LITHIUM SALTS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Camcolit
2) Candamide
3) Carbolith
4) Carbonic Acid Lithium Salt
5) Carbonic Acid, Dilithiuim Salt
6) Ceglution
7) CP 154671-61
8) Dilithium Carbonate
9) Eskalith
10) Hypnorex
11) Limas
12) Liskonum
13) Lithane
14) Lithicarb
15) Lithii Carbonas
16) Lithinate
17) Lithium Carbonate
18) Lithium Carb
19) Lithobid
20) Lithonate
21) Lithotabs
22) Lithium metal
23) NSC-16895
24) Phasal
25) Plenur
26) Priadel
27) Quilonorm-Retard
28) Quilonum Retard
29) Teralithe (French)
30) CAS 554-13-2

1) Citric acid, trilithium salt, hydrate
2) Lithium citrate hydrate
3) 1,2,3-propanetricarboxylic acid, 2-hydroxy-, trilithium salt, hydrate
4) 2-hydroxy-1,2,3-propanetricarboxylic acid trilithium salt hydrate
5) CAS 919-16-4

1) CAS 5266-20-6

1) Lithium sulphate
2) Sulfuric acid, lithium salt (1:2)
3) Sulfuric acid, dilithium salt
4) CAS 10377-48-7

1.2.1) MOLECULAR FORMULA
1) LITHIUM CARBONATE: Li2CO3
2) LITHIUM CITRATE: C6H5Li3O7
3) LITHIUM OROTATE: Li-C5H3-N2-O4
4) LITHIUM SULFATE: Li2-S-O4

Available Forms Sources

1) MEDICINAL

a) LITHIUM CARBONATE is available as:

1) GENERIC: Oral capsule: 150 mg, 300 mg, 600 mg; Oral tablet: 300 mg; Oral table, extended release: 300 mg, 450 mg
2) ESKALITH-CR: Oral tablet, extended release: 450 mg
3) ESKALITH: Oral capsule: 300 mg
4) LITHOBID: Oral tablet, extended release: 300 mg

b) LITHIUM OROTATE: Lithium orotate (Find Serenity Now(R)) is marketed as a dietary supplement, manufactured by Urban Nutrition, LLC, and is available via the internet. Each tablet is listed as containing 120 mg of lithium orotate (3.83 mg of elemental lithium per 100 mg of (organic) lithium orotate compared to 18.8 mg of elemental lithium per 100 mg of (inorganic) lithium carbonate) (Pauze & Brooks, 2007).
c) LITHIUM CITRATE: 8 mEq (as citrate equivalent to 300 mg lithium carbonate) per 5 mL syrup.

2) Lithium carbonate is available in a technical grade as a fine white powder and a CP grade (HSDB , 2001; Lewis, 1997).

1) Lithium bromide, lithium chloride, lithium hydroxide, and lithium silicate are synthesized from lithium carbonate which acts as a chemical intermediate (HSDB , 2001).
2) LITHIUM BATTERY: Lithium batteries may vent toxic gases, such as sulfur dioxide and thionyl chloride, when there is a malfunction. Trauma due to explosive fragmentation, chemical or thermal burns, laryngeal and pulmonary edema, and bronchiolitis obliterans may result from such exposure. Lithium toxicity does NOT occur from ingesting lithium batteries (Ducatman et al, 1988). Refer to "DISC BATTERY INGESTION" or "FOREIGN BODY" managements for more information.
3) Lithium carbonate is manufactured by the following methods: (1) lithium-bearing ores, sulfuric acid, sodium carbonate, calcium hydroxide, by an acid extraction process; (2) lithium-bearing ores and sodium carbonate, by a carbonate extraction process; (3) brine, residual and calcium oxide/ dolomite, calcined as a byproduct of magnesium hydroxide production; (4) roast lithium-bearing ores with a sulfuric acid at 250 degrees C, leach the lithium sulfate, and convert it to carbonate with soda ash by precipitation (Ashford, 1994; HSDB , 2001; Lewis, 1997).

1) MEDICINAL

a) LITHIUM CARBONATE is used therapeutically, primarily to treat bipolar disorder (Prod Info LITHOBID(R) extended-release oral tablets, 2009; Prod Info lithium carbonate oral tablets, capsules, 2009); it is less commonly used today due to the wide availability of other psychiatric medications with lesser side effects.
b) LITHIUM OROTATE: Lithium orotate (Find Serenity Now(R)) is marketed as a dietary supplement, used to treat stress, manic depression, Alzheimer's disease, and alcoholism (Pauze & Brooks, 2007).

2) INDUSTRIAL

a) Lithium is used in batteries, alloys, and lubricating greases. Lithium carbonate also has properties that make it suitable for industrial uses. Flux (glass, enamel, ceramics and porcelain production); aluminum melt electrolysis adjunct; coating of arc-welding electrodes; luminescent paints; varnishes and dyes; nucleonics; and a catalyst (Ashford, 1994; HSDB , 2001; ILO , 1998; Lewis, 1997).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Lithium carbonate is used therapeutically, primarily to treat bipolar disorder; it is less commonly used today due to the wide availability of other psychiatric medications with lesser side effects. It is available in oral formulations, both regular and extended release. Lithium orotate is a dietary supplement. Lithium is an important industrial material used to make batteries, alloys, and flux.
B) PHARMACOLOGY: Lithium is a naturally occurring alkali metal and monovalent cation chemically similar to Na+ and K+. The exact mechanism by which it stabilizes mood is not known. It is thought to affect the CNS by altering nerve conduction, cortisol and monoamine metabolism, and increasing serotonin.
C) TOXICOLOGY: In the kidney, lithium competes with Na+ and K+ in the renal tubules; conditions that increase renal sodium reabsorption (dehydration) decrease lithium elimination. Chronic toxicity is typically due to decreased clearance caused by dehydration, medication interactions, or renal impairment.
D) EPIDEMIOLOGY: Acute poisoning is typically less severe than chronic toxicity. Chronic toxicity develops primarily in elderly patients, those with intercurrent illnesses, and those started on drugs that decrease lithium clearance.
E) WITH THERAPEUTIC USE

1) At therapeutic doses, effects such as blurred vision, nystagmus, GI irritation, tremors, slowed mentation, cerebellar dysfunction may occur. Polyneuropathy and Parkinsonian syndrome have been described. ECG changes such as nonspecific ST/T changes, sinus node blocks may be present. Brugada Syndrome has been reported in several chronic lithium users. Nephrogenic Diabetes Insipidus, reduced glomerular filtration, and thyroid abnormalities, particularly hypothyroidism, may also occur. Lithium carbonate crosses the placenta and is also present in breast milk. Congenital malformations have been documented after exposure to lithium during pregnancy.
2) DRUG INTERACTIONS: Lithium clearance is decreased by concomitant use of ACE inhibitors, angiotensin II antagonists, thiazide and loop diuretics, and nonsteroidal anti-inflammatory drugs.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Toxicity is categorized as acute or chronic. Acute overdose is typically less severe than chronic toxicity and results in gastrointestinal upset, while CNS manifestations are less common due to slow absorption into the brain. Chronic effects are usually less gastrointestinal and more neurological due to prior CNS saturation. Mild to moderate poisoning can cause nausea, vomiting, diarrhea, dehydration, nystagmus, and tremors. Hyperreflexia, cogwheel rigidity, ataxia, agitation, confusion, and lethargy are common. Bradycardia, T-wave abnormalities, hypoventilation may also occur.
2) SEVERE POISONING: Severe effects in acute exposures are rare. Patients with chronic toxicity may manifest severe toxicity despite relatively modestly elevated serum lithium concentrations. Effects include photophobia, dehydration, electrolyte imbalances, thyroid dysfunction, hyperthermia, seizure, coma, rigidity, myoclonus, serotonin syndrome. ECG changes such as nonspecific T-wave abnormalities, QTc prolongation, bundle branch block, bradycardia, junctional rhythm, and hypotension may occur. Hypoventilation, respiratory failure, and ARDS may rarely develop. Bezoars may form in large ingestions.

0.2.20)

A) Lithium is classified as FDA pregnancy category D. Congenital malformations have been reported. The use of lithium should be avoided during pregnancy, especially in the first trimester and one week prior to delivery. Cardiovascular and other teratogenic or toxic effects have been reported in infants born to lithium-treated mothers. In addition, a prospective, observational study showed that significantly more miscarriages and preterm deliveries occurred with lithium exposure during pregnancy (n=183) compared with a group of women who were not exposed to any teratogen during pregnancy (n=748). However, other studies have revealed that outcomes of most pregnancies with in utero exposure to lithium have resulted in normal infants, and that use of lithium during pregnancy may possess a lower fetal risk than previously believed. Lithium is present in breast milk at 33% to 50% of the plasma lithium concentration, and may cause hypertonia, hypothermia, cyanosis, and ECG changes in nursing infants and neonates.

0.2.21)

A) At the time of this review, the manufacturer does not report any carcinogenic potential for lithium in humans.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Most acute lithium overdoses may be safely managed with supportive care that includes: antiemetics for nausea and vomiting, intravenous normal saline hydration to enhance renal lithium elimination, and correction of any electrolyte abnormalities. For chronic toxicity, address underlying causes of decreased renal clearance, including intravenous fluids for dehydration or ceasing medications that impair renal function.

B) MANAGEMENT OF SEVERE TOXICITY

1) Orotracheal intubation for airway protection should be performed if recurrent seizures, increasing somnolence or coma develop. Consider gastric lavage for recent, large ingestion if airway is protected. Whole bowel irrigation with polyethylene glycol may be considered in large ingestions, especially if a sustained-release formulation. Administer intravenous normal saline to enhance renal elimination of lithium (Goal: urine output of 2 to 3 mL/kg/hr). Intravenous fluids and vasopressors (dopamine, norepinephrine) may be needed to treat hypotension. Treat agitation, rigidity, seizures, hyperthermia, serotonin syndrome with sedation (benzodiazepines, propofol), and cooling measures; intubation and paralysis may be necessary with severe toxicity. Consider hemodialysis for patients with severe toxicity not responding to hydration, or congestive heart failure or renal insufficiency. Dysrhythmias are treated with standard ACLS protocols.

C) DECONTAMINATION

1) PREHOSPITAL: Charcoal does not adsorb lithium well; it is not recommended.
2) HOSPITAL: Consider gastric lavage in a patient with recent life-threatening ingestion, if airway is protected or patient is alert. Whole bowel irrigation with polyethylene glycol should be considered with a large ingestion or ingestion of a sustained-release product.

D) AIRWAY MANAGEMENT

1) Intubate if unable to protect airway due to worsening agitation, somnolence or coma, or if respiratory distress develops.

E) ANTIDOTE

1) None.

F) ENHANCED ELIMINATION

1) Hemodialysis increases lithium clearance and decreases half-life. The decision to perform hemodialysis is largely clinical. The international expert Extracorporeal Treatments in Poisoning (EXTRIP) workgroup reviewed the available literature and despite a low quality of evidence recommended the following guidelines for extracorporeal treatment (ECTR) in patients with severe lithium toxicity with any of the following clinical conditions:

a) In the presence of a reduced level of consciousness, seizures, or life-threatening dysrhythmias irrespective of lithium concentration.
b) If kidney function is impaired and lithium concentration is greater than 4 mEq/L.

2) ECTR was also suggested for patients with any of the following clinical conditions:

a) If lithium concentration is greater than 5 mEq/L, if confusion is present, or if the expected time to obtain a lithium concentration less than 1 mEq/L with optimal management is greater than 36 hours.

3) DISCONTINUATION of ECTR is recommended:

a) In patients with apparent clinical improvement or lithium concentration less than 1 mEq/L.
b) After a minimum of 6 hours of ECTR if the lithium concentration is not readily available.

4) Serum lithium levels typically rebound 6 to 12 hours after dialysis in chronically intoxicated patients due to equilibration with intracellular and CNS lithium stores. In order to determine the use of subsequent ECTR sessions, serial lithium concentrations should be determined over 12 hours after the cessation of ECTR. The preferred ECTR is intermittent hemodialysis, with an acceptable alternative being continuous renal replacement therapy (RRT), if intermittent hemodialysis is not available. Both continuous RRT and intermittent hemodialysis are equally acceptable after the first treatment.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Accidental ingestions in asymptomatic lithium naive patients who ingest less than the maximum daily dose (Children less than 6 years old: 900 mg/square meter/day; Children 6 to 12 years old: 30 mg/kg/day; Adults: less than 2400 mg) who have no synergistic co-ingestions may be monitored at home. Those chronically taking lithium that are accidentally exposed to additional doses needed to be evaluated on a case by case basis, but typically tolerate a double dose without significant effects.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions, symptomatic patients, children and adults with ingestions of greater than maximum daily dose, acute-on-chronic ingestions, unknown dosing errors in chronic patients, synergistic co-ingestions, or those with unclear history should be sent to a health care facility for evaluation and observation. Patients should be monitored until serum lithium concentration has peaked and is consistently declining and clinical condition is improved.
3) ADMISSION CRITERIA: Patients with persistent or worsening gastrointestinal irritation, renal impairment, altered mentation, respiratory depression, dysrhythmias, unstable vital signs, or persistently rising serum lithium concentrations should be admitted. Intensive care admission is indicated for aggressive airway, cardiac monitoring, and emergent hemodialysis.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (agitation, hyperthermia, need for hemodialysis, respiratory depression, coma), concerns about decontamination, or in whom the diagnosis is not clear. Consult a nephrologist for emergent hemodialysis in patients with severe poisoning.

H) PITFALLS

1) Patients with chronic toxicity often exhibit neurologic toxicity at levels lower than those with acute exposures. Close monitoring of electrolytes, renal function, urine output, neurologic exam, mental status, and temperature should be correlated with serial levels to assess efficacy of treatment. Anticipate early the need to transfer the patient to a higher level of care if unable to check serial lithium concentration, or if hemodialysis is not available. Diuretics should be avoided as they increase lithium reabsorption in the renal tubules.

I) PHARMACOKINETICS

1) Well absorbed; peak concentrations within 2 to 5 hours. Lithium is not bound to plasma proteins. The volume of distribution is 0.79 L/kg. Primarily renal (8% to 98%) elimination. Initial half-life is 6 to 12 hours, slowing to 24 hours or greater due to slow redistribution from intracellular compartment. Nearly 80% of filtered lithium is reabsorbed in proximal tubule; reabsorption increases with sodium depletion or dehydration. Half-life in therapeutic dose is approximately 19 hours (14 to 24 hours).

J) TOXICOKINETICS

1) Peak lithium concentrations delayed 4 to 17 hours after overdose of sustained release formulations. Half-life is shorter in acute overdose (10 to 20 hours) and prolonged in patients with chronic intoxication (mean 32 hours). Hemodialysis reduces half-life to 2 to 5 hours. Serum concentrations rebound after hemodialysis due to redistribution from intracellular compartments.

K) DIFFERENTIAL DIAGNOSIS

1) Extrapyramidal effects from other medications, neuroleptic malignant syndrome, serotonin syndrome from other agents, sepsis, CNS infections, or intracranial catastrophes (massive hemorrhage or stroke).

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH THERAPEUTIC USE

1) HYPOTHERMIA: Gradual hypothermia occurred during hospitalization for adjuvant chemotherapy for a gastric tumor in a 74-year-old male treated chronically with lithium carbonate. The serum lithium level was 1.2 mmol/L and no other cause for the rectal temperature of 35.7 degrees C could be found. The patient's temperature normalized within 48 hours of stopping lithium therapy (Follezou & Bleibel, 1985).
2) HYPERTHERMIA may develop in patients with serotonin syndrome or a disorder similar to neuroleptic malignant syndrome (NMS) associated with lithium therapy (Cohen & Cohen, 1974; Spring & Frankel, 1981; Koehler & Mirandolle, 1988; Quinn et al, 1986; Susman & Addonizio, 1987; Mills, 1997).

