Lithium poisoning

INTRODUCTION — Lithium has been used as a mood stabilizer for over a century, initially as "lithia" water followed by lithium tablets [1,2]. Lithium toxicity was first described in 1898, and the extent of its toxic effects was recognized in 1949 when lithium chloride was used as a salt substitute in patients with heart failure [1,3]. In the 1970s, lithium carbonate was approved in the United States for the treatment of acute mania and bipolar disorder after appropriate serum monitoring became readily available. There are approximately 6000 to 7000 cases of lithium intoxication reported annually to the American Association of Poison Control Centers [4-7]. A large proportion of patients on chronic lithium therapy experience at least one episode of toxicity during treatment given its narrow therapeutic index [8].

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. A table and algorithm to facilitate management of lithium toxicity are provided (table 1 and algorithm 1).

●(See "General approach to drug poisoning in adults".)

●(See "Initial management of the critically ill adult with an unknown overdose".)

●(See "Bipolar mania and hypomania in adults: Choosing pharmacotherapy".)

●(See "Bipolar disorder in adults: Choosing maintenance treatment".)

●(See "Renal toxicity of lithium".)

●(See "Lithium and the thyroid".)

PHARMACOLOGY AND PHARMACOKINETICS

●Pharmacology – The exact mechanism of action of lithium is not clearly understood, but it does affect two intracellular signaling pathways, inositol monophosphate and glycogen synthase kinase-3 [9]. Lithium decreases intracellular inositol, which may be a potential mechanism for its effects on mood stabilization. Lithium also inhibits glycogen synthase kinase-3, a component of diverse signaling pathways involved in energy metabolism, neuroprotection, and neuroplasticity.

●Pharmacokinetics

•Absorption – Lithium is rapidly absorbed from the gastrointestinal tract following oral administration. Peak blood concentrations are reached in one to two hours following therapeutic ingestion of immediate-release products, and four to six hours after therapeutic ingestion of sustained-release products. In acute overdose, it may take up to 12 hours or longer before peak concentrations are reached [10,11].

•Distribution – Lithium is a small ion (74 daltons) with no protein or tissue binding and is therefore amenable to hemodialysis. Lithium is freely distributed throughout total body water with a volume of distribution between 0.6 and 0.9 L/kg, although the volume may be smaller in older adults, who have less lean body mass and less total body water. The highest intracellular lithium concentrations are found in the brain and the kidneys. Steady-state serum concentrations are typically reached within five days at the usual oral dose of 1200 to 1800 mg/day.

•Elimination – Lithium is excreted almost entirely by the kidneys and is handled in a manner similar to sodium. Lithium is freely filtered, but over 60 percent is then reabsorbed by the proximal tubules. The half-life for lithium is approximately 18 hours in adults and 36 hours in older adults.

CLINICAL PRESENTATION

Important history to obtain

Dose and formulation — As with any potential ingestion, determine the formulation of the drug (eg, immediate versus extended release), the amount or dose ingested, the timing (eg, acute or chronic), and the intent (eg, intentional or accidental). Lithium can be prescribed as lithium carbonate or more commonly as a sustained-release formulation (eg, Lithobid and Eskalith). Anticipated toxic effects of any lithium exposure will depend on dose, kidney function, volume status, and whether the patient takes lithium chronically. (See 'Effect of chronicity on signs and symptoms' below.)

The "toxic dose" of lithium is not well defined. Death has been reported after acute ingestion of a "handful" of pills in a patient on chronic lithium therapy [12], while other patients have survived large ingestions of up to 84 grams. Any adult who ingests more than 2400 mg or child who ingests more than 30 mg/kg requires clinical and laboratory evaluation to assess for toxicity.

Chronicity of exposure

●Acute toxicity – Acute toxicity refers to an intentional lithium overdose in a patient who does not regularly take lithium as a prescribed medication.

●Acute-on-chronic toxicity – Acute-on-chronic toxicity is an acute overdose in a patient who takes lithium daily. A sudden decline in kidney function (eg, from hypovolemia due to gastrointestinal illness) in a patient taking lithium can also lead to acute-on-chronic toxicity.

