CONTENTS

• Pharmacokinetics
• Presentations
• Evaluation
  • Lithium level & ingested dose
• Treatment
  • Decontamination
  • Medications to avoid
  • Fluid resuscitation & diuresis
  • Nephrogenic diabetes insipidus
  • Dialysis
  • Resumption of lithium
• Prognosis & SILENT syndrome
• Podcast
• Questions & discussion
• Pitfalls

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pharmacokinetics

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absorption

• Lithium is typically absorbed within ~1-2 hours (immediate release formulations) or ~4-6 hours (sustained release formulations).
• In acute overdose, absorption may occur more gradually (e.g., in one case, over 48 hours). Furthermore, with controlled release preparations, there may be multiple delayed peak concentrations due to pharmacobezoar formation. (27516079)
• Lithium is a positive ion, so it does not adsorb to activated charcoal in the gut.

distribution

• The volume of distribution is roughly equal to the total body water (~0.6 L/kg).
• A relatively low volume of distribution and high water solubility render lithium dialyzable.
• Distribution of lithium into the brain is relatively slow, taking up to 24 hours.

elimination

• Lithium is excreted by the kidneys. It is handled similarly to sodium, with reabsorption occurring largely in the proximal tubule.
  • Anything which stimulates the kidneys to retain sodium (e.g., volume depletion) will cause the kidneys to likewise retain lithium as well.
• The half-life is typically ~18 hours, but will become extended in renal dysfunction (e.g., with older age).

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presentations

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spectrum of symptoms that may occur

gastrointestinal

• Nausea/vomiting, ileus
• Diarrhea

neurologic

• Movement disorder:
  • Initially: Fine tremor (can occur with therapeutic use, but is worsened with intoxication)
  • May eventually cause ataxia/dysarthria, choreiform movements, coarse tremors, fasciculations, myoclonus (including ocular myoclonus and axial myoclonus), nystagmus, hyperreflexia.
• Delirium, seizure, nonconvulsive status epilepticus, coma.

cardiovascular

• Generally doesn't have prominent cardiac effects. However, it may be linked to hypotension and bradycardia.
• EKG abnormalities include:
  • QTc prolongation.
  • Brugada phenocopy.
  • Pseudoinfarction patterns.
  • Bradycardia related to AV block or sinus node dysfunction. (36940005)

other

• Hyperthermia can occur.
• Polyuria and polydipsia, due to impaired urinary concentrating ability. (Murphy 2023)

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roughly three forms of lithium intoxication

acute

• Large ingestion in a previously lithium-naive patient.
• Usually presents with gastrointestinal symptoms (ingested lithium acts directly as a gastrointestinal irritant).
• Neurological symptoms may occur several hours later, in a delayed fashion.

acute-on-chronic

• Acute ingestion in a patient who is chronically on lithium.
• This may be the most dangerous form, because there is already a lot of lithium in the tissue before the acute ingestion. This increases the risk of acute decompensation as tissue levels elevate further.

chronic

• This is the most common form of intoxication.
• The patient is taking their usual lithium dose, but lithium accumulates (usually due to renal dysfunction).
• The clinical course is usually dominated by neurologic symptoms.
• Gastrointestinal symptoms will typically be absent (the patient didn't ingest a lot of lithium).

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evaluation

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The differential diagnosis and evaluation will vary considerably, depending on the clinical presentation. Some common considerations include:

basic evaluations for all patients

• History
  • Amount ingested and the timing
  • Formulation (e.g., immediate release versus sustained release)
  • Potential coingestants
  • Historical clues regarding volume status (e.g., nausea/vomiting, diarrhea, adequacy of fluid intake)
  • Recent changes in medication regimen, with a focus on agents which could affect lithium clearance or volume status
• Laboratory studies
  • Basic chemistries, including evaluation of renal function.
    • Lithium may reduce the anion gap.
    • Chronic lithium use causes a leukocytosis.
  • Lithium level (including repeat levels as discussed below).
  • Thyroid stimulating hormone (chronic lithium use is associated with hypothyroidism).
  • Calcium level (chronic lithium use is associated with hyperparathyroidism).
• Physical examination
  • POCUS evaluation of cardiac function and volume status
  • Evaluation for neurologic manifestations of lithium (figure below)

additional evaluations to consider in acute ingestion

• Evaluation for coingestants (e.g., salicylate and acetaminophen).