B) WITH POISONING/EXPOSURE

1) HYPERTHERMIA can develop in patients with serotonin syndrome that is associated with lithium toxicity (Achong et al, 1975; Naramoto et al, 1993).
2) CASE REPORT: After ingesting approximately 210 lithium carbonate (400 mg) tablets, a 39-year-old male developed dehydration, vomiting, incoordination, drowsiness, coarse tremors, aggression episodes, blood pressure 100/60 mmHg, fever (39.3 degrees Celsius), and verbal non-responsiveness. Following treatment with hemodialysis and 6 days after admission, he was discharged without symptoms or residual side-effects (Kerbusch et al, 2002).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) BLEPHAROSPASM AND EYELID APRAXIA: A 72-year-old woman, upon a dose increase in lithium from 800 mg/day to 1200 mg/day, developed a confusional state a few days later which was accompanied by severe blepharospasm and inability to open her eyes. Symptoms resolved 2 weeks after lithium discontinuation (Micheli et al, 1999).

B) WITH POISONING/EXPOSURE

1) PHOTOPHOBIA developed in a 32-year-old woman with chronic lithium intoxication and a serum lithium concentration of 1.6 mEq/L (Caplan & Fry, 1982; Grant, 1993). A similar case, with recurrence on repeated challenge has been reported (Pridmore et al, 1996).
2) VISUAL CHANGES: Transitory blurred vision and blindness may occur at toxic lithium blood levels of 2 mEq/L and greater (Fraunfelder, 1983).
3) ABNORMAL EXTRAOCULAR MOTION: Down beat nystagmus, horizontal gaze palsy and symptoms of oscillopsia have been reported despite discontinuing lithium carbonate therapy (Grant, 1993; Rosenberg, 1989; Williams et al, 1988; Corbett et al, 1989).

3.4.5)

A) WITH POISONING/EXPOSURE

1) Air concentrations below 0.025 mg/m3 did not cause nasal irritations (Clayton & Clayton, 1994).
2) Air concentrations ranging from 0.025 and 0.10 mg/m3 caused some nasal discharge combined with a tickling sensation but was tolerable (Clayton & Clayton, 1994).
3) Nasal irritation and coughing was experienced when air concentrations reached 0.10 to 0.50 mg/m3 and could not be tolerated by workers (Clayton & Clayton, 1994).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) ECG changes and hypotension can occur in serious overdoses (Anantha Narayanan et al, 2015; Bosak et al, 2014; Kansagra et al, 2014; Tilkian et al, 1976; Perrier et al, 1991; Jaeger et al, 1993).
b) CASE REPORT: Profound hypotension (blood pressure 80/60 mmHg), with severe vasodilatation refractory to norepinephrine (noradrenaline), was reported in a 51-year-old female with lithium toxicity as a result of a drug interaction when bendrofluazide and perindopril were added to her treatment. Hemodynamic monitoring showed decreased peripheral vascular resistance. Blood pressure was eventually maintained with norepinephrine (noradrenaline), epinephrine (adrenaline), and dobutamine (Vipond et al, 1996).
c) CASE REPORT: After ingesting approximately 210 lithium carbonate (400 mg) tablets, a 39-year-old man developed dehydration, vomiting, incoordination, drowsiness, coarse tremors, aggression episodes, blood pressure 100/60 mmHg, fever (39.3 degrees Celsius), and verbal non-responsiveness. Following treatment with hemodialysis and 6 days after admission, he was discharged without symptoms or residual side-effects (Kerbusch et al, 2002).

B) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) One case of severe hypertension accompanying acute lithium intoxication has been reported (Michaeli et al, 1984). The pathophysiology is not clear.

C) VENTRICULAR TACHYCARDIA

1) WITH THERAPEUTIC USE

a) ADULT

1) CHRONIC LITHIUM TOXICITY (CASE REPORT): A 74-year-old man who had been taking lithium carbonate 300 mg BID for bipolar disorder, presented with a 3-day history of progressive encephalopathy, tremor, and weakness, and a 1-day history of diarrhea. His medical history included bipolar disorder, hypertension. benign prostatic hypertrophy, recent prostate cancer, and undiagnosed chronic kidney disease. In addition to lithium carbonate, he was taking bupropion, lisinopril, finasteride, lovastatin, clonazepam, and tamsulosin. On presentation, his symptoms included lower extremity hyperreflexia and clonus, upper extremity hypertonia and tremor, tongue fasciculations, and difficulty speaking interspersed with muteness. An ECG showed a junctional rhythm with a heart rate of 51 beats/min, corrected prolonged QT interval of 476 ms, and multiple premature ventricular and supraventricular complexes. Laboratory results revealed an elevated lithium concentration of 2.2 mmol/L and a normal serum potassium. A month before presentation, his lithium concentration was 1.2 mmol/L and an ECG showed first-degree AV block, intraventricular conduction delay, T wave flattening, and QT interval prolongation. During transport to the ICU, another ECG showed nonsustained monomorphic ventricular tachycardia (120 to 130 beats/min) lasting up to 1 minute, alternating with sinus bradycardia and wandering atrial pacemaker (34 beats/min). Monomorphic ventricular tachycardia episodes were observed greater than 100 times. His symptoms gradually improved over the first 4 hours of hemodialysis. Following further supportive care, including a norepinephrine infusion for hypotension, his condition resolved and he was discharged on day 5 (Bosak et al, 2014).

b) PEDIATRIC

1) CASE REPORT: A 10-year-old boy with a complex history of bipolar disorder with psychotic features, seizures, and attention deficit hyperactivity disorder, and taking multiple medications, which included methylphenidate, oxcarbazepine, clonidine, depakote, and levothyroxine and lithium carbonate developed a complaint of chest pain, palpitations, and vomiting. During a recent psychiatric admission his lithium was increased to 600 mg twice daily. ECG revealed a widened QRS tachyarrhythmia and ventricular tachycardia (VT) was confirmed. Serum lithium level was 3.1 mEq/L (therapeutic range 0.5 to 1.5 mEq/L) on admission Initial treatment with lidocaine was ineffective. He remained hemodynamically stable, but required a procainamide drip to convert to normal sinus rhythm. Because the patient continued to have episodes of nonsustained VT over the next 36 hours, he was aggressively hydrated with close monitoring of serum lithium levels and electrolytes. Nephrotoxicity was absent and the patient gradually improved. Medications were resumed with the exception of lithium; no further dysrhythmias were reported, although minimal intraventricular conduction delay and first degree AV block persisted (Francis et al, 2004).

D) CONDUCTION DISORDER OF THE HEART

1) WITH THERAPEUTIC USE

a) Sinus node dysfunction has been reported with therapeutic doses of lithium (HSDB , 2001; Montalescot et al, 1984).
b) CASE REPORTS

1) ADULT: A 57-year-old taking 900 mg/day for 4 years developed periods of atrial fibrillation followed by bradycardia or asystole. Serum levels were 1.2 to 1.46 mmol/liter (Wong, 1981).

2) WITH POISONING/EXPOSURE

a) ADULT

1) CASE REPORTS

a) A 35-year-old woman with a history of bipolar disorder and multiple prior suicidal attempts, was found unconscious after taking an unknown amount of lithium. On presentation, she had a Glasgow Coma Scale of 10, heart rate of 35 beats/min. respiratory rate of 10 breaths/min, blood pressure of 90/63 mmHg, and temperature of 97 degrees F. A venous blood draw revealed hypoxia with metabolic acidosis. An ECG revealed severe bradycardia (heart rate 34 beats/min) with junctional rhythm. Laboratory results revealed elevated troponin 3.14 ng/mL (reference range, less than 0.04 ng/mL), creatine kinase of 146 Units/L, creatine kinase-MB of 6 ng/L with relative index of 5.76, serum creatinine of 1.7 mg/dL, and elevated serum lithium concentration of 3.7 mEq/L. On an echocardiography, severe left ventricular systolic dysfunction with an ejection fraction of 15% and severe global hypokinesis were observed. At this time, she was intubated for hypoxic respiratory failure and altered mental status. Despite supportive care, she remained hypotensive and bradycardic (heart rate low 30s) and her condition deteriorated. She underwent hemodialysis and her heart rate improved, but an ECG revealed diffuse T-wave inversions with QT prolongation (QTc 531 milliseconds). Her lithium serum concentration decreased to 0.55 mEq/L after hemodialysis and following continued supportive care, her condition gradually improved. A nuclear stress test revealed no evidence of reversible ischemia or infarction with an ejection fraction of 61%. On day 4, a significant improvement in ejection fraction (from 60% to 65%) was observed in a repeat echocardiogram (Anantha Narayanan et al, 2015).
b) A 39-year-old woman with bipolar disorder who had been taking lithium (1200 mg/day 3 times daily) presented with the complaints of fainting, altered mental status, and motor weakness particularly of lower extremities. Laboratory results revealed hypokalemia (potassium level 2.72 mEq/L; normal range 3.2 to 5.1), and hypophosphatemia (1.26 mEq/L; normal range, 2.7 to 4.5), and serum lithium of 2.96 mEq/L; therapeutic level, 0.8 to 1.2). ECG revealed prolonged p-wave (180 msec), QRS widening QRS (120 msec), prolonged QT (640 msec) and PR (320 msec) intervals, ST wave depression in leads V2 and V3, and T-wave inversion. Following supportive care, including hemodialysis and correction of her electrolyte abnormalities, her lithium level declined to 0.57 mEq/L. Another ECG showed no abnormalities except T-wave inversions and slight ST depression in leads V2 and V4 (Canan et al, 2008).
c) A 42-year-old woman developed severe bradycardia with dizziness, frequent falls and a seizure followed by loss of consciousness associated with chronic lithium intoxication (level 3.86 mmol/L) and hypokalemia (2.7 mmol/L). ECG showed sinus bradycardia (41 beats/minute) with inverted T waves, prominent U waves and a QTc of 462 msec. T wave abnormalities and U waves corrected with potassium repletion. An electrophysiologic study revealed marked prolongation of the sinus node recovery time. Bradycardia and QTc prolongation resolved with resolution of her lithium intoxication (Lai et al, 2000).
d) A 75-year-old woman with a previously normal ECG who had been treated with phenytoin and lithium for 20 years developed junctional bradycardia associated with syncope. Serum lithium level was 2.13 mmol/L. Her ECG returned to normal and symptoms resolved with discontinuation of her lithium (Farag et al, 1994).
e) A 72-year-old man with pre-existing right bundle branch block developed lithium toxicity associated with sinus arrest, junctional rhythm, QTc prolongation and recurrent asystole (Ong & Handler, 1991).
f) A 41-year-old woman developed junctional rhythm and hypotension unresponsive to dopamine and dobutamine after ingesting lithium carbonate, lorazepam and maprotiline (serum lithium level 9.6 mmol/L) (Guerin et al, 1990).
g) A 30-year-old woman developed first degree AV block, widened QRS, and a prolonged QT interval following chronic exposure to excessive doses of lithium over a period of several weeks. Serum lithium concentration was 3.7 mEq/L. No life threatening dysrhythmias were noted (Mateer & Clark, 1982).

2) CASE SERIES

a) Shannon et al (1989) reported 29 patients with either acute or chronic lithium intoxication (serum levels of 1.5 mEq/L or greater). Chronically intoxicated patients showed a significantly greater incidence of cardiovascular deterioration than acutely intoxicated individuals. Furthermore, none of the acutely intoxicated patients exhibited T-wave abnormalities, whereas 50% of the chronically intoxicated patients did show such abnormalities (Shannon et al, 1989).

b) PEDIATRIC

1) Severe bradycardia was associated with severe lithium toxicity in an 11-year-old girl (junctional bradycardia 30 to 40 beats/minute, serum lithium 6.54 mEq/L) and a 72-year-old woman (junctional bradycardia 39 beats/minute, serum lithium 4.1 mEq/L) (Hahn et al, 2001a; Hahn et al, 2001b).

E) ELECTROCARDIOGRAM ABNORMAL

1) WITH THERAPEUTIC USE

a) GENERAL

1) In patients treated with lithium chronically, T wave flattening is the most common EKG abnormality found in 20% to 100%, occurring within 5 days of starting treatment and disappearing within 3 to 5 days after discontinuing treatment (HSDB , 2001).

a) Sinus node dysfunction is the most frequently reported conduction defect. An increased frequency of ventricular dysrhythmias was reported in a randomly selected group of patients started on lithium who had a therapeutic serum lithium concentration (Brady & Horgan, 1988).

b) CASE REPORT

1) A 66-year-old woman with a history of chronic renal insufficiency, diabetes, chronic obstructive lung disease, and hypothyroidism had a baseline ECG demonstrating first degree atrioventricular (AV) block with normal sinus rhythm. Lithium therapy was initiated and electrocardiograms were taken on days 6, 15, 18, and 20. Day 6 indicated incomplete right bundle branch block and possible left atrial enlargement, day 15 showed sinus bradycardia in addition to first- degree AV block, and day 18 showed development of junctional rhythm with prolonged QT interval. The final ECG (day 20) showed improvement in cardiac function after lithium was discontinued (Delva & Hawken, 2001).

2) WITH POISONING/EXPOSURE

a) Dyson et al (1987) reported 16 lithium intoxicated patients with ECGs that showed 14 minor abnormalities including U waves (4/14), intraventricular conduction defects (5/14), prolongation of the QTc interval (8/14), and T wave flattening or inversion (11/14)(Dyson et al, 1987).
b) In a study of 76 patients on chronic lithium therapy, 11 of whom had supratherapeutic levels (>1.2 mEq/L), ECG changes were more common in the patients with high lithium concentrations. Patients with supratherapeutic lithium concentrations had lower but still normal heart rates (68 +/-20 vs 80 +/-14 beats/min), longer PR intervals (180 +/-21 ms vs 164 +/-19 ms), longer QT (406 +/-41 ms vs 360 +/-38 ms), and QTc intervals (440 +/-45 ms vs 409 +/-26 ms). QTc interval was greater than 440 ms in 55% of the patients with supratherapeutic lithium concentrations compared with 8% of patients with normal levels. T-wave inversions were present in 73% of the patients with supratherapeutic lithium concentrations compared with 17% of those with therapeutic levels (Hsu et al, 2005).
c) CASE REPORT: A 46-year-old man with a history of diabetes, hypertension, and schizoaffective/bipolar disorder who had been taking lithium 1200 mg twice daily presented with confusion, ataxia, and anorexia. Laboratory results showed lithium concentration of 4.69 mmol/L. ECG changes (normal sinus rhythm with elevated ST segments in the anterior leads with downward concavity, and biphasic T waves) suggested an acute myocardial infarction. Troponin I was less than 0.1 mcg/L and echocardiogram was normal without wall motion abnormalities. Following supportive care, including hemodialysis for 6 hours and whole-bowel irrigation, his lithium concentration decreased to 0.64 mmol/L (6 hours after hemodialysis) and the ECG normalized (Puhr et al, 2008).

F) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) One case of a severe lithium intoxication with the development of acute myocardial infarction without coronary artery lesions has been reported (Perrier et al, 1991).

G) BRUGADA SYNDROME

1) WITH THERAPEUTIC USE

a) Two patients on chronic lithium therapy without clinical or laboratory evidence of toxicity had ECGs consistent with Brugada syndrome (type 1 pattern with increased J-wave amplitude, coved ST-T configuration with negative T waves in V1-V3). Both patients had ICD implantation. ECG abnormalities resolved with reduction in the lithium dose in one patient and discontinuation of the lithium in the other (Darbar et al, 2005).
b) CASE REPORT: A 42-year-old man who had been taking lithium for 5 months presented with ECG changes (ST-segment elevation in leads V1 through V3) during a routine preoperative testing. His lithium dosage was increased to 300 mg 3 times daily 2 weeks before presentation. His lithium concentration was 1.49 mg/dL (reference range, 0.8 to 1.4 mEq/L). A second ECG showed similar ST-segment elevation in leads V1 through V3 and a new T-wave inversion in V2 consistent with a type 1 Brugada pattern. Five days after presentation, another ECG revealed a biphasic or "saddleback" pattern of ST elevation in leads V1 and V2 consistent with type 2 Brugada syndrome. He was discharged home after the placement of an implanted cardioverter/defibrillator was discussed (Pirotte et al, 2008).

