Lithium Toxicity

By Josef G. Thundiyil, MD

Introduction

The medical use of lithium has evolved considerably since it was first used for gout and rheumatism in the 1800’s. It was also used as a salt substitute in patients with hypertension, and was at one point present in the soft drink 7-Up. In the 1970’s, the US FDA approved the use of lithium for the treatment of acute mania following studies in the 1950’s by Cade and Schou. Currently, lithium is used to treat a variety of disorders including cluster headaches, alcoholism, and Grave’s disease. Lithium is most commonly used, however, as the treatment of choice for recurrent bipolar disorder (manic-depressive illness).

Case presentation

A 46 year old man presented with drowsiness and slurred speech after an intentional ingestion of his sustained release lithium capsules. His roommate described multiple episodes of vomiting and diarrhea with some pill fragments seen in the vomitus. The patient’s pulse was 105 beats/min, blood pressure was 140/73 mmHg, and respirations 18/min. He did not respond to naloxone (Narcan). His fingerstick glucose was normal so he was not given dextrose, but the paramedics administered activated charcoal en route to the hospital. In the emergency department his oral temperature was 98 F, and pulse oximetry was 100% on room air. There was no tremor and he was fully oriented, although slightly drowsy. His initial ECG appeared normal. Intravenous normal saline was initiated with a bolus of one liter followed by 150 mL/hour to maintain adequate urine output. Whole bowel irrigation was performed using polyethylene glycol – electrolyte solution (GoLytely) at 2 liters/hour by nasogastric tube for several hours. The patient’s initial laboratory values revealed a white blood cell count of 15,000, normal hemoglobin and platelets, sodium 142, potassium 4.3, chloride 105, bicarbonate 23, blood urea nitrogen 17, creatinine 1.5, and an initial lithium level of 3.4 mEq/L. The patient was admitted to telemetry and serial lithium levels were obtained. His lithium level peaked at 4.0 mEq/L and then began to descend. Although a nephrology consultation was obtained, the patient did not receive hemodialysis because his mental status gradually improved. On hospital day number three, the patient’s lithium level was 1.0 mEq/L, he was asymptomatic and was transferred to a psychiatric facility.

Questions

1. What are the important pharmacokinetic characteristics of lithium?
2. What are the clinical signs and symptoms of lithium poisoning?
3. How well do serum lithium levels correlate with toxicity?
4. What are treatment options for lithium toxicity? What is the role for hemodialysis?
5. What can cause a falsely positive or elevated serum lithium level?

Epidemiology

Each year approximately four to five thousand cases of lithium exposure are reported to poison control centers. About three quarters of these seek help at a health care facility. The American Association of Poison Control Centers (AAPCC) Toxic Exposures Surveillance System (TESS) reported 4954 cases of lithium exposure in 2002. Approximately one third of these were unintentional exposures. Moderate to severe intoxication was reported in 1527 cases and 15 patients died. Although the number of deaths is small, appropriate management is essential to avoid morbidity and prolonged hospitalization.

Pathophysiology

Lithium, the lightest alkali metal (others include sodium and potassium), has no known physiologic role in the body. Its mechanism of action is not well understood, but is believed to involve a decrease in neuronal responsiveness to neurotransmitters. Once ingested, regular release preparations produce peak serum lithium levels in 1-3 hours, compared with 4-12 hours after ingestion of sustained release preparations (such as Lithobid^R). Lithium initially occupies a volume of distribution of 0.4 liters per kg of body weight (approximately equivalent to the vascular space). Then, over the next 6-8 hours, the drug gradually moves intracellularly and achieves a final volume of distribution of 0.6-0.9 L/kg (equivalent to the total body water). The highest levels are found in the brain and the kidney where lithium exerts most of its toxic effects.

