eMedicine Specialties > Emergency Medicine > Toxicology
Toxicity, Lithium
Updated: Mar 24, 2009
Introduction
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.
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.
Clinical
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.
- Diuretics that promote renal sodium wasting
- Angiotensin-converting enzyme (ACE) inhibitors that reduce glomerular filtration rate (GFR) and enhance the tubular reabsorption of lithium
- Nonsteroidal anti-inflammatory drugs (NSAIDs) that reduce GFR and interrupt of renal prostaglandin synthesis
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.
Differential Diagnoses
| Delirium, Dementia, and Amnesia | Toxicity, Anticholinergic |
| Depression and Suicide | Toxicity, Heavy Metals |
| Hypoglycemia | Toxicity, Mercury |
| Neuroleptic Malignant Syndrome | Toxicity, Neuroleptic Agents |
| Schizophrenia | Toxicity, Organophosphate and Carbamate |
| Stroke, Ischemic | Toxicity, Sedative-Hypnotics |
| Toxicity, Alcohols |
Workup
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.
Treatment
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.
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.2,3
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
The goal of therapy is to remove or reduce the excess amounts of lithium resulting from an overdose.
GI decontaminants
Because adsorption to activated charcoal is minimal, whole-bowel irrigation is the GI decontamination method of choice.
Polyethylene glycol bowel prep (GoLYTELY, Colyte)
Laxative with strong electrolytic and osmotic effects that has cathartic actions in the GI tract.
Dosing
Adult
1500-2000 mL/h PO or NG tube until rectal effluent is clear
Pediatric
Administer as in adults
Interactions
Reduces effectiveness and absorption of oral medications
Contraindications
Documented hypersensitivity; colitis, megacolon, bowel perforation, gastric retention, or GI obstruction
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in ulcerative colitis and hot loop polypectomy
Follow-up
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
- Truncal and gait ataxia
- Nystagmus
- Short-term memory deficits
- Dementia
- SILENT (syndrome of irreversible lithium-effectuated neurotoxicity) syndrome
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.
Miscellaneous
Medicolegal Pitfalls
- Failure to consider lithium exposure in any patient with history of bipolar disease, with altered mental status, neurological symptoms, and/or history of suicide attempt.
- Failure to consider lithium poisoning in a patient known to take lithium medications with altered mental status is a pitfall. Symptoms of presentation, particularly in chronic toxicity, are vague and nonspecific.
- Failure to determine thyroid function status in a patient with altered mental status chronically taking lithium is a medical pitfall. Lithium can cause hypothyroidism, and the findings of lithium poisoning, bipolar disease, and thyroid dysfunction can be similar.
- Treating patients with medications that will alter lithium elimination is a medical pitfall. In the emergency department, this typically relates to the ubiquitous use of NSAIDs.
- Failure to order consequential serum levels to follow up on the trends of lithium distribution
- Failure to engage renal service earlier in the treatment of a lithium poisoned patient in order to initiate timely extracorporeal lithium removal
- Failure to repeat serum lithium level and to treat the patient accordingly after initial hemodialysis is complete due to possibility of rebound and redistribution of lithium
- Prescribing medication in the ED that can ultimately increase lithium concentration/toxicity, namely NSAIDs, ACE inhibitors, and diuretics
References
Linakis JG, Savitt DL, Wu TY, Lockhart GR, Lacouture PG. Use of sodium polystyrene sulfonate for reduction of plasma lithium concentrations after chronic lithium dosing in mice. J Toxicol Clin Toxicol. 1998;36(4):309-13. [Medline].
Menghini VV, Albright RC Jr. Treatment of lithium intoxication with continuous venovenous hemodiafiltration. Am J Kidney Dis. Sep 2000;36(3):E21. [Medline].
van Bommel EF, Kalmeijer MD, Ponssen HH. Treatment of life-threatening lithium toxicity with high-volume continuous venovenous hemofiltration. Am J Nephrol. Sep-Oct 2000;20(5):408-11. [Medline].