H) TAKOTSUBO CARDIOMYOPATHY

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 78-year-old woman who had been taking lithium (600 mg/day) for 2 years for bipolar disorder, presented with ataxia, tremor, and myoclonus. After being admitted, she vomited and lost consciousness. An EEG revealed diffuse slowing and laboratory results showed renal dysfunction and an elevated serum lithium concentration (2.9 mEq/L). Despite supportive care and the discontinuation of lithium treatment, she developed difficulty breathing 2 days later. At this time, she had a blood pressure of 96/54 mmHg and a pulse rate of 94 beats/min. An ECG revealed ST-segment elevation in the anterior leads and an elevated serum troponin T level. She was treated for possible ST-segment elevation myocardial infarction, but did not undergo a coronary angiography because of her renal dysfunction. An echocardiography revealed left ventricular dysfunction (an ejection fraction of 0.3) caused by apical kinesis and basal hyperkinesis, resulting in a diagnosis of Takotsubo cardiomyopathy. Following the discontinuation of lithium, her condition gradually improved within the next 3 weeks. Her serum lithium concentrations on day 8 was 0.06 mEq/L (Kitami et al, 2014).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Chronic lithium toxicity was associated with respiratory distress syndrome in 3 adult patients with peak lithium levels of 4.5 mEq/L, 3.8 mEq/L and 4.9 mEq/L (Lawler & Cove-Smith, 1986; Friedman et al, 1992).
b) CASE REPORT: A 42-year-old woman with a history of chronic lithium use presented with nausea and vomiting, aphasia, truncal and gait ataxia, cogwheel rigidity, hypertonicity, tremor, mutism, mild tachycardia, and stupor. Serum lithium level was 4.4 mmol/L. On 3rd hospital day, she developed acute respiratory distress syndrome (ARDS) and presented with severe hypoxia (pulse oximetry-68%) and bilateral pulmonary infiltrates on chest x-ray. She recovered after 2 months of mechanical ventilation and supportive care (Toronjadze et al, 2005).
c) CASE REPORT: A 46-year-old woman with bipolar disorder presented with a 2-week history of shortness of breath, generalized weakness, a 3-week history of diarrhea, and hypotension (BP 90/55 mmHg). Laboratory results showed a lithium concentration of 3.3 mmol/L (therapeutic range: 0.8 to 1.5 mmol/L). Following supportive care, including hemodialysis and dopamine treatment, her blood pressure normalized and lithium concentration decreased to 1 mmol/L. Once again, she underwent hemodialysis 12 hours later when her lithium concentration rebounded to 2.2 mmol/L. She developed hypoxic respiratory failure 3 days later and was intubated. Her blood gases were pH 7.2, PCO2 93.6, PO2 63.8 on a 100% non-rebreather mask. A chest x-ray revealed bilateral ground-glass opacities, with mild diffuse interstitial prominence. Bilateral infiltrates and alveolar consolidation were also observed in a CT scan. An echocardiogram of her heart revealed a right ventricular systolic pressure of 65 to 70 mmHg and pulmonary artery dilatation, and the left ventricular ejection fraction of 55%. Following supportive care for ARDS, her condition improved within the next 5 days and she was extubated successfully. At this time, she was still nonverbal and unresponsive, but her condition gradually improved until she was discharged home within the next 10 days (Kansagra et al, 2014).

B) APNEA

1) WITH THERAPEUTIC USE

a) Lithium reportedly resulted in hypoventilation and reversible respiratory failure in a 60-year-old female with stable chronic obstructive lung disease and manic-depressive illness (Wolpert et al, 1985).

2) WITH POISONING/EXPOSURE

a) Respiratory depression requiring mechanical ventilation developed in a 63-year-old woman who accidentally took 450 milligrams of lithium carbonate four times a day for 8 days (Corbett et al, 1989), and in a 52-year-old woman who overdosed on 9,000 milligrams of lithium (El-Mallakh & Lee, 1987).
b) Respiratory failure was reported in 3 of 14 patients in another study (Jaeger et al, 1993).

Neurologic

3.7.2)

A) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 37-year-old man developed non-convulsive status epilepticus 3 weeks after starting lithium therapy; his lithium serum level was 1.9 mmol/L. An EEG showed a background 5-6 Hz theta rhythm, independent sharp discharges over both hemispheres and intermittent bursts of high amplitude generalized electrographic seizure activity seen bilaterally. The patient demonstrated gradual improvement over the next week and EEG waves returned to normal (Kuruvilla & Alexander, 2001).

2) WITH POISONING/EXPOSURE

a) Seizures have occurred in nonepileptic patients with plasma concentrations in the therapeutic range to those classified as severe intoxication (Dyson et al, 1987; El-Mallakh & Lee, 1987; Hansen & Amdisen, 1978; HSDB , 2001; Jaeger et al, 1993; Ramchandani & Schindler, 1993).
b) CASE REPORT: An 84-year-old woman presented with altered mental state (confusion and decreased spontaneous speech) and postural tremor after the accidental ingestion of at least 10 tablets of lithium carbonate (eg; 3000 mg) over 2 consecutive days. Later she became mute and facial and limb myoclonus was noted. Approximately 48 hours later, an EEG revealed spike-wave discharges occurring every 2 to 4 seconds, consistent with the diagnosis of nonconvulsive status epilepticus. Following 10 mg diazepam her EEG and mentation improved. With supportive treatment, her symptoms resolved gradually over the next few days and EEG waves returned to normal. Her blood lithium concentrations were 0.9 mEq/L on day 1 and 0.2 mEq/L on day 4 (Roccatagliata et al, 2002).

B) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 30-year-old man with bipolar disorder who had been taking lithium 900 mg lithium daily presented with drowsiness, slurred speech, bilateral nystagmus, ataxia dysdiadokinesis, hypotonia, and hyporeflexia. His serum lithium concentration was 0.5 mEq/L. Following the discontinuation of lithium and supportive care, he recovered gradually and was asymptomatic in 48 hours (Kumar et al, 1999).

2) WITH POISONING/EXPOSURE

a) Mild CNS depression may develop in about 40% to 50% of patients, ranging from lethargy, confusion, black out spells, psychosomatic retardation, increased thirst and agitation, to coma in severe cases (Bailey & McGuigan, 2000; Corbett et al, 1989; Dyson et al, 1987; Hansen & Amdisen, 1978; HSDB , 2001; Perrier et al, 1991; Ramchandani & Schindler, 1993; Vipond et al, 1996).
b) The magnitude of the toxicity parallels the extent of CNS dysfunction (Clayton & Clayton, 1994).
c) Since lithium clears from the plasma much faster than from the brain, patients with chronic lithium toxicity may still have neurological toxicity when lithium levels have fallen into or below the therapeutic range (Spinewine et al, 2005).
d) De Haro et al (2002) observed 306 cases of lithium intoxication between January 1991 and December 2000, of which 190 were suicide attempts. The most frequent signs of intoxication included: drowsiness (76%), muscle rigidity (21%), tremor (16%), and coma (15%). The average lithium blood level was 2.35 mmol/L (average ingested quantities 25 tablets); 56% of the patients were admitted to intensive care and 4 deaths occurred. The accidental ingestion of lithium (average, 2 pills) in 13 children resulted only in drowsiness (De Haro et al, 2002).
e) CASE REPORT: After ingesting approximately 210 lithium carbonate (400 mg) tablets, a 39-year-old man developed dehydration, vomiting, incoordination, drowsiness, coarse tremors, aggression episodes, blood pressure 100/60 mmHg, fever (39.3 degrees Celsius), and verbal non-responsiveness (Glasgow Coma Scale eye movement score, 3 of 5; motoric movements score, 5 of 5; verbal response score, 4 of 5). Following treatment with hemodialysis and 6 days after admission, he was discharged without symptoms or residual side-effects (Kerbusch et al, 2002).
f) CASE REPORT: A 42-year-old woman with a history of chronic lithium use presented with nausea and vomiting, aphasia, truncal and gait ataxia, cogwheel rigidity, hypertonicity, tremor, mutism, mild tachycardia, and stupor. Serum lithium level was 4.4 mmol/L. On 3rd hospital day, she developed acute respiratory distress syndrome (ARDS) and presented with severe hypoxia (pulse oximetry-68%) and bilateral pulmonary infiltrates on chest x-ray. She recovered after 2 months of mechanical ventilation and supportive care (Toronjadze et al, 2005).
g) DIFFERENTIAL DIAGNOSIS: Some neurologic manifestations (eg, cognitive decline, myoclonus, tremor) of lithium intoxication can mimic Creutzfeldt-Jakob syndrome (Kim et al, 2013).

1) CASE REPORT: A 65-year-old woman with bipolar II disorder who had been taking lithium carbonate 600 mg/day for 2 months, presented with subacute cognitive dysfunction (ie, memory decline, spatial disorientation, difficulty in naming and conversation) and myoclonus, suggestive of Creutzfeldt-Jakob syndrome. A brain MRI showed no abnormalities; however, a brain single-photon emission computed tomography (SPECT) showed decreased perfusion in the cerebellar cortex and the entire cerebral cortex. Following the discontinuation of lithium, her symptoms gradually improved and her serum lithium concentration decreased from 2.08 mmol/L to 0.59 mmol/L on day 4. On a follow-up visit a month later, another brain SPECT revealed improved cerebellar and cortical perfusion. When the follow-up SPECT image was compared with the initial SPECT image (subtraction images), it was found that brain areas with 20% increased ligand uptake were localized in the cerebellar and cerebral cortices, including the frontal, pariental, and cingulate areas (Kim et al, 2013).

C) TREMOR

1) WITH THERAPEUTIC USE

a) Generalized coarse tremor may be observed. Fine tremor of the hands is usually seen in 45% to 50% of patients starting lithium therapy. Less than 10% of patients experience tremor after one year of therapy.

2) WITH POISONING/EXPOSURE

a) Coarse tremor is usually spread through out the body and may indicate intoxication (HSDB , 2001; Perrier et al, 1991; Bailey & McGuigan, 2000).
b) CASE REPORT: An 18-year-old woman experienced nausea, vomiting, and mild tremors after intentionally ingesting 18 tablets (120 mg of lithium orotate per tablet) of Find Serenity Now(R). Her serum lithium level, obtained approximately 90 minutes post-ingestion, was 0.31 mEq/L. One hour later, a repeat serum lithium level was 0.40 mEq/L. After 3 hours of observation (4.5 hours post-ingestion), the patient's signs and symptoms resolved (Pauze & Brooks, 2007).
c) CASE REPORT: After ingesting approximately 210 lithium carbonate (400 mg) tablets, a 39-year-old male developed dehydration, vomiting, incoordination, drowsiness, coarse tremors, aggression episodes, blood pressure 100/60 mmHg, fever (39.3 degrees Celsius), and verbal non-responsiveness. Following treatment with hemodialysis and 6 days after admission, he was discharged without symptoms or residual side-effects (Kerbusch et al, 2002).
d) De Haro et al (2002) observed 306 cases of lithium intoxication between January 1991 and December 2000, of which 190 were suicide attempts (De Haro et al, 2002). The most frequent signs of intoxication included: drowsiness (76%), muscle rigidity (21%), tremor (16%), and coma (15%). The average lithium blood level was 2.35 mmol/L (average ingested quantities 25 tablets); 56% of the patients were admitted to intensive care and 4 deaths occurred.

D) ATAXIA

1) WITH THERAPEUTIC USE

a) Ataxia may develop with therapeutic use (Dyson et al, 1987; Matsis et al, 1989).

2) WITH POISONING/EXPOSURE

a) Ataxia may develop with toxic doses (Bailey & McGuigan, 2000; Dyson et al, 1987; Matsis et al, 1989).
b) CASE REPORT: After an acute overdose, a 32-year-old man had ataxia which persisted for 2 years; a CT scan showed cortical cerebellar atrophy (Bejar, 1985).
c) CASE REPORT: A 46-year-old developed persistent ataxia after acute on chronic lithium overdose. Her ataxia improved with high doses of buspirone (120 to 160 milligrams/day) (Megna & O'Dell, 2001).

E) DISTURBANCE IN SPEECH

1) WITH POISONING/EXPOSURE

a) Slurred speech and mutism have been reported and is an early sign of intoxication (Dyson et al, 1987; HSDB , 2001; Matsis et al, 1989).
b) STUTTERING: A 86-year-old woman with a history of dementia, epilepsy, and bipolar disorder who had been taking lithium carbonate, developed stuttering. All physical and neurological examinations were normal; however, laboratory analysis revealed elevated lithium concentration of 2 mmol/L (0.6 to 1.2 mmol/L) 3 months after the onset of stuttering. Her stuttering resolved 2 weeks after the discontinuation of lithium carbonate (Sabillo et al, 2012).

F) HYPERREFLEXIA

1) WITH POISONING/EXPOSURE

a) Ankle clonus, extensor plantar responses, and increased muscle tone have been reported (Bailey & McGuigan, 2000; Dyson et al, 1987; Matsis et al, 1989; Perrier et al, 1991; Vipond et al, 1996; Bosinski et al, 1998).

G) CHRONIC POISONING

1) WITH POISONING/EXPOSURE

a) In a retrospective analysis of 97 cases of lithium intoxication, 28 patients were identified with severe neurotoxicity (delirium or physically incapacitated from neurological symptoms attributable to lithium intoxication). Of these, 26 patients had chronic intoxication, two had acute on chronic poisoning and none had acute poisoning alone (Oakley et al, 2001).
b) Shannon et al (1989) demonstrated that patients with chronic lithium intoxication (serum levels of 1.5 mEq/L or greater) were at greater risk of developing neurologic findings (disorientation, depressed mental status, hyperreflexia, cerebellar dysfunction, and hypertonicity) than those acutely intoxicated (Shannon et al, 1989).
c) Follow-up studies of patients with lithium intoxication who have neurologic sequelae lasting more than 2 months show that cerebellar findings (ataxia, scanning speech, incoordination, dysdiadochokinesia, cerebellar atrophy on CT) are typical (Schou, 1984; Tesio et al, 1987); Lacome, 1987).

1) Improvement usually occurred over the first 6 to 12 months but rarely thereafter (Schou, 1984).

d) REVIEW: Kores and Lader (1997) have published a review of the evidence for and nature of the chronic sequelae seen after lithium intoxication(Kores & Lader, 1997).
e) CASE REPORT: A 62-year-old woman taking 2 times the prescribed dose of lithium for 3-4 weeks (serum lithium 3.9 mEq/L upon admission) developed lithium intoxication, confusion, and ataxia. After detoxification, the patient continued to have chronic neuropsychological deficits, including memory impairment, attention deficit, impairment in executive functions, and visuospatial deficits that were still present 2 years after overdose (Brumm et al, 1998).

H) CHOREOATHETOSIS

1) WITH POISONING/EXPOSURE

a) Choreoathetosis has been reported in lithium intoxication (Reed et al, 1989; Matsis et al, 1989; Minden et al, 1993; Podskalny & Factor, 1996).
b) Choreoathetosis has been described as a result of lithium therapy in patients with serum lithium levels between 2.5 mEq/L and 1.4 mEq/L (Walevski & Radwan, 1986).
c) CASE REPORT: A 75-year-old woman with a history of bipolar type I disorder treated with lithium, presented with a 3-day history of aphasia (difficulty finding words), confusion, dysarthria, tremor, impaired short-term memory, and ataxia. Laboratory results revealed a serum creatinine of 2 mg/dL (baseline: 1.1 mg/dL) and lithium level of 2.2 mEq/L (normal: 0.8 to 1.2 mEq/L). She developed choreoathetosis (ie, involuntary irregular, nonrhythmic, high amplitude, dance-like writhing) the next day. Her renal function and lithium level normalized, but her choreoathetosis persisted. Her symptoms gradually improved over the next few days. On day 10, she was discharged with complete resolution of choreoathetosis and cognitive and physical dysfunctions (Cobb et al, 2015).

