Lithium toxicity: Difference between revisions

(Update: improved pharmacokinetics, EXTRIP HD indications with recommendation grades, SILENT syndrome, fluid targets, serial level monitoring, post-HD rebound, added references with PMIDs)
(Strip excess bold)
 
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==Background==
==Background==
*Lithium remains the '''most effective treatment for [[bipolar disorder]]''' despite availability of newer agents
*Lithium remains the most effective treatment for [[bipolar disorder]] despite availability of newer agents
*Mechanism of action poorly understood; modulates neurotransmitter signaling
*Mechanism of action poorly understood; modulates neurotransmitter signaling
*'''Narrow therapeutic index''' (therapeutic level: '''0.6-1.2 mEq/L''')
*Narrow therapeutic index (therapeutic level: 0.6-1.2 mEq/L)
*Pharmacokinetics:
*Pharmacokinetics:
**Rapidly absorbed (peak 1-2h for immediate release; 4-12h for sustained release)
**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''')
**Initially distributes in extracellular fluid → gradually redistributes to CNS (up to 24 hours)
**'''95% renally excreted'''; handled like sodium by proximal tubule
**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>
*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===
*'''Volume depletion''': vomiting, diarrhea, diaphoresis, decreased PO intake
*Volume depletion: vomiting, diarrhea, diaphoresis, decreased PO intake
*'''Medications that decrease lithium excretion''':
*Medications that decrease lithium excretion:
**[[NSAIDs]], [[ACE inhibitors]]/ARBs, [[thiazide diuretics]]
**[[NSAIDs]], [[ACE inhibitors]]/ARBs, [[thiazide diuretics]]
*[[Acute kidney injury]] or chronic kidney disease
*[[Acute kidney injury]] or chronic kidney disease
*Intentional overdose
*Intentional overdose
*[[Hyperthermia]], [[CHF]], [[sepsis]]
*[[Hyperthermia]], [[CHF]], [[sepsis]]
*'''Nephrogenic [[diabetes insipidus]]''' (caused by chronic lithium use) → dehydration → ↑ lithium levels
*Nephrogenic [[diabetes insipidus]] (caused by chronic lithium use) → dehydration → ↑ lithium levels


==Clinical Features==
==Clinical Features==
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===Acute Ingestion===
===Acute Ingestion===
*Patient '''not''' previously on lithium (no body stores)
*Patient not previously on lithium (no body stores)
*'''GI symptoms predominate''': nausea, vomiting, diarrhea, abdominal pain (earliest/most common)
*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>
*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)
*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 levels may be very high but '''do not correlate with clinical toxicity'''


===Acute-on-Chronic===
===Acute-on-Chronic===
*Patient on chronic lithium who takes supra-therapeutic dose
*Patient on chronic lithium who takes supra-therapeutic dose
*'''Mixed GI and CNS symptoms'''
*Mixed GI and CNS symptoms


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


===SILENT Syndrome<ref>Adityanjee, et al. The syndrome of irreversible lithium-effectuated neurotoxicity. ''Clin Neuropharmacol''. 2005;28(1):38-49. PMID 15681811</ref>===
===SILENT Syndrome<ref>Adityanjee, et al. The syndrome of irreversible lithium-effectuated neurotoxicity. ''Clin Neuropharmacol''. 2005;28(1):38-49. PMID 15681811</ref>===
*'''Syndrome of Irreversible Lithium-Effectuated Neurotoxicity'''
*Syndrome of Irreversible Lithium-Effectuated Neurotoxicity
*Neurologic dysfunction persisting '''>2 months''' after cessation of lithium
*Neurologic dysfunction persisting >2 months after cessation of lithium
*Cerebellar dysfunction (dysarthria, ataxia, gait instability), peripheral neuropathy, dementia
*Cerebellar dysfunction (dysarthria, ataxia, gait instability), peripheral neuropathy, dementia


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==Evaluation==
==Evaluation==
*'''Lithium level''':
*Lithium level:
**Therapeutic: '''0.6-1.2 mEq/L'''
**Therapeutic: 0.6-1.2 mEq/L
**Levels >1.5 mEq/L may be associated with toxicity ('''chronic > acute for same level''')
**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
**'''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
**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)
**Serial levels every 2-4 hours (especially after overdose or post-HD)
*'''BMP''': creatinine, sodium (often hyponatremic or hypernatremic), calcium
*BMP: creatinine, sodium (often hyponatremic or hypernatremic), calcium
*'''TSH''' (chronic use → hypothyroidism)
*TSH (chronic use → hypothyroidism)
*'''ECG''': QT prolongation, T-wave changes, bradycardia, Brugada pattern
*ECG: QT prolongation, T-wave changes, bradycardia, Brugada pattern
*'''Acetaminophen and salicylate levels''' (possible coingestants)
*Acetaminophen and salicylate levels (possible coingestants)
*Urinalysis (urine specific gravity to evaluate concentrating ability)
*Urinalysis (urine specific gravity to evaluate concentrating ability)


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


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


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


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


==See Also==
==See Also==

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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