●Chronic toxicity – The history generally involves a patient on chronic lithium therapy who, due to toxic drug effects, physical disability, or concurrent illness, becomes hypovolemic, leading to reduced renal excretion of lithium. Alternatively, toxicity can develop solely from the effects of medications that reduce kidney function.

Concurrent illnesses and medications — When evaluating a patient for possible lithium toxicity, ask about concurrent illnesses, co-ingestants, and any new medications or changes in the dose of long-standing medications.

Any condition causing hypovolemia, such as vomiting, diarrhea, fever, heat-related illness, anorexia, acute decompensated heart failure, or infection, may contribute to lithium toxicity. Lithium toxicity can also develop solely from the effects of volume depletion, such as in hot climates, even in the absence of illness.

Concurrent medications may cause a decrease in renal lithium excretion. Examples of medications that can precipitate lithium toxicity include diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), nonsteroidal antiinflammatory drugs (NSAIDs), verapamil, beta blockers, metronidazole, and phenytoin [13-17].

Risk factors for toxicity — Lithium toxicity often occurs in vulnerable populations, such as patients with mental illness and poor living conditions. Older adults generally suffer more severe chronic toxicity than younger adults despite being prescribed lower doses of lithium [18]. This is likely due to age-related decline in glomerular filtration rate and reduced volume of distribution (secondary to reductions in lean body mass and total body water).

Signs and symptoms

Effect of chronicity on signs and symptoms — The history of how excess lithium accumulates in the body determines the clinical symptoms and type of toxicity. The symptoms and signs of toxicity differ based upon the total body burden of lithium and the rate of onset of toxicity.

●Acute toxicity – Gastrointestinal symptoms of nausea, vomiting, and diarrhea predominate, and neurologic symptoms are delayed.

●Acute-on-chronic toxicity – The presentation is similar to acute, but gastrointestinal symptoms are more severe at lower lithium concentrations.

●Chronic toxicity – Chronic lithium toxicity presents with early and predominate neurologic signs and symptoms. The clinical manifestations of toxicity (eg, agitation, confusion, slurred speech) are often superimposed on complications from chronic use (eg, neuromuscular irritability, tremor).

Gastrointestinal — Patients with acute lithium toxicity often develop and present with symptoms of nausea, vomiting, and diarrhea. Even though nausea can be a common side effect of lithium therapy, vomiting is uncommon and raises concern for toxicity. If vomiting and diarrhea are severe, hypovolemia and compromised kidney function can develop, impairing the ability to excrete lithium and exacerbating lithium toxicity.

Neurologic — In acute and acute-on-chronic toxicity, neurologic findings develop later in the course of illness because time is required for the drug to be distributed within the central nervous system (CNS). Patients with chronic toxicity often present with neurologic findings. Potential neurologic symptoms and signs include sluggishness, ataxia, confusion or agitation, and neuromuscular excitability, which can manifest as irregular coarse tremors, fasciculations, or myoclonic jerks. Severe lithium intoxication can lead to seizures, nonconvulsive status epilepticus, and encephalopathy.

A fine action tremor (ie, lithium tremor) is common in patients taking lithium at therapeutic doses and can develop at any time during treatment. Therapeutic lithium tremor is generally symmetric, limited to the arms, and nonprogressive. Tremor from lithium toxicity is coarser and more disabling, may also affect the legs, and occurs with other symptoms of toxicity. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and management of adverse effects", section on 'Tremor'.)

In a retrospective review of 97 patients with lithium toxicity, risk factors for developing severe neurotoxicity include age over 50 years, chronic lithium therapy (rather than acute overdose), development of arginine vasopressin resistance (AVP-R, previously called nephrogenic diabetes insipidus), hyperthyroidism, and impaired kidney function [19].

Long-term neurologic sequelae — The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) consists of prolonged neurologic and neuropsychiatric symptoms following lithium toxicity [20]. In some cases of lithium toxicity, and in typical cases of SILENT, neurologic toxicity develops along with an elevated lithium concentration, but symptoms persist despite successful removal of the drug.

