Lithium Toxicity

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Background

Lithium has been in use since the 1870s. Lithium was initially used to treat depression, gout, and neutropenia, and for cluster headache prophylaxis, but it fell out of favor because of its side effects. In the 1940s, the US Food and Drug Administration (FDA) banned the use of lithium because of fatalities but lifted the ban in 1970. Presently, lithium is commonly used as maintenance treatment of bipolar disorder. Lithium poisoning occurs frequently, since it is used in a population at high risk for overdose. Furthermore, lithium has a relatively narrow therapeutic index that predisposes patients on chronic lithium maintenance treatment to poisoning with relatively minor changes in medications or health status.

Pathophysiology

The central nervous system (CNS) is the major organ system affected, although the renal, gastrointestinal (GI), endocrine, and cardiovascular (CV) systems also may be involved.

Lithium is available only for oral administration. It is almost completely absorbed from the GI tract. Peak levels occur 2-4 hours postingestion, although absorption can be much slower in massive overdose or with ingestion of sustained-release preparations.

Lithium dosing

Lithium is minimally protein bound (< 10%) and has an apparent volume of distribution of 0.6-1 L/kg. The therapeutic dose is 300-2700 mg/d with desired serum levels of 0.6-1.2 mEq/L.

Lithium clearance is predominantly through the kidneys. Because it is minimally protein bound, lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate (GFR). Consequently, dosing must be adjusted based on renal function. Individuals with chronic renal insufficiency must be closely monitored if placed on lithium therapy.

Most filtered lithium is reabsorbed in the proximal tubule; thus, drugs known to inhibit proximal tubular reabsorption, such as carbonic anhydrase inhibitors and aminophylline, may increase excretion. Diuretics acting distally to the proximal tubule, such as thiazides and spironolactone, do not directly affect the fractional excretion of lithium (although they may affect serum lithium levels indirectly through their effects on volume status). Reabsorption of lithium is increased and toxicity is more likely in patients who are hyponatremic or volume depleted, both of which are possible consequences of diuretic therapy.

Lithium half-life

The plasma elimination half-life of a single dose of lithium is from 12-27 hours (varies with age). The half-life increases to approximately 36 hours in elderly persons (secondary to decreased GFR). Additionally, half-life may be considerably longer with chronic lithium use.

Epidemiology

Frequency

United States

An estimated 10,000 toxic exposures occur per year. These data indicate a gradual increase over the past 10 years.

Mortality/Morbidity

An estimated 2000 moderate-to-severe outcomes occur in the United States each year; lethal outcomes are generally secondary to severe CNS effects with subsequent cardiovascular collapse.

Race

No predilection exists.

Age

Approximately 10% of toxic lithium exposures occur in children younger than 19 years.

History

As with all toxic ingestions, it is important to determine the amount, time, co-ingestants, and reason for ingestion. Toxicity does not often correlate with the measured lithium level since clinical toxicity is affected by the type of the poisoning.

Clinical features

Three main categories of patients who are poisoned are as follows: acute, acute-on-chronic, and chronic.

Acute: These patients usually do not have a tissue body burden and symptoms are predominately GI including nausea, vomiting, cramping, and sometimes diarrhea. Progression of acute toxicity can involve neuromuscular signs such as tremulousness, dystonia, hyperreflexia, and ataxia. Cardiac dysrhythmias have been reported but rarely occur. The most common ECG finding is T-wave flattening.

Acute-on-chronic: These patients take lithium regularly and have taken a larger dose recently. These patients may display both GI and neurologic symptoms, and serum levels can be difficult to interpret. Patients should be treated according to their clinical manifestations.

Chronic: These patients typically have a large body burden of lithium and may be difficult to treat. Chronic lithium toxicity is usually precipitated with introduction of new medication that may impair renal function/excretion or cause a hypovolemic state. Symptoms are primarily neurologic. Mental status is often altered and can progress to coma and seizures if the diagnosis is unrecognized. Many severely poisoned patients can develop a syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) such as cognitive impairment, sensorimotor peripheral neuropathy, and cerebellar dysfunction.

Drug interactions

Three major drug classes have been identified as potential precipitants of lithium toxicity:

Systemic effects

Renal toxicity is common with chronic lithium therapy, with nephrogenic diabetes insipidus being the most severe manifestation. Lithium inhibits the action of antidiuretic hormone (ADH) on the distal renal tubule, impairing sodium and water reabsorption. Other manifestations of lithium toxicity on the kidney include renal tubular acidosis, chronic tubulointerstitial nephritis, and nephrotic syndrome.

The most common endocrine disorder secondary to chronic toxicity is hypothyroidism. Lithium is taken up avidly by thyroid cells and blocks thyroid hormone release from thyroglobulin, which inhibits adenylate cyclase and prevents thyroid-stimulating hormone (TSH) from activating thyroid cells via the TSH receptor. It may also affect thyroid hormone synthesis. Myxedema coma has been reported as a complication of toxicity.

Acute exposure to lithium can cause leukocytosis, whereas chronic exposure can produce aplastic anemia.

Patients who are on chronic lithium therapy can develop localized edema, dermatitis, and skin ulcers.

Physical

Neurologic effects of lithium toxicity include tremors, lethargy, confusion, seizures, and coma.

GI effects of lithium toxicity include nausea, vomiting, crampy abdominal pain, and diarrhea.

Mild-to-moderate lithium toxicity is characterized by tremor, weakness, and mild confusion.

Moderate-to-severe lithium toxicity is characterized by altered mental status, muscle fasciculations, stupor, seizures, coma, hyperreflexia, and cardiovascular collapse.

