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Lithium

OVERVIEW

Lithium has a narrow therapeutic range with serious adverse effects, predominantly central nervous system, and thus requires routine monitoring. Acute poisoning is well tolerated, even when taken on a background of lithium therapy (acute on chronic poisoning), and does not usually require significant intervention unless renal failure or sodium depletion is present. Chronic toxicity is more severe than acute toxicity and has a different clinical presentation. Repeated haemodialysis is often required in severe chronic poisoning. Long term neurological damage may occur.

MECHANISM OF TOXICITY

The mechanisms of both the therapeutic and toxic effects are unknown. Lithium is a small cation that distributes uniformly in body water replacing normal cations. Its effects are presumed to relate to interference with processes that involve these ions, such as renal tubular transport, and ion channels involved in neurotransmission.

KINETICS IN OVERDOSE

Absorption

Lithium is rapidly absorbed from the small intestine. Peak concentrations occur in therapeutic use within 2-3 hours. However, sustained release preparations are available and may result in greatly prolonged absorption.
Concentrations of lithium after very large acute lithium overdoses are often much lower than could be expected from the known kinetics in therapeutic dose suggesting there is a saturable process of absorption that limits lithium exposure in acute poisoning.

Distribution

Lithium is not protein bound and has a volume of distribution equal to body water (0.6 L/kg). Thus its clearance can be substantially increased by haemodialysis. It distributes into cells, where it exerts its major toxic effects, quite slowly. Complete equilibrium between serum and tissue concentrations may take several days to weeks. The same is true when serum concentrations are falling and thus CNS effects may persist for weeks.

Metabolism - Elimination

Lithium is excreted unchanged in urine. After filtration, lithium is reabsorbed in the proximal tubule by the sodium transport mechanism. Reabsorption in the kidneys is proportional to that of sodium reabsorption. Therefore sodium depletion causes increased lithium reabsorption and increased lithium concentrations. This is also the site of bicarbonate reabsorption. An alkaline urine increases lithium clearance as do diuretics that act on the proximal tubule. Hyponatraemia, dehydration and diuretics that act more distally (loop diuretics, thiazides and potassium sparing diuretics) all reduce lithium clearance. NSAIDs also reduce lithium clearance in some patients, presumably related to their effects on renal prostaglandin production and analogous to their effect on sodium clearance in patients with heart failure. (Harvey & Merriman, 1994) 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.

CLINICAL EFFECTS

Acute or acute on chronic poisoning

Acute lithium poisoning is well tolerated when renal function is normal and the patient is sodium replete. This is true even if the patient is already on lithium (acute on chronic poisoning). In spite of much of the literature there are no significant clinical differences between acute poisoning in a lithium naive individual and acute poisoning in someone already on lithium (Oakley et al, 2001). Thus, it is unusual to see much in the way of clinical toxicity even with very high concentrations as the lithium is excreted before CNS penetration can occur. However, if renal failure is present or supervenes then the features of chronic toxicity may appear.

Chronic poisoning

Lithium has dose related toxicity in therapeutic use. The major adverse effects are predominantly in the central nervous system and develop over several days. Chronic poisoning is thus much more severe than acute poisoning for a given serum concentration. The initial symptoms which can occur within the therapeutic range are tremor and polyuria (due to nephrogenic diabetes insipidus (DI). DI, if pre-existing, is a major risk factor for chronic toxicity. Later symptoms are impaired level of consciousness, myoclonus, dysarthria and ataxia. With more severe poisoning the patient becomes comatose, has convulsions, acute renal failure and death. Patients with signs of lithium toxicity and a lithium concentration over 1.5 mmol/L should be admitted. A concentration over 2.5-3.0 mmol/L, with corresponding clinical signs, would be an indication for haemodialysis in chronic lithium toxicity. The central nervous system findings are protean and dose dependent. A rough correlation between serum concentrations and clinical findings at presentation in chronic poisoning is shown below. Note that adverse effects are common at the upper end of the therapeutic range. The correlation at high concentrations (> 3.0 mmol/L) is less clear as serum concentrations are usually rising rapidly even in chronic poisoning at this time due to dehydration.

Concentration (mmol/L)	Observed effects
0.5	None
1.0	mild tremor
1.5	Coarse tremor
2.0	Hyperreflexia, dysarthria
2.5	Myoclonic and other involuntary movements Ataxia and confusion
3.0	Marked delirium, coma, seizures

The non CNS clinical features and the difference between acute and chronic poisoning are shown below. Some patients with an overdose who are on chronic therapy do not fit neatly into this acute/chronic dichotomy.