Cerebellar dysfunction, extrapyramidal symptoms, brainstem dysfunction, and dementia can develop as part of SILENT [20,21]. Other neurologic sequelae may include nystagmus, choreoathetoid movements, myopathy, and blindness. A review of 90 published cases identified cerebellar dysfunction as the most common sequelae, potentially due to demyelination at multiple sites in the CNS [20]. SILENT can persist for months and, in rare cases, for years [22].

Kidney — Patients on chronic lithium therapy are at risk for developing AVP-R, caused by a concentrating defect in the kidneys, resulting in the excretion of dilute urine [23]. Normally, the resulting thirst and increased intake of free water compensate for these fluid losses. Thus, many patients on chronic lithium therapy have polyuria and polydipsia without hypernatremia. However, hypernatremia can occur when other toxic effects (eg, confusion), physical disability, concurrent illness, or hospitalization with inadequate fluid administration prevent these patients from drinking free water. Lithium-induced AVP-R is discussed in detail separately. (See "Renal toxicity of lithium", section on 'Arginine vasopressin resistance (nephrogenic diabetes insipidus)'.)

Cardiac — Although lithium toxicity can cause changes in the electrocardiogram (ECG), dangerous dysrhythmias or other important clinical effects are rare [24,25]. Flattened T waves, prolonged QTc intervals, and bradycardia have been reported [25-27]. Lithium toxicity is not associated with elevations in cardiac biomarkers or left ventricular dysfunction.

Severe symptoms — The following are considered symptoms of severe lithium toxicity and increase risk of death and long-term neurologic sequelae:

●Coma, stupor, seizures, nonconvulsive status epilepticus, encephalopathy

●Hypotension that does not resolve quickly with intravenous (IV) fluids

●Rigidity, hypertonicity, myoclonus

●Cardiopulmonary collapse

●Life-threatening dysrhythmia

LABORATORY TESTING

General approach to testing — The following laboratory studies should be performed in patients who take lithium or with suspected lithium toxicity:

●Serum lithium concentration

●Complete blood count

●Serum electrolytes, blood urea nitrogen (BUN), and creatinine

Lithium by itself can elevate the white blood cell count in the absence of infection [28]. Acid base disorders do not typically occur as a result of lithium toxicity and if present should raise suspicion for other ingestions, such as aspirin or toxic alcohols.

Serum lithium concentration

●When to obtain measurements – Obtain a serum lithium concentration in any patient with suspected toxicity when the patient presents to the emergency department. Early concentrations can be helpful to confirm exposure but may not represent peak serum concentrations in a patient who has ingested sustained-release tablets. Lithium concentrations should be repeated (every four to six hours initially) to evaluate for continued absorption and distribution. (See 'Post-diagnostic Testing' below.)

Lithium concentrations are just one tool in the assessment of the severity of an overdose and help to determine the need for hemodialysis. (See 'Candidates for hemodialysis' below.)

●Interpreting concentrations – The recommended therapeutic concentration for lithium is between 0.8 and 1.2 mEq/L (0.8 and 1.2 mmol/L). (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and management of adverse effects", section on 'Lithium dose and serum concentrations' and "Bipolar disorder in adults: Choosing maintenance treatment", section on 'Lithium'.)

In chronic toxicity, mild symptoms such as increased tremor, slurred speech, and mild lethargy generally occur when the serum lithium concentration is between 1.5 and 2.5 mEq/L (1.5 to 2.5 mmol/L).

Clinical findings of moderate to severe toxicity, such as worsening lethargy, coarse tremors, and clonus, can be seen when lithium concentrations are between 2.5 and 3.5 mEq/L (2.5 to 3.5 mmol/L). Severe toxicity generally occurs when lithium concentrations exceed 3.5 mEq/L (3.5 mmol/L). (See 'Signs and symptoms' above.)

●Concentrations do not always correlate with degree of toxicity – Serum lithium concentrations correlate more closely with clinical signs in patients with chronic toxicity because drug distribution has reached a steady state [8].