Laboratory Studies

Therapeutic drug monitoring is readily available in most settings, and symptomatic patients should have their lithium levels measured. Levels may not correlate with clinical symptoms due to the kinetic profile of lithium. A repeat level should be checked several hours later after intravenous hydration to disclose any trend. Serial levels may be warranted in cases of sustained-release tablets.

The sample must be sent in a lithium-free tube, as falsely elevated levels have been obtained in plasma samples obtained in lithium-containing tubes.

Urinalysis, electrolyte levels, and renal function should also be sent. A low anion gap or a low urine specific gravity may suggest lithium toxicity due to sodium loss.

Thyroid function panel may also be considered in patients presenting with symptoms suggestive of hypothyroidism.

Co-ingestants should also be considered in cases of intentional overdose.

Acetaminophen level should be obtained in every patient suspected of intentional overdose.

Lumbar puncture should be considered in patients with altered mental status and suspicion of CNS infection.

Imaging Studies

Consider a CT scan of the head in individuals with severe movement disorders, seizures, stupor, or coma. CT scan may be needed to rule out other etiologies and to examine for trauma secondary to intoxication.

Other Tests

Electrocardiography

Chronic lithium toxicity is frequently associated with nonspecific and diffuse depressed ST segments and T-wave inversion unassociated with symptoms or significant sequelae.

Lithium intoxication may result in dysrhythmias, including complete heart block.

Serious cardiac toxicity is uncommon and generally only occurs in individuals with underlying heart disease.

Prehospital Care

Stabilize life-threatening conditions and initiate supportive therapy according to local EMS protocols.

Obtain intravenous access with isotonic sodium chloride solution.

Monitor cardiac function to assess rhythm disturbances.

Obtain all pill bottles available to the patient.

Emergency Department Care

Supportive therapy is the mainstay of treatment of lithium toxicity. Airway protection is crucial due to emesis and risk of aspiration. Seizures can be controlled with benzodiazepines, phenobarbital, or propofol.

GI decontamination

Gastric lavage may be attempted if the patient presents within one hour of ingestion.

Lithium is a monovalent cation that does not bind to charcoal; therefore, activated charcoal has no role. However, activated charcoal might be considered in the case of exposure to co-ingestants. The clinician also has to be aware that acute lithium toxicity can produce vomiting and precipitate aspiration of activated charcoal.

Whole-bowel irrigation with polyethylene glycol lavage can be effective in preventing absorption from extended-release lithium.

Because of its similarity to potassium, the use of sodium polystyrene sulfonate has been proposed as a method of eliminating lithium.[1] However, hypokalemia has been reported and studies have still not shown definite evidence of benefit. One retrospective review showed a possible decrease in lithium half-life with administration of sodium polystyrene sulfonate in patients presenting with chronic lithium toxicity.[2] However, it is unknown if this was clinically relevant or if patient outcome was improved.

Enhanced elimination

The mainstay of treatment is fluid therapy. The goal of saline administration is to restore glomerular filtration rate (GFR), normalize urine output, and enhance lithium clearance.

Lithium is readily dialyzed because of water solubility, low volume of distribution, and lack of protein binding.

Hemodialysis is indicated for patients who have renal failure and are unable to eliminate lithium. It is also indicated in patients who cannot tolerate hydration such patients with congestive heart failure (CHF) or liver disease. Hemodialysis should be considered in patients who develop severe signs of neurotoxicity such as profound altered mental status and seizures. An absolute level of 4 mEq/L in acute toxicity and a level of 2.5 mEq/L in chronic toxicity in patients with symptoms should also be considered for hemodialysis (GF), although guidelines for hemodialysis based on levels alone are controversial.

Because postdialysis rebound elevations in lithium levels have been documented, continuous venovenous hemofiltration (CVVH) has been advocated.[3, 4]

Patients who are already on peritoneal dialysis should continue with it while awaiting hemodialysis or CVVH.

Consultations

Consult renal service personnel for hemodialysis in severe intoxications.

Consult psychiatric service personnel for patients with intentional overdose.

Consult the poison control center and a medical toxicologist regarding appropriate treatment.

Medication Summary

The goal of therapy is to remove or reduce the excess amounts of lithium resulting from an overdose.

Polyethylene glycol bowel prep (GoLYTELY, Colyte)

Clinical Context:  Laxative with strong electrolytic and osmotic effects that has cathartic actions in the GI tract.

Class Summary

Because adsorption to activated charcoal is minimal, whole-bowel irrigation is the GI decontamination method of choice.

Further Inpatient Care

Admit patients with significant signs or symptoms of toxicity.

Admit symptomatic patients, regardless of serum lithium levels; admit patients on chronic lithium therapy with serum lithium levels higher than 2 mEq/L.

Admit patients with signs of severe neurotoxicity pending hemodialysis to an intensive care unit (ICU).

Further Outpatient Care

Unintentional overdose: Asymptomatic patients and patients with serum lithium concentrations in the therapeutic range and minor toxicity may be discharged with scheduled follow-up in 1-2 days.

Intentional overdose: Coordinate care with mental health care providers before discharge from the hospital.

Transfer

Transfer may be indicated if hemodialysis facilities are not available locally.

Complications

Complications of lithium toxicity may include the following:

Prognosis

Most cases of lithium poisoning result in a favorable outcome; however, up to 10% of individuals with severe lithium toxicity develop chronic neurologic sequelae.

Author

David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Amit Gupta, MD, Department of Emergency Medicine, Staten Island University Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Mark S Slabinski, MD, FACEP, FAAEM, Vice President, EMP Medical Group

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

John G Benitez, MD, MPH, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

Disclosure: Nothing to disclose.

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, James G Linakis, PhD, MD, to the development and writing of this article.

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