Acute vs Chronic toxicity

TOXICITY	ACUTE	CHRONIC
Correlation of Li concentrations with clinical features	Poor	Good
Gastrointestinal effects (nausea, vomiting, diarrhoea)	42%	20%
Seizures, CNS effects	delayed, less common, avoidable	common with concentrations > 2.0 mmol/L
Renal effects	usually insignificant	universal
ECG changes	Generally normal	QT prolongation is usual. Ventricular arrhythmias may occur
Thyroid Disease	No	Hypothyroidism 20%, Goitre very common
Recovery	rapid and usual	delayed up to 2-3 weeks, long term disability in 10%

Recovery after chronic poisoning may be delayed up to 2-3 weeks (until CNS lithium is cleared). Death and long term disability each occur in about 10% of chronic poisonings. The major residual neurological signs are cerebellar ataxia and dysarthria and little improvement occurs after 6 months.

INVESTIGATIONS

Blood concentrations

Lithium concentrations are helpful in making the diagnosis of lithium exposure and guiding treatment in chronic poisoning. The lithium concentration alone should not be used to guide treatment in acute poisoning.

Biochemistry

Patients should have electrolytes and renal function measured at regular intervals. Renal tubular abnormalities can lead to acidosis, hypokalaemia, hyponatraemia and hypernatraemia.

TREATMENT

Supportive

All patients should have generous fluid replacement using normal saline. Interacting drugs should be ceased. Patients with abnormal ECG should be monitored.

Indications for admission

Patients with central nervous system symptoms
Lithium concentration > 1.5 mEq/L

Admission to ICU should be done for all patients requiring haemodialysis and for those with ECG changes.

GI Decontamination

Activated charcoal does not bind to lithium. Since little clinical effect occurs after acute poisoning in the presence of normal renal function aggressive measures to decontaminate the bowel are not generally indicated. Whole bowel irrigation with polyethylene glycol could be considered in patients presenting within 1-2 hours of ingestion of a very large dose (> 50 g). Sustained release preparations may have a longer course because of delayed absorption but if renal function remains normal and the patient is sodium replete the lithium is rapidly cleared without much clinical effect and decontamination is not particularly indicated. Again, whole bowel irrigation could be considered for very large overdoses.

Elimination enhancement

Haemodialysis increases lithium clearance. Repeated haemodialysis is frequently required due to rebound in lithium concentrations within 6-12 hours of ceasing haemodialysis. This occurs due to redistribution of lithium from peripheral tissues. Lithium concentrations should be measured 6-12 hours post dialysis to determine if further dialysis is indicated.

For symptomatic lithium toxicity, continuous veno-venous haemodialysis (CVVHD) can be used to continue enhanced lithium clearance after initial haemodialysis has reduced the initial peak in lithium concentration. CVVHD for 24 hours is about as effective as a 4 hour haemodialysis and may be used without prior haemodialysis in asymptomatic patients with elevated lithium concentrations and renal failure.

Indications for haemodialysis

The major indication for haemodialysis is lithium toxicity in the setting of impaired renal lithium excretion. If renal lithium clearance is normal most patients can be managed conservatively.

Renal failure (calculated creatinine clearance < 60 mL/min) and acute or chronic lithium poisoning
A lithium concentration > 2.5-3.0 mEq/L in chronic poisoning
Seizures
Coma
Hypotension not responsive to fluids

Dialysis should be continued until serum lithium concentration 6-12 hours following dialysis is below 1 mEq/L. Rebound in lithium concentrations is not usually a problem after CVVHD.

LATE COMPLICATIONS, PROGNOSIS

REFERENCES

Amdisen A. Clinical features and management of lithium poisoning. Med Toxicol 1988;3:18-32.
Bocchetta A, Bernardi F, Pedditzi M, Loviselli A, Velluzzi F, Martino E, Del Zompo M. Thyroid abnormalities during lithium treatment. Acta Psychiatr Scand 1991;83:193-198.
Ellenhorn MJ: Medical Toxicology: Diagnosis and Treatment of Human Poisoning. Williams & Wilkens, Baltimore, 1997.
Harvey NS & Merriman S. Review of clinically important drug interactions with lithium. Drug Safety 1994;10(6):455-63.
Schou M. Long lasting neurological sequelae after lithium intoxication. Acta Psychiatr Scand 1984;70:594-602 Therapeutic Drugs. Colin Dollery. Churchill Livingstone.
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
Beckmann U, Oakley PW, Dawson AH, Byth PL. Efficacy of continuous venovenous haemodialysis in the treatment of severe lithium toxicity. J Toxicol Clin Toxicol 2001;39(4):393-7
Oakley PW, Dawson AH, Whyte IM. Lithium: thyroid effects and altered renal handling. J Toxicol Clin Toxicol 2000;38(3):333-7
23/12/99 7:22:54. Revised IMW 15/6/02