Lithium is mainly used to treat bipolar disorder; it has a narrow therapeutic range and requires monitoring of levels in therapeutic use.

Toxicity can broadly be classified as acute (including acute-on-chronic ingestions) or chronic.

Symptoms in acute toxicity are normally restricted to the gastrointestinal system, as serum levels rise and fall too quickly for redistribution to the central nervous system. Intervention beyond maintenance of hydration is unlikely to be needed unless renal failure or sodium depletion is present.

Chronic toxicity is more commonly associated with significant toxicity, most notably central nervous system toxicity due to the sustained elevation in serum levels. Haemodialysis is often required for its management.

Lithium is a small cation that distributes uniformly in body water replacing normal cations. Its therapeutic effect is not directly receptor mediated but appears to be due to downstream effects on intracellular enzymes including a large variety of lithium-sensitive, magnesium dependent phosphodiesterase. The CNS toxicity seen in chronic toxicity is likely multifactorial and includes effects on cellular ATP production, osmolar and sodium shifts and possibly exacerbated by thiamine deficiency.

Nephrogenic diabetes insipidus (NDI) is common in patients on long term lithium therapy and is a major risk factor for the development of chronic lithium toxicity. Lithium reduces the expression of water transporting aquaporins in the renal collecting ducts reducing the ability to concentrate urine.

Acute ingestion (including acute-on-chronic):

Ingestions of less than 25g are unlikely to cause major effects unless renal impairment is present. GI symptoms (diarrhoea and vomiting) are common.

Serum lithium concentrations are difficult to interpret as they do not correlate well with toxicity. Persistently elevated levels, 24 hours post ingestion, are more likely to redistribute to the CNS and may be an indication for enhanced elimination (see below).

Chronic Toxicity:

Chronic toxicity generally occurs in the setting of dose increase, kidney injury, medication changes (e.g. commencement of ACEi) or concomitant illness leading to dehydration (especially in the setting of NDI).

Serum levels are more predictive of toxicity as they more closely reflect CNS levels, although clinical features should also be considered when making treatment decisions.

The half-life in therapeutic use is 8–12 hours with normal renal function and hydration.
The half-life with toxic concentrations is often substantially longer (2–3 days even with active treatment to enhance elimination) as patients are usually significantly dehydrated and may have renal failure.

Therapeutic doses of lithium have high bioavailability and are rapidly absorbed from the small intestine. Peak concentrations occur at 2-3 hours in therapeutic use. Sustained release preparations are available and can results in greatly prolonged absorption, particularly in overdose. Following overdose, lithium concentrations are normally much lower than concentrations predicted by extrapolating therapeutic kinetics. This suggests either a saturable process of absorption and/or maintenance of high urinary lithium clearance.

Lithium is not protein bound and has a volume of distribution equal to body water (0.6L/kg). Distribution into cells is slow, with complete equilibration taking days to weeks. This is also true in reverse, meaning that there is often a delay to improvement of CNS effects even once serum levels are normalised. There is good placental transfer with maternal use of lithium prior to delivery associated with floppy babies.

Lithium is excreted unchanged in the urine. After filtration, lithium is reabsorbed in the proximal tubule by the sodium transport system and in patients with hyponatraemia lithium clearance will be reduced due to increased reabsorption. Diuretics that act on the proximal tubule increase lithium clearance whilst those that act more distally will reduced clearance.

Reduction in glomerular filtration for any reason (including NSAIDs) will also reduce lithium clearance.

Acute ingestion (including acute-on-chronic):

• Gastrointestinal: Symptoms are generally restricted to the GI system where lithium has an irritative effect leading to vomiting, diarrhoea and abdominal pain.
• CNS: Rarely, in very large ingestions, with sustained elevation on serum levels, neurological symptoms can develop like those see in chronic toxicity.
• CVS: QT prolongation can occur but is uncommon.

Chronic toxicity:

• CNS: Chronic elevations in serum lithium levels give time for lithium to redistribute to the CNS leading to more predictable symptoms for a given serum lithium level:

• CVS: Uncommonly: QT prolongation, conduction blocks.
• Renal: Chronic treatment is associated with declining renal function due to glomerular and tubulointerstitial nephropathy.

• Serum lithium level: This is more reflective of toxicity in chronic ingestions and will aid decisions regarding the need for enhanced elimination. In acute ingestions it should be measured every 6 hours to establish when peak has passed. Maintainance levels are typically 0.4-0.8mmol/L. Some laboratories still report the upper limit of the therapeutic range as 1.2mmol/L, this was derived from early naive interpreatations of kinetics.
• Renal function: Lithium is renally cleared and the presence of renal failure significantly increases the risk of CNS toxicity developing.
• Serum sodium concentration: Lithium clearance will be reduced in hyponatraemia. Hypernatraemia will be seen in dehydration and is particularly important to detect in those with NDI who are unwell and unable to manage their water intake as normal.
• ECG: Detection of long QT or conduction bloods.

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Rehydration and correction of any hyponatraemia are the cornerstone of initial management. In the case of acute ingestion this is normally all that is needed.

