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==Background==
==Background==
*Mechanism of action is poorly understood.
*Lithium remains the most effective treatment for [[bipolar disorder]] despite availability of newer agents
*Despite availability of newer drugs, [[Lithium]] remains most effective treatment for bipolar disorder, and it is still in use
*Mechanism of action poorly understood; modulates neurotransmitter signaling
*Lithium initially distributes in extracellular fluid, then gradually redistributes to other areas including the brain (takes up to 24 hours after absorption)
*Narrow therapeutic index (therapeutic level: 0.6-1.2 mEq/L)
*95% renal excretion
*Pharmacokinetics:
**[[NSAIDs]], [[diuretics]], [[ACE-inhibitors]] → ↑ Lithium serum concentration by ↓ lithium excretion
**Rapidly absorbed (peak 1-2h for immediate release; 4-12h for sustained release)
*Lithium toxicity rarely fatal (only 11 deaths out of 6815 reported toxic exposures in 2012)<ref> Mowry JB, Spyker DA, Cantilena LR Jr., Bailey JE, Ford M: 2012 annual report of the American association of poison control centers’ national poison data system (NPDS): 30th annual report. Clin Toxicol (Phila) 51: 949–1229, 2013</ref>
**Initially distributes in extracellular fluid → gradually redistributes to CNS (up to 24 hours)
**95% renally excreted; handled like sodium by proximal tubule
*Lithium toxicity rarely fatal (only 11 deaths out of 6815 reported toxic exposures in 2012)<ref>Mowry JB, et al. 2012 annual report of the AAPCC NPDS. ''Clin Toxicol (Phila)''. 2013;51:949-1229. PMID 24359283</ref>


===Common Precipitants===
===Common Precipitants===
*[[Overdose]]
*Volume depletion: vomiting, diarrhea, diaphoresis, decreased PO intake
*[[Renal failure]]
*Medications that decrease lithium excretion:
*Volume depletion
**[[NSAIDs]], [[ACE inhibitors]]/ARBs, [[thiazide diuretics]]
**[[Diuretic]] use, [[vomiting]], [[diarrhea]], diaphoresis, decreased oral intake
*[[Acute kidney injury]] or chronic kidney disease
*[[Hyperthermia]]
*Intentional overdose
*Infection
*[[Hyperthermia]], [[CHF]], [[sepsis]]
*[[CHF]]
*Nephrogenic [[diabetes insipidus]] (caused by chronic lithium use) → dehydration → ↑ lithium levels
*Surgery
*[[Cirrhosis]]


==Clinical Features==
==Clinical Features==
''Three recognized patterns of Lithium toxicity - "Acute", "Acute-on-chronic", and "Chronic".<ref>Waring WS, Laing WJ, Good AM, Bateman DN. Pattern of lithium exposure predicts poisoning severity: evaluation of referrals to a regional poisons unit. QJM. 2007 May;100(5):271-6. Epub 2007 Apr 5.</ref>''
Three recognized patterns of toxicity<ref>Waring WS, et al. Pattern of lithium exposure predicts poisoning severity. ''QJM''. 2007;100(5):271-6. PMID 17410291</ref>:


===Acute===
===Acute Ingestion===
Occurs in patients not previously receiving lithium (i.e. with no current body stores)
*Patient not previously on lithium (no body stores)
 
*GI symptoms predominate: nausea, vomiting, diarrhea, abdominal pain (earliest/most common)
Serum concentrations can fall rapidly as lithium redistributes to tissues, and serum level does not correlate with degree of toxicity. GI symptoms predominate.
*Cardiac: [[bradycardia]], QT prolongation, T-wave flattening/inversion, Brugada-like pattern<ref>Canan F, et al. Lithium intoxication related multiple temporary ECG changes. ''Cases Journal''. 2008;1:156. PMID 18801176</ref>
 
*CNS depression is a late finding (takes time for lithium to redistribute to brain)
*GI - [[nausea/vomiting]], [[diarrhea]], [[abdominal pain]]
*Serum levels may be very high but '''do not correlate with clinical toxicity'''
**Earliest and most common symptoms
*Cardiac effects - [[bradycardia]], [[QT prolongation]], T-wave flattening or inversion<ref>Canan F, Kaya A, Bulur S, Albayrak ES, Ordu S, Ataoglu A. Lithium intoxication related multiple temporary ecg changes: A case report. Cases Journal. 2008;1:156. doi:10.1186/1757-1626-1-156.</ref>
**Can also cause [[Brugada]]-like ECG pattern
*CNS Depression - late finding (takes time for lithium to distribute to CNS), indicates progression of toxicity


===Acute-on-Chronic===
===Acute-on-Chronic===
Also called "Acute-on-therapeutic", occurs in patients currently taking lithium due to acute ingestion of supra-therapeutic doses.
*Patient on chronic lithium who takes supra-therapeutic dose
*Mixed GI and CNS symptoms


