Lithium Toxicity
Lithium Overdose, Lithium Adverse Effect, Lithobid Toxicity, Eskalith Toxicity, Lithium Intoxication
Nephrogenic Diabetes Insipidus, Hypothyroidism, Hyperthyroidism, Hyperparathyroidism, Ebstein’s Anomaly
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1. Description of the problem
What every clinician needs to know
Lithium is available in normal and extended-release preparations.
It is an effective treatment for bipolar affective disorder with a complex and incompletely understood mechanism of action involving inositol depletion and possibly dopamine and serotonin.
Acute toxicity and chronic toxicity have different clinical features. Acute toxicity presents with GI distress. Chronic toxicity presents with neurologic symptoms.
Lithium is a monovalent cation metal handled much like sodium by the kidneys. Hyponatremia causes the kidney to retain lithium.
Chronic lithium therapy may cause polyuria and nephrogenic DI, increasing risk for toxicity.
Lithium has complex and lengthy distribution and elimination phases, which are expected to be prolonged in overdose.
With therapeutic use, peak serum concentration occurs in 1 – 2 hrs after ingestion of normal preparations, and 2 – 6 hrs or more after sustained-release preparations.
Serum levels may not correlate with CNS (“target organ”) levels in toxicity.
The goal of treating toxicity is to avoid CNS and renal effects, which prolong recovery and increase morbidity and mortality.
Adverse effects of chronic use include: nephrogenic DI, thyroid disorders, hyperparathyroidism, renal dysfunction of various types, including polyuria.
Clinical features
Acute toxicity
Symptoms: nausea, vomiting, diarrhea, EKG abnormalities (ST- and T-wave abnormalities, bradycardia, Brugada pattern, long QT).
With time and increasing CNS penetration, symptoms may progress to include drowsiness, confusion, stupor, seizure, coma.
Clinical scenarios: intentional or unintentional overdose
Lithium-naive patients have no whole body stores and experience less toxicity than patients taking lithium chronically.
Patients taking lithium chronically with an acute overdose experience symptoms consistent with CNS penetration and toxicity earlier at lower serum lithium levels compared with lithium-naive patients.
Chronic toxicity
Symptoms: drowsiness, weakness, ataxia, tremor, dysarthria, blurred vision, nystagmus, tinnitus, hyperreflexia, choreoathetoid movements, clonus, confusion, stupor, seizure, coma.
Clinical scenarios: therapeutic use of lithium with new dehydration, worsening GFR, increased dose, hyponatremia, new drug introduced with interaction, salt restriction.
Drugs that are known to significantly increase serum lithium levels: thiazide diuretics, loop diuretics, ACE inhibitors, NSAIDs.
Neurotoxicity may be irreversible.
Adverse effects
Nephrogenic DI often underrecognized until patient without free access to water.
Thyroid disease: hypothyroidism more common than hyperthyroidism.
Hyperparathyroidism with elevated serum calcium.
Ebstein’s anomaly occurs more frequently in infants exposed in utero.
Key management points
Recognize the problem.
Rule out differential diagnosis.
Hydration with normal saline.
Correct electrolyte abnormalities.
Consider GI decontamination with whole-bowel irrigation (WBI) in select cases.
Symptomatic supportive care.
Consider hemodialysis in patients meeting criteria.
Consider if patient should restart lithium or discontinue use after toxicity is resolved.
2. Emergency Management
ABCs
IV fluid hydration with normal saline, as patients are often volume-depleted.
No specific antidote, but consider WBI and hemodialysis in select cases.
Benzodiazepines for seizures, barbiturates if refractory.
Management points not to be missed
Consider WBI for large ingestions of sustained-release preparations.
Indications for hemodialysis: moderate to severe toxicity (e.g., altered mental status and other CNS manifestations of toxicity), renal failure, patient unable to tolerate normal saline therapy (e.g., congestive heart failure, liver disease).
3. Diagnosis
Diagnostic criteria and tests
Clinical signs and symptoms consistent with lithium toxicity.
Serum lithium concentration (collected in lithium-free tube).
Serum electrolytes and renal function studies.
Urine output measurements to identify potential nephrogenic DI.
Serum salicylate and acetaminophen levels (if intentional overdose, to rule out co-ingestion).
