Lithium toxicity

Lithium

• Modulates two signal transduction pathways and three neurotransmitters
• Suppresses inositol signaling
• Inhibits glycogen synthase kinase-3
• Decreases release of NA and dopamine
• May transiently increase release of serotonin
• Variants
  • Acute poisoning – Never taken before
  • Acute on chronic – Chronic use then large acute overdose
  • Chronic– Chronic use then increase in usual dose, renal impairment or impaired elimination from drug-drug interaction

Lithium

• Therapeutic steady-state 0.6-1.2mEq/L
• Mild lithium toxicity at steady-state 1.5-2.5mEq/L
• Moderate toxicity 2.5-3.5mEq/L
• Severe toxicity >3.5mEq/L
• Clinical features though are highly variable and dependent on the pattern of poisoning
  • This is due to the delayed diffusion of lithium

Acute overdose

• Risk assessment
  • If normal renal fx, <25g causes only mild GI upset
  • >25g can lead to more significant GI sx but rarely leads to significant neurotox as long as renal fx remains intact
  • Acute or chronic renal impairment, dehydration or sodium depletion all significantly impair lithium excretion, leading to redistribution to lipid stores incl. CNS with progressive neurotoxicity
  • If present late with established neurotoxicity, risk assess as for chronic OD
• Toxic mechanism
  • Direct irritant to GI. Substitute for Na and K and modulate intracellular second messengers
  • May also affect serotonin production and release

Acute overdose

• Toxicokinetics
  • Absorption
    • Standard release peaks at 30 min to 2 hours and completely absorbed by 6
    • Slow-release at therapeutic doses peaks around 4-5 hours
    • Slow-release in overdose peak levels can be delayed up to 12 hours due to clumping of insoluble aggregates (especially lithium carbonate)
  • Distribution – Steady state Vd 0.7-0.9L/kg
    • Widely distributed in total body water
    • Slowly redistributed from intravascular compartment to lipid stores incl. CNS delayed around 24 hours
  • Metabolism – Nil
  • Elimination – Entirely renal and dependent on GFR, hydration and sodium level
  • Fractional excretion of lithium is 25% of GFR
    • Half-life 8-12 hours but can be 2-3 days with toxic concentrations or as high as 58 hours in the elderly who take it regularly
    • Sodium depletion leads to lithium retention as kidneys Rx it as sodium
    • 80% of filtered lithium is reabsorbed 

Acute overdose

• Clinical features
  • GI symptoms with fluid losses
  • Neurological symptoms, if occur, are delayed as relies on redistribution
  • Tremor is earliest and most frequent
  • If reduced renal elimination or delayed presentation can have established neurotoxicity like chronic overdose
    • Typically >1g/kg or 50g where serum concentrations are elevated for a prolonged period
  • Minor St-T wave changes on ECG, prolonged QT, bradycardia, sinus node dysfunction and TWI
• Investigations
  • Serum lithium in acute overdose is useful for risk assessment, confirmation and monitoring of therapy
  • Serum lithium – Confirms OD and following large overdoses, q6h serial levels monitor progress until peaks and falling and determination of safety for discharge
    • Peak >5mmol/L at 4-8 hours are not unusual

Acute overdose

• Management
  • Resus
  • Fluids to target UO 1mL/kg/hr and ensure normal Na
  • Monitor hydration status, renal fx, serum lithium levels, neurotoxicity and Na
  • Continuous cardiac monitoring not required
  • Identify and manage nephrogenic DI (fluids to match outputs)
  • Thiamine supplementation
  • Identify and treat hypo/hyperthyroidism
• Decontamination – AC not effective
  • WBI can be considered for >50g lithium SR (no data to show benefit of this)
  • Possibly lower doses if renal impairment
• Enhanced elimination
  • HD: Not useful unless massive OD, renal failure or late presenters with neurotoxicity

Acute overdose

• Tox modules
  • Indications for dialysis
    • Li >2.5 with neurotoxicity
    • Seizures
    • Coma