*Symptoms are a mix of both acute and chronic - includes both GI and CNS effects
===Chronic Toxicity===
*Insidious onset in patients on chronic therapy
*Due to increased absorption or decreased elimination
*CNS symptoms predominate (generally more severe than acute):
**Mild: fine tremor, drowsiness, muscle weakness
**Moderate: hyperreflexia, confusion, coarse tremor, ataxia, slurred speech
**Severe: [[seizures]], myoclonus, coma, extrapyramidal symptoms
*Hypothyroidism (lithium inhibits thyroid hormone release)


===Chronic===
===SILENT Syndrome<ref>Adityanjee, et al. The syndrome of irreversible lithium-effectuated neurotoxicity. ''Clin Neuropharmacol''. 2005;28(1):38-49. PMID 15681811</ref>===
Occurs insidiously in patients on chronic lithium therapy. Toxicity is secondary to increased absorption or decreased elimination. CNS symptoms predominate.
*Syndrome of Irreversible Lithium-Effectuated Neurotoxicity
*Neurologic dysfunction persisting >2 months after cessation of lithium
*Cerebellar dysfunction (dysarthria, ataxia, gait instability), peripheral neuropathy, dementia


Chronic lithium therapy is associated with nephrogenic diabetes insipidus, which → hyponatremia, fluid loss → ↑ lithium levels (can precipitate toxicity)
==Differential Diagnosis==
*[[Serotonin syndrome]]
*[[Neuroleptic malignant syndrome]]
*[[Thyroid storm]] / [[hypothyroidism]]
*[[Alcohol]] or sedative-hypnotic intoxication
*Structural CNS lesion
*Other [[heavy metals]] toxicity
*[[Uremia]]


*Neurotoxicity is major finding, and is generally more profound than that seen in acute toxicity
{{Heavy metals DDX}}
**Mild symptoms include [[tremor]], drowsiness
**Progressive symptoms include hyperreflexia, [[confusion]], [[ataxia]], [[seizures]], [[extrapyramidal symptoms]], [[coma]]
*[[Hypothyroidism]] (lithium inhibits thyroid hormone release)


===Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT)<ref>Adityanjee, Munshi KR, Thampy A. The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol. 2005 Jan-Feb;28(1):38-49.</ref>===
==Evaluation==
Persistent sequelae of lithium toxicity. Defined as neurologic dysfunction persisting more than 2 months after cessation of lithium therapy. Exact mechanism unknown (possibly related to CNS demyelination).
*Lithium level:
**Therapeutic: 0.6-1.2 mEq/L
**Levels >1.5 mEq/L may be associated with toxicity (chronic > acute for same level)
**'''Do NOT use green top (lithium heparin) tube''' — falsely elevates level
**Serum levels '''do not predict CNS levels''' and only roughly correlate with clinical symptoms
**Serial levels every 2-4 hours (especially after overdose or post-HD)
*BMP: creatinine, sodium (often hyponatremic or hypernatremic), calcium
*TSH (chronic use → hypothyroidism)
*ECG: QT prolongation, T-wave changes, bradycardia, Brugada pattern
*Acetaminophen and salicylate levels (possible coingestants)
*Urinalysis (urine specific gravity to evaluate concentrating ability)


Symptoms
==Management==
*Cerebellar dysfunction
===GI Decontamination===
*Peripheral neuropathy
*Whole bowel irrigation (WBI): only for sustained-release tablet ingestion
*Extrapyramidal symptoms
**PEG solution via NG at 1-2 L/hr (adults)
*Brainstem dysfunction
*Activated charcoal is NOT effective (lithium is not adsorbed)
*Dementia
*Gastric lavage generally not effective and potentially harmful


==Differential Diagnosis==
===Fluid Resuscitation===
{{Heavy metals list}}
*Most important initial intervention — most patients have volume/sodium deficit
*NS is preferred (restores sodium, promotes renal lithium excretion)
*Give 2L NS bolus, then 200 mL/hr (or 2× maintenance)
*Target UOP 1-2 mL/kg/hr
*Avoid forced diuresis with loop diuretics (may worsen lithium toxicity)