I) PARKINSONISM

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 74-year-old woman who had been taking lithium carbonate (300 mg twice daily), clomipramine, and valsartan plus hydrochlorothiazide, presented with a 1-week history of progressively worsening and disabling parkinsonism, characterized by tremor, bradykinesia, rigidity, postural instability/ataxia, associated with lethargy and bradycardia. Laboratory results revealed increased lithium and TSH serum concentrations and decreased serum concentration of circulating thyroid hormone. Her clinical condition improved rapidly after the discontinuation of lithium, replacement of valsartan/hydrochlorothiazide with amlodipine, and levothyroxine and IV saline therapy. However, her neurological symptoms resolved about 5 months after presentation (Basile et al, 2014).
b) CASE REPORT: A 67-year-old woman who had been taking lithium (400 mg/day) for bipolar affective disorder for 10 years developed acute Parkinsonism. She presented with psychomotor slowness with significant cognitive impairment, masked face, severe bradykinesia, severe rigidity of four limbs and postural tremor. Laboratory results showed mild leukocytosis, renal dysfunction, hypercalcemia, and hypermagnesemia. Lithium was discontinued after a high serum lithium level (3.6 mEq/L) was noted. Her condition was complicated with hyperparathyroidism and nephrogenic diabetes insipidus. Following supportive therapy that included levodopa (400 mg/day in 2 divided doses), her condition improved gradually; only the residual extrapyramidal symptoms and mania were noted one month later (Shen et al, 2007).

J) DEMENTIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Rapidly progressive dementia and EEG changes suggestive of Creutzfeldt-Jakob syndrome were described in two elderly patients taking lithium chronically. Clinical and EEG findings normalized within 2 to 3 weeks after discontinuation of lithium (Smith & Kocen, 1988).

K) NEUROPATHY

1) WITH THERAPEUTIC USE

a) In a controlled study of 34 lithium treated patients, lithium therapy was associated with reduced nerve conduction velocity and amplitude in both motor and sensory nerves (Faravelli et al, 1999).
b) CASE REPORT: A 27-year-old woman with manic-depression on chronic lithium therapy developed polyneuropathy associated with a lithium level of 3.84 mEq/L. A cause and effect relationship could not be established (Chang et al, 1988).
c) CASE REPORT: Vanhooren et al (1990) reported a 54-year-old taking 900 mg/day and a 37-year-old taking 1250 mg/day who developed polyneuropathy(Vanhooren et al, 1990).
d) CASE REPORT: A 69-year-old woman taking 1,000 milligrams/day developed a peripheral sensory motor axonal neuropathy associated with an episode of lithium toxicity (level 1.89 mmol/liter and significant CNS toxicity). Clinical recovery occurred over 3 months (Johnston et al, 1991).
e) CASE REPORT: A 38-year-old woman with bipolar disorder and a 4-day history of diarrhea, developed lower limb weakness and difficulty concentrating on daily tasks 7 days before presentation. She had been taking citalopram 20 mg/day, lithium 400 mg/day, and olanzapine 10 mg/day. Her lithium levels were within target range in the past 2 years. Physical examination revealed Medical Research Council grade 4/5 proximally and distally in the lower limbs, with hyporeflexia and normal sensation. Laboratory results revealed trough lithium levels of 1.9 mmol/L (normal range, 0.5 to 1.2 mmol/L), a serum sodium of 116 mmol/L (normal range, 132 to 144 mmol/L), and serum potassium of 3.1 mmol/L (normal range, 3.5 to 5 mmol/L). A stool sample was positive for Clostridium difficile toxin. Despite the discontinuation of lithium therapy, her level of awareness and attention deteriorated and lithium concentration remained within toxic range for the next 11 days. Intermittent rhythmical delta activity and triphasic complexes were observed in an electroencephalogram. All neurophysiological findings suggested the diagnosis of acute sensorimotor axonal polyneuropathy. Following supportive therapy, including 0.9% saline, her sodium levels normalized and lithium levels rapidly decreased. Although her symptoms improved, she had persistent bilateral foot drop at 3 months follow up. Approximately a year later, an electromyograph revealed marked reduction in motor and sensory amplitudes bilaterally, with spontaneous activity in lower limbs with polyphasic motor units (Merwick et al, 2011).

L) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) CHRONIC LITHIUM TOXICITY (CASE REPORT): A 74-year-old man who had been taking lithium carbonate 300 mg BID for bipolar disorder, presented with a 3-day history of progressive encephalopathy, tremor, and weakness, and a 1-day history of diarrhea. His medical history included bipolar disorder, hypertension. benign prostatic hypertrophy, recent prostate cancer, and undiagnosed chronic kidney disease. In addition to lithium carbonate, he was taking bupropion, lisinopril, finasteride, lovastatin, clonazepam, and tamsulosin. On presentation, his symptoms included lower extremity hyperreflexia and clonus, upper extremity hypertonia and tremor, tongue fasciculations, and difficulty speaking interspersed with muteness. An ECG showed a junctional rhythm with a heart rate of 51 beats/min, corrected prolonged QT interval of 476 ms, and multiple premature ventricular and supraventricular complexes. Laboratory results revealed an elevated lithium concentration of 2.2 mmol/L and a normal serum potassium. A month before presentation, his lithium concentration was 1.2 mmol/L and an ECG showed first-degree AV block, intraventricular conduction delay, T wave flattening, and QT interval prolongation. During transport to the ICU, another ECG showed nonsustained monomorphic ventricular tachycardia (120 to 130 beats/min) lasting up to 1 minute, alternating with sinus bradycardia and wandering atrial pacemaker (34 beats/min). Monomorphic ventricular tachycardia episodes were observed greater than 100 times. His symptoms gradually improved over the first 4 hours of hemodialysis. Following further supportive care, including a norepinephrine infusion for hypotension, his condition resolved and he was discharged on day 5 (Bosak et al, 2014).

2) WITH POISONING/EXPOSURE

a) Effects may include disorientation, poor memory, incoherence, distractibility, incontinence, choreoathetoid movement, and generalized seizures (Bailey & McGuigan, 2000) Newman & Sanders, 1979; (Apte & Langston, 1983; Agulnik et al, 1972; Bassingthwaighte & Rummans, 1991).
b) CASE REPORT: A case of Creutzfeldt-Jakob like disorder, resolving on drug discontinuation has been reported (Casanova et al, 1996).
c) CASE REPORT: A 21-year-old man developed memory impairment associated with an ingestion of 50 lithium carbonate tablets. Slow improvement in concentration ability and memory was noted in a 2-month follow-up (Saxena & Mallikarjuna, 1988).
d) CASE REPORT: A 65-year-old woman with a history of progressive dementia and Parkinsonian syndrome developed coma, tremor, myoclonus and hyperreflexia with a serum lithium level of 1.3 mM. EEG revealed slowed background activity and generalized periodic activity suggesting Creutzfeldt-Jakob encephalopathy. Fifteen days after presentation she began improving and by day 78 her neurologic exam revealed only impaired recent memory, temporospatial disorientation and a slight speech disorder (Slama et al, 2000).

M) CEREBELLAR DISORDER

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 26-year-old woman who was taking 1500 mg/day of lithium carbonate for 5 years, presented with a 2-week history of fever, productive cough, vomiting, tremor and gait changes. On arrival, neurological examination revealed a sleepy, disoriented, dysarthric patient with tremors in extremities, symmetrical deep reflexes and flexor plantar responses. She was diagnosed with bacterial pneumonia and sub-acute lithium intoxication (serum lithium, 1.9 mEq/L; therapeutic range 0.6 to 1.2 mEq/L). Following the discontinuation of lithium carbonate and supportive therapy, her respiratory infection and level of consciousness improved gradually. However, over the next 6 months, she experienced persistent cerebellar signs such as ataxia, dysarthria, dysmetria and discreet hypotonia. Two years after the initial presentation, an MRI of the skull revealed significant cerebellar atrophy (de Cerqueira et al, 2008).
b) CASE REPORT: Persistent cerebellar syndrome is reported in a 67-year-old man with lithium intoxication. The patient presented with lithium toxicity manifested as coma and encephalopathy followed by persistent dysarthria and ataxia. The patient deteriorated and died.

1) Neuronal loss and gliosis in the cerebellar cortex and dentate nuclei was shown at autopsy. The cerebellar white matter had prominent spongy change, consistent with persistent cerebellar syndrome (Schneider & Mirra, 1994).

N) NEUROLEPTIC MALIGNANT SYNDROME

1) WITH THERAPEUTIC USE

a) A disorder similar to neuroleptic malignant syndrome (NMS) or serotonin syndrome has been associated with lithium therapy and toxicity (Cohen & Cohen, 1974; Spring & Frankel, 1981; Achong et al, 1975; Koehler & Mirandolle, 1988; Quinn et al, 1986; Susman & Addonizio, 1987; Naramoto et al, 1993).

1) Clinical findings in NMS include muscle rigidity, hyperthermia, mental status depression, autonomic instability, elevated creatinine phosphokinase, tachycardia, tachypnea, hypertension, sweating, and leukocytosis.

b) CASE REPORT: A 53-year-old woman treated with fluoxetine and lorazepam developed symptoms consistent with serotonin syndrome including confusion, ataxia, fever, tremor, and movement disorders 48 hours after beginning lithium 900 mg/day (Noveske et al, 1989). Symptoms resolved 4 days after discontinuation of her lithium.

2) WITH POISONING/EXPOSURE

b) CASE REPORT: A 45-year-old man was admitted to the hospital for lithium overdose after ingesting 90 sustained-released lithium tablets (450 mg each). Following supportive therapy and 3 sessions of hemodialysis, he was stabilized, and his lithium concentration fell from the peak of 6.9 mEq/L to 0.5 mEq/L (on day 7). On day 10 of his hospital stay, he developed symptoms consistent with neuroleptic malignant syndrome, including high fever, tachypnea, hypotension, muscle rigidity, rhabdomyolysis (CK 698 International Units/L), acute renal insufficiency (serum creatinine 3.5 mg/dL), confusion, and obtundation. The patient's condition continued to deteriorate and he developed acute renal failure and acute respiratory distress syndrome. Care was withdrawn on day 14, and the patient died (Gill et al, 2003).

O) DYSTONIA

1) WITH POISONING/EXPOSURE

a) A 3.5-year-old woman who ingested 20 mg/kg of lithium carbonate developed lethargy, slurred speech, incoordination, dystonic movements, hypertonicity, and hyperreflexia with a lithium level of 1 mEq/L 11 hours post-ingestion (Goetting, 1985).

P) BENIGN INTRACRANIAL HYPERTENSION

1) WITH POISONING/EXPOSURE

a) Pseudotumor cerebri, documented by funduscopic exam, CT scan and lumbar puncture, was reported in 3 patients taking therapeutic doses of lithium. The condition resolved after lithium was discontinued in 2 patients.
b) Papilledema persisted in the third patient who required reinstitution of lithium (Saul et al, 1985).

Q) MUSCLE WEAKNESS

1) WITH THERAPEUTIC USE

a) Symptoms associated with myasthenia gravis may worsen with lithium therapy (HSDB , 2001).
b) Approximately 30% of patients on lithium/lithium carbonate therapy experience transient muscle weakness. The percentage decreases to 1% after a year of therapy (HSDB , 2001).

2) WITH POISONING/EXPOSURE

a) A myasthenia-like episode complicated the clinical course of a 41-year-old who presented after a polydrug overdose which included lithium. As he regained muscle strength, cerebellar ataxia lasting 4 months was noted (Lippman et al, 1985). Additional cases have been reported (Ronziere et al, 2000).

R) EXTRAPYRAMIDAL DISEASE

1) WITH THERAPEUTIC USE

a) A parkinsonian syndrome characterized by tremor, fasciculations and cogwheel rigidity may occur with or without other signs of toxicity (Sansone & Ziegler, 1985; Ramchandani & Schindler, 1993).
b) COGWHEEL RIGIDITY occurs in about 5% of patients and is generally mild to moderate (HSDB , 2001). It has been reported without other signs of toxicity (Shopsin & Gershon, 1975); but this is uncommon (Branchey et al, 1976; Kane et al, 1978).
c) TREMOR: A mild to moderate tremor may be seen with therapeutic use (Branchey et al, 1976).

S) FLACCID PARALYSIS

1) WITH THERAPEUTIC USE

a) Neuromuscular blockade induced by succinylcholine and pancuronium bromide is potentiated or prolonged by lithium (Borden et al, 1974; Hill et al, 1976; HSDB , 2001; Reimherr et al, 1977).

T) NEUROTOXICITY

1) WITH THERAPEUTIC USE

a) Neurotoxic reactions can occur with therapeutic levels (Lewis, 1983).
b) Patients may present with ataxia as an initial toxic symptom (Salem et al, 1980).
c) Patients may experience fatigue, lethargy, dulled senses, and ataxia but these symptoms are usually resolved 2 to 3 weeks after beginning therapy. Dysarthria and aphasia have also been reported (HSDB , 2001).
d) CONTROLLED STUDY: In a study of electroneuronographic parameters in bipolar patients, those receiving chronic lithium treatment had significantly reduced motor and sensory nerve conduction velocities and decreased amplitude of sensory action potentials. None of the impairments noted was significant enough to warrant a clinical diagnosis of peripheral nerve abnormality (Faravelli et al, 1999).

U) HALLUCINATIONS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Visual and auditory hallucinations developed in a 58-year-old woman after 7 years of lithium therapy (Hambrecht, 1995). Hallucinations resolved when lithium was discontinued and reappeared when it was reinstituted.

V) ELECTROENCEPHALOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An EEG performed in a 73-year-old man 2 weeks after beginning lithium therapy revealed moderately severe generalized slowing. The next day he manifested clinical evidence of toxicity including myoclonus, hyperreflexia, tiredness and disorientation with a serum lithium of 1.12 mmol/L. EEG normalized when lithium was discontinued (Gallinat et al, 2000).

W) HEADACHE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 62-year-old woman developed a new daily bilateral, intense holocranial headache two weeks prior to a laboratory test confirming a serum lithium concentration of 2.5 mEq/L. Lithium dose was reduced, and one week later (lithium level 1.4 mEq/L) the headache had resolved (Bigal et al, 2001).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 51-year-old woman developed nausea and headache after ingesting 50 slow-release lithium carbonate tablets (450 mg each) in a suicide attempt. Thirteen hours after ingestion, her serum lithium level was 10.6 mmol/L; level fell to 5.8 mmol/L 24 hours post-ingestion. Headache gradually resolved with time (Nagappan et al, 2002).

X) AGGRESSIVE BEHAVIOR

1) WITH POISONING/EXPOSURE

a) CASE REPORT: After ingesting approximately 210 lithium carbonate (400 mg) tablets, a 39-year-old man developed dehydration, vomiting, incoordination, drowsiness, coarse tremors, aggression episodes, blood pressure 100/60 mmHg, fever (39.3 degrees Celsius), and verbal non-responsiveness. Following treatment with hemodialysis and 6 days after admission, he was discharged without symptoms or residual side-effects (Kerbusch et al, 2002).

Gastrointestinal

3.8.2)

A) NAUSEA, VOMITING AND DIARRHEA

1) WITH THERAPEUTIC USE

a) GI effects are usually mild and reversible; 10% to 20% of patients experience diarrhea, vomiting, abdominal pain, nausea, and anorexia in the early stages of treatment (HSDB , 2001).
b) Lithium toxicity frequently results in nausea, anorexia, vomiting, and diarrhea (Bosinski et al, 1998; Hansen & Amdisen, 1978).
c) Lithium administered by the rectal route produces painful diarrhea (Amdisen & Carson, 1986; Perrier et al, 1991).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting are common effects (Toronjadze et al, 2005; Bailey & McGuigan, 2000). Diarrhea may be noted, particularly following overdose with sustained release lithium preparations (Kansagra et al, 2014; Bosinski et al, 1998; Ehrlich & Diamond, 1983).
b) CASE REPORT: An 18-year-old woman experienced nausea, vomiting, and mild tremors after intentionally ingesting 18 tablets (120 mg of lithium orotate per tablet) of Find Serenity Now(R). Her serum lithium level, obtained approximately 90 minutes post-ingestion, was 0.31 mEq/L. One hour later, a repeat serum lithium level was 0.40 mEq/L. After 3 hours of observation (4.5 hours post-ingestion), the patient's signs and symptoms resolved (Pauze & Brooks, 2007).
c) CASE REPORT: After ingesting approximately 210 lithium carbonate (400 mg) tablets, a 39-year-old man developed dehydration, vomiting, incoordination, drowsiness, coarse tremors, aggression episodes, blood pressure 100/60 mmHg, fever (39.3 degrees Celsius), and verbal non-responsiveness. Following treatment with hemodialysis and 6 days after admission, he was discharged without symptoms or residual side-effects (Kerbusch et al, 2002).
d) CASE REPORT: A 51-year-old woman developed nausea and headache after ingesting 50 slow-release lithium carbonate tablets (450 mg each) in a suicide attempt. Thirteen hours after ingestion, her serum lithium level was 10.6 mmol/L; level fell to 5.8 mmol/L 24 hours post-ingestion. Headache gradually resolved with time (Nagappan et al, 2002).