Patients with NDI need very careful management of their fluid status. Along with IV hydration (preferably with 0.9% Sodium Chloride to maintain sodium levels) they should be allowed to drink to thirst as normal and should not have their oral intake restricted (a common mistake when medical staff see how much water they are drinking). In those who have an altered level of consciousness, fluid status should be followed closely with regular monitoring of serum sodium levels and matching of fluid intake to urinary output to ensure the patient does not become fluid deplete.

Nephrotoxins should be withheld, and supplemental thiamine given to those with CNS involvement.

Activated charcoal does not bind to lithium.

There is a potential role for whole bowel irrigation in very large acute ingestions (>50g). This is particularly true in the case of a sustained release preparation overdose as it is more likely that the ingestion will lead to prolonged elevation in lithium levels and risk CNS toxicity. Discuss potential cases with a clinical toxicologist.

Haemodialysis increases lithium clearance.

It is rarely needed in acute ingestion as lithium is normally cleared by the kidneys before significant CNS toxicity develops. Before starting dialysis for acute lithium toxicity, discuss with a clinical toxicologist. Potential indications for dialysis in acute ingestions include:

• Features of severe toxicity especially neurotoxicity (e.g. coma, seizures)
• Lithium concentration >4mmol/L with renal impairment
• Lithium concentration >5mmol/L

Dialysis is more commonly required to treat chronic lithium toxicity, although most patients will still be managed successfully with supportive care alone. Indications for dialysis in chronic toxicity are not clearly defined and may depend on the trend of the lithium level after initial management. The most commonly used indications are those given by EXTRIP:

ECTR is recommended:

• If kidney function is impaired and the lithium level > 4.0 mmol/L.
• In the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of lithium level.

ECTR is suggested:

• if the lithium level > 5.0 mmol/L
• If confusion is present
• If the expected time to obtain a lithium level < 1.0 mmol/L with optimal management is >36 h

The lithium nomogram (below) can be used to predict the level at 36hrs.

There is no antidote for lithium toxicity.

Acute: Discharge patients who remain asymptomatic after 6 hours observation if their lithium level is below 1.5mmol/L and falling.

Chronic: In patients requiring dialysis, dialysis should continue until lithium level <1mmol/L. A repeat level should be taken after cessation of dialysis to ensure there is not a rebound as lithium redistributes from the CNS.

On discharge consider the risk-benefit to continuing ongoing lithium therapy.

1. Baird-Gunning J, Lea-Henry T, Hoegberg LCG, Gosselin S, Roberts DM. Lithium Poisoning. J Intensive Care Med. 2017 May;32(4):249-263. doi: 10.1177/0885066616651582. Epub 2016 Aug 11. PMID: 27516079. PDF
2. Buckley NA, Cheng S, Isoardi K, Chiew AL, Siu W, Vecellio E, Chan BS. Haemodialysis for lithium poisoning: Translating EXTRIP recommendations into practical guidelines. Br J Clin Pharmacol. 2020 May;86(5):999-1006. doi: 10.1111/bcp.14212. Epub 2020 Feb 11. PMID: 31912536; PMCID: PMC7163377. PDF
3. Farag S, Watson RD, Honeybourne D. Symptomatic junctional bradycardia due to lithium intoxication in patient with previously normal electrocardiogram. Lancet. 1994 May 28;343(8909):1371. doi: 10.1016/s0140-6736(94)92512-7. PMID: 7910365. PDF
4. Hussain KM, Kostandy G, Kurz L, Pachter BR. Hemodynamic, electrocardiographic, metabolic, and hematologic abnormalities resulting from lithium intoxication. A case report. Angiology. 1997 Apr;48(4):351-4. doi: 10.1177/000331979704800408. PMID: 9112883. PDF
5. Mehta N, Vannozzi R. Lithium-induced electrocardiographic changes: A complete review. Clin Cardiol. 2017 Dec;40(12):1363-1367. doi: 10.1002/clc.22822. Epub 2017 Dec 16. PMID: 29247520; PMCID: PMC6490621. PDF
6. Oakley PW, Whyte IM, Carter GL. Lithium toxicity: an iatrogenic problem in susceptible individuals. Aust N Z J Psychiatry. 2001 Dec;35(6):833-40. doi: 10.1046/j.1440-1614.2001.00963.x. PMID: 11990895. PDF
7. Waring WS. Management of lithium toxicity. Toxicol Rev. 2006;25(4):221-30. doi: 10.2165/00139709-200625040-00003. PMID: 17288494. PDF
8. Decker BS, Goldfarb DS, Dargan PI, Friesen M, Gosselin S, Hoffman RS, Lavergne V, Nolin TD, Ghannoum M; EXTRIP Workgroup. Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup. Clin J Am Soc Nephrol. 2015 May 7;10(5):875-87. doi: 10.2215/CJN.10021014. Epub 2015 Jan 12. PMID: 25583292; PMCID: PMC4422246. PDF
9. Bailey B, McGuigan M. Comparison of patients hemodialyzed for lithium poisoning and those for whom dialysis was recommended by PCC but not done: what lesson can we learn? Clin Nephrol. 2000 Nov;54(5):388-92. PDF
10. Finlay PR. Drug interactions with lithium: an update. Clin Pharmacokinet 2016; 55:925-941. PDF