Continuing Education Activity

Lithium, a monovalent cation similar to sodium with an unknown mechanism, was first approved by the U.S. Food and Drug Administration (FDA) as a mood-stabilizing medication for the treatment of mania in the 1970s. Lithium is a very powerful, antimanic medication with a narrow therapeutic index. This activity reviews the indications, mode of action, the toxicity of lithium and highlights the role of the interprofessional team in the management of patients with drug toxicity.

Objectives:

• Describe the pathophysiology of lithium toxicity.
• Review lithium toxicokinetics.
• Summarize the treatment of lithium toxicity.
• Outline interprofessional team strategies for improving care coordination and communication to advance care bundle approaches to manage lithium toxicity and improve patient outcomes.

Introduction

The drug of choice for recurrent bipolar illness management remains to be lithium[1]. Lithium, a monovalent cation similar to sodium with an unknown mechanism, was first approved by the U.S. Food and Drug Administration (FDA) as a mood-stabilizing medication for the treatment of mania in the 1970s[2]. Lithium is a very powerful, antimanic medication with a narrow therapeutic index[3].

PharmacodynamicsLithium's physiologic role is unknown, and its mechanism is not well understood; however, some proposed mechanisms include:

• Producing brain inositol depletion, leading to reduced responsiveness to alpha-adrenergic stimulation [4].
• Reducing neuronal responsiveness to neurotransmitters due to inhibitory effects on adenylate cyclase and G proteins vital for ion channel opening[5].
• Stimulating serotonin release from the hippocampus [6].
• Being a cation, acting similar to potassium and sodium, thus affecting ion transport and cell membrane potential [7].

Etiology

Too much lithium can cause lithium toxicity. Factors increasing lithium concentration in the body include excessive intake and impaired excretion[8].

Epidemiology

A study evaluated a group of patients treated with lithium between 1997 and 2013 and the recurrence of lithium intoxication along with changes in renal functionality was to be assessed. 96 patients out of 1340 experienced at least one episode of lithium levels greater than 1.5 mmol/L. a cohort of seventy-seven participants had experienced 91 episodes, of whom 34% needed intensive care and 13% required hemodialysis with no deaths. Acute kidney injury occurred, but renal function at baseline was not different from renal function after the episode [9].

Pathophysiology

Excessive intake or impaired excretion can result in lithium accumulation.                                                                           

Excessive Intake

Suicidal intent or accidental ingestion of excessive amounts of lithium tablets result in acute or acute-on-chronic overdose settings [10]. Moreover, excessive intake might arise from dose modifications for the patient chronically administering lithium [11].

Impaired Excretion

Several factors might lead to impairment in lithium secretion. Sodium and volume depletion due to any conditions like vomiting, diarrhea, febrile illness, renal insufficiency, excessive exercise, water restriction, excessive sweating, low sodium diet, and congestive heart failure may enhance lithium reabsorption in the kidneys [11]. Furthermore, drugs reducing the glomerular filtration rate might inflict chronic toxicity.

• Chronic therapy with lithium can precipitate nephrogenic diabetes insipidus, which might elicit a cascade of symptoms and signs of lithium toxicity. This can be attributed to the diminished urinary concentrating capacity of the kidneys[12].
• Noteworthy, a vicious cycle of lithium toxicity might result from the concomitant existence of intercurrent illness with the reduced kidney concentrating capacity precipitated by lithium.
• For example, reduced clearance and excretion of lithium in case of sodium and volume depletion will result in increased lithium concentration in the serum, which in turn continues to affect the kidneys’ ability to concentrate urine negatively.

Toxicokinetics

• Different types of lithium formulations are present including sustained-release preparations[3].
• Lithium is neither metabolized nor protein-bound, thus its bioavailability usually is close to 100%. Moreover, lithium absorption is rapid[3].
• Serum lithium levels reflect only the extracellular lithium concentration. However, lithium exerts its effects once it has moved to its intracellular compartment. This phenomenon illustrates the reason why patients with significantly elevated serum levels might be asymptomatic[12].
• Lithium is more susceptible to accumulation in the liver, bone, muscle, or thyroid with brain and kidney showing the highest levels[13].
• The kidneys are responsible for 95% of lithium excretion, and the rest is removed through sweat and feces. The kidneys treat lithium and sodium similarly which is the reason sodium depletion can significantly elevate lithium reabsorption[14].
• Volume depletion from diuretics, dehydration, febrile illness, or gastrointestinal loss can lead to elevated lithium levels in the serum[9].
• The serum elimination half-life of lithium can vary from 12 to 27 hours. In patients with chronic intoxication, the half-life can be prolonged up to 48 hours[15].
• The renal clearance of lithium is usually 10 to 40 mL/ min. However, the clearance may be decreased to 15 mL/min, and the elimination half-life can be as long as 58 hours in elder patients[16].
• Lithium freely crosses the placenta and is also excreted in breast milk. It is labeled as pregnancy class D and has been implicated in the increased risk of congenital cardiac defects, particularly the Ebstein anomaly. Breastfeeding infants of mothers taking lithium have been reported to have signs of cyanosis, hypotonia, and lethargy[14].

History and Physical

History

In the late 1800s, lithia water was first introduced as a mania and gout treatment [17]. Afterward, lithium tablets with higher lithium concentration largely replaced lithia water. However, the higher lithium concentration found in the tablets was associated with tremors and weakness, and in 1898 lithium toxicity was first described. To determine the extent of lithium toxicity, one must determine the ingested amount, time of ingestion, whether there are co-ingestants, and if the ingestion was intentional or unintentional. It is worth noting that lithium toxicity signs do not often conform to the measured lithium level[18].