B) SERUM AMYLASE RAISED

1) WITH POISONING/EXPOSURE

a) Hyperamylasemia without clinical evidence of pancreatitis has been reported rarely (Matsis et al, 1989).

Genitourinary

3.10.2)

A) OLIGURIA

1) WITH THERAPEUTIC USE

a) BUN and serum creatinine may be slightly elevated and oliguria has been reported (Kuruvilla & Alexander, 2001; Schou et al, 1968; Vipond et al, 1996). Long term lithium therapy has been shown to result in decreased renal glomerular function (Bendz et al, 1994; DePaulo et al, 1981; HSDB , 2001).

B) DIABETES INSIPIDUS

1) WITH THERAPEUTIC USE

a) CASE SERIES: In a study of 142 patients with at least 15 years of lithium treatment, 12% had nephrogenic diabetes insipidus (Bendz et al, 1994).

2) WITH POISONING/EXPOSURE

a) Nephrogenic diabetes insipidus and resulting hypernatremia may develop, particularly with chronic overdose (Shen et al, 2007; Bayliss & Heath, 1981; Dyson et al, 1987; Friedman et al, 1992; Ramchandani & Schindler, 1993; Wetzel et al, 2000).
b) CASE REPORT: A 69-year-old man who was using lithium (1200 mg/day) for bipolar disorder for the last 14 years, presented with a respiratory infection and fluctuations in consciousness. His medical history included osteoarthritis, metabolic syndrome with hypertension, obesity, mixed dyslipidemia, and an ischemic stroke 2 years earlier. His lithium dose had remained stable for the last year and his family confirmed strict treatment adherence. His laboratory values revealed serious hypernatremia (sodium: 161 mmol/L). Despite fluid therapy, his cognitive deterioration became more pronounced; fluid balance revealed polyuria (4.5 L/day). The patient's blood lithium levels and ADH plasma levels were within normal limits, therefore a diagnosis of nephrogenic diabetes insipidus (NDI) secondary to chronic lithium treatment was made. Lithium treatment was suspended and hydrochlorothiazide (50 mg/day) and ketorolac (50 mg/8 hr) were initiated. The patient's fluid and electrolyte imbalances and his cognitive status resolved 48 hours later (Prieto Tenreiro, 2012).

C) RENAL TUBULAR DISORDER

1) WITH THERAPEUTIC USE

a) Pitressin-resistant impaired renal concentrating ability has been found. This nephrogenic diabetes insipidus is reversible with cessation of the drug. Lithium also causes distal renal tubular acidosis and increases urinary excretion of sodium, potassium, uric acid, and phosphate (Wahlin & Bucht, 1981).
b) Sixty-one percent of patients on chronic lithium (average 4.5 years) had an impaired ability to concentrate urine. Twelve percent had a moderate reduction in creatinine clearance. Neither condition was clinically dangerous(Udall et al, 1981).
c) Another study with levels in the 0.5 to 0.8 mEq/liter range did not show renal structural or functional changes (Conte et al, 1989).
d) Long-term use of lithium may cause impairment in concentrating ability, progressing to tubulointerstitial nephropathy and advanced chronic kidney disease. Renal biopsy findings in patients with lithium-induced chronic tubulointerstitial nephropathy revealed tubular atrophy and interstitial fibrosis interspersed with tubular cysts and dilatations (Tuazon et al, 2008).

D) ACUTE RENAL FAILURE SYNDROME

1) WITH THERAPEUTIC USE

a) Acute renal failure has been reported rarely (Kitami et al, 2014; Dyson et al, 1987; Rose et al, 1988; Goddard et al, 1991).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 32-year-old woman on chronic lithium therapy presented 2 days after an acute lithium overdose with vomiting and lethargy, renal failure (BUN 79 mg/dL, creatinine 8.1 mg/dL) and blood lithium 2.06 mEq/L. She was treated with hemodialysis with gradual improvement in her mental status and partial recovery of renal function. Renal biopsy revealed acute interstitial nephritis and chronic interstitial nephropathy; pyuria and hematuria worsened after renal function improved and she had persistent renal insufficiency on follow up (Hung et al, 2001).
b) De Haro et al (2002) observed 306 cases of lithium intoxication between January 1991 and December 2000, of which 15 treated patients developed renal failure. The average lithium blood level was 2.1 mmol/L; 6 patients were admitted to intensive care and one death occurred (De Haro et al, 2002).

E) CREATININE CLEARANCE-GLOMERULAR FILTRATION ABNORMAL

1) WITH THERAPEUTIC USE

a) A prospective study of 51 manic-depressive patients (during a 3 year period) receiving lithium therapy were found to have a statistically significant decrease in creatinine clearance in males but not in females (Jorkasky et al, 1988).
b) In a group of 142 patients receiving lithium carbonate therapy for at least 15 years, 21% had a reduced glomerular filtration rate and 44% had reduced maximum urinary concentrating capacity (Bendz et al, 1994).
c) In a study of 24 patients on chronic lithium therapy with renal insufficiency, 42 percent had proteinuria, 25 percent had nephrotic range proteinuria, 87% had nephrogenic diabetes insipidus, and 33 percent had hypertension. Biopsy revealed chronic tubulointerstitial nephropathy in all patients with associated cortical and medullary tubular cysts in 62% and dilatation in 33% (Markowitz et al, 2000).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: After ingesting approximately 210 lithium carbonate (400 mg) tablets, a 39-year-old male developed renal insufficiency (creatinine clearance 12.5 mL/hour). Following treatment with hemodialysis and 6 days after admission, he was discharged without symptoms or residual side-effects (Kerbusch et al, 2002).

F) POLYURIA

1) WITH THERAPEUTIC USE

a) Polyuria is often reported as a side effect in therapy (Shen et al, 2007; George, 1989; HSDB , 2001).

G) NEPHROTIC SYNDROME

1) WITH THERAPEUTIC USE

a) Nephrotic syndrome associated with chronic lithium therapy and demonstrating glomerular lesions was reported in two patients (Alexander & Martin, 1981).
b) CASE REPORT: An 11-year-old boy with a mood disorder developed generalized edema, bilateral pulmonary effusions, proteinuria, and hypoalbuminemia after taking lithium carbonate (450 mg twice daily) for 4 months. He was also being treated with amphetamine, guanfacine, topiramate, olanzapine, and sertraline but multiple medication changes were made during the previous 6 months. Renal biopsy showed pathologic changes consistent with minimal-change nephropathy. Following the discontinuation of lithium therapy, his symptoms resolved (Petersen et al, 2008).

H) VAGINAL IRRITATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: VAGINAL INSERTION: A 48-year-old woman ingested ninety-seven 300 mg tablets of lithium carbonate. She developed repeated rebound in serum lithium levels despite gastric decontamination and hemodialysis. She then reported vaginal burning and admitted to having inserted eighty 300 milligram lithium tablets intravaginally. Speculum exam revealed extensive chemical burns of the vaginal mucosa. Serum lithium levels began to decline after removal of intravaginal pill fragments, suggesting that there may have been transvaginal absorption of lithium (Temte et al, 1994).

3.10.3)

A) ANIMAL STUDIES

1) TESTIS DISORDER

a) TESTICULAR FUNCTION/ANIMALS: When tested in rats, 0.2 mg of lithium for 21 days caused a significant reduction of plasma follicle stimulating hormones luteinizing hormone, prolactin, testosterone, and testicular activity (Ghosh et al, 1990).

Acid-Base

3.11.2)

A) ANION GAP

1) WITH POISONING/EXPOSURE

a) Lithium carbonate intoxication causes a low anion gap (Hoffman, 1994).
b) CASE REPORT: A patient with concomitant lithium carbonate and ethylene glycol intoxication did not develop an anion gap metabolic acidosis despite an ethylene glycol level of 500 mg/dL (Leon & Graeber, 1994). This was felt to be the result of the bicarbonate generated from lithium carbonate; however, the validity of this conclusion is questionable as the patient was treated within 4 hours of ingestion.

Hematologic

3.13.2)

A) LEUKOPENIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe leukopenia with a WBC of 0.2 x 10(9)/L was seen 3 days after a lithium, chlorpromazine, flurazepam, and temazepam overdose which resulted in a fatal cardiac arrest (Green & Dunn, 1985).

1) Chlorpromazine is a well-documented cause of dose-related leukopenia, and was probably responsible for the effects seen in this case.

B) LEUKOCYTOSIS

1) WITH THERAPEUTIC USE

a) Neutrophilia is a reported side effect of treatment with lithium, and significant leukocytosis may develop with lithium toxicity (Minden et al, 1993). Lithium has been used therapeutically to prevent chemotherapy-induced leukopenia in cancer patients.

2) WITH POISONING/EXPOSURE

a) Mild leukocytosis may occur (Shen et al, 2007).

C) THROMBOCYTOPENIC DISORDER

1) WITH POISONING/EXPOSURE

a) Thrombocytopenia may be a side effect of very severe lithium intoxication (Perrier et al, 1991).

3.13.3)

A) ANIMAL STUDIES

1) LEUKOCYTOSIS

a) In mice treated with cyclophosphamide a statistically significant increase in total peripheral blood granulocytes, platelets, and bone marrow-derived stem cells occurred in the group pretreated with lithium compared with controls (Gallicchio, 1988).

Dermatologic

3.14.2)

A) NAIL FINDING

1) WITH THERAPEUTIC USE

a) Dark transverse bands developed across several fingernails of a 62-year-old man 3 weeks after initiation of treatment with lithium carbonate 900 mg/day, followed 2 weeks later by transverse ridges proximal to the pigmentation. Onychomadesis also was present proximal to the pigmentation. These changes resolved after lithium was discontinued (Don & Silverman, 1988).

B) LICHENOID DERMATITIS

1) WITH THERAPEUTIC USE

a) Lichenoid lesions have been reported following lithium therapy. On drug discontinuation the lesions improved, and on drug rechallenge the lesions reappeared (Thompson & Skaehill, 1994).

C) FIXED DRUG ERUPTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 17-year-old boy experienced a lithium-induced Darier's disease, with papules, which on histologic examination revealed hyperkeratosis and focal areas of acantholysis. Tretinoin cream was used successfully to clear the skin eruptions (Rubin, 1995).

D) SKIN FINDING

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 68-year-old man developed severe follicular hyperkeratosis on extensor surfaces 6 months after beginning lithium therapy. The patient improved following drug withdrawal (Wakelin et al, 1996).

E) DERMATITIS

1) WITH THERAPEUTIC USE

a) Only 1% of lithium therapy patients experience dermatologic effects. Acne, folliculitis, psoriasis, alopecia, cutaneous ulcers, xerosis cutis, anesthesia of the skin, and exfoliate dermatitis usually resolved when therapy was temporarily discontinued (HSDB , 2001).

2) Two cases of halogenoderma (vegetating plaques with peripheral pustules usually associated with halogen exposure) have been reported associated with lithium use (Alagheband & Engineer, 2000).

Musculoskeletal

3.15.2)

A) DRUG-INDUCED MYOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Reversible myopathy was reported in a 62-year-old who had a potentially toxic level (Julien et al, 1979).

B) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Rhabdomyolysis was reported in a patient with increased muscle tone, myoclonus, and opisthotonus secondary to lithium toxicity (Unger et al, 1982).
b) CASE REPORT: Rhabdomyolysis, secondary to lithium intoxication (serum lithium level 3.12 mg/dL), was reported in a 61-year-old female taking lithium 900 mg/day for 11 years. Measured CPK and CK-MB levels were 60,000 Units/L and 934 Units/L, respectively, 3 days after admission. Seven days before admission the patient had taken an unknown pain medication (Su et al, 1999).

Endocrine

3.16.2)

A) HYPERTHYROIDISM

1) WITH THERAPEUTIC USE

a) The symptoms of Graves' disease may be masked by lithium therapy (Thompson & Bayliss, 1986; Santiago & Rushkin, 1990).

2) WITH POISONING/EXPOSURE

a) Oakley et al (2000) describe two patients with chronic lithium intoxication and undiagnosed hyperthyroidism in whom lithium intoxication suppressed the clinical manifestations of hyperthyroidism. One of these patients developed thyroid storm after hemodialysis was initiated for her lithium intoxication (Oakley et al, 2000).

B) HYPOTHYROIDISM

1) WITH THERAPEUTIC USE

a) CASE REPORT: Hypothyroidism and hyperparathyroidism were associated with lithium toxicity in a 50-year-old woman (Clur, 1989). These effects resolved after lithium was withdrawn.
b) Hypothyroidism has been associated with chronic lithium intoxication. In systematic studies, the incidence has been consistently elevated (10.4% of cases), especially in females (14%) and in older individuals (Johnston & Eagles, 1999; Ramchandani & Schindler, 1993). Kusalic & Englesman (1999) had similar findings, including a very high risk of hypothyroidism in female patients age greater than 60 (34.6%) and in patients with a family history of thyroid disease(Kusalic & Engelsmann, 1999).
c) CASE REPORT: A 74-year-old woman who had been taking lithium carbonate (300 mg twice daily), clomipramine, and valsartan plus hydrochlorothiazide, presented with a 1-week history of progressively worsening and disabling parkinsonism. Laboratory results revealed increased lithium and TSH serum concentrations and decreased serum concentration of circulating thyroid hormone. Her clinical condition improved rapidly after the discontinuation of lithium, replacement of valsartan/hydrochlorothiazide with amlodipine, and levothyroxine and IV saline therapy. However, her neurological symptoms resolved about 5 months after presentation (Basile et al, 2014).
d) CASE REPORT: A 74-year-old woman who had been taking lithium carbonate (300 mg twice daily), clomipramine, and valsartan plus hydrochlorothiazide, presented with a 1-week history of progressively worsening and disabling parkinsonism, characterized by tremor, bradykinesia, rigidity, postural instability/ataxia, associated with lethargy and bradycardia. Laboratory results revealed increased lithium and TSH serum concentrations and decreased serum concentration of circulating thyroid hormone. Her clinical condition improved rapidly after the discontinuation of lithium, replacement of valsartan/hydrochlorothiazide with amlodipine, and levothyroxine and IV saline therapy. However, her neurological symptoms resolved about 5 months after presentation (Basile et al, 2014).

C) HYPERPARATHYROIDISM

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 67-year-old woman who had been taking lithium (400 mg/day) for bipolar affective disorder for 10 years developed acute Parkinsonism complicated with hyperparathyroidism (a high intact parathyroid hormone, 135 pg/mL; ref: 15 to 76 pg/mL) and nephrogenic diabetes insipidus. An enlarged superior parathyroid was found during sonography suggesting an enlarged parathyroid adenoma. Lithium was discontinued after a high serum lithium level (3.6 mEq/L) was noted. Following supportive therapy, her condition improved gradually; only the residual extrapyramidal symptoms and mania were noted one month later (Shen et al, 2007).
b) CASE REPORT: Hypothyroidism and hyperparathyroidism were associated with lithium toxicity in a 50-year-old woman. These effects resolved after lithium was withdrawn (Clur, 1989).

