Lithium toxicity: Difference between revisions
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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)
*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)
*Serum levels may be very high but '''do not correlate with clinical toxicity'''


Serum concentrations can fall rapidly as lithium redistributes to tissues, and serum level does not correlate with degree of toxicity. GI symptoms predominate.
===Acute-on-Chronic===
*Patient on chronic lithium who takes supra-therapeutic dose
*Mixed GI and CNS symptoms


*GI - [[nausea/vomiting]], [[diarrhea]], [[abdominal pain]]
===Chronic Toxicity===
**Earliest and most common symptoms
*Insidious onset in patients on chronic therapy
*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>
*Due to increased absorption or decreased elimination
**Can also cause [[Brugada]]-like ECG pattern
*CNS symptoms predominate (generally more severe than acute):
*CNS Depression - late finding (takes time for lithium to distribute to CNS), indicates progression of toxicity
**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)


===Acute-on-Chronic===
===SILENT Syndrome<ref>Adityanjee, et al. The syndrome of irreversible lithium-effectuated neurotoxicity. ''Clin Neuropharmacol''. 2005;28(1):38-49. PMID 15681811</ref>===
Also called "Acute-on-therapeutic", occurs in patients currently taking lithium due to acute ingestion of supra-therapeutic doses.
*Syndrome of Irreversible Lithium-Effectuated Neurotoxicity
*Neurologic dysfunction persisting >2 months after cessation of lithium
*Cerebellar dysfunction (dysarthria, ataxia, gait instability), peripheral neuropathy, dementia


*Symptoms are a mix of both acute and chronic - includes both GI and CNS effects
==Differential Diagnosis==
*[[Serotonin syndrome]]
*[[Neuroleptic malignant syndrome]]
*[[Thyroid storm]] / [[hypothyroidism]]
*[[Alcohol]] or sedative-hypnotic intoxication
*Structural CNS lesion
*Other [[heavy metals]] toxicity
*[[Uremia]]


===Chronic===
{{Heavy metals DDX}}
Occurs insidiously in patients on chronic lithium therapy. Toxicity is secondary to increased absorption or decreased elimination. CNS symptoms predominate.


Chronic lithium therapy is associated with nephrogenic diabetes insipidus, which → hyponatremia, fluid loss → ↑ lithium levels (can precipitate toxicity)
==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)


*Neurotoxicity is major finding, and is generally more profound than that seen in acute toxicity
==Management==
**Mild symptoms include [[tremor]], drowsiness
===GI Decontamination===
**Progressive symptoms include hyperreflexia, [[confusion]], [[ataxia]], [[seizures]], [[extrapyramidal symptoms]], [[coma]]
*Whole bowel irrigation (WBI): only for sustained-release tablet ingestion
*[[Hypothyroidism]] (lithium inhibits thyroid hormone release)
**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


===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>===
===Fluid Resuscitation===
*Persistent sequelae of lithium toxicity
*Most important initial intervention — most patients have volume/sodium deficit
*Defined as neurologic dysfunction persisting > 2 months after cessation of lithium therapy
*NS is preferred (restores sodium, promotes renal lithium excretion)
*Exact mechanism unknown (possibly related to CNS demyelination).
*Give 2L NS bolus, then 200 mL/hr (or 2× maintenance)
*Symptoms
*Target UOP 1-2 mL/kg/hr
**Cerebellar dysfunction ([[dysarthria]], [[ataxia]], [[tremor]], gait instability)
*Avoid forced diuresis with loop diuretics (may worsen lithium toxicity)
**Peripheral neuropathy
**[[Extrapyramidal symptoms]]
*Brainstem dysfunction
*[[Dementia]]


==Differential Diagnosis==
===Hemodialysis===
{{Heavy metals list}}
*Most effective method of lithium removal
 
*Must follow '''serial lithium levels post-HD''' — levels will rebound due to tissue redistribution
==Evaluation==
*May require multiple sessions
*Lithium level
*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>:
**Therapeutic level = 0.6-1.2 meq/L
**Recommended (1D): impaired kidney function AND Li >4.0 mEq/L
**''Serum level may be falsely elevated if placed in a green top tube due to the heparin lithium interaction''
**'''Recommended (1D)''': clinical deterioration (decreased LOC, seizures, life-threatening dysrhythmias) regardless of level
**''Serum levels do not predict CNS levels and only roughly correlate with clinical symptoms''
**Suggested (2D): Li >5.0 mEq/L
*Metabolic Panel
**Suggested (2D): expected time to Li <1.0 mEq/L with optimal management >36 hours
*TSH
*Contraindication to aggressive fluids ([[CHF]]) lowers threshold for HD
*[[ECG]]
*Consult toxicology and nephrology — complex decision
*Acetaminophen and Salicylate Levels (possible coingestants)


==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]]

Latest revision as of 09:30, 22 March 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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