Serum lithium concentrations often do not correlate with clinical signs in acute toxicity because they do not necessarily reflect central nervous system (CNS) concentrations of lithium. Patients with acute ingestions may be relatively asymptomatic despite serum concentrations above 4 mEq/L (4 mmol/L) due to slow distribution into the CNS. Conversely, patients with therapeutic lithium concentrations can develop severe clinical toxicity [29-31]. Thus, treatment should be based upon clinical manifestations and not solely upon serum concentrations.

●Avoid lithiated heparin blood tubes – Lithium must be measured in a lithium-free tube. Some blood tubes are treated with lithiated heparin, which can cause falsely elevated lithium concentrations [32].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes illnesses that cause vomiting and diarrhea and those that cause altered mental status and neuromuscular excitability. The former differential diagnosis is broad and is discussed elsewhere. (See "Approach to the adult with nausea and vomiting" and "Approach to the adult with acute diarrhea in resource-abundant settings" and "Approach to the adult with acute diarrhea in resource-limited settings".)

In patients with neuromuscular excitability who take psychiatric medications, the differential diagnosis includes serotonin syndrome and neuroleptic malignant syndrome (NMS). Both disorders can cause hyperthermia, altered mentation, and profound neuromuscular findings. However, NMS is clinically very different from serotonin syndrome or lithium toxicity, and these should be easily differentiated by physical examination alone. NMS is characterized by bradykinesia and "lead pipe" rigidity while serotonin syndrome and lithium toxicity are both hyperkinetic (ie, tremor, myoclonus). (See "Serotonin syndrome (serotonin toxicity)" and "Neuroleptic malignant syndrome".)

There is some overlap between the clinical symptoms of lithium toxicity and serotonin syndrome, and when taken in combination with other serotonergic medications, lithium can precipitate serotonin syndrome. Definitively distinguishing these syndromes is not essential since management of lithium toxicity and serotonin syndrome can occur concurrently (eg, cessation of precipitating medications, control of neuromuscular excitability and hyperpyrexia, intravenous [IV] fluids).

Lithium toxicity may be confused with acute ethanol or benzodiazepine withdrawal. Signs and symptoms occurring in both can include tachycardia, hypertension, hyperthermia, agitation, and possibly seizures and hallucinations. Neuromuscular findings are more prominent with lithium toxicity and less commonly seen with either ethanol or benzodiazepine withdrawal. (See "Management of moderate and severe alcohol withdrawal syndromes" and "Benzodiazepine poisoning" and "Benzodiazepine withdrawal".)

Other important diagnoses to consider in patients who present with ataxia, altered mental status, or neuromuscular excitability include:

●Hypoglycemia

●Central nervous system (CNS) infection (see "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Viral encephalitis in adults")

●Head trauma (see "Management of acute moderate and severe traumatic brain injury")

●Stroke (see "Clinical diagnosis of stroke subtypes")

●Other medications and intoxications that cause seizures and status epilepticus (table 2)

●Nontoxicologic causes of seizures (see "Evaluation and management of the first seizure in adults" and "Evaluation and management of the first seizure in adults", section on 'Causes of seizures')

●Myxedema coma or thyrotoxicosis (see "Lithium and the thyroid")

DIAGNOSIS — The diagnosis of lithium toxicity should be suspected in a patient who takes lithium and presents with typical symptoms of lithium toxicity, such as vomiting, diarrhea, sluggishness, ataxia, confusion, agitation, seizure, or signs of neuromuscular excitability such as tremor or clonus.

In such patients, the diagnosis is confirmed with a supratherapeutic lithium concentration (algorithm 1).

●Acute or acute-on-chronic toxicity – A supratherapeutic serum lithium concentration confirms the diagnosis but may not correlate with the degree of toxicity. A single therapeutic concentration does not rule out the diagnosis, and serial concentrations should be performed.

●Chronic toxicity – Lithium concentrations may correlate more closely with clinical signs in patients with chronic toxicity. However, patients may still have significant symptoms with therapeutic or slightly supratherapeutic serum concentrations.