additional evaluations to consider in chronic intoxication

• Chronic intoxication is often precipitated by another medical illness (e.g., renal failure).
• Evaluation should include both evaluation of the lithium toxicity and also evaluation for underlying triggers (e.g., evaluation of acute kidney injury).

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lithium levels & ingested doses

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when to obtain levels & how often

• Lithium levels should be checked whenever a patient on lithium is admitted to the hospital, or whenever lithium intoxication is a possibility.
  • Lithium intoxication may cause a pathologically low anion gap.
• [1] Cycle levels q2-4 hours until they peak (this may not occur for >24 hours with sustained release lithium).
• [2] Once decreasing, continue to check levels q6-12 hours. (Murphy 2023)

interpretation of lithium levels

• Levels don't always correlate well with clinical toxicity, because the danger from lithium poisoning is the lithium level in brain tissue (not in the blood).
  • In acute intoxication, patients may have high blood levels without symptoms (because lithium hasn't had time to penetrate the brain).
  • In chronic intoxication, toxicity can occur at a lower serum lithium level.
  • Some reports suggest the possibility of clinical lithium toxicity despite serum levels in the “therapeutic” range.
• Very rough guide to lithium levels
  • 0.5 – 1.25 mM is therapeutic (when measured as a trough level, 12 hours after the prior dose).
  • >1.5 mM can be consistent with intoxication.
  • >3.5-4 mM can be consistent with severe intoxication.

interpretation of the ingested dose

• Why this is complicated:
  • i) Reports of the ingested amount of lithium are notoriously unreliable, so they cannot be depended upon for medical decision making. However, they may provide a rough concept of how severe the intoxication is likely to be.
  • ii) Toxicity depends on total brain levels of lithium, which are heavily dependent on the chronic lithium level. Thus, the impact of an acute ingestion depends on both the baseline brain lithium level and the amount which is acutely ingested.
• A typical therapeutic dose of lithium is ~1.5 grams per day.
• Increased risk of toxicity occurs at >7.5 mg/kg elemental lithium (equal to 40 mg/kg lithium carbonate, or ~3 grams). (27516079)

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decontamination

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• Lithium will not be adsorbed by activated charcoal, so this is not indicated.
• Whole bowel irrigation with polyethylene glycol (e.g., GoLytely) may be considered following large ingestion of sustained release tablets (e.g., >80 mg/kg lithium carbonate). (27516079)

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medications to avoid

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medications that increase lithium levels

• NSAIDs.
• Renin-angiotensin system inhibitors (e.g., ACE inhibitors & ARBs).
• Thiazide diuretics.

medications that could increase neurotoxicity or cardiovascular consequences:

• Medications that may reduce blood pressure (e.g., beta-blockers).
• Medications that may prolong the QT interval.
• Medications that may depress mental status or reduce the seizure threshold. (Murphy 2023)

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fluid resuscitation & diuresis

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[#1] adequately aggressive initial fluid repletion

• Patients may be severely volume depleted (e.g., due to poor oral intake, nausea, and vomiting).
• Initial resuscitation may require large volume fluid resuscitation initially (e.g., 4-6 liters crystalloid).
  • 🔑 One of the most common treatment errors is inadequate volume resuscitation. Do not provide a fixed amount (e.g., two liters) and assume that it is enough.
• Ideally this should be guided by hemodynamic monitoring (e.g., bedside echocardiography).
• Fluid composition may be selected based on the patient's electrolytes, using the principles of pH-guided fluid resuscitation (more on this here). In most situations, Lactated Ringer's is a reasonable choice.