Physical

Neurologic Effects

Symptoms of intoxication include coarse tremor, hyperreflexia, nystagmus, and ataxia. Patients often show varying consciousness levels, ranging from mild confusion to delirium. Although the neurological symptoms are mostly reversible, some reports indicate that symptoms might persist for 12 months never resolve[9].

Renal Toxicity 

Renal toxicity is more common in patients on chronic lithium treatment. Toxicity includes impaired urinary concentrating ability, nephrogenic diabetes insipidus (the most common cause of drug-induced NDI), sodium-losing nephritis, nephrotic syndrome along with other manifestations is prescribed[19].

Cardiovascular Effects

These are usually mild and non-specific. Almost all patients treated with lithium will develop T wave flattening. Sinus node dysfunction is the most common reported conduction defect followed by QT prolongation, intraventricular conduction defects, and U waves. These findings are reversible[20].

Gastrointestinal Effects

Symptoms typically occur within 1 hour of ingestion and are more common in the acute overdose setting [15].

Endocrine Effects

Lithium administration leads to the inhibition of thyroid hormone synthesis and subsequent release, resulting in hypothyroidism. Hyperthyroidism is less commonly manifested, which can mask symptoms of lithium toxicity and boost its toxicity by prompting cellular unresponsiveness and altered renal tubular handling of lithium [21].

Evaluation

Initially, the studies should include cardiac monitoring, electrocardiogram, assessment of oxygenation and monitoring of urine output, serum electrolytes, calcium, renal function, glucose, serum lithium level, and thyroid-stimulating hormone [22]. Moreover, both therapeutic lithium usage and intoxication can be accompanied by leukocytosis. Furthermore, interference by the carbonate anion after lithium carbonate acute ingestion in the calculation of anion gap might lead to a low anion gap[23].

• Patients are susceptible to renal insufficiency with elevated blood urea nitrogen and creatinine in case of chronic intoxication [24].
• If the initial diagnosis is unclear, brain imaging may be required[25].
• Lithium serum levels normally range from approximately 0.6 to 1.2 mEq/L. Measurement of the serum levels should be carried out at least 6 to 12 hours after the last therapeutic dose to avoid misinterpretation of pre-distributional levels.

Of note, lithium heparin is used as an anticoagulant in some specimen tubes which can falsely increase results of serum lithium [26].

Treatment / Management

Decontamination

• In-vitro studies showed that lithium does not adhere effectively to activated charcoal [27]; however, if co-ingestants are unknown, charcoal should be administered [8].
• Gastric lavage should be considered, particularly in the case of regular-release preparations and patients presenting early to the emergency department. On the other hand, in case of sustained-release preparations, administration, or massive ingestion of regular-release products, whole-bowel irrigation should also be considered [8].                         

Elimination

• The most appropriate method of lithium removal is hemodialysis, particularly if the patient demonstrates signs and symptoms of severe lithium poisoning or is having a renal failure due to its small volume of distribution and marginal protein binding [28].
• Peritoneal dialysis should not replace hemodialysis; however, if the hemodialysis facilities are not available (e.g., in remote areas), peritoneal dialysis can be initiated[28].

Disposition

• All patients with toxicity signs and symptoms, even those with normal serum lithium levels, should be admitted for monitoring in the hospital.
• In case of moderate or severe symptoms, the patient has to be admitted to an intensive care unit.
• Serial levels of lithium in the serum should be obtained every 6 hours in case of asymptomatic patients after acute ingestion. This should be continued until a descending drift has been established.
• Patients should not be discharged until they are asymptomatic and have a serum lithium level less than 1.5 mEq/L.

Differential Diagnosis

• Acute hypoglycemia

• Alcohol toxicity

• Anticholinergic toxicity

• Delirium

• Dementia

• Depression

• Heavy metal toxicity

• Mercury toxicity

• Neuroleptic agent toxicity

• Stroke, ischemic

Staging

Lithium toxicity can be classified into three major categories:

1. Acute overdose in a lithium-naive patient [9].
2. Acute overdose in a patient on chronic therapy (acute-on-chronic)[29].
3. Chronic over-medication or drug accumulation (associated with the most serious toxicity) [30].

Prognosis

Lithium toxicity signs are obvious and can be identified and managed easily; however, ignoring it can be fatal. Indeed, in some cases, lithium toxicity can lead to coma, brain damage, or even death. Moreover, lithium can induce serotonin syndrome, a potentially fatal and life-threatening condition[31]. The use of serotonergic drugs or drugs inhibiting serotonin metabolism concomitantly with lithium will increase the risk of lithium precipitating serotonin syndrome[32].

Complications

Intoxication degree is of utmost importance for understanding lithium toxicity diagnosis and management.

The severity of lithium toxicity is often divided into the following three grades: mild, moderate, and severe.

• Mild symptoms: nausea, vomiting, lethargy, tremor, and fatigue (Serum lithium concentration between 1.5-2.5 mEq/L)[33] [34].
• Moderate intoxication: confusion, agitation, delirium, tachycardia, and hypertonia (serum lithium concentration between 2.5-3.5 mEq/L)[33] [34].
• Severe intoxication: Coma, seizures, hyperthermia, and hypotension (serum lithium concentration (more than 3.5 mEq/L)[33] [34].

Enhancing Healthcare Team Outcomes

During lithium treatment, the healthcare team including physicians and nurses should make sure serum levels are checked regularly to make sure of the treatment course. Lithium is classified as pregnancy category D which means that there is positive evidence of human fetal risk. Therefore, the nurses or clinician should educate the patient on a proper contraceptive method during treatment with lithium. If any signs of early toxicity appear, the patient should stop the medication and seek medical counsel. Extra care should be taken if any activity, illness, or medication might precipitate a profound loss of water and/or salt is taken in a patient administering lithium. [Level 5]