Acute overdose

• EXTRIP
  • Recommended for severe toxicity as evidenced by:
    • Kidney function impaired and Li > 4.0
    • Reduced consciousness, seizure or life-threatening dysrhythmias irrespective of Li concentration
  • Suggested if:
    • Li >5.0 (as neurotoxicity will likely occur irrespective of clearance)
    • Significant confusion
    • Expected time to reduce Li to <1.0 with optimal management is > 36 hours
  • IHD is preferred
  • Cease once Li <1.0 or clinical improvement is apparent and after a minimum of 6 hours if the Li concentration is not readily measurable

Acute overdose

• Disposition
  • If no neurotoxicity, lithium <1.5mmol/L and falling can be d/c
• Handy tips
  • Coma in the context of acute OD is never due to lithium
  • Patients on long-term lithium are managed in the same manner and do not have increased risks of toxicity

Chronic poisoning

• Risk assessment
  • Consider in any patient on lithium with neurological signs or symptoms
  • Significant obtundation or seizure carries risk of permanent neurological sequelae
  • Serum lithium concentrations correlate poorly with clinical features
    • Only use is to aid early diagnosis
• Clinical features
  • Hansen and Amdisen Grades
    • Grade 1 (mild): Tremor, hyperreflexia, agitation, muscle weakness, ataxia
    • Grade 2 (moderate): Stupor, rigidity, hypertonia, hypotension
    • Grade 3 (severe): Coma, seizures, myoclonus
  • GI symptoms are not prominent
  • Clinical features frequently include the underlying precipitating illness

Chronic poisoning

• Levels
  • 0.5 mmol/L – None
  • 1.0 – Mild tremor
  • 1.5 – Coarse tremor
  • 2.0 – Hyperreflexia, dysarthria
  • 2.5 – Myoclonic, ataxia, confusion
  • 3.0 – Marked delirium, coma, seizures

Chronic poisoning

• Most common causes
  • Impaired lithium excretion: Impaired renal fx, diabetes insipidus, sodium depletion, dehydration and drug interactions
  • Drugs that impair lithium excretion: NSAID’s, ACEi, thiazides and topiramate
  • Nephrogenic diabetes insipidus and hypothyroidism
    • Both associated with chronic lithium poisoning
• Ix
  • Serum lithium – Confirms dx and serial levels can monitor progress
  • EUC
  • TFT

Chronic poisoning

• Management
  • Volume resus
  • Correct any water or sodium deficits and target UO 1mL/kg/hr
  • Cease lithium and any drugs that may have impaired excretion
  • Monitor renal fx, UO, electrolytes and lithium levels
• Decontamination n/a
• Enhanced elimination
  • See EXTRIP slide

Chronic poisoning

• Disposition
  • Always need admission and resolution of neurology may takes weeks and sometimes is incomplete
• Handy tips
  • Consider diagnosis in any neurological presentation of someone on lithium
  • Clinical condition may initially worsen with inpatient management
  • Neurotoxicity can be prolonged due to slow redistribution and clearance from CNS
• Pitfalls
  • Failure to check level in unwell patient on lithium therapy

SILENT

• Syndrome of irreversible lithium-effectuated neurotoxicity (SILENT)
• Prevalence unknown and limited to case reports
• Chronic, largely cerebellar sequelae even once non-detectable lithium levels
• Tremor, EPSE, gait difficulties, nystagmus, dysarthria and cognitive deficits

Buckley et al. Translating EXTRIP guidelines into clinical practice

• Need to identify patients who are likely to have elevated lithium concentrations for a prolonged period of time – It is these patients that may benefit from dialysis
• Acute on chronic toxicity – No clear pattern and no clear CNS effects attributable to Lithium
  • New flowchart advises:
    • q6h Li levels until <1.0
    • If Li >5 or Li >4 + eGFR <45 = Dialyse until Li <1.0
• Nomogram developed for chronic toxicity
  • Hansen and Amdisen suggested dialysis for patients whose lithium level would be >1.0 at 30 hours
  • Nomogram aims to predict this in chronic toxicity based on GFR and level on arrival
  • Dialyse until Li < 1.0

Buckley Nomogram

Last Updated on October 28, 2020 by Andrew Crofton