POST-DIAGNOSTIC TESTING

●Serial lithium concentrations – Repeat lithium concentrations are initially needed every four to six hours to determine the adequacy of therapy (intravenous [IV] fluids or hemodialysis), evaluate for continued absorption, and determine peak serum concentrations in a patient who has ingested sustained-release tablets. Once concentrations approach the therapeutic range or are consistently trending downwards, and the patient is improving clinically, serum lithium concentrations may be obtained less frequently (eg, every 6 to 12 hours) until symptoms resolve.

●Serial measurements of kidney function – Obtain serial creatinine and blood urea nitrogen (BUN) concentrations daily until the clinical manifestations of lithium toxicity have resolved and kidney function has returned to baseline if there is concurrent acute kidney injury. (See "Renal toxicity of lithium".)

●Serial sodium concentrations – In patients admitted with chronic lithium toxicity, measure the serum sodium concentration every 6 to 12 hours for the first 24 to 48 hours. Arginine vasopressin resistance (AVP-R) is a known complication of chronic lithium toxicity. In patients suspected of having concomitant AVP-R, especially those receiving IV hydration or with altered mentation who may not drink in response to thirst, care must be taken to avoid hypernatremia. Lithium-induced AVP-R is discussed in detail separately. (See "Renal toxicity of lithium", section on 'Arginine vasopressin resistance (nephrogenic diabetes insipidus)'.)

●Thyroid and parathyroid function – It is reasonable to obtain a thyrotropin (TSH) concentration in patients with suspected lithium toxicity. Both hypothyroidism and hyperthyroidism, as well as calcium disturbances secondary to hyperparathyroidism, have been reported with lithium toxicity. (See "Lithium and the thyroid" and "Renal toxicity of lithium", section on 'Hyperparathyroidism and hypercalcemia'.)

●Patients with intentional ingestion – In a patient with an intentional lithium ingestion, obtain serum concentrations of potential common co-ingestants such as acetaminophen, salicylate, and ethanol. Although commonly obtained, drug of abuse testing typically does not alter management. (See "Testing for drugs of abuse (DOAs)".)

●Female patients of childbearing age – Obtain a pregnancy test as part of routine care.

●Electrocardiogram (ECG) – Obtain an ECG as a screening test for co-ingestion of medications that prolong the QRS or QTc intervals (eg, tricyclic antidepressants, atypical antipsychotics). Although lithium toxicity can cause changes in the ECG, dangerous dysrhythmias or other important clinical effects are rare [24]. Flattened T waves, prolonged QTc intervals, and bradycardia have been reported [26,27].

MANAGEMENT

Overview of management — Management goals are not just to prevent death, but also to avoid the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). The treatment for lithium toxicity includes intravenous (IV) fluids to correct hypovolemia and increase renal lithium elimination (even when euvolemic), gastrointestinal decontamination in selected circumstances, and hemodialysis in cases of severe toxicity (table 1 and algorithm 1).

Serial lithium concentrations should be followed since absorption and distribution are slow, with a goal of a serum concentration less than 1 mEq/L. If the patient develops altered mental status, it may take weeks to months to improve.

ABCs and supportive care — The general approach to any poisoned patient begins with assessment and stabilization of the airway, breathing, and circulation ("ABCs"). Any patient with altered mental status should have a fingerstick glucose to exclude hypoglycemia. Benzodiazepines are first-line therapy for seizures. In a patient having continued seizures from suspected lithium toxicity, definitively secure the airway for the anticipated clinical course. (See "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose".)

Intravenous fluids — IV fluids with isotonic (0.9%) saline should be administered at a high rate (ie, bolus) until the patient is clinically euvolemic, followed by infusion at twice the maintenance rate, depending upon the patient's fluid status and cardiac function (if known). Restoration of sodium and water balance in hypovolemic patients with lithium toxicity is essential to maximize intrinsic lithium clearance. Once euvolemic, it is important to continue isotonic saline to maintain glomerular filtration rate and increase kidney elimination of lithium. IV fluids should be continued even while a patient is receiving hemodialysis for lithium toxicity to maintain kidney clearance in addition to the hemodialysis clearance. Monitor urine output and serial lithium concentrations to ensure adequate kidney perfusion and appropriate clearance. The IV saline infusion rate should be adjusted to maintain adequate urine output (eg, at least 1.5 to 3 mL/kg per hour).