Alexander MP, Farag YM, Mittal BV, Rennke HG, Singh AK. Lithium toxicity: a double-edged sword. Kidney Int. Jan 2008;73(2):233-7. [Medline].
Aral H, Vecchio-Sadus A. Toxicity of lithium to humans and the environment--a literature review. Ecotoxicol Environ Saf. Jul 2008;70(3):349-56. [Medline].
Burkhart, K. Lithium. In: Rosen's Emergency Medicine: Concepts and Clinical Practice. Sixth Edition. Mosby Elsevier; 2006:2442-2444.
Chen KP, Shen WW, Lu ML. Implication of serum concentration monitoring in patients with lithium intoxication. Psychiatry Clin Neurosci. Feb 2004;58(1):25-9. [Medline].
Eyer F, Pfab R, Felgenhauer N, et al. Lithium poisoning: pharmacokinetics and clearance during different therapeutic measures. J Clin Psychopharmacol. Jun 2006;26(3):325-30. [Medline].
Freeman MP, Freeman SA. Lithium: clinical considerations in internal medicine. Am J Med. Jun 2006;119(6):478-81. [Medline].
Giles JJ, Bannigan JG. Tetatogenic and developmental effects of lithium. Curr Pharm Des. 2006;12(12):1531-41.
Gitlin M. Lithium and the kidney: an updated review. Drug Saf. Mar 1999;20(3):231-43. [Medline].
Greller, H. Lithium. In: Goldfrank's Toxicologic Emergencies. Eighth. McGraw-Hill; 2006:1052-1058.
Groleau G. Lithium toxicity. Emerg Med Clin North Am. May 1994;12(2):511-31. [Medline].
Hsu CH, Liu PY, Chen JH, Yeh TL, Tsai HY, Lin LJ. Electrocardiographic abnormalities as predictors for over-range lithium levels. Cardiology. 2005;103(2):101-6. [Medline].
Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc. May 2004;52(5):794-8. [Medline].
Lee DC, Klachko MN. Falsely elevated lithium levels in plasma samples obtained in lithium containing tubes. J Toxicol Clin Toxicol. 1996;34(4):467-9. [Medline].
Ng YW, Tiu SC, Choi KL, Chan FK, Choi CH, Kong PS. Use of lithium in the treatment of thyrotoxicosis. Hong Kong Med J. Aug 2006;12(4):254-9. [Medline].
Rosenqvist M, Bergfeldt L, Aili H, Mathe AA. Sinus node dysfunction during long-term lithium treatment. Br Heart J. Oct 1993;70(4):371-5. [Medline].
Scharman EJ. Methods used to decrease lithium absorption or enhance elimination. J Toxicol Clin Toxicol. 1997;35(6):601-8. [Medline].
Timmer RT, Sands JM. Lithium intoxication. J Am Soc Nephrol. Mar 1999;10(3):666-74. [Medline].
Zimmerman JL. Poisonings and overdoses in the intensive care unit: general and specific management issues. Crit Care Med. Dec 2003;31(12):2794-801. [Medline].
Keywords
lithium toxicity, lithium exposure, lithium overdose, lithium intoxication, chronic lithium therapy, long-term lithium therapy, lithium in the treatment of depressive and bipolar disorders, lithium poisoning, lithium carbonate, Li2 CO3, lithium citrate, Li3 C6 H5 O7 ·4H2 O, treatment of depressive disorders, treatment of bipolar affective disorders, lithium ingestion
Contributor Information and Disclosures
Author
David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Amit Gupta, MD, Fellow, Department of Toxicology, North Shore Hospital
Amit Gupta, MD is a member of the following medical societies: American College of Emergency Physicians and Emergency Medicine Residents Association
Disclosure: Nothing to disclose.
Medical Editor
Mark S Slabinski, MD, FACEP, FAAEM, Vice President, EMP Medical Group
Mark S Slabinski, MD, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, and Ohio State Medical Association
Disclosure: Nothing to disclose.
Pharmacy Editor
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.
Managing Editor
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Medicine, Clinical Pharmacology Division, Vanderbilt University; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society
Disclosure: Nothing to disclose.
CME Editor
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
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Chief Editor
Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.