Lithium is excreted almost entirely by the kidney. However, anywhere from 60-75% of the filtered load is reabsorbed in the proximal tubule. Since lithium is handled by the kidney in a manner very similar to sodium, any underlying condition with volume or sodium depletion will result in increased lithium reabsorption. For example, patients with vomiting, diarrhea, dehydration, congestive heart failure, excessive exercise, or even a low sodium diet are at risk for lithium toxicity via increased reabsorption of the cation at the level of the proximal tubule.

Lithium toxicity typically occurs in one of three scenarios: acute overdose in a patient who does not normally take the drug, acute overdose in a patient chronically taking lithium (acute-on-chronic), or chronic toxicity resulting from accumulation of the drug during therapeutic use. Acute and acute-on-chronic lithium exposures occur as the result of accidental or suicidal ingestion of excessive amounts of lithium. Generally, toxicity resulting from chronic accumulation of lithium is more severe. In addition to sodium depletion, other factors that can contribute to chronic toxicity include concomitant drug therapy with drugs that decrease glomerular filtration rate (GFR) such as angiotensin converting enzyme (ACE) inhibitors or nonsteroidal anti inflammatory agents, and the development of nephrogenic diabetes insipidus. Lithium is the most common cause of drug induced nephrogenic diabetes insipidus which is characterized by polyuria, polydipsia, hypernatremia, and low urine osmolality. This condition causes volume depletion, which in turn results in increased lithium reabsorption and subsequent toxicity.

Clinical presentation

Although lithium toxicity predominantly affects the kidneys and central nervous system, other organ systems may also be adversely affected. Particularly in the acute or acute-on-chronic settings, gastrointestinal symptoms such as nausea, vomiting, diarrhea and abdominal bloating are common. Cardiovascular side effects are usually mild and manifest as nonspecific ECG changes, such as ST-T flattening and T-wave inversion. However, in severe overdose, QT prolongation and tachyarrhythmias such as torsade de pointes have been reported. Neurologic symptoms range from tremor, dysarthria, ataxia, nystagmus, slurred speech, hyperreflexia and myoclonus to alterations in level of consciousness including mild confusion, delirium, agitation, seizures and coma. Neurologic symptoms are commonly used to grade the degree of severity of lithium intoxication: Mildsymptoms include nausea, vomiting, lethargy, tremor, and fatigue. Symptoms of moderate intoxication are confusion, agitation, delirium, tachycardia, occaisional heart blocks, and hypertonia. Coma, seizures, hyperthermia and hypotension characterize severe intoxication.

As mentioned previously, renal toxicity is more common in patients on chronic lithium therapy. Toxicity includes impaired urinary concentrating ability, nephrogenic diabetes insipidus, and sodium-losing nephropathy.

Diagnosis

The diagnosis of lithium poisoning can be difficult because symptoms are often nonspecific, and as many as one third of patients are victims of chronic lithium intoxication and are usually unaware that their symptoms are related to lithium. It is important to get a thorough history focusing on the use of other medications, recent illnesses, and baseline level of functioning. During physical examination, particular attention should be focused on vital signs, cardiovascular status and neurological involvement.

Initial lab tests should include complete blood count, electrolytes, blood urea nitrogen, creatinine, and serum lithium levels. Mild leukocytosis and a low anion gap may be present initially. Most laboratories report normal serum lithium levels to be between 0.6mEq/L- 1.2 mEq/L. Note: do NOT measure serum lithium levels from specimen tubes that contain lithium heparin, green top tubes, because this can falsely elevate the levels. Serum lithium levels should ideally be drawn at least 6-12 hours after the last therapeutic dose to avoid falsely elevated results. Because lithium undergoes a distributional phase, serum lithium levels drawn too soon after an acute ingestion can be misleading. Reported cases of minimally symptomatic patients with serum levels of 10.6 mEq/L exist, reflecting high serum but low tissues levels. There is relatively poor correlation between initial serum levels and systemic toxicity, particularly after an acute or acute-on-chronic overdose. Currently, most authors agree that clinical symptoms are more reliable than serum lithium levels.