Quantifying urine output and frequent serum sodium measurement (eg, obtaining with lithium concentrations) can provide evidence for the possibility of concomitant arginine vasopressin resistance (AVP-R). The combination of IV isotonic saline to restore euvolemia and hypotonic urinary losses can lead to hypernatremia, which can exacerbate the neurotoxicity of lithium poisoning. Early adjustments of saline therapy and the addition of free water can prevent hypernatremia in patients with AVP-R. Lithium-induced AVP-R is discussed in detail separately. (See "Renal toxicity of lithium", section on 'Arginine vasopressin resistance (nephrogenic diabetes insipidus)'.)

Gastrointestinal decontamination with PEG for acute ingestion — We suggest that whole-bowel irrigation with polyethylene glycol (PEG) solution be given to awake, asymptomatic patients who present within four hours after a presumed potentially toxic ingestion of sustained-release lithium (greater than 10 to 15 tablets) or within one hour after a large ingestion of immediate-release lithium [33-35]. The dose is 500 mL to 2 L of PEG per hour via nasogastric tube, continued until the rectal effluent is clear. Whole-bowel irrigation is contraindicated in patients with altered mentation or lethargy unless the airway is protected. There is no benefit from whole-bowel irrigation in patients with chronic toxicity.

We do not use the following decontamination strategies:

●Activated charcoal (AC) – Oral AC does not prevent the absorption of charged particles such as lithium and has no role in the management of an isolated lithium ingestion [36-38].

●Kayexalate – We do not recommend oral sodium polystyrene sulfonate (Kayexalate) because of the impracticality of giving the large dose required and the potential for hypokalemia [39]. Kayexalate has been shown to reduce lithium concentrations after a single dose or multiple doses in both humans and animals [40-43]. A retrospective study of 48 patients with chronic lithium toxicity describes significant reductions in the half-life of lithium among patients treated with polystyrene sulfonate as an adjunct to supportive care [43].

Role of extracorporeal removal

Candidates for hemodialysis — Hemodialysis is the treatment of choice for severe lithium toxicity. Lithium is readily dialyzable due to its low molecular weight, negligible protein binding, and small volume of distribution. Our approach is consistent with the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) guidelines [44-52].

We recommend hemodialysis for lithium toxicity in the following scenarios (although indications for hemodialysis remain controversial):

●Severe symptoms of toxicity, irrespective of the lithium concentration (see 'Severe symptoms' above)

●Serum lithium concentration >4 mEq/L (4 mmol/L) in patients with impaired kidney function (eGFR <45 mL/min, serum creatinine of ≥2 mg/dL in adults, serum creatinine ≥1.5 mg/dL in older adults or patients with low muscle mass, doubling of baseline serum creatinine [if known], or serum creatinine greater than two times upper limit of normal for age and sex in children)

We suggest hemodialysis for lithium toxicity in the following scenarios:

●Serum lithium concentration >5 mEq/L (5 mmol/L)

●If the expected time to obtain a serum lithium concentration <1 mEq/L with optimal management is more than 36 hours (in patients with symptoms suggestive of chronic lithium toxicity, an approximate guideline is a serum lithium concentration >1.8 mEq/L if eGFR <50 mL/min and serum lithium concentration >2.2 mEq/L if eGFR >50 mL/min)

The final criteria are challenging to apply; thus, a nomogram was derived to predict which patients would continue to have lithium concentrations greater than 1 mEq/L after 36 hours of treatment and benefit from hemodialysis [52]. However, a validation study found this nomogram had only moderate sensitivity [53], and we do not believe it should be used routinely. Other criteria, such as lithium concentration >2.5 mEq/L in a patient with kidney insufficiency or other conditions that limit lithium excretion, have been proposed, but we believe these are vague and not sufficiently sensitive [54]. The thresholds of 1.8 and 2.2 mEq/L are a rough guideline and are based on the expected lithium clearance in patients with chronic lithium toxicity from data in these studies. Given the heterogeneity of presentations, lack of strong evidence, and variability in guidelines, we believe that clinical judgement is important in decision-making. Also, since a patient with clinically significant lithium toxicity may not fall neatly into these categories, we recommend consultation with a poison control center or medical toxicologist when the decision regarding hemodialysis is unclear. (See 'Regional poison control centers' below.)

