Lithium Toxicity

INTRODUCTION

Background: Lithium is commonly used in the treatment of depressive and bipolar affective disorders. As such, it is used in a population at relatively high risk for overdose. Because it has a comparatively narrow therapeutic index, lithium intoxication is also a frequent complication of chronic lithium therapy.

Pathophysiology: The central nervous system (CNS) is the major organ system affected, although the renal, gastrointestinal (GI), endocrine, and cardiovascular (CV) systems also may be involved.

Lithium is available only for oral administration. It is almost completely absorbed from the GI tract. Peak levels occur 2-4 hours postingestion, although absorption can be much slower in massive overdose or with ingestion of sustained-release preparations.

Lithium dosing

Lithium is minimally protein bound and has an apparent volume of distribution of 0.6 L/kg. The therapeutic dose is 300-2700 mg/d with desired serum levels of 0.7-1.2 mEq/L.

Lithium clearance is predominantly through the kidneys. Because it is minimally protein bound, lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate (GFR). Consequently, dosing must be adjusted based on renal function. Individuals with chronic renal insufficiency must be closely monitored if placed on lithium therapy.

Most filtered lithium is reabsorbed in the proximal tubule; thus, drugs known to inhibit proximal tubular reabsorption, such as carbonic anhydrase inhibitors and aminophylline, may increase excretion. Diuretics acting distally to the proximal tubule, such as thiazides and spironolactone, do not directly affect the fractional excretion of lithium (although they may affect serum lithium levels indirectly through their effects on volume status). Reabsorption of lithium is increased and toxicity is more likely in patients who are hyponatremic or volume depleted, both of which are possible consequences of diuretic therapy.

Lithium half-life

The plasma elimination half-life of a single dose of lithium is from 12-27 hours (varies with age). The half-life increases to approximately 36 hours in elderly persons (secondary to decreased GFR). Additionally, half-life may be considerably longer with chronic lithium use.

Frequency:

In the US: An estimated 10,000 toxic exposures occur per year. These data indicate a gradual increase over the past 10 years.

Mortality/Morbidity: An estimated 2000 moderate-to-severe outcomes occur in the United States each year; lethal outcomes are generally secondary to severe CNS effects with subsequent cardiovascular collapse.

Race: No predilection exists.

Age: Approximately 10% of toxic exposures occur in children younger than 19 years.

CLINICAL

History: An accurate history documenting amount ingested, time of ingestion, period of ingestion, and reason for ingestion is important. Toxicity does not necessarily correlate with the measured lithium level because toxicity is affected by the nature and type of the poisoning.

Acute poisoning - Voluntary or accidental ingestion in a previously untreated patient

Acute-on-chronic - Voluntary or accidental ingestion in a patient currently using lithium

Chronic or therapeutic poisoning - Progressive lithium toxicity, generally in a patient on lithium therapy

An accurate medication list is important because many drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], diuretics, tetracyclines, phenytoin, and cyclosporine) increase lithium toxicity at therapeutic levels.

Symptoms

Nausea and vomiting

Diarrhea

Weakness and fatigue

Lethargy and confusion

Tremor

Seizure

Physical: Depending on the degree of toxicity, the physical examination may reveal no abnormalities, subtle signs of toxicity, or overt abnormalities.

Mild-to-moderate toxicity

Generalized weakness

Fine resting tremor

Mild confusion

Moderate-to-severe toxicity

Severe tremor

Muscle fasciculations

Choreoathetosis

Hyperreflexia

Clonus

Opisthotonos

Stupor

Seizures

Coma

Signs of cardiovascular collapse

Causes: Overdose may occur as a result of intentional or unintentional ingestion or as a consequence of extraneous factors that contribute to an elevation in serum lithium levels in patients undergoing treatment with lithium.

WORKUP

Lab Studies:

The extent of the laboratory workup depends upon the degree of toxicity suspected and other diagnoses under consideration.

Measure serum lithium concentration if any degree of toxicity is suspected; however, keep in mind that suspicion of toxicity should be high in any patient with known lithium use because early toxic symptoms are very vague and nonspecific.

A second serum lithium level measurement 2 hours after the first may disclose any trend.

Sustained-release lithium preparations may take several hours to reach peak concentrations.

