Some patients abnormally sensitive to lithium may exhibit toxic signs at serum concentrations that are considered within the therapeutic range [see Boxed Warning, Dosage and Administration. Contact online >>
Some patients abnormally sensitive to lithium may exhibit toxic signs at serum concentrations that are considered within the therapeutic range [see Boxed Warning, Dosage and Administration...
Explanation: FDA has concluded that lithium is a narrow therapeutic index drug based on the following evidence: The range between the effective lithium concentrations and the concentrations...
Lithium, a monovalent cation similar to sodium with an unknown mechanism, was first approved by the U.S. Food and Drug Administration (FDA) as a mood-stabilizing medication for the treatment of mania in the 1970s[2].
This topic will review the diagnosis and management of acute and chronic lithium toxicity. The therapeutic use of lithium, side effects of routine lithium therapy, and other aspects of the management of patients with acute poisoning are discussed separately.
Clinically, the three main categories of lithium poisoning are as follows (seePresentation):
Lithium levels should be measured in symptomatic patients. However, levels may not correlate with clinical symptoms due to the kinetic profile of lithium. Multiple measurements may be indicated to evaluate the effects of treatment and in patients who have taken sustained-release tablets (seeWorkup).
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. SeeTreatment.
Lithium has been used in medicine 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 adverse effects. The US Food and Drug Administration (FDA) banned the use of lithium in the 1940s because of fatalities but lifted the ban in 1970.
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 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 depends on the glomerular filtration rate (GFR). Consequently, dosing must be adjusted on the basis of 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.
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.
The American Association of Poison Control Centers'' National Poison Data System reported 5952 case mentions and 3341 single exposures to lithium in 2022.Of the single exposures reported, 2725 (82%) were in patients aged 20 years or older; 437 (13%) were in patients 13 to 19 years old, and 67 (2%) were in children younger than 6 years. [3]
Most cases of lithium poisoning have a favorable outcome; however, up to 10% of individuals with severe lithium toxicity develop chronic neurologic sequelae. Complications of lithium toxicity may include the following:
SILENT comprises both neurologic and neuropsychiatric signs and symptoms. Despite successful removal of the drug, these manifestations may persist for months or, in rare cases, for years. [4]
In the 3341 single exposures to lithium reported to the American Association of Poison Control Centers'' National Poison Data System in 2022, outcomes were moderate in 1317 cases and major in 168 cases, with seven deaths. [3] Lethal outcomes in lithium toxicity are generally secondary to severe CNS effects with subsequent cardiovascular collapse. Kidney, gastrointestinal, and endocrine morbidity may also occur.
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, Society for Academic Emergency MedicineDisclosure: Nothing to disclose.
Amit Gupta, MD Department of Emergency Medicine, Staten Island University Hospital Amit Gupta, MD is a member of the following medical societies: American College of Emergency PhysiciansDisclosure: Nothing to disclose.
John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph''s Hospitals John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System PharmacistsDisclosure: Nothing to disclose.
John G Benitez, MD, MPH Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center John G Benitez, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Undersea and Hyperbaric Medical Society, Wilderness Medical Society, American College of Occupational and Environmental MedicineDisclosure: Nothing to disclose.
Michael A Miller, MD Clinical Professor of Emergency Medicine, Medical Toxicologist, Department of Emergency Medicine, Texas A&M Health Sciences Center; CHRISTUS Spohn Emergency Medicine Residency Program Michael A Miller, MD is a member of the following medical societies: American College of Medical ToxicologyDisclosure: Nothing to disclose.
Mark S Slabinski, MD, FACEP, FAAEM Vice President, USACS Central 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, Ohio State Medical AssociationDisclosure: Nothing to disclose.
A recent paper by McKnight et al. in The Lancet has provided the first formal meta-analysis of the more common adverse reactions to lithium. The authors analyzed 385 studies and focused mainly on the harmful effects of lithium on the kidney, the thyroid and parathyroid glands, body weight, skin and congenital malformations. Their contribution is important and welcome, but as a guide for practice, it needs to be complemented by other relevant observations and individual patient-focused perspectives.
The findings from that meta-analysis somewhat underestimate the renal side-effects, and distort to some degree or exclude other adverse effects. The glomerular filtration rate is reduced but not more than 0 to 5 ml/min/year of observation; this may not fully reflect the present state of knowledge. A quarter of patients in the study had abnormalities of the thyroid and/or parathyroid gland, and lithium was found to increase body weight significantly less than did olanzapine. Unfortunately, the authors did not consider the observations from spontaneous reporting systems, which may have changed the picture.
We feel that some specific limitations of the study were related to the inclusion of patients regardless of adequacy of treatment, quality of monitoring, drug combinations, age and sex, and stabilization response.
In all treatment guidelines for bipolar disorder (BD), lithium has been recommended as a first-line maintenance treatment. Some directives have gone further; recent evidence-based and consensus-based German guidelines [1] firmly endorse lithium salts as the only first-line maintenance treatment in BD, and some investigators qualify lithium as the only proven mood stabilizer [2]. However, the potential side-effects and risks of lithium treatment may at times make the implementation of these recommendations in daily practice challenging.
McKnight et al. [4] discuss in detail the effects of long-term lithium on renal function particularly. They found that the reduction in the glomerular filtration rate (GFR) was relatively small: 0 to 5 ml/min over each year of observation, while urinary concentration ability was on average reduced by 15%. As for long-term consequences, the authors refer to a Swedish registry showing that renal failure occurred in 18 of 3369 patients (0.5%), that is, double the incidence in the general Swedish population. McKnight et al. [4] conclude that ''there is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low.''
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