Lithium clearance with hemodialysis ranges from 70 to 170 mL/min compared with normal renal clearance of 10 to 40 mL/min (due to extensive reabsorption of lithium by the proximal tubules) and only 15 mL/min with peritoneal dialysis [55].

Duration of hemodialysis — In most cases, unless serum lithium concentrations are extremely high (eg, >4 mEq/L), one session of hemodialysis is usually sufficient. However, duration and frequency of hemodialysis ultimately depends on the patient's symptoms and signs, serial lithium concentrations, and nephrologist general practice (algorithm 1).

Some experts recommend extending the duration of hemodialysis to minimize the rebound phenomenon and repeating dialysis as necessary until the serum lithium concentration remains below 1 mEq/L (1 mmol/L) for six to eight hours after dialysis [36,55-58]. Nine hours of hemodialysis removes approximately 60 percent of the total body lithium stores [39]. Some experts suggest that at least two sessions of hemodialysis are required for adequate treatment [15]. We suggest obtaining consultation with a medical toxicologist or poison control center if unsure if additional hemodialysis treatment may be needed. (See 'Regional poison control centers' below.)

Rebound effect — Measure serum lithium concentrations immediately after hemodialysis is completed and again six hours after dialysis to assess for rebound effect. Lithium equilibrates slowly between the extracellular and intracellular fluid compartments [59]. As a result, a rebound increase in serum lithium concentrations occurs after the cessation of hemodialysis, as intracellular lithium diffuses back into the extracellular space. Ongoing gastrointestinal drug absorption may also contribute to the rebound effect [60]. A rebound in concentration may suggest that another session of dialysis is required.

Continuous venovenous hemofiltration for hypotensive patients — Continuous kidney replacement therapies are acceptable alternatives if intermittent hemodialysis is not available or in hemodynamically unstable patients who cannot tolerate hemodialysis [39,61,62]. Continuous venovenous hemofiltration (CVVH) has been used successfully to treat acute-on-chronic lithium toxicity. Case reports suggest that lithium clearance is significantly lower with these methods compared with hemodialysis; however, CVVH minimizes lithium rebound elevations and is better tolerated in hypotensive patients. According to other reports, the combination of hemodialysis, followed by CVVH with hemodialysis, provided safe and effective treatment for two children [63] and one adult who developed hypotension [58]. Experience with methods of extracorporeal removal other than conventional hemodialysis for the treatment of severe lithium toxicity is limited.

Disposition — Patients with symptoms of lithium toxicity should be admitted to a monitored setting for observation regardless of the serum lithium concentration. Patients with severe symptoms (eg, altered mental status, seizures) should be admitted to an intensive care setting. Discharge is appropriate once patients are asymptomatic with a serum lithium concentration below 1 mEq/L (1 mmol/L). Psychiatric evaluation is recommended for any patient with an intentional ingestion.

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

●History – The symptoms of lithium toxicity differ based upon the total body lithium burden and the rate of accumulation and are characterized as acute, acute-on-chronic, or chronic. Ask patients about co-ingestants, concurrent illnesses that may lead to hypovolemia, and any medications changes. Toxicity can occur with even a minor decline in kidney function or from nephrotoxic medications. A table and algorithm to facilitate emergency management of lithium toxicity are provided (table 1 and algorithm 1). (See 'Important history to obtain' above.)

●Clinical presentation

•Acute or acute-on-chronic toxicity – Patients present with symptoms of nausea, vomiting, and diarrhea; neurologic findings develop late in the clinical course. Acute-on-chronic toxicity can have more severe symptoms with lower lithium concentrations. The history generally involves an acute overdose or a sudden decline in kidney function (eg, from hypovolemia due to gastrointestinal illness) in a patient chronically taking lithium.