D) GOITER

1) WITH THERAPEUTIC USE

a) In a study of 100 bipolar patients, goiter frequency was higher in those patients treated with lithium, and the incidence of goiter was related to the duration of lithium therapy (Perrild et al, 1990).
b) Lithium carbonate and potassium iodide or other compounds containing iodine used concurrently, can enhance the probabilities of hypothyroid or goitrogenic effects of the drug (HSDB , 2001).

E) THYROIDITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 42-year-old woman developed thyrotoxicosis and granulomatous thyroiditis (de Quervain's) two years after beginning lithium therapy (Sinnott et al, 1992).

F) KETOSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Diabetic ketoacidosis developed in a 41-year-old obese man with no prior history of diabetes 4 months after he was begun on lithium carbonate therapy for mania (Kondziela et al, 1985).

Reproductive

3.20.1)

3.20.2)

A) PLACENTAL BARRIER

1) Lithium and lithium carbonate readily pass the placental barrier and are present in the mother and fetus in the same concentrations (HSDB , 2001; Schardein, 1993; Stevens et al, 1974).

B) CONGENITAL ANOMALY

1) Congenital malformations, including cardiac defects have been reported in infants of mothers receiving lithium therapy in the first trimester (HSDB , 2001; Iqbal et al, 2001; Schardein, 1993; Schou & Amdisen, 1973; Warkany, 1988). In one study, the incidence was about 10 percent (Briggs et al, 1986).
2) In a prospective, observational study, significantly more fetal cardiovascular anomalies occurred with lithium exposure during pregnancy (n=183) compared with a group of women who not exposed to any teratogen during pregnancy (n=748). After excluding genetic or cytogenetic anomalies, the overall rate of major congenital anomalies was not significantly different between the following 3 groups: lithium exposed in the first trimester (8 of 123; 6.5%), bipolar group with no exposure to lithium (2 of 61; 3.3%), and nonteratogenic exposure group (19 of 711; 2.7%). However, cardiovascular anomalies were significantly more frequent in the group with lithium exposure in the first trimester compared with the nonteratogenic exposure group (4.1% vs 0.6%), but after excluding anomalies that spontaneously resolved, there was no significant difference (2.4% vs 0.3%; relative risk, 5.78; 95% CI, 0.82 to 40.65). The rate of noncardiovascular anomalies was not significantly different between the 3 groups (lithium exposed in the first trimester, 4.1%; bipolar group with no exposure to lithium, 1.6%, and nonteratogenic exposure group, 2.1%) (Diav-Citrin et al, 2014).
3) Tricuspid valve involvement has been especially prevalent (63%) (Arnon et al, 1981). The frequency of Ebstein's anomaly is approximately 1:20,000 live births (Schardein, 1993).
4) A prospective study of 138 women using lithium during the first trimester of pregnancy found no increase in major congenital malformations (2.8%) compared with a control group (2.4%). Ebstein's anomaly was detected by prenatal echocardiogram in one lithium-exposed fetus and the pregnancy was terminated (HSDB , 2001; Jacobson et al, 1992).
5) OTHER CONGENITAL ANOMALIES: Other adverse effects of lithium during pregnancy are perinatal mortality; prematurity; macrosomia; hydrocephalus plus spina bifida with meningomyelocele and talipes; goiter and hypothyroidism; microtia; and heart and large vessel abnormalities (Schardein, 1993).
6) CASE REPORT: An infant was born with oromandibular-limb hypogenesis spectrum deformities following intrauterine lithium exposure (Tekin & Ellison, 2000).

3.20.3)

A) PREGNANCY CATEGORY

1) The manufacturer has classified lithium as FDA pregnancy category D (Prod Info LITHOBID(R) extended-release oral tablets, 2009; Prod Info lithium carbonate oral tablets, capsules, 2009).
2) Cardiovascular and other teratogenic or toxic effects have been reported in infants born to lithium-treated mothers (Linden & Rich, 1983; Tunnessen & Hertz, 1972). However, more recent epidemiological data have revealed that outcomes of most pregnancies with in utero exposure to lithium have resulted in normal infants, and that use of lithium during pregnancy may possess a lower fetal risk than previously believed (Cohen et al, 1994; Jacobson et al, 1992a). Lithium has been suggested as the mood stabilizer of choice, given the greater teratogenic risks associated with antiepileptic drugs (Marcus et al, 2001).

B) MISCARRIAGE AND PREMATURE BIRTH

1) In a prospective, observational study, significantly more miscarriages and preterm deliveries occurred with lithium exposure during pregnancy (n=183) compared with a group of women who were not exposed to any teratogen during pregnancy (n=748). After adjusting for potential confounders, there was a significantly increased risk of miscarriage with the lithium-exposed group compared with the nonteratogenic exposure group (adjusted odds ratio, 1.94; 95% CI, 1.08 to 3.48). The rate of preterm deliveries was more than 2-fold higher in the lithium group (18 of 131; 13.7%) compared with the nonteratogenic exposure group (41 of 683; 6%) (Diav-Citrin et al, 2014).

C) PERINATAL DISORDER

1) Administration of lithium throughout pregnancy has resulted in hypotonia, hypothyroidism (HSDB , 2001; Nars & Girard, 1977), cyanosis and neurologic depression (Arnon et al, 1981; HSDB , 2001), and cardiac abnormalities with concomitant therapeutic to toxic serum concentrations in neonates (Pinelli et al, 2002; HSDB , 2001; Tunnessen & Hertz, 1972a).
2) The use of lithium should be avoided during pregnancy, especially in the first trimester and one week prior to delivery (Pinelli et al, 2002; Amdisen & Carson, 1986; HSDB , 2001).
3) CASE REPORT - An infant born to a mother with a toxic serum lithium concentration (2.6 mEq/L) developed lethargy and poor suck/swallow coordination which resolved by the seventh day of life. The infant's lithium level at birth was 2.1 mEq/L and the half-life was greater than 24 hours (Flaherty et al, 1995; Flaherty & Krenzelok, 1997).
4) CASE REPORT: An infant who was born to a mother on high dose lithium (1650 mg/day) developed nephrogenic diabetes insipidus, hypoglycemia, cardiomegaly, and hyperbilirubinemia. The infant's lithium level was 1.73 mEq/L, however this decreased to 0.73 mEq/L on day 4 of life. One month follow-up with endocrinologic and cardiologic examinations revealed a normal, thriving infant (Pinelli et al, 2002).
5) CASE REPORT: An infant born to a mother on chronic lithium therapy had initial temperature instability, bradycardia, tachypnea, feeding difficulties, and hypotonia. Hypotonia, depressed reflexes, and diminished social responses were noted on follow-up, gradually improving to near normal by 13 months of age (Kozma, 2005).

D) NEONATAL JAUNDICE

1) Neonatal jaundice was associated with, but not proven to be caused by, long-term maternal lithium ingestion (Connoley & Menahem, 1990).

E) MATERNAL COMPLICATIONS

1) Limited data suggest that women with bipolar disorder may be at risk for development of postpartum depression or mania. In some patients, prophylactic reinstitution of lithium therapy during the third trimester may be beneficial. Lithium should be decreased or discontinued during the peripartum period to avoid fetotoxicity (Yonkers et al, 1998).

F) LACK OF EFFECT

1) In a retrospective observational cohort study, 15 children aged 3 to 15 years who experienced prenatal exposure to lithium exhibited normal physical, neurological, cognitive, and behavioral development. Their mothers had been treated during pregnancy with lithium therapy for bipolar disorder. Assessments were based on neonatal data collected in the 24 hours after birth; maternal questionnaires eliciting information on child development, growth, and behavior; neurological testing using the Hempel examination (for children aged 2 to 5 years) and Touwen protocol (for older children); and psychologist-led cognitive testing with the Bayley Scale of Infant Development (for children aged 16 to 30 months), the Wechsler Preschool and Primary Scale of Intelligence, and the Wechsler Intelligence Scale for Children. Mild neurological dysfunction was found in one child that had no further clinical implications. Four of the children were also exposed to fluoxetine, haloperidol, nortriptyline, or lorazepam prenatally. None of the children had been breastfed (van der Lugt et al, 2012).

3.20.4)

A) BREAST MILK

1) Lithium is present in breast milk at 33% to 50% of the plasma lithium concentration (HSDB , 2001; Schou & Amdisen, 1973). Reports of lithium toxicity in nursing infants and neonates have included hypertonia, hypothermia, cyanosis, and ECG changes (Prod Info LITHOBID(R) extended-release oral tablets, 2009).
2) CASE REPORT: Cyanosis and T-wave inversions on ECG occurred in the breast-fed infant of a woman receiving lithium carbonate therapy (Tunnessen & Hertz, 1972a).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS554-13-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) At the time of this review, the manufacturer does not report any carcinogenic potential for lithium in humans.

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs, mental status, and urine output.
B) Serial lithium levels should be followed until concentration has clearly peaked and declined. The correlation between clinical toxicity and serum concentration is poor; an acute overdose is often asymptomatic despite high serum concentration; chronic exposure may have neurologic manifestations at therapeutic concentrations.
C) Monitor electrolytes (particularly sodium), urinalysis, and serum creatinine.
D) Obtain thyroid function tests and arterial blood gases; lithium intoxication may cause a low anion gap.
E) CT scan of brain may be indicated if etiology of altered mentation is in question. Monitor EEG if there is a concern for subclinical seizures. Chest x-ray may be indicated to monitor pulmonary edema. In those with worsening symptoms or known large ingestions, closely monitor airway, breathing, circulation, cardiac ectopy via continuous cardiac monitoring (including pulse oximetry, capnography), and ECGs.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Determine SERUM ELECTROLYTES (especially sodium) and lithium concentration. Correct any sodium deficiency.
2) MONITORING - Serum levels should be monitored regularly during treatment of intoxication. After termination of drug the plasma level drops by 1/2 every 2 to 3 days.
3) ANION GAP - Because lithium may be an unmeasured cation, an elevated level may result in a decreased or absent anion gap (Kelleher et al, 1986).
4) LITHIUM INDUCED RENAL DISEASE - Serum B2 microglobulin has been found to be a more sensitive indicator than serum creatinine for monitoring glomerular filtration rates in patients on chronic lithium therapy (Samiy & Rosnick, 1987). This is not routinely used in clinical practice.

B) TOXICITY

1) THERAPEUTIC LEVELS - 0.6 to 1.2 mEq/L (Friedberg et al, 1991)
2) MILD-MODERATE SYMPTOMS - 1.5 to 2.5 mEq/L
3) POTENTIALLY LETHAL - 3 to 4 mEq/L
4) SIGNIFICANCE OF LEVELS - In all cases the level of lithium in the serum is of less clinical importance than the symptoms and signs of lithium toxicity seen.
5) Chronic toxicity generally causes more severe symptoms than acute toxicity at comparable serum levels (Gadallah et al, 1988).
6) RBC LITHIUM - Several authors have found that RBC lithium levels correlate better with neurotoxicity than do serum lithium levels (Martin et al, 1991; Gangadhar et al, 1993); however RBC lithium concentrations are not determined in most clinical labs.

a) Lithium clearance from plasma during hemodialysis was greater than from RBC's. The slower decline in RBC lithium levels more closely correlated with the patient's clinical status.
b) Neurotoxic concentrations in red cells begin at about 0.6 mmol/L (Elizur et al, 1982).

C) ENDOCRINE

1) THYROID - Periodic monitoring of thyroid function may help detect preexisting hypothyroidism or lithium-induced hypothyroidism (Santiago & Rushkin, 1990).

4.1.3)

A) URINALYSIS

1) Perform urinalysis and determine serum creatinine to rule out impaired renal function. Non-lithium induced renal failure, due to prostatic hypertrophy and outlet obstruction for example, may result in lithium toxicity (Stern & Brotman, 1985).
2) Monitor urine output.

4.1.4)

A) OTHER

1) ECG

a) The predominant change during intoxication is slowing of the dominant rhythm. These changes may persist for up to 11 days (Barrat et al, 1968; Fetzer et al, 1981).

2) MAGNETIC RESONANCE IMAGING

a) Brain and tissue lithium levels can be quantified using Li-7 magnetic resonance imaging (Kato et al, 1996). This is not done in routine clinical practice.

3) EEG

a) Some authors recommend preforming an EEG on all patients who present with altered sensorium, to assist in diagnosis of seizure activity(Kuruvilla & Alexander, 2001).

Methods

1) Lithium is easily measured atomic spectrophotometry, ion selective electrode, or by emission photometry (Baselt, 1997).

1) The InstaRead Lithium System (ReliaLAB) requires one or two drops of blood, which is then separated, and the plasma is added to a microcuvette with a colorimetric reagent; absorbance determined by a photometer. It appears to be accurate for concentrations in the range of 0 to 2.5 mEq/L and requires 2 to 5 minutes to complete (Anon, 2005).

1) Lithium concentrations may be falsely elevated when using green-top lithium heparin-containing tubes (LHT). In one study, blood samples of 5 healthy volunteers who have never ingested lithium were added into a control serum separator tube (SST, volume, full-draw), a light green heparin-containing tube, and a dark green heparin tube (volumes, full-draw, 2 cc, and 1 cc). Mean serum lithium concentration for the control SST was 0.16 (range, 0.1 to 0.2). Lithium concentrations for light-green and dark-green tubes were as high as 4 mmol/L (range, 1 to 4.4) (Wills et al, 2006).

a) CASE REPORT - A 12-year-old patient with no signs or symptoms of lithium toxicity, was diagnosed with lithium intoxication after serum analysis revealed a toxic lithium concentration (9.2 mmol/L; normal 0.5 to 1). It was found later that the lithium concentrations were falsely elevated due to LHT blood tubes (Wills et al, 2006).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with persistent or worsening gastrointestinal irritation, renal impairment, altered mentation, respiratory depression, dysrhythmias, unstable vital signs, or persistently rising serum lithium concentrations should be admitted. Intensive care admission is indicated for aggressive airway, cardiac monitoring, and emergent hemodialysis.

6.3.1.2) HOME CRITERIA/ORAL

A) Accidental ingestions in asymptomatic lithium naive patients who ingest less than the maximum daily dose (Children less than 6 years old: 900 mg/square meter/day; Children 6 to 12 years old: 30 mg/kg/day; Adults: less than 2400 mg) who have no synergistic coingestants may be monitored at home. Those chronically taking lithium that are accidentally exposed to additional doses needed to be evaluated on a case by case basis, but typically tolerate a double dose without significant effects.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (agitation, hyperthermia, need for hemodialysis, respiratory depression, coma), concerns about decontamination, or in whom the diagnosis is not clear. Consult a nephrologist for emergent hemodialysis in patients with severe poisoning.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions, symptomatic patients, children and adults with ingestions of greater than the maximum daily dose, acute-on-chronic ingestions, unknown dosing errors in chronic patients, synergistic coingestants, or those with unclear history should be sent to a health care facility for evaluation and observation. Patients should be monitored until serum lithium concentration has peaked and is consistently declining and the clinical condition is improved.

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) Activated charcoal does not adsorb lithium well; it is not recommended.

6.5.2)

A) SUMMARY

1) Consider gastric lavage in a patient with recent life-threatening ingestion, if airway is protected or patient is alert. Whole bowel irrigation with polyethylene glycol should be considered with a large ingestion or ingestion of a sustained-release product.

B) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

C) ACTIVATED CHARCOAL

1) In vitro studies using simulated gastric fluid (Favin et al, 1988) and in vivo studies in mice (Linakis et al, 1989) have not shown adsorption of lithium to charcoal or any effect on serum lithium levels.

D) WHOLE BOWEL IRRIGATION

1) Whole bowel irrigation with polyethylene glycol electrolyte lavage solution may be a relatively safe and effective means of rapid gastrointestinal decontamination, as lithium is not well adsorbed by activated charcoal and is often ingested as a sustained release formulation (Smith et al, 1991).

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

3) STUDIES

a) Smith et al (1991) reported a 67 percent reduction in lithium absorption if whole bowel irrigation is started within 1 hour of an acute ingestion of a sustained-release preparation.
b) In a two-phase, cross-over protocol, 10 normal volunteers ingested 0.8 mEq/kg sustained-release lithium carbonate. Whole bowel irrigation was begun 1 hour after ingestion, and 10 liters of polyethylene glycol solution were administered over 5 hours.