[#2] maintenance fluid infusion

• Following fluid repletion, it may be beneficial to continue a generous rate of crystalloid infusion (e.g., 200 ml/hr LR).
• Ideally, this fluid will stimulate increased urine production by the kidneys, resulting in an even fluid balance. Many patients with lithium intoxication are young (with good renal and cardiac function), so they may tend to normally excrete any excess fluid. If the patient isn't excreting fluid appropriately and is running a positive fluid balance, then stop the infusion or consider the addition of diuretics.
  • The goal is to encourage adequate urine output, while achieving a roughly even fluid balance.
• Lithium is handled by the kidneys similarly to sodium. Therefore, stimulating the kidney to excrete sodium may cause it to excrete lithium as well. This may be the most effective approach, because administration of a single agent (e.g., Lactated Ringer's) may modulate sodium handling across many sites within the nephron (by taking advantage of normal homeostatic mechanisms).

forced diuresis

• Lithium is mostly reabsorbed in the proximal tubule, with some additional reabsorption in the ascending loop of Henle and the distal tubules.
• Acetazolamide, furosemide, and amiloride should increase lithium excretion. However,  available data suggest that the effect isn't impressive.
• Diuretics are not generally recommended due to concern about the possibility that volume depletion could occur, which would worsen lithium clearance. (36940005)
• Adding diuretics may be reasonable in the intensive care unit, if there is very close monitoring and avoidance of volume depletion (e.g., urinary output is replaced by lactated ringers to avoid net fluid loss).
  • ⚠️ If diuretics are used to facilitate lithium excretion, it is of paramount importance to closely monitor volume status with strict avoidance of hypovolemia. If hypovolemia is allowed to develop, this will counteract any potential benefit of diuresis. Additionally, close monitoring of other electrolytes is important (e.g., potassium and magnesium).
• The context in which forced diuresis might be most beneficial could be an acute ingestion, wherein there is a high lithium level within the serum (but lithium hasn't yet entered into the tissues).

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nephrogenic diabetes insipidus

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• Patients on chronic lithium therapy will often develop nephrogenic diabetes insipidus, wherein the kidneys waste free water.
• Normally, hypothalamic thirst mechanisms will allow people to compensate for nephrogenic diabetes insipidus by drinking lots of water (to keep up with renal water losses).
• If patients lose access to free water for any reason, they may develop hypernatremia.
• Electrolytes and urine output should be followed. If hypernatremia occurs, this must be treated aggressively with an appropriately calculated dose of free water (more on the treatment of hypernatremia here).
• These considerations apply to any patient on chronic lithium who is admitted to the hospital (whether or not they have lithium intoxication).

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dialysis

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widespread confusion exists regarding when to dialyze

• There is no high-quality data regarding who should be dialyzed.
• Studies demonstrate deficiencies in expert recommendations and guidelines regarding when to perform dialysis:
  • One study evaluated 18 patients whom the poison control recommended undergoing dialysis. Only six patients actually ended up receiving dialysis, with no differences in outcomes between both groups of patients. (11105800)
  • A larger study described 128 patients with lithium poisoning. Among 101 patients in whom the EXTRIP guidelines recommended or suggested dialysis, only 22% actually received dialysis (less than one quarter!). Clinical outcomes were similar between dialyzed and nondialyzed patients, suggesting that the EXTRIP guidelines frequently recommend dialysis in situations where it isn't mandatory. (31378954)
• Use of dialysis is often motivated by a desire to avoid long-term neurologic complications. However, among patients who are chronically on lithium, rapidly dropping the lithium level might increase the risk of chronic neurologic injury (discussed further here).
• The table below shows recommended indications to initiate dialysis, based on the most reputable sources available. (27516079) As you can observe, these are arbitrary and contradictory.
  • The EXTRIP guidelines recommend dialysis if the lithium level is >5 mM, or >4 mM with renal dysfunction. (25583292)