Treatment

Initial treatment measures include appropriate airway management, assessment of vital signs, and continuous cardiac monitoring. In patients with altered mental status, check the fingerstick glucose and use dextrose and naloxone as appropriate. Treat hypothermia or hyperthermia appropriately. If seizures develop, treat initially with benzodiazepines, followed by barbiturates if needed.

Since activated charcoal binds very poorly to lithium, its use should be reserved for patients who are suspected of ingesting other substances. Consider gastric lavage for very recent ingestion (less than 1 hour), and whole bowel irrigation if very large amounts have been ingested or if a sustained release product was used. Although a few studies suggest that sodium polysterene sulfonate (Kayexelate) can bind ingested lithium, the magnitude of benefit was small and evidence of clinical efficacy is lacking. Intravenous fluid therapy is very important. Replace volume losses with isotonic saline boluses, followed by an infusion to maintain good urine output. Fluid replacement will help prevent the continued reabsorption of lithium by the kidney. However, there is no evidence that forced diuresis with very large volumes is any more effective, and it may lead to fluid and electrolyte disturbances.

Hemodialysis is an effective method for enhanced removal of lithium. Lithium has a small volume of distribution and minimal protein binding, and modern dialysis machines can achieve fairly high clearance rates for the ion. However, there is poor agreement about the selection of patients for dialysis, particularly the precise serum lithium levels at which to dialyze. As mentioned earlier, patients with very high levels after an acute overdose may remain asymptomatic, while patients with chronic intoxication may be seriously ill with only modest levels. In general, toxicologists agree that patients who have symptoms of severe toxicity, renal failure, or clinical deterioration should be dialyzed. During hemodialysis, serum lithium levels drop rapidly but symptoms often persist for hours or days, and serum levels often rebound as the drug re-equilibrates slowly from the intracellular space to the extracellular space. For this reason, repeated hemodialysis sessions are usually required. While hemodialysis may enhance the elimination of lithium there remains controversy in the available literature as to whether hemodialysis confers any short or long term benefits to the lithium poisoned patient.

Reports of successful lithium removal with use of continuous renal replacement therapy (CRRT, also known as continuous veno-venous hemofiltration or CVVH) do exist. Although CRRT does not achieve clearance rates as high as those with hemodialysis, it has the advantage of being easier to implement and requiring less specialized staff and facilities, and can be performed continuously 24 hours a day. To date, there are no controlled studies demonstrating an advantage of CRRT over hemodialysis.

All patients with symptoms of lithium intoxication not attributable to another cause should be admitted to a monitored setting. If symptoms are moderate or severe, they should be admitted to an intensive care unit. After an acute ingestion in asymptomatic patients, serial serum lithium levels should be obtained every 6 hours until there is a downward trend, serum levels are less than 1.5 mEq/L, and patients remain asymptomatic.

Discussion of case questions

1. Lithium has a two compartment volume of distribution. It initially occupies a volume of distribution of 0.4 L/kg in the extracellular space but then gradually moves intracellularly and occupies a final volume of distribution of 0.9L/kg. Once it is inside the cell, lithium exerts its therapeutic and toxic effects.
2. Clinical signs of lithium toxicity include nausea, vomiting, diarrhea, tremor, dysarthria, nystagmus, ataxia, and slurred speech. Patients will also exhibit alterations in the level of consciousness, which may vary from confusion to agitation, delirium, and coma.
3. Serum lithium levels do not correlate well with systemic toxicity, particularly after an acute overdose.
4. Since charcoal is ineffective in binding lithium, treatment measures include whole bowel irrigation, volume replacement, and supportive care. Hemodialysis should be considered for patients who have renal insufficiency, clinical deterioration, or symptoms of severe toxicity.
5. Collecting blood in a green top tube which contains lithium heparin. Specimens should be collected in a plain red top tube. Consult the local laboratory for possible variations.