Diagnostic tests as indicated to rule out differential diagnosis.
Normal lab values
Therapeutic serum lithium concentration controversial, but approximately 0.5 – 1.2 mmol/L (at steady-state concentration).
Ideally, therapeutic goal should be measurement of brain lithium level, but additional research is needed to define the therapeutic brain lithium level and its clinical utility in treatment and overdose.
Lithium with complex and lengthy distribution time to target organs.
Toxicity often occurs when serum level is above therapeutic range, but considering complex distribution pharmacokinetics, clinical presentation is more important than serum level in considering treatment.
Level may continue to rise for more than a day after ingestion of a sustained-release product.
Serum lithium levels may not correlate well with CNS levels or toxicity after overdose.
Lithium elimination half-life is longer in the elderly and those taking lithium chronically.
Leukocytosis is observed after lithium exposure, granulocyte predominance.
Establishing the diagnosis
Elevated serum lithium concentration, signs and symptoms of lithium toxicity, other potential causes ruled out, and improvement with treatment.
If patient has elevated serum lithium concentration without signs consistent with toxicity, consider (1) was sample collected prior to drug distribution out of serum and into large organs (CNS), and (2) was serum collected in lithiated-heparin tube, causing a false elevation in the reported lithium concentration.
Differential diagnosis
For chronic or acute-on-chronic toxicity
Note: Because lithium has a narrow therapeutic index, serum and CNS levels do not always correlate well. It may be especially difficult to distinguish patients who take lithium therapeutically and have meningitis with chronic lithium toxicity.
CNS infection (e.g., meningitis) (altered mental status, tremor, rigidity, leukocytosis, seizure).
Serotonin syndrome (altered mental status, tremor, rigidity).
Neuroleptic malignant syndrome (altered mental status, tremor, rigidity).
Malignant catatonia (altered mental status, tremor, rigidity).
Dystonic reaction (tremor, rigidity).
Strychnine toxicity (tremor, rigidity).
Carisoprodol, tricyclic antidepressant, antipsychotic agent toxicity (altered mental status, tremor, myoclonus).
GABA agonist withdrawal (e.g., ethanol, benzodiazepine, barbiturate, carisoprodol) (altered mental status, tremor, seizure).
Thiamine deficiency (ataxia, nystagmus, altered mental status).
Urosepsis (altered mental status, leukocytosis).
For acute toxicity
Viral or bacterial gastroenteritis (nausea, vomiting, diarrhea, leukocytosis).
Confirmatory tests
Serial lithium levels.
Consider CT brain, lumbar puncture, EEG.
Consider cardiac enzymes and echocardiogram to rule out myocardial infarction if abnormal EKG and lithium
toxicity in question, or in high-risk patients.
If clinical signs of hypothyroidism or hyperthyroidism, obtain serum TSH.
4. Specific Treatment
First-line therapy
Forced emesis not recommended (patients with acute toxicity often experience emesis anyway, risk of aspiration with altered mental status, no proven benefit).
Gastric lavage of limited utility and not recommended in most cases.
Activated charcoal does not bind lithium well and is not recommended.
WBI decreases serum lithium levels after ingestion of sustained-release preparations and is recommended after a large overdose of this formulation if no contraindication exists (e.g., obstruction, ileus).
IV hydration with normal saline, as hydration increases perfusion to the kidneys and therefore increases lithium secretion, and sodium increases renal excretion of lithium.
SPS (Kayexalate®) increases fecal elimination of lithium and decreases serum lithium concentrations, but also decreases serum potassium. Unknown if this treatment changes clinical outcomes after overdose.
Unknown if coadministration of IV potassium decreases the amount of lithium eliminated prior to absorption. Not recommended for routine use, unless concomitant hyperkalemia requires treatment.
Drugs and dosages
WBI: Polyethylene glycol solution PO (e.g. GoLytely®, Colyte®), 2 L/hr PO or via nasogastric tube for 5 hours has been shown to decrease adult’s area under the serum lithium concentration curve after acute ingestion of sustained-release preparations. Contraindications to WBI: bowel obstruction, ileus. Expected adverse effects of abdominal discomfort and watery diarrhea.
