute poisoning is typically less severe than chronic for a given serum concentration. Mild to moderate toxic reactions may occur at 1.2 to 2.5 mEq/L in chronic intoxications. Patients with chronic toxicity and serum concentrations above 2.5 mEq/L may have more severe effects, and serum concentrations above 4 mEq/L are generally associated with severe CNS effects in patients with chronic toxicity. Patients with an acute lithium toxicity can develop high serum concentrations with limited distribution to the brain (which can be delayed up to 24 hours), and limited neurologic toxicity. Conversely, in patients on chronic therapy the serum lithium concentration is closer to steady state and correlates better with brain lithium levels. ADULTS: A 45-year-old man died after an acute ingestion of 90 sustained-release lithium tablets (450 mg each) with a peak level of 6.9 mEq/L despite hemodialysis. A 28-year-old man survived an acute ingestion with a lithium level of 10 mEq/L. An adult recovered after an acute ingestion of 84 grams (210 tablets of 400 mg) of lithium. Levels up to 14 mmol/L have been recorded in survivors of acute ingestions. PEDIATRIC: Accidental ingestions of an average of 2 pills typically causes drowsiness, while neurotoxicity has resulted after chronic therapy of 40 mg/kg/day. Mortality due to lithium as a single exposure is rare if recognized quickly and treated aggressively. THERAPEUTIC DOSE: ADULT: Daily dose ranges from 600 to 2400 mg. PEDIATRIC: EXTENDED-RELEASE TABLETS: 12 YEARS OF AGE AND OLDER: The recommended dose is 900 to 1800 mg/day orally in 2 to 4 divided doses. IMMEDIATE-RELEASE AND CAPSULES: 12 YEARS OF AGE AND OLDER: maintenance, 300 mg orally 3 to 4 times daily; desired serum lithium levels ranging between 0.6 to 1.2 mEq/L. YOUNGER THAN 12 YEARS OF AGE: Safety and effectiveness have not been established.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Most acute lithium overdoses may be safely managed with supportive care that includes: antiemetics for nausea and vomiting, intravenous normal saline hydration to enhance renal lithium elimination, and correction of any electrolyte abnormalities. For chronic toxicity, address underlying causes of decreased renal clearance, which may include: intravenous fluids for dehydration or the discontinuation of medications that impair renal function. MANAGEMENT OF SEVERE TOXICITY: Orotracheal intubation for airway protection should be performed if recurrent seizures, increasing somnolence or coma develop. Consider gastric lavage for recent, large ingestion if airway is protected. Whole bowel irrigation with polyethylene glycol may be considered in large ingestions, especially if sustained-release formulations. Administer intravenous normal saline to enhance renal elimination of lithium (Goal: urine output of 2 to 3 mL/kg/hr). Intravenous fluids and vasopressors (dopamine, norepinephrine) may be needed to treat hypotension. Treat agitation, rigidity, seizures, hyperthermia, serotonin syndrome with sedation (benzodiazepines, propofol), and cooling measures; intubation and paralysis may be necessary with severe toxicity. Consider hemodialysis for patients with severe toxicity not responding to hydration, or congestive heart failure or renal insufficiency. Dysrhythmias are treated with standard ACLS protocols.
- Decontamination: PREHOSPITAL: Activated charcoal does not adsorb lithium well; it is not recommended. HOSPITAL: Consider gastric lavage in a patient with recent life-threatening ingestion, if airway is protected or patient is alert. Whole bowel irrigation with polyethylene glycol should be considered with a large ingestion or ingestion of sustained-release products.
- Airway management: Intubate if unable to protect airway due to worsening agitation, somnolence or coma, or if respiratory distress develops.
- Antidote: None
- Enhanced elimination procedure: Hemodialysis increases lithium clearance and decreases half-life. The decision to perform hemodialysis is largely clinical. It should be considered in patients with significant neurologic manifestations, those with renal insufficiency, and acute overdoses with high or rapidly rising levels despite aggressive hydration (some sources list levels greater than 3.5 mEq/L).. Serum lithium levels typically rebound 6 to 12 hours after dialysis in chronically intoxicated patients due to equilibration with intracellular and CNS lithium stores. Therefore, serial levels should be checked for 12 hours postdialysis. Continuous venovenous hemodialysis (CVVH) clears lithium more slowly than does hemodialysis, but decreases the occurrence of rebound lithium levels.
- Monitoring of patient: Monitor vital signs, mental status, and urine output. Serial lithium levels should be followed until the concentration has clearly peaked and declined. The correlation between clinical toxicity and serum concentration is poor; an acute overdose is often asymptomatic, despite high serum concentrations. Chronic exposure may have neurologic manifestations at therapeutic concentrations. Monitor electrolytes (particularly sodium), urinalysis, and serum creatinine. Obtain thyroid function tests and arterial blood gases; lithium intoxication may cause a low anion gap. CT scan of brain may be indicated if etiology of altered mentation is in question. Monitor EEG if there is a concern for subclinical seizures. Chest x-ray may be indicated to monitor pulmonary edema. In those with worsening symptoms or known large ingestions, closely monitor airway, breathing, circulation, cardiac ectopy via continuous cardiac monitoring (including pulse oximetry, capnography), and ECGs.
- Patient disposition: HOME CRITERIA: Accidental ingestions in asymptomatic lithium naive patients who ingest less than the maximum daily dose (Children less than 6 years old – 900 mg/square meter/day. Children 6 to 12 years old – 30 mg/kg/day. Adults – less than 2400 mg) who have no synergistic co-ingestions may be monitored at home. Those chronically taking lithium that are accidentally exposed to additional doses needed to be evaluated on a case by case basis, but typically tolerate a double dose without significant effects. OBSERVATION CRITERIA: Patients with deliberate ingestions, symptomatic patients, children and adults with ingestions of greater than the maximum daily dose, acute-on-chronic ingestions, unknown dosing errors in chronic patients, synergistic co-ingestions, or those with unclear history should be sent to a health care facility for evaluation and observation. Patients should be monitored until serum lithium concentration has peaked and is consistently declining and the clinical condition is improved. ADMISSION CRITERIA: Patients with persistent or worsening gastrointestinal irritation, renal impairment, altered mentation, respiratory depression, dysrhythmias, unstable vital signs, or persistently rising serum lithium concentrations should be admitted. Intensive care admission is indicated for aggressive airway, cardiac monitoring, and emergent hemodialysis. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (agitation, hyperthermia, need for hemodialysis, respiratory depression, coma), concerns about decontamination, or in whom the diagnosis is not clear. Consult a nephrologist for emergent hemodialysis in patients with severe poisoning.