Consider toxicology screens in intentional overdoses. Co-ingestions are common in cases of intentional lithium overdose. Lithium is generally not included in a toxicology screen.

Electrolyte disturbances, particularly hyponatremia, may predispose an individual to lithium toxicity.

Similarly, lithium treatment may predispose an individual to electrolyte (sodium) disturbances, which are usually mild.

Lithium toxicity is one of the few clinical entities that may be associated with a decrease in the anion gap.

bun and creatinine measurements are important for determining the patient's ability to excrete lithium.

Imaging Studies:

Consider a CT scan of the head in individuals with severe movement disorders, seizures, stupor, or coma. It may be needed to rule out other etiologies and to examine for trauma secondary to intoxication.

Other Tests:

Electrocardiogram

Chronic lithium toxicity is frequently associated with depressed ST segments and T wave inversion unassociated with symptoms or significant sequelae.

Lithium intoxication may result in dysrhythmias, including complete heart block.

Serious cardiac toxicity is uncommon and generally only occurs in individuals with underlying heart disease.

TREATMENT

Prehospital Care:

Stabilize life-threatening conditions and initiate supportive therapy according to local EMS protocols.

Obtain IV access with isotonic sodium chloride solution.

Monitor cardiac function to assess rhythm disturbances.

Obtain all pill bottles available to the patient.

Emergency Department Care: Supportive therapy should take precedence. Assess airway and breathing and control the airway with endotracheal intubation, as needed. Initiate volume resuscitation in volume-depleted patients. Subsequently, direct efforts toward gastric decontamination and enhancement of lithium elimination, as appropriate.

Gastric decontamination

Gastric lavage is appropriate in acute ingestions if the time of presentation is within 1 hour of ingestion.

Activated charcoal does not bind lithium effectively, but it should be given if the possibility of significant co-ingestion exists.

Consider whole bowel irrigation, particularly in acute ingestions of sustained-release lithium preparations.

Preliminary studies in animals and humans suggest that sodium polystyrene sulfonate (Kayexalate) is capable of binding lithium and may prevent lithium absorption and enhance its elimination. Hypokalemia is a potential adverse effect of this drug; conversely, in patients with concomitant hyponatremia, the sodium load from Kayexalate can be beneficial.

Enhanced elimination

Volume resuscitation with normal saline or one-half isotonic sodium chloride solution may be effective in enhancing renal elimination of lithium in individuals with mild-to-moderate toxicity. Avoid onset of hypernatremia.

Hemodialysis has been the mainstay of therapy in severe lithium intoxication, although the specific indications are poorly established.

In general, consider dialysis in patients with chronic toxicity and serum lithium concentrations higher than 4 mEq/L; also consider dialysis in unstable chronic patients with lithium levels higher than 2.5 mEq/L.

Guidelines for hemodialysis are more controversial in patients with acute lithium intoxication but generally refer to higher serum lithium levels despite relatively minor symptoms. Change in mental status assists in determining need for dialysis.

Consultations:

Consult renal service personnel for hemodialysis in severe intoxications.

Consult psychiatric service personnel for patients with intentional overdose.

Consult the poison control center and a medical toxicologist regarding appropriate treatment.

MEDICATION

The goal of therapy is to remove or reduce the excess amounts of lithium resulting from an overdose.

Drug Category: GI decontaminants -- Because adsorption to activated charcoal is minimal, whole bowel irrigation is the GI decontamination method of choice.

Drug Name


Polyethylene glycol bowel prep (GoLYTELY, Colyte) -- Laxative with strong electrolytic and osmotic effects that has cathartic actions in the GI tract.

Adult Dose


1-2 mL/kg/h PO or NG tube until rectal effluent is clear

Pediatric Dose


Administer as in adults

Contraindications


Documented hypersensitivity; colitis, megacolon, bowel perforation, gastric retention, or GI obstruction

Interactions


Reduces effectiveness and absorption of oral medications

Pregnancy


C - Safety for use during pregnancy has not been established.