Normal saline IV: Initial bolus of 1 – 2 L in adults with dehydration; 1.5 – 2 times normal maintenance rate reasonable. Overly aggressive normal saline hydration may cause hypernatremia in those with subclinical nephrogenic DI. Follow serum sodium levels to guide treatment (if low = risk factor for lithium toxicity; if high = look for other signs of nephrogenic DI). Follow serum creatinine (should improve if dehydration-related elevation on presentation).
SPS (Kayexalate®) optimal dose not known. In a small human prospective study, 857 mg/kg SPS was safely given PO within one hour of lithium ingestion and decreased lithium absorption. Insufficient human data to recommend routine use.
Refractory cases
Lithium has properties amenable to hemodialysis (Vd = 0.4 – 1.4 L/kg, negligible protein binding, MW = 6.94 daltons), and hemodialysis is effective at removing lithium.
Recommend hemodialysis: moderate to severe toxicity (e.g., altered mental status), renal failure, patient unable to tolerate normal saline therapy (e.g., CHF, liver disease). But no rigid indications established based on studies.
Serum lithium level expected to rebound within 6 – 8 hr after hemodialysis as lithium is drawn out of target tissues down its concentration gradient (goal of therapy). Therefore, repeat hemodialysis is often required.
Although a rough guideline of serum lithium concentration > 4.0 mmol/L in acute toxicity or > 2.5 mmol/L in chronic toxicity has been proposed, clinical status, not serum lithium concentration, should guide therapy.
Bicarbonate hemodialysis may prevent lithium being driven into cells by the sodium-hydrogen antiporter, as likely occurs during acetate hemodialysis.
In patients unable to tolerate hemodialysis due to hypotension, continuous veno-venous hemodialysis also effectively removes lithium, but at a slower continuous rate.
5. Disease monitoring, follow-up and disposition
Expected response to treatment
Patients suffering from acute toxicity without whole body stores are expected to improve clinically rapidly (hours to days) with treatment.
Patients with whole body stores and an acute ingestion (acute-on-chronic toxicity) or chronic toxicity often take days to weeks to completely recover clinically.
Neurotoxicity may be irreversible after acute or chronic toxicity.
Elimination half-life in toxicity varies widely (average 12.9 – 50.1 hr).
Incorrect diagnosis
Undetectable serum lithium in lithium-naive patient or therapeutic serum level in patient taking lithium.
No clinical improvement or worsening condition.
Clinical signs and symptoms not consistent with acute or chronic lithium toxicity.
Follow-up
Psychiatry for alternate drug selection if patient no longer candidate to use lithium, as decreased creatinine clearance is relative contraindication to lithium therapy.
Regular monitoring of drug levels and signs/symptoms of toxicity and adverse effects if lithium is continued.
Consider Neurology evaluation for persistent neurologic complications.
Physical and/or Occupational Therapy as needed for rehabilitation or persistent neurologic complications.
Pathophysiology
Lithium is primarily excreted by the kidneys as a free ion.
Under normal circumstances, it is reabsorbed in the proximal tubule, and handled by the kidney like sodium.
Lithium is known to cause a number of adverse effects on the kidneys with therapeutic use (e.g., oliguria, polyuria, renal tubular acidosis, nephropathy, nephrogenic DI, decreased creatinine clearance, end-stage renal disease).
Many of the renal disease states induced by lithium make the kidneys more susceptible to retaining lithium and contributing to toxicity.
The mechanism by which lithium causes neurotoxicity is not known, but may be related to its transport through sodium ion channels or exaggerated therapeutic effects, which have also not been completely discovered.
Lithium concentrates in the thyroid and interferes with its metabolism, commonly causing hypothyroidism, which may be subclinical.
Epidemiology
Elderly patients are at greater risk of lithium toxicity due to decreased GFR.
Increased risk of hypothyroidism if lithium is combined with valproate or carbamazepine.
No difference in gender or race and predisposition to lithium toxicity.
Prognosis
SILENT is defined by new irreversible neurotoxicity after lithium discontinued for 2 months or more.
Cerebellar toxicity is the most common permanent neurotoxicity, possibly due to demyelination.
After lithium toxicity has resolved, renal impairment may persist.
Special considerations for nursing and allied health professionals.
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What's the evidence?
(Describes how the therapeutic effect of lithium in bipolar affective disorder relates to inositol.)
