Lithium Toxicity

PathophysiologyTop

Lithium is a univalent ion that has long been used in the treatment of psychiatric conditions, particularly bipolar disorder. The mechanism of action of lithium largely remains unknown but it is thought to be related to reduction in intracellular levels of inositol monophosphate and glycogen synthase kinase-3, which are signaling proteins involved in mood stabilization, neuroplasticity, and energy metabolism.

When given in a tablet form, the drug is highly absorbed through the gut and reaches peak levels within 1 to 2 hours or 4 to 6 hours following ingestion of immediate-release or sustained-release products, respectively. Plasma drug is highly non–protein-bound and has a small volume of distribution. The drug in its soluble form is univalent and handled entirely by the kidneys (very similar to sodium handling). The half-life is ~24 hours with a range typically between 14 and 30 hours. Glycogen synthase kinase-3 is also present in the principal cells of the nephrons, predominantly responsible for the action of arginine vasopressin (AVP). The epithelial sodium channel in the principal cells allows for the drug uptake into the cells, where it exerts its renal effects. In the presence of lithium in the principal cells, the cells are less receptive to the effects of AVP (the main mechanism of AVP is resorption of free water from that segment of the nephron), leading to volume loss.

Toxicity

Lithium tends to concentrate in the brain as well as kidneys, making these organs largely prone to acute and chronic toxicity. Volume depletion, chronic lithium use, advanced age, reduced glomerular filtration rate (GFR), and concomitant use of other nephrotoxic agents (nonsteroidal anti-inflammatory drugs [NSAIDs], angiotensin-converting enzyme inhibitors [ACEIs], thiazides) are among the major risk factors for toxicity. Acute toxicity typically occurs with doses >40 mg/kg (1 mEq/kg). In patients receiving long-term lithium therapy much lower doses can lead to clinically important toxicity, since tissues are already saturated with lithium. In patients with renal impairment even standard therapeutic doses can lead to lithium intoxication.

Clinical FeaturesTop

Lithium toxicity can be acute, acute-on-chronic, or chronic. Acute and acute-on-chronic toxicity present similarly and include gastrointestinal and neurologic dysfunction, rarely with cardiac dysfunction. Gastrointestinal manifestations include nausea, vomiting, and diarrhea. Neurologic manifestations are similar those present in chronic toxicity (see below). Prolongation of QT interval occurs rarely and may lead to arrhythmias.

Chronic toxicity usually presents with renal manifestations and/or neurologic dysfunction. Aside from its effects on the principal cells, lithium is thought to cause significant interstitial fibrosis, and this combination is likely a reason for the development of nephrogenic diabetes insipidus (NDI). Due to NDI, many patients have polyuria and, if compensated for, polydipsia. If other neurologic manifestations develop or the patient has restricted access to free water, severe hypernatremia due to significant reduction in total body free water content can occur.

Neurologic toxicity manifestations are broad and nonspecific. Presentation can vary and may include headaches, tremors, lethargy, ataxia, confusion, or agitation; and in extreme situations, seizures, rigidity, hyperpyrexia, status epilepticus, and death. A syndrome of irreversible lithium toxicity can develop, which may fail to improve despite drug cessation; this is called the SILENT syndrome (syndrome of irreversible lithium-effectuated neurotoxicity). It occurs due to demyelination at various levels of the central nervous system. The manifestations of SILENT syndrome include cerebellar and brainstem dysfunction, myopathy, nystagmus, blindness, extrapyramidal symptoms, and dementia. Lithium can precipitate or aggravate serotonin syndrome in the presence of other serotonergic drugs.

Some other rare manifestations may include both hypothyroidism and hyperthyroidism along with parathyroid cell hyperplasia causing hyperparathyroidism and hypercalcemia.

Diagnosis Top

The diagnosis of acute or acute-on-chronic toxicity can be made based on history and physical examination in patients suspected to have lithium toxicity, which can be confirmed with measurements of lithium levels (if available). The diagnosis of chronic toxicity is predominantly made on the basis of clinical presentation but in most patients the severity of toxicity corresponds to serum drug levels.