==Evaluation==
===Hemodialysis===
*Lithium level
*Most effective method of lithium removal
**Therapeutic level = 0.6-1.2 meq/L
*Must follow '''serial lithium levels post-HD''' — levels will rebound due to tissue redistribution
**''Serum level may be falsely elevated if placed in a green top tube due to the heparin lithium interaction''
*May require multiple sessions
**''Serum levels do not predict CNS levels and only roughly correlate with clinical symptoms''
*EXTRIP Workgroup Indications<ref>Decker BS, et al. Extracorporeal treatment for lithium poisoning: systematic review and recommendations from the EXTRIP Workgroup. ''Clin J Am Soc Nephrol''. 2015;10(5):875-887. PMID 25583293</ref>:
*Metabolic Panel
**Recommended (1D): impaired kidney function AND Li >4.0 mEq/L
*TSH
**'''Recommended (1D)''': clinical deterioration (decreased LOC, seizures, life-threatening dysrhythmias) regardless of level
*[[ECG]]
**Suggested (2D): Li >5.0 mEq/L
*Acetaminophen and Salicylate Levels (possible coingestants)
**Suggested (2D): expected time to Li <1.0 mEq/L with optimal management >36 hours
*Contraindication to aggressive fluids ([[CHF]]) lowers threshold for HD
*Consult toxicology and nephrology — complex decision


==Management==
===Endpoint of Dialysis===
===GI decontamination===
*Continue HD until lithium level <1.0 mEq/L
*[[Whole bowel irrigation]] (only for extended release tablets)
*Recheck level 6-8 hours post-HD for rebound
*[[Gastric lavage]] and [[activated charcoal]] not effective and potentially harmful
===[[Fluid resuscitation]]===
*Average patient has Na/volume deficit; giving fluid helps reestablish normal renal Lithium excretion
*Give 2L NS bolus, then start 200mL/hr or 2x maintenance rate
===[[Hemodialysis]]===
''Most effective method of removal. Must follow serial lithium levels - levels will likely rise after HD due to redistribution from tissues; additional HD may be required.''
'''Indications:'''
*Kidney function is impaired and the [Li+] >4.0 mEq/L (1D recommendation)<ref name="extra">Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup. Decker BS et al. Clin J Am Soc Nephrol 2015 Jan 12 [http://www.extrip-workgroup.org/#!recommendations/cy1f Extrip Recs]</ref>
*Clinical deterioration
*In the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of [Li+] (1D)<ref name="extra"></ref>
*[Li+].>5.0 mEq/L (2D suggestion)
*If the expected time to obtain a [Li+]<1.0 mEq/L with optimal management is >36 h (2D suggestion)<ref name="extra"></ref>
*Baseline renal failure
*Contraindication to aggressive fluid resuscitation (CHF, etc)


==Disposition==
==Disposition==
*Consider discharge for patients who are asymptomatic after 4-6hr obs, 2 downtrending lithium levels, and no worsening of renal function
*Discharge considerations (acute ingestion):
*Admit all patients with Li level >1.5
**Asymptomatic after 4-6 hours observation
*Admit all patients with ingestion of sustained-release preparation (regardless of Li level)
**Two downtrending lithium levels
**No worsening renal function
*Admit:
**All patients with Li level >1.5 mEq/L
**All sustained-release preparation ingestions (regardless of Li level)
**Any patient with neurologic symptoms
**Any patient requiring hemodialysis
*Poison control: 1-800-222-1222


==See Also==
==See Also==
*[[Toxicology (Main)]]
*[[Toxicology]]
*[[Lithium]]
*[[Heavy metals]]
*[[Bipolar disorder]]
*[[Serotonin syndrome]]
*[[Neuroleptic malignant syndrome]]


==References==
==References==
<references/>
<references/>
*Baird-Gunning J, et al. Lithium poisoning. ''J Intensive Care Med''. 2017;32(4):249-263. PMID 27055773
*Ott M, et al. Lithium intoxication: incidence, clinical course and renal function — a population-based retrospective cohort study. ''J Psychopharmacol''. 2016;30(10):1008-1019. PMID 27530173


[[Category:Toxicology]]
[[Category:Toxicology]]

Revisión actual - 09:30 22 mar 2026

Background

  • Lithium remains the most effective treatment for bipolar disorder despite availability of newer agents
  • Mechanism of action poorly understood; modulates neurotransmitter signaling
  • Narrow therapeutic index (therapeutic level: 0.6-1.2 mEq/L)
  • Pharmacokinetics:
    • Rapidly absorbed (peak 1-2h for immediate release; 4-12h for sustained release)
    • Initially distributes in extracellular fluid → gradually redistributes to CNS (up to 24 hours)
    • 95% renally excreted; handled like sodium by proximal tubule
  • Lithium toxicity rarely fatal (only 11 deaths out of 6815 reported toxic exposures in 2012)[1]

Common Precipitants

Clinical Features

Three recognized patterns of toxicity[2]:

Acute Ingestion

  • Patient not previously on lithium (no body stores)
  • GI symptoms predominate: nausea, vomiting, diarrhea, abdominal pain (earliest/most common)
  • Cardiac: bradycardia, QT prolongation, T-wave flattening/inversion, Brugada-like pattern[3]
  • CNS depression is a late finding (takes time for lithium to redistribute to brain)
  • Serum levels may be very high but do not correlate with clinical toxicity