Precautions


Caution in ulcerative colitis and hot loop polypectomy

Drug Name


Sodium polystyrene sulfonate (Kayexalate) -- May bind lithium, preventing its absorption, and may enhance its elimination. Exchanges sodium for potassium and binds it in the GI tract, primarily the large intestine, and decreases total body potassium. Onset of action after oral administration ranges from 2-12 h, and is longer when administered rectally. Has not been studied extensively for lithium intoxication in humans.

Adult Dose


25-50 g in 25-50 cc sorbitol PO q6h
25-50 g in 25-50 cc sorbitol PR as a retention enema q6h

Pediatric Dose


1 g/kg in sorbitol PO q6h
2 g/kg in sorbitol PR as a retention enema q6h

Contraindications


Documented hypersensitivity; hypernatremia

Interactions


Systemic alkalosis may occur if administered concurrently with magnesium hydroxide, aluminum carbonate or similar antacids, and laxatives

Pregnancy


C - Safety for use during pregnancy has not been established.

Precautions


Caution in patients who can be adversely affected by small increases in sodium loads (eg, those with severe hypertension, severe congestive heart failure, and marked edema); constipation, with the possibility of fecal impaction may occur; treat constipation with 10-20 mL of 70% sorbitol every 2 h or prn to produce at least 1 or 2 watery stools daily

Drug Category: Alkalinizing agent -- Used to alkalinize the urine and prevent intoxications resulting from drug overdose.

Drug Name


Sodium bicarbonate (Neut) -- Alkalinizes urine, causing lithium excretion to increase. The bicarbonate ion produced from disassociation neutralizes hydrogen ions and raises urinary and blood pH. Effectiveness has not been demonstrated.

Adult Dose


48 mEq (4 g) IV initial; followed by 12-24 mEq (1-2 g) IV q4h; titrate to desired pH

Pediatric Dose


1-10 mEq (84-840 mg)/kg/d IV divided q4-6h; titrate to desired pH

Contraindications


Alkalosis, hypernatremia, hypocalcemia, severe pulmonary edema, and unknown abdominal pain

Interactions


Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may cause decreased levels of tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine

Pregnancy


C - Safety for use during pregnancy has not been established.

Precautions


Rapid administration may result in paradoxical CSF acidosis, intracellular acidosis, hypokalemia, impaired oxygen delivery, and hypocalcemia; hypernatremia, overshoot alkalosis, and hyperosmolality also may occur

FOLLOW-UP

Further Inpatient Care:

Admit patients with significant signs or symptoms of toxicity.

Admit symptomatic patients, regardless of serum lithium levels; admit patients with serum lithium levels higher than 2 mEq/L.

Admit to an ICU patients with chronically elevated lithium levels higher than 4 mEq/L.

Perform serial serum lithium determinations approximately 4 hours apart to confirm a declining trend.

Further Outpatient Care:

Accidental overdose: Asymptomatic patients and patients with serum lithium concentrations in the therapeutic range and minor toxicity may be discharged with scheduled follow-up in 1-2 days.

Intentional overdose: Obtain psychiatric clearance before discharge from the hospital.

Transfer:

In potentially severe overdoses, transfer may be indicated if hemodialysis facilities are not available locally.

Complications:

Truncal and gait ataxia

Nystagmus

Hypertonicity

Short-term memory deficits

Dementia (rare)

Prognosis:

Most cases of lithium toxicity result in a favorable outcome; however, up to 10% of individuals with severe toxicity develop chronic neurologic sequelae.

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* taken from emedicine.

http://www.emedicine.com/emerg/TOPIC301.HTM

Author: James G Linakis, PhD, MD, Associate Professor of Emergency Medicine and Pediatrics, Brown Medical School; Associate Director, Department of Pediatric Emergency Medicine, Rhode Island Hospital, Hasbro Children's Hospital
James G Linakis, PhD, MD, is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, American Pediatric Society, Rhode Island Medical Society, and Society for Pediatric Research
Editor(s): Mark S Slabinski, MD, Director, Emergency Services, Southeastern Ohio Regional Medical Center; John T VanDeVoort, PharmD, Clinical Assistant Professor, College of Pharmacy, University of Minnesota; John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Emergency Medicine, Pediatrics, and Environmental Medicine, University of Rochester; Managing Director, Associate Medical Director, Ruth A Lawrence Poison and Drug Information Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Asim Tarabar, MD, Assistant Clinical Professor of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

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