factors to consider when deciding whether to dialyze

• (1) Lithium levels & trajectory:
  • Rising levels and/or ingestion of controlled release lithium may suggest that the intoxication will get worse before it gets better.
  • Stable levels in a patient with chronic toxicity suggest that the patient is unlikely to suddenly deteriorate.
• (2) Renal function:
  • Lithium is cleared entirely by the kidneys.
  • In severe renal dysfunction, dialysis may be required to clear lithium.
• (3) Clinical trajectory:
  • Signs and symptoms are helpful, because these reflect the brain lithium level.
  • Worsening clinical examination is potentially the most worrisome sign.
• (4) Acuity vs. chronicity:
  • Dialysis seems to be safe for acute lithium intoxication. Removal of lithium prior to its absorption in the brain could prevent toxicity.
  • Dialysis may be more dangerous and less useful for patients with chronic toxicity who are clinically OK. In such patients, rapid clinical deterioration is unlikely (since they are often close to a steady state). Rapid reduction in lithium levels might increase the risk of SILENT syndrome in this context (more on this below).

bottom line on dialysis?

• There is no simple answer to this, no single cutoff that is appropriate for every patient. Each case is unique and requires very careful consideration.
• The best approach is to very carefully assess the patient and then confer with a clinical toxicologist.
• When in doubt about whether to dialyze, a reasonable approach is to volume resuscitate aggressively and follow very carefully.
  • This approach might be considered only at a hospital capable of providing emergent dialysis.
  • Follow lithium levels and patient course very carefully, with ongoing consultation with a toxicologist.

Given that the time course of lithium poisoning is relatively long compared to other poisons, evolving over days, it is not unreasonable that a conservative approach is initially adopted in some circumstances as long as frequent monitoring of renal function and serum lithium concentrations are performed so that treatment can be adjusted, if required. –Roberts 2014

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resumption of lithium

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• For patients on chronic lithium, abrupt discontinuation may be problematic:
  • i) This could leave them with an untreated psychiatric disorder.
  • ii) Rapid discontinuation of lithium could increase the risk of chronic neurologic impairment (SILENT syndrome).
• Re-initiation of lithium needs to take into account the risk of recurrent ingestion.
• Once the serum lithium level has been within or below a therapeutic range for >24 hours, lithium may be resumed. (Murphy 2023)

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prognosis & SILENT syndrome

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mortality

• Mortality is low, on the order of 1%. (27516079)
• With modern supportive care modalities, it's uncommon for lithium to cause death.

SILENT (Syndrome of Irreversible Lithium-Effectuated NeuroToxicity)

• Potentially permanent neurologic injury resulting from lithium toxicity, due to an unclear mechanism.
• Manifestations may include cerebellar dysfunction and cognitive dysfunction.
• SILENT is more common with chronic intoxication than acute toxicity. It may result from chronic adaptations of the brain in response to ongoing lithium exposure. Shifts in tonicity experienced during lithium intoxication might contribute as well.
• There is no good evidence that dialysis can prevent SILENT syndrome. Indeed, it's conceivable that dialysis could even promote the development of SILENT syndrome.
  • Rapid reduction in lithium levels may correlate with increased risk of SILENT syndrome. (7962676) This could relate to the effects of osmotic shifts and rapid withdrawal of lithium.

While hyperlithemia can be toxic, its rapid correction can be more toxic. –Swartz et al. 1994

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failure to provide adequate fluid resuscitation initially. Patients with chronic lithium toxicity can be several liters depleted. Resuscitate aggressively to euvolemia with hemodynamic monitoring (e.g., echocardiography).
• Don't dialyze based on simple guidelines and cutoffs. The decision to dialyze is complex, and requires taking numerous factors into account. When in doubt, discuss with a toxicologist and/or nephrologist. In the most confusing situations, serial discussions along with observation of the patient and lithium levels can be helpful.
• Make sure to treat additional problems which the patient may have (e.g., acute kidney injury, diabetes insipidus, thyroid disorders, hypercalcemia).

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to Medscape monograph about a drug.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• = Link to supplemental media.