Acute-on-Chronic

  • Patient on chronic lithium who takes supra-therapeutic dose
  • Mixed GI and CNS symptoms

Chronic Toxicity

  • Insidious onset in patients on chronic therapy
  • Due to increased absorption or decreased elimination
  • CNS symptoms predominate (generally more severe than acute):
    • Mild: fine tremor, drowsiness, muscle weakness
    • Moderate: hyperreflexia, confusion, coarse tremor, ataxia, slurred speech
    • Severe: seizures, myoclonus, coma, extrapyramidal symptoms
  • Hypothyroidism (lithium inhibits thyroid hormone release)

SILENT Syndrome[4]

  • Syndrome of Irreversible Lithium-Effectuated Neurotoxicity
  • Neurologic dysfunction persisting >2 months after cessation of lithium
  • Cerebellar dysfunction (dysarthria, ataxia, gait instability), peripheral neuropathy, dementia

Differential Diagnosis

Template:Heavy metals DDX

Evaluation

  • Lithium level:
    • Therapeutic: 0.6-1.2 mEq/L
    • Levels >1.5 mEq/L may be associated with toxicity (chronic > acute for same level)
    • Do NOT use green top (lithium heparin) tube — falsely elevates level
    • Serum levels do not predict CNS levels and only roughly correlate with clinical symptoms
    • Serial levels every 2-4 hours (especially after overdose or post-HD)
  • BMP: creatinine, sodium (often hyponatremic or hypernatremic), calcium
  • TSH (chronic use → hypothyroidism)
  • ECG: QT prolongation, T-wave changes, bradycardia, Brugada pattern
  • Acetaminophen and salicylate levels (possible coingestants)
  • Urinalysis (urine specific gravity to evaluate concentrating ability)

Management

GI Decontamination

  • Whole bowel irrigation (WBI): only for sustained-release tablet ingestion
    • PEG solution via NG at 1-2 L/hr (adults)
  • Activated charcoal is NOT effective (lithium is not adsorbed)
  • Gastric lavage generally not effective and potentially harmful

Fluid Resuscitation

  • Most important initial intervention — most patients have volume/sodium deficit
  • NS is preferred (restores sodium, promotes renal lithium excretion)
  • Give 2L NS bolus, then 200 mL/hr (or 2× maintenance)
  • Target UOP 1-2 mL/kg/hr
  • Avoid forced diuresis with loop diuretics (may worsen lithium toxicity)

Hemodialysis

  • Most effective method of lithium removal
  • Must follow serial lithium levels post-HD — levels will rebound due to tissue redistribution
  • May require multiple sessions
  • EXTRIP Workgroup Indications[5]:
    • Recommended (1D): impaired kidney function AND Li >4.0 mEq/L
    • Recommended (1D): clinical deterioration (decreased LOC, seizures, life-threatening dysrhythmias) regardless of level
    • Suggested (2D): Li >5.0 mEq/L
    • Suggested (2D): expected time to Li <1.0 mEq/L with optimal management >36 hours
  • Contraindication to aggressive fluids (CHF) lowers threshold for HD
  • Consult toxicology and nephrology — complex decision

Endpoint of Dialysis

  • Continue HD until lithium level <1.0 mEq/L
  • Recheck level 6-8 hours post-HD for rebound

Disposition

  • Discharge considerations (acute ingestion):
    • Asymptomatic after 4-6 hours observation
    • Two downtrending lithium levels
    • No worsening renal function
  • Admit:
    • All patients with Li level >1.5 mEq/L
    • All sustained-release preparation ingestions (regardless of Li level)
    • Any patient with neurologic symptoms
    • Any patient requiring hemodialysis
  • Poison control: 1-800-222-1222

See Also

References

  1. ↑ Mowry JB, et al. 2012 annual report of the AAPCC NPDS. Clin Toxicol (Phila). 2013;51:949-1229. PMID 24359283
  2. ↑ Waring WS, et al. Pattern of lithium exposure predicts poisoning severity. QJM. 2007;100(5):271-6. PMID 17410291
  3. ↑ Canan F, et al. Lithium intoxication related multiple temporary ECG changes. Cases Journal. 2008;1:156. PMID 18801176
  4. ↑ Adityanjee, et al. The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol. 2005;28(1):38-49. PMID 15681811
  5. ↑ Decker BS, et al. Extracorporeal treatment for lithium poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin J Am Soc Nephrol. 2015;10(5):875-887. PMID 25583293
  • Baird-Gunning J, et al. Lithium poisoning. J Intensive Care Med. 2017;32(4):249-263. PMID 27055773
  • Ott M, et al. Lithium intoxication: incidence, clinical course and renal function — a population-based retrospective cohort study. J Psychopharmacol. 2016;30(10):1008-1019. PMID 27530173
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