(Describes how the dopamine D1 receptor may play a role in lithium's therapeutic effect in bipolar affective disorder.)
(Investigated how gene polymorphism in serotonin receptor genes may play a role in lithium treatment for bipolar affective disorder.)
(Reviews and summarizes the vast and varied literature pertaining to lithium pharmacology and pharmacodynamics, including drug interactions.)
(Reviews the literature pertaining to brain lithium nuclear magnetic resonance spectroscopy and the findings when these brain concentrations are compared with serum lithium concentrations in therapeutic lithium use.)
(Describes elimination of lithium in a group of patients with lithium toxicity in whom hemodialysis was recommended but not performed.)
(Describes pharmacokinetics of two sustained-release lithium preparations.)
(Describes a case of lithium toxicity associated with transient EKG abnormalities consistent with cardiac ischemia, but normal troponin and echocardiogram.)
(Case study and review of the literature of neonatal adverse effects after in utero exposure to lithium, including Ebstein's anomaly.)
3. Diagnosis
(Examines the relationship between serum lithium concentrations and the target organ (brain) lithium levels using magnetic resonance spectroscopy.)
(Studies the pharmacokinetics of lithium in two patients after massive intentional ingestions of sustained-release preparations.)
(Reviews 68 cases of lithium overdose and contrasts serum lithium levels and degree of toxicity in patients with acute and acute-on-chronic toxicity.)
(A study designed to determine a dose-response relationship between lithium and granulocyte production discovered that doses adequate to produce a serum lithium level of 0.55 mmol/L are sufficient to induce granulocytosis.)
(Describes a case of lithium toxicity associated with transient EKG abnormalities consistent with cardiac ischemia, but normal troponin and echocardiogram.)
4. Specific Treatment
(This in vitro study demonstrates that activated charcoal binds lithium in water, but they do not bind significantly in simulated gastric fluid.)
(In this study activated charcoal did not reduce serum lithium levels in mice with acute toxicity, but sodium polystyrene sulfonate did reduce serum lithium levels significantly.)
(In this small human study whole-bowel irrigation was shown to decrease the area under the lithium serum concentration curve and mean serum lithium concentration when administered 1 hour after a sustained-release lithium preparation.)
(A report of cases of lithium toxicity with a focus on toxicity in patients chronically on lithium and their renal function and unique requirements regarding treatment.)
(In this small human study healthy volunteers experienced decreased lithium absorption after a single dose of lithium followed by sodium polystyrene sulfonate, and no hypokalemia was noted.)
(Reviews 14 cases of lithium poisoning in patients who received hemodialysis, and comments on hemodialysis indications based on information obtained.)
(Reviews cases of lithium toxicity with and without hemodialysis after hemodialysis was recommended by a poison center, and while the result of withholding hemodialysis resulted in one death, other patients recovered without the therapy.)
(A case of lithium toxicity treated with hemodialysis and illustrates how serum lithium concentration does not correlate well with clinical signs of toxicity)
(Reviews a case of lithium toxicity in which both bicarbonate and acetate hemodialysis were utilized and compares the differences between the two types of dialysate in lithium toxicity.)
(Describes a case of lithium toxicity in which continuous venovenous hemodialysis was successfully used, including calculations of lithium clearance and serial serum lithium concentrations.)
5. Disease monitoring, follow-up and disposition
(Reviews 90 cases of irreversible neurotoxicity associated with lithium and discusses the clinical manifestations.)
(Reviews cases of lithium toxicity with and without hemodialysis after hemodialysis was recommended by a poison center, and pharmacokinetics are characterized in lithium toxic patients without hemodialysis.)
(A review that makes recommendations for monitoring renal function of patients taking lithium.)
(Reviews a large number of cases of patients with bipolar affective disorder with and without hypothyroidism and reports odds ratios of hypothyroidism associated with lithium, carbamazepine and valproate use.)
(Reviews the literature and makes recommendations regarding treatment of hypothyroidism in patients using lithium therapeutically.)
(A study reviewing the renal function of 61 patients taking lithium therapeutically over a mean of 11.5 years.)
(A report of cases of lithium toxicity with a focus on toxicity in patients chronically on lithium and their renal function and unique requirements regarding treatment.)
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