1) The author recommended whole bowel irrigation as the decontamination method of choice after acute ingestion of sustained-release lithium.

c) In a crossover human study of lithium ingestion, whole bowel irrigation was as effective as sodium polystyrene sulfonate in reducing area under the lithium concentration-time curve (Tillman et al, 1994).

E) SODIUM POLYSTYRENE SULFONATE

1) SUMMARY: Sodium polystyrene sulfonate (SPS) (Kayexalate (R)) has been shown to reduce lithium absorption in animal studies and human volunteers. It has never been shown to remove a clinically significant amount after overdose in humans. More studies are needed before this compound can be recommended for routine use in treatment of lithium ingestions.
2) STUDIES

a) HUMAN: Concomitant administration of 30 grams of sodium polystyrene sulfonate and 600 milligrams of lithium carbonate reduced the area under the concentration time curve by 11%, reduced the peak lithium level by 0.07 millimole/liter, and delayed the time to peak lithium concentration by two hours in a crossover study using 12 volunteers (Belanger et al, 1992).
b) HUMAN: Administration of 857 milligrams/kilogram of sodium polystyrene sulfonate 1 hour after ingestion of 18.5 milligrams/kilogram of lithium carbonate reduced the area under the concentration vs time curve and the peak serum lithium level without effecting urinary lithium excretion, or serum sodium or potassium levels (Tomaszewski et al, 1992).
c) IN VITRO: Driscoll et al (1987) reported a lithium binding capacity in vitro at pH 7 and pH 1 of 0.7 milliequivalents of lithium/gram of SPS.
d) IN VITRO: Watling et al (1995) reported a lithium binding capacity in vitro at pH 10 of 83.9% with SPS as compared to 23.8% with charcoal when using 2 grams of lithium.
e) MICE: An in vivo study in mice showed a significant reduction in serum lithium levels after administration of SPS 10 grams/kilogram immediately following lithium dosing (Linakis et al, 1989). The dose of SPS used in this study is more than 10 times the usual dose given in humans.
f) MICE: Another study in mice showed that after single oral doses of lithium chloride 250 milligrams/kilogram, administration of multiple doses of SPS 2.5 grams/kilogram/dose and 5 grams/kilogram/dose at 30, 90, 180, and 360 minutes postingestion significantly lowered serum lithium concentrations compared to controls.

1) The effect of SPS on lithium levels was dose-related, and repetitive dosing of SPS appeared to enhance lithium elimination (Linakis et al, 1989a). It should be noted, that these doses of SPS are far higher than those recommended for human use in hyperkalemia.

g) MICE: Multiple dose SPS (5 grams/kilogram/dose at 20, 40, 60, 90, 150, and 210 minutes after lithium) enhanced the elimination of intravenously administered lithium (125 milligrams/kilogram) (Linakis et al, 1990; Linakis et al, 1997).
h) MICE: Linakis et al (1995) reported giving a single dose SPS (5 grams/kilogram) at 0, 15, 30, 45 or 90 minutes after lithium to one group of mice and another group receiving a single dose SPS (2.5 grams/kilogram) at the same times. The single SPS doses significantly lowered serum Li levels and the effect was dose-related. The delays in giving SPS did not significantly reduce its ability to lower serum Li levels.
i) MICE: In a mouse model, administration of intraperitoneal potassium did not interfere with the reduction in serum lithium concentrations induced by sodium polystyrene sulfonate (Linakis et al, 2001).
j) CASE REPORT: A 23-year-old woman with acute-on-chronic lithium overdose and a peak lithium level of 4.2 mEq/L ten hours after ingestion was treated with SPS 30 grams orally every 6 hours for 5 doses starting 13 hours after ingestion. Her calculated elimination half life was 12 hours compared with 20 to 32 hours reported in similar cases. She required 52 mEq of potassium during therapy and never developed clinical evidence of lithium toxicity (Roberge et al, 1993).

3) DOSE

a) ADULT

1) ORAL: Usual dose is 15 to 60 g, best provided by administering 15 g, 1 to 4 times daily (Prod Info KAYEXALATE(R) oral powder for suspension rectal powder for suspension, 2010).
2) ORAL SUSPENSION (powdered formula): Each dose should be given as a suspension in water, or for greater palatability, in syrup. The amount of fluid usually ranges from 20 to 100 mL, depending on the dose, or 3 to 4 mL/gram resin (Prod Info KAYEXALATE(R) oral powder for suspension rectal powder for suspension, 2010).
3) ENEMA: 30 to 50 g rectally every 6 hours as a warm emulsion in 100 mL aqueous vehicle (sorbitol or 20% Dextrose in Water); retain for as long as possible (Prod Info KAYEXALATE(R) oral powder for suspension rectal powder for suspension, 2010).

b) CHILD

1) The effectiveness of sodium polystyrene sulfonate has not been established in pediatric patients. However, in infants and smaller children, lower doses than those used for adults should be employed by utilizing the exchange rate of 1 milliequivalent of potassium per gram of resin as the basis for calculation. In both children and neonates, rectal administration should be performed with caution, as excessive dosage or inadequate dilution could result in impaction of the resin (Prod Info KAYEXALATE(R) oral suspension, rectal suspension, 2003).

4) ADVERSE EFFECTS

a) SODIUM OVERLOAD: It has been reported secondary to sodium polystyrene sulfonate therapy in 2 patients with renal failure (Berlyne, 1966).
b) HYPERTENSIVE ENCEPHALOPATHY: Severe headaches and hypertensive encephalopathy occurred during resin therapy (Berlyne, 1966).
c) ELECTROLYTE ABNORMALITIES: Electrolyte imbalances including hypocalcemia, hypokalemia, and significant sodium retention may occur (Prod Info, 1989).
d) GI EFFECTS: Nausea, vomiting, constipation, fecal impaction, colonic necrosis, and gastrointestinal obstruction have been reported (Steinmetz & Kiley, 1961; Scherr, 1961; Lillemoe et al, 1987; Townsend, 1973).

5) PRECAUTIONS

a) Commercially prepared SPS suspensions contain 20 grams of sorbitol per 15 grams of resin. Some of the adverse effects have been attributed to the sorbitol.
b) If you are using activated charcoal/sorbitol therapy for a multiple-drug ingestion, adjust the sorbitol dose or give aqueous activated charcoal.
c) Do not use SPS therapy in hypokalemic patients.

F) OTHER

1) SUMMARY - Bentonite has been shown to reduce lithium absorption in vitro.
2) IN VITRO - Bentonite reduced the lithium concentration by 20.5% in deionized water (pH 7) and by 48.1% in simulated gastric fluid (pH 1.2) at a bentonite lithium ratio of 30.1 (p value 0.0001) (Ponampalam et al, 1999).

G) BEZOARS

1) Lithium carbonate, the least soluble of the lithium salts, can form bezoars within the gastrointestinal tract after large overdoses.

a) A 47-year-old woman developed lithium toxicity with persistent rebound in blood levels despite repeated runs of hemodialysis. A bezoar of hair and lithium tablets was discovered and removed via endoscopy (Thornley-Brown et al, 1992).
b) Friedberg et al (1991) report the initiation of enteral feedings may stimulate the dissolution of drug mass and result in an increase in serum lithium concentration. The author recommends oral fluid restriction until serum lithium levels are in the non-toxic range.

6.5.3)

A) SUPPORT

1) Determine whether the patient has mild, moderate or severe intoxication by history, physical findings and serum lithium concentrations. Determine whether or not the patient has normal or impaired renal function and is sodium depleted.
2) Severity of intoxication is related both to serum concentration and duration of exposure (see section on Range of Toxicity).

B) MONITORING OF PATIENT

1) Monitor vital signs, mental status, and urine output.
2) Serial lithium levels should be followed until concentration has clearly peaked and declined. The correlation between clinical toxicity and serum concentration is poor; an acute overdose is often asymptomatic despite high serum concentration; chronic exposure may have neurologic manifestations at therapeutic concentrations.
3) Monitor electrolytes (particularly sodium), urinalysis, and serum creatinine.
4) Obtain thyroid function tests and arterial blood gases; lithium intoxication may cause a low anion gap.
5) CT scan of brain may be indicated if etiology of altered mentation is in question. Monitor EEG if there is a concern for subclinical seizures. Chest x-ray may be indicated to monitor pulmonary edema. In those with worsening symptoms or known large ingestions, closely monitor airway, breathing, circulation, cardiac ectopy via continuous cardiac monitoring (including pulse oximetry, capnography), and ECGs.

C) FLUID/ELECTROLYTE BALANCE REGULATION

1) If the patient has good renal function, maintain at least a normal urine flow and sodium excretion by administering sodium chloride (0.45% or 0.9%) intravenously.
2) AVOID SODIUM RESTRICTION and replace sodium if depleted by dehydration, diuretics, or disease states.
3) SALINE DIURESIS may not be of added benefit once the patient is well hydrated and normonatremic. In one overdose patient, renal clearance after dialysis while the patient was receiving alkaline diuresis was no different than during dialysis (Jacobsen et al, 1987).

D) VENTRICULAR ARRHYTHMIA

1) Treatment of the specific arrhythmias observed in a lithium intoxicated patient should follow the standard lines of management for that arrhythmia.
2) Successful use of intravenous magnesium sulfate in one patient with lithium induced ventricular tachycardia that was resistant to other pharmacologic measures was reported (Worthley, 1974).

E) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

F) HYPERTENSIVE EPISODE

1) Monitor vital signs regularly.
2) For mild/moderate asymptomatic hypertension, pharmacologic intervention is seldom necessary and 4 to 6 hours of observation is usually adequate.
3) For SEVERE hypertension:

a) NITROPRUSSIDE: 0.5 to 10 micrograms/kilogram/minute (Average dose is 3 micrograms/kilogram/minute) as an intravenous infusion to control blood pressure.
b) ESMOLOL: May be used as an alternative to nitroprusside.

G) CONTRAINDICATED TREATMENT

1) FORSKOLIN: This direct adenylate cyclase stimulator was tested in the mouse model and found to be NOT effective (Kaplan et al, 1988).
2) INOSITOL: This sugar was tested in the mouse model and found to be INEFFECTIVE (Kaplan et al, 1988).

H) SEROTONIN SYNDROME

1) SUMMARY

a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).

2) HYPERTHERMIA

a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c) Non-depolarizing paralytics may be used in severe cases.

3) CYPROHEPTADINE

a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

4) HYPERTENSION

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

5) HYPOTENSION

a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
c) NOREPINEPHRINE

1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
2) INITIAL DOSE

a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.

3) MAINTENANCE DOSE

a) 0.5 to 1 mL (2 to 4 mcg)/minute.

6) SEIZURES

a) DIAZEPAM

1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

b) LORAZEPAM

1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

c) RECURRING SEIZURES

1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.

d) PHENOBARBITAL

1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

7) CHLORPROMAZINE

a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

8) NOT RECOMMENDED

a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

I) ACUTE LUNG INJURY

1) Prolonged requirement (2 months) for ventilatory support has been reported in a woman with lithium carbonate overdose. A 42-year-old woman with a history of chronic lithium use presented with nausea and vomiting, aphasia, truncal and gait ataxia, cogwheel rigidity, hypertonicity, tremor, mutism, mild tachycardia, and stupor. Serum lithium level was 4.4 mmol/L. On 3rd hospital day, she developed acute respiratory distress syndrome (ARDS) and presented with severe hypoxia (pulse oximetry of 68%) and bilateral pulmonary infiltrates on chest x-ray. She recovered after 2 months of mechanical ventilation and supportive care (Toronjadze et al, 2005).

J) ELECTROCONVULSIVE THERAPY

1) CATATONIA

a) CASE REPORT: A 16-year-old girl with a 6-week history of severe depressive episode with psychotic symptoms, was started on olanzapine and escitalopram; however, escitalopram was changed to lithium (increased up to 1200 mg/day; serum lithium level of 0.91 mmol/L) after she developed manic symptoms. Her symptoms improved over the next 5 months, but she returned with symptoms of decreased talk and appetite, mutism, immobility, and refusing food and fluids. Physical examination revealed mild dehydration, brisk deep tendon reflexes with flexor plantar response, and mild postural tremor. Mutism, staring catalepsy, stupor, and passive negativism were observed using the Catatonia Rating Scale. Following 5 electroconvulsive therapy (ECT) alternative-day sessions, her catatonia resolved completely within 10 days of presentation. Laboratory results revealed serum lithium levels of 2.22 mM, 0.6 mM, and 0 mM on day 1, 4, and 7, respectively (Desarkar et al, 2007).

Enhanced Elimination

1) SUMMARY

a) Hemodialysis increases lithium clearance and decreases half-life. The decision to perform hemodialysis is largely clinical. The international expert Extracorporeal Treatments in Poisoning (EXTRIP) workgroup reviewed the available literature and despite a low quality of evidence recommended the following guidelines for extracorporeal treatment (ECTR) in patients with severe lithium toxicity with any the following clinical conditions:

1) In the presence of a reduced level of consciousness, seizures, or life-threatening dysrhythmias irrespective of lithium concentration.
2) If kidney function is impaired and lithium concentration is greater than 4 mEq/L.

b) ECTR was also suggested for patients with any of the following clinical conditions:

1) If lithium concentration is greater than 5 mEq/L, if confusion is present, or if the expected time to obtain a lithium concentration less than 1 mEq/L with optimal management is greater than 36 hours.

c) DISCONTINUATION of ECTR is recommended:

1) In patients with apparent clinical improvement or lithium concentration less than 1 mEq/L.
2) After a minimum of 6 hours of ECTR if the lithium concentration is not readily available.

d) Serum lithium levels typically rebound 6 to 12 hours after dialysis in chronically intoxicated patients due to equilibration with intracellular and CNS lithium stores. In order to determine the use of subsequent ECTR sessions, serial lithium concentrations should be determined over 12 hours after the cessation of ECTR. The preferred ECTR is intermittent hemodialysis, with an acceptable alternative being continuous renal replacement therapy (RRT), if intermittent hemodialysis is not available. Both continuous RRT and intermittent hemodialysis are equally acceptable after the first treatment.

2) INDICATIONS

a) Hemodialysis increases lithium clearance and reduces half-life (Jaeger et al, 1993). The indications for hemodialysis in lithium intoxication are inexact; some authors recommend hemodialysis for any patient with a level above 2.5 mEq/L (Bazilinski & Mathew, 1986) or above 3.5 mEq/L (Bosinski et al, 1998). Other authors recommended hemodialysis for all patients with more than prodromal symptoms and slightly increased 12-hour serum lithium concentration (Amdisen, 1988).
b) Patients with acute intoxication and serum levels of 3.5 mEq/L or higher with mild symptoms have done well without hemodialysis (Nagappan et al, 2002).
c) SYSTEMATIC REVIEW AND RECOMMENDATIONS: In a systematic review of literature that included 166 studies, including 156 case reports/case series (235 patients), 5 descriptive cohorts (101 patients), 3 observational studies (80 patients), and 2 pharmacokinetic studies (2 patients), the international expert Extracorporeal Treatments in Poisoning (EXTRIP) workgroup recommended the use of ECTR in patients with severe lithium toxicity. Despite a low quality of evidence for all recommendations, the following guideline was developed (Decker et al, 2015):

1) ECTR is recommended for patients with any of the following clinical conditions (Decker et al, 2015):

a) If kidney function is impaired and lithium concentration is greater than 4 mEq/L.
b) In the presence of a reduced level of consciousness, seizures, or life-threatening dysrhythmias irrespective of lithium concentration.

2) ECTR is suggested for patients with any of the following clinical conditions (Decker et al, 2015):

a) If lithium concentration is greater than 5 mEq/L.
b) If confusion is present.
c) If the expected time to obtain a lithium concentration less than 1 mEq/L with optimal management is greater than 36 hours.