If available, other toxicity screening including other drug levels and serum glucose should be obtained in addition to renal function, electrolyte levels, and electrocardiography (ECG). ECG abnormalities may include T-wave flattening or inversion, depression of ST segments, bradycardia, or heart block. Consider measuring levels of thyroid-stimulating hormone (TSH), calcium, and serum parathyroid hormone (PTH).

TreatmentTop

General treatment of any toxicity includes management and stabilization of the airway, breathing, and circulation (ABC). Specific therapy involves reducing uptake from the gut, rapid removal via IV hydration, and/or hemodialysis. Discussion or consultation with a toxicology expert should be considered.

1. Gastrointestinal decontamination: Activated charcoal has no role in lithium toxicity as lithium particles cannot be removed/bound from the gut. For large ingestions of sustained-release products, whole bowel irrigation with 2 L/h of a bowel preparation agent may be administered until the rectal effluent is clear or ≥10 L is administered. Sodium polystyrene sulfonate may reduce the half-life of lithium but can induce hypokalemia; potassium levels should be closely monitored if this agent is used.

2. Hydration: The hallmark of lithium toxicity management is IV hydration to enhance lithium excretion through the kidneys. Target IV infusion rates can be approximately 2 × the maintenance doses (eg, in a 75-kg patient use 200-250 mL/h of isotonic IV fluids). Caution should be taken in patients at high risk for volume overload (eg, with advanced chronic kidney disease or congestive heart failure). Serum sodium, lithium, and creatinine levels can be monitored serially to ensure normalization (if possible). In patients thought to be intravascularly depleted, crystalloid repletion with 1 to 2 L can be provided up front. Because of the risk of lithium-induced NDI, serum sodium levels should be followed and maintenance fluids may need to be switched to hypotonic fluids, such as half-normal (0.45%) saline. The goal of hydration is to enhance lithium elimination by establishing normal urine output. The use of diuretics is not recommended as only marginal gains in lithium excretion are obtained and many patients with lithium toxicity are dehydrated.

3. Renal replacement therapy: Hemodialysis is highly effective thanks to lithium being a small particle, not being protein-bound, and having a relatively small volume of distribution. Nephrology consultation should be obtained, where available, for assistance with decision-making and delivery of hemodialysis. Hemodialysis should be performed (if available) in patients with serum lithium levels >5.0 mmol/L; with serum levels of >4.0 mmol/L and renal impairment (creatinine >2 mg/dL [175 micromol/L]); or with serum levels >2.5 mmol/L and neurologic manifestations of seizures, coma, or conditions that prevent aggressive volume resuscitation (severe decompensated heart failure or advanced renal disease). Hemodialysis can also be considered (if available) in severe life- threatening situations (depressed level of consciousness, seizures, coma) regardless of the serum lithium level. Some patients do not meet any specific criteria, and in such situations toxicology and nephrology consultations are recommended. Because of equilibration of extracellular and intracellular lithium, a rebound in serum lithium levels can occur after cessation of a short session of hemodialysis. This may necessitate a longer session (6-8 h, depending on ingested quantity and initial serum levels) or another session. Lithium levels can be measured 2 to 4 hours after cessation of dialysis to assess for a rebound rise in serum levels. Continuous venovenous hemodiafiltration (CVVHDF) may be used, as it has the advantage of reducing the risk of rebound toxicity. However, CVVHDF provides limited lithium clearance and is not as efficient as hemodialysis in the case of massive ingestions.

4. Psychiatric consultation should be considered for further management of mood disorders, alternative mood stabilizing therapies, and/or suicidal attempts in patients with large ingestions.

5. NDI: Thiazides, amiloride, and indomethacin have been used for the treatment of nephrogenic diabetes insipidus. While these drugs may be used in the chronic management of lithium nephrotoxicity, they should not be used in patients with acute kidney injury or suspected intravascular volume depletion or dehydration. Also see Nephrogenic Diabetes Insipidus.