•Chronic toxicity – Patients present with neurologic symptoms and signs, which can include sluggishness, ataxia, confusion or agitation, and neuromuscular excitability. Severe toxicity can lead to seizures, nonconvulsive status epilepticus, and encephalopathy. The presentation generally involves a patient on chronic lithium therapy who, due to toxic drug effects, physical disability, or concurrent illness, does not drink enough, leading to hypovolemia and reduced renal excretion of lithium. (See 'Signs and symptoms' above.)

•Syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) – Patients can develop prolonged neurologic and neuropsychiatric symptoms following lithium toxicity that persist despite successful removal of the drug. (See 'Long-term neurologic sequelae' above.)

●Laboratory testing – Serum lithium concentrations should be obtained in any patient with suspected toxicity and repeated to assess for continued absorption, redistribution, and adequacy of therapy. Lithium concentrations often do not correlate with clinical signs of toxicity, especially in patients with acute or acute-on-chronic toxicity. Obtain a complete blood count, serum electrolytes, blood urea nitrogen (BUN), creatinine, and concentrations of common co-ingestants. (See 'Laboratory testing' above.)

●Differential diagnosis – The differential diagnosis for lithium toxicity includes serotonin syndrome, neuroleptic malignant syndrome, ethanol and benzodiazepine withdrawal, and nontoxicologic etiologies. (See 'Differential diagnosis' above.)

●Diagnosis – Lithium toxicity should be suspected in a patient who takes lithium and presents with vomiting, diarrhea, sluggishness, ataxia, confusion, agitation, seizure, or signs of neuromuscular excitability such as tremor or clonus. The diagnosis is confirmed with a supratherapeutic lithium concentration. (See 'Diagnosis' above.)

●Management

•Intravenous (IV) fluids – Restoration of sodium and water balance in hypovolemic patients with isotonic (0.9%) saline is required to maximize lithium clearance. Continuing isotonic saline even once euvolemic will increase kidney lithium excretion since lithium and sodium are both reabsorbed by the proximal tubules. A reasonable rate is twice maintenance but should be sufficient to maintain adequate urine output. (See 'Intravenous fluids' above.)

•Gastrointestinal decontamination – In an awake, asymptomatic patient who presents within four hours after a presumed significant ingestion of sustained-release lithium (greater than 10 to 15 tablets) or within one hour of a large ingestion of immediate-release lithium, we suggest performing whole-bowel irrigation with polyethylene glycol (PEG) solution (Grade 2C). (See 'Gastrointestinal decontamination with PEG for acute ingestion' above.)

•Hemodialysis – Hemodialysis is the treatment of choice for severe lithium toxicity because lithium is readily dialyzable due to its low molecular weight, negligible protein binding, and small volume of distribution. Our approach to hemodialysis is as follows (see 'Role of extracorporeal removal' above):

In a patient with any of the following indications, we recommend hemodialysis (Grade 1C):

-Severe symptoms of toxicity irrespective of the lithium concentration (see 'Severe symptoms' above)

-Serum lithium concentration >4 mEq/L (4 mmol/L) in patients with impaired kidney function (eGFR <45 mL/min, serum creatinine of ≥2 mg/dL in adults, serum creatinine ≥1.5 mg/dL in older adults or patients with low muscle mass, doubling of baseline serum creatinine [if known], or serum creatinine greater than two times upper limit of normal for age and sex in children)

In a patient with any of the following indications, we suggest hemodialysis (Grade 2C):

-Serum lithium concentration >5 mEq/L (5 mmol/L)

-If the expected time to obtain a serum lithium concentration <1 mEq/L with optimal management is more than 36 hours (in patients with symptoms suggestive of chronic lithium toxicity, an approximate guideline is a serum lithium concentration >1.8 mEq/L if eGFR <50 mL/min and serum lithium concentration >2.2 mEq/L if eGFR >50 mL/min)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Pia Chatterjee, MD, who contributed to earlier versions of this topic review.