3) Discontinuation of ECTR is recommended (Decker et al, 2015):

a) In patients with apparent clinical improvement or lithium concentration less than 1 mEq/L.
b) After a minimum of 6 hours of ECTR if the lithium concentration is not readily available.

4) In order to determine the use of subsequent ECTR sessions, serial lithium concentrations should be determined over 12 hours after the cessation of ECTR (Decker et al, 2015).
5) The preferred ECTR is intermittent hemodialysis, with an acceptable alternative being continuous renal replacement therapy (RRT), if intermittent hemodialysis is not available. Both continuous RRT and intermittent hemodialysis are equally acceptable after the first treatment (Decker et al, 2015).

d) Lithium clearance during hemodialysis is approximately 100 to 120 mL/min, thus 4 hours of hemodialysis is equivalent to 24-hour clearance of 16-20 mL/min. Renal lithium clearance is 20% to 30% of creatinine clearance, thus those with renal impairment (calculated creatinine clearance less than 60 mL/min) are generally candidates for hemodialysis (Dawson & Whyte, 1999).
e) In one case series lithium half life during dialysis ranged from 3.6 to 5.7 hours, compared with half lives of 15.9 to 36.8 hours in patients not receiving dialysis (Jaeger et al, 1993). In the same study lithium clearance by dialysis ranged between 63 and 114 milliliters/minute compared with a total body clearance of 13 to 56 milliliters/minute in patients not receiving dialysis (Jaeger et al, 1993).
f) In an observational, retrospective study of 14 patients with lithium poisoning (acute: 1 patient [7%]; acute-on-chronic: 9 patients [64%]; chronic: 4 patients [29%]), clinical and biochemical data of patients requiring one dialysis session with those requiring more than one dialysis session were compared. High lithium concentrations (p=0.006, r=0.69), low creatinine clearance (p=0.04, r=-0.55), and low blood sodium concentrations (p=0.024, r=-0.59) were associated with higher dialysis requirements in severe lithium intoxication. When adjustment for creatinine clearance and initial lithium concentrations was made, the correlation remained significant for blood sodium concentration (p=0.016, r=-0.67) (Lopez et al, 2012).
g) Patients with chronic intoxication are more likely to present with moderate or severe symptoms at lower serum levels, and should be considered for dialysis (Gadallah et al, 1988).
h) In a chronically poisoned patient 18 hours of hemodialysis was shown to remove 65.5 percent of the total lithium eliminated over 12 days (Jaeger et al, 1986).
i) Patients with severely compromised renal function and lithium toxicity require hemodialysis (Hauger et al, 1990).
j) Simard et al (1989) recommended hemodialysis if the serum lithium concentration is: Greater than 4 millimoles/liter, regardless of patient disposition. Greater than 2.5 millimoles/liter in symptomatic patients. Levels are not anticipated to be less than 0.6 millimole/liter within 36 hours (Simard et al, 1989).

3) ENDPOINT OF THERAPY

a) Hemodialysis should be carried out as long as necessary to reduce the serum lithium concentration to less than 1 milliequivalent/liter after redistribution (Baselt & Cravey, 1995; Hansen & Amdisen, 1978).

4) BICARBONATE DIALYSIS

a) A case report suggests that conventional hemodialysis using acetate dialysate (34 millimole/liter) removes lithium primarily from the extracellular fluid, thus causing a rebound in blood levels after dialysis is terminated. During dialysis using bicarbonate dialysate (35 millimole/liter) in the same patient, lithium clearance was similar to that achieved with acetate dialysate, but 61% of the lithium came from intracellular fluid (Szerlip et al, 1992). Dialysis using a bicarbonate bath may be more effective in treating lithium intoxication than is acetate dialysis.

5) OUTCOME

a) A retrospective study of all published cases of lithium intoxication with cognitive dysfunction revealed that patients treated with dialysis had a greater incidence of persistent neurologic sequelae (62% vs 22%) and deterioration during hospitalization (86% vs 46%) than those not receiving dialysis (Swartz & Jones, 1994). The authors suggested that rapid correction of lithium toxicity may increase neurologic damage. Multiple potential sources of bias in this study make interpretation of the results difficult. Prospective studies are needed to address this issue.
b) In a retrospective study of 103 patients (age 13 years or older) with lithium toxicity, neurologic outcomes of patients receiving dialysis for high lithium concentrations (n=8, including 2 with altered mental status and/or 3 with acute kidney injury) were compared with those who received just supportive care (n=95). All patients in both groups returned to their neurological baseline before hospital discharge and dialysis did not alter neurologic outcomes. Patients in the dialysis group had significantly longer hospital stay (13 days [3.91 to 22.1 days] vs 4.41 days [3.58 to 5.24 days]), which was likely due to confounding or increased morbidities (eg, older average age, higher baseline creatinine, and higher peak lithium concentration) (Iannone et al, 2015).
c) CASE REPORT: Full recovery was reported after a 39-year-old man ingested 210 lithium carbonate tablets (400 mg each) following a suicide attempt. At 40 hours post-ingestion, the lithium serum level was 5.89 mmol/L. Following treatment with hemodialysis and 6 days after admission, he was discharged with lithium level at 0.2 mmol/L (Kerbusch et al, 2002).
d) CHRONIC LITHIUM TOXICITY (CASE REPORT): A 74-year-old man who had been taking lithium carbonate 300 mg BID for bipolar disorder, presented with a 3-day history of progressive encephalopathy, tremor, and weakness, and a 1-day history of diarrhea. His medical history included bipolar disorder, hypertension. benign prostatic hypertrophy, recent prostate cancer, and undiagnosed chronic kidney disease. In addition to lithium carbonate, he was taking bupropion, lisinopril, finasteride, lovastatin, clonazepam, and tamsulosin. On presentation, his symptoms included lower extremity hyperreflexia and clonus, upper extremity hypertonia and tremor, tongue fasciculations, and difficulty speaking interspersed with muteness. An ECG showed a junctional rhythm with a heart rate of 51 beats/min, corrected prolonged QT interval of 476 ms, and multiple premature ventricular and supraventricular complexes. Laboratory results revealed an elevated lithium concentration of 2.2 mmol/L and a normal serum potassium. A month before presentation, his lithium concentration was 1.2 mmol/L and an ECG showed first-degree AV block, intraventricular conduction delay, T wave flattening, and QT interval prolongation. During transport to the ICU, another ECG showed nonsustained monomorphic ventricular tachycardia (120 to 130 beats/min) lasting up to 1 minute, alternating with sinus bradycardia and wandering atrial pacemaker (34 beats/min). Monomorphic ventricular tachycardia episodes were observed greater than 100 times. His symptoms gradually improved over the first 4 hours of hemodialysis. Following further supportive care, including a norepinephrine infusion for hypotension, his condition resolved and he was discharged on day 5 (Bosak et al, 2014).

6) HIGH-FLUX MEMBRANES

a) The use of high-flux dialysis membranes may increase the rate of lithium removal during hemodialysis. In one case report lithium half life was reduced to 1.36 to 1.91 hours during dialysis compared with 9.65 to 12.37 hours without dialysis (Peces & Pobes, 2001). The patient required repeated dialysis sessions despite this and neurologic recovery was slow (extubated 13 days after admission).

7) REBOUND

a) The peak level occurring after hemodialysis redistribution or rebound reflects the magnitude of persistent intracellular lithium and may indicate the need for additional hemodialysis (Baselt & Cravey, 1995; Jaeger et al, 1986).
b) This reduction in lithium levels may require greater than 12 hours of dialysis and several periods of dialysis depending on the initial lithium concentration and the patient's endogenous lithium clearance.
c) Despite a rapid decrease in serum concentrations of lithium during dialysis, serum concentrations will rebound afterwards peaking usually at 6 to 12 hours after dialysis has been stopped (Jacobsen et al, 1987).

1) CASE REPORT: A postdialysis rebound was responsible for an increase to 86% of predialysis levels, which began minutes after stopping dialysis, and peaked at 15 hours postdialysis in a 54-year-old man with chronic lithium toxicity. The authors speculate that chronic large lithium doses may result in a huge body pool of lithium, from which redistribution may occur after dialysis (Bosinski et al, 1998).

d) If serum lithium concentrations are greater than 1 milliequivalent/liter (1 millimole/liter) at 6 to 8 hours after dialysis, dialysis should be repeated (Amdisen & Carson, 1986).
e) After dialysis serum lithium concentrations must be determined every 2 to 4 hours to ensure that the concentration remains low.
f) Even though the lithium serum concentration may remain low, there may be a lag time before the patient recovers neurological function due to the lag time in equilibration between lithium concentrations in brain and serum (Amdisen & Skjoldborg, 1969; Newman & Saunders, 1979).

8) CONTINUOUS VENOVENOUS HEMODIALYSIS

a) CASE REPORT: Beckman et al (2001) described a case in which continuous venovenous hemodialysis was used to treat a woman with severe lithium intoxication complicated by acute renal failure. She was initially treated with 6 hours of traditional hemodialysis with decline in her serum lithium level from 5.4 to 2.4 mmol/L. Continuous venovenous hemodialysis was performed for 72 hours, with a calculated average lithium clearance of 23 milliliters/minute (Beckman et al, 2001).

1) Bellomo et al (1991) reported the successful treatment of a patient with acute lithium intoxication by increasing lithium clearance through continuous arteriovenous hemodiafiltration. Continuous arteriovenous hemodiafiltration was continued for 14 hours (equivalent to 5.75 hours of hemodialysis) achieving a lithium clearance of 20.5 milliliters/minute. Although arteriovenous hemodiafiltration may prove to be a significant contribution to the treatment of the lithium intoxicated patient, further investigation of its effectiveness is necessary (Bellomo et al, 1991).
2) Hazouard et al (1999) reported that continuous veno-venous hemodiafiltration was equally as effective as continuous veno-venous hemofiltration in an overdose case of 49-year-old woman. Serum lithium levels upon admission were 4.14 mEq/L, which decreased to 1.49 mEq/L 4 hours after initiation of hemodiafiltration (Hazouard et al, 1999). Successful use of veno-venous filtration has been reported in other isolated case reports (Menghini & Albright, 2000; Leblanc et al, 1996).
3) Menghini & Albright (2000) described a patient with severe lithium intoxication and mild hypotension (BP 90/62 with oliguria) who was treated with continuous venovenous hemodiafiltration for 12 hours with a lithium clearance of 31 to 35 mL/min (Menghini & Albright, 2000).

1) Meyer et al (2001) described two children with lithium intoxication treated by hemodialysis followed by continuous hemofiltration for 22 and 32 hours respectively. Serial lithium levels declined during hemofiltration without rebound and mental status returned to normal in both patients during hemofiltration. Lithium clearance rates were not calculated (Meyer et al, 2001).
2) Van Bommel et al (2000) reported a case in which 15.5 hours of high-volume continuous venovenous hemofiltration was used to treat severe lithium poisoning. Lithium clearance was 4.45 mmol/hr during the procedure. The patient's mental status improved during the procedure and there was no rebound in serum lithium levels after it was discontinued (Van Bommel et al, 2000).

1) Peritoneal dialysis (dialysis clearance 13 to 15 milliliters/minute) is less effective than hemodialysis (hemodialysis clearance 30 to 50 milliliters/minute).
2) Peritoneal dialysis should only be utilized when hemodialysis is not possible or when there will be a delay before hemodialysis can be begun.
3) CASE REPORT: Peritoneal dialysis was successfully used to treat a level of 9.6 mEq/liter in a 55-year-old (Marshall & Kesson, 1981).

1) Spontaneous renal elimination of lithium in a patient with moderate renal impairment was shown to be very similar to that which can be removed by hemodialysis. This was believed to be due to a decrease in renal clearance during the extracorporeal procedure (Bismuth et al, 1986). However, subsequent authors have stated that extracorporeal removal of lithium does not decrease renal clearance of lithium (Jaeger et al, 1993).
2) DIURETICS: Do not significantly enhance lithium excretion (Hansen & Amdisen, 1978). Increase in urinary sodium due to a diuretic was not associated with increased lithium excretion (Davis & Fann, 1971).
3) LOW DOSE DOPAMINE

a) SUMMARY: Additional studies are needed to assess the efficacy of this treatment.
b) McDonald et al (1964) proposed that dopamine would be expected to increase lithium excretion in the presence of optimal saline loading (McDonald et al, 1964).
c) The proposed mechanism was by increasing renal blood flow and increasing sodium excretion by a specific action on the proximal tubule (McDonald et al, 1964).
d) MacDonald et al (1988) reported a 2-fold increase in lithium clearance in a 72-year-old woman associated with an infusion of dopamine (2 micrograms/kilogram per minute) (MacDonald et al, 1988).

1) In a review of lithium toxicity and elimination, studies using theophylline to increase lithium elimination were described. The effect of theophylline on lithium elimination was highly variable among patients, and in evaluation of risk versus benefit, theophylline was NOT recommended as a therapeutic tool (Scharman, 1997).

Abstracts

Case Reports

1) A 52-year-old Asian man became tremulous 6 weeks prior to admission and was noted to have a lithium level of 1.2 mEq/L. His dose of lithium carbonate was decreased from 1200 mg/day to 900 mg/day. His wife then reported that the patient was displaying increased irritability and an expansive mood, and she was instructed to monitor his medication intake. One week prior to admission he had ataxia and lethargy, and he was admitted for lithium toxicity. Admission lithium level was 3.12 mEq/L, chlorpromazine level was 2.1 mEq/L (greater than 2 mEq/L is toxic), and creatinine was 1.3 mg/dL. After recovery the patient denied taking more than his prescribed medications. The patient's wife reported that for 1 to 2 weeks prior to admission, the patient had been drinking his own urine believing that it was "holy water." The authors attributed the patient's lithium toxicity to this unusual source of poisoning (Pristach, 1987).
2) A 63-year-old man had been taking lithium carbonate for 16 years. The patient was taking 900 mg every AM and 600 mg every PM, and his lithium level was 1 mmol/L 9 days prior to admission. He had a history of polydipsia and polyuria for several months prior to admission. He was admitted for nausea, vomiting, and change in mental status. On physical examination, the patient was oriented x 2, responded to verbal stimuli, had upper extremity tremors, ankle clonus, and an unsteady gait. Lithium level on admission was 4.3 mmol/L. Treatment with IV hydration produced a reduction of the lithium level to 0.9 mmol/L over 3 days. However, on the third day of admission the patient was comatose and required mechanical ventilation. Neurological status remained unchanged for 9 days. CT of the head and LP were normal. The patient's course was complicated by nephrogenic diabetes insipidus with a maximal urine output of 15 L on hospital day 5, nonketotic hyperglycemia, hypophosphatemia, and hypomagnesemia. On hospital day 13, the patient's mental status improved, and he was able to follow commands. Sequelae included tremor, dysarthria, ataxia, and polyuria which resolved over 3 months (Simard et al, 1989).
3) A 65-year-old woman taking lithium carbonate 600 mg/day for one year was admitted following an ingestion of a "handful" of lithium tablets 8 to 10 hours prior to arrival. At 14 hours postingestion she was alert and oriented but slightly lethargic. She was mildly dehydrated with a supine blood pressure of 130/88 mmHg, pulse 91 beats/minute, respiratory rate 18/minute, and oral temperature 37 degrees C. Physical examination revealed decreased bowel sounds and hyporeflexia. ECG showed sinus rhythm of 94 beats/minute with inverted T waves in leads V1-V3 and ST depression in leads V3-V5. On admission BUN was 22 mg/dL, and serum creatinine was 2.1 mg/dL. Serum lithium concentration was reported as 8.3 mEq/L. She was given intravenous fluids for dehydration. At 48 hours postingestion she was noted to be disoriented and her urine output decreased to 20 mL/hour despite adequate hydration. Hemodialysis was instituted. The patient succumbed to intractable hypotension and ventricular fibrillation with electromechanical dissociation 4.5 days postingestion (Rose et al, 1988).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) LITHIUM CARBONATE

1) BIPOLAR DISORDER

a) The recommended dose is 900 to 1800 mg/day orally in 2 to 4 divided doses (Prod Info lithium carbonate oral tablets, capsules, 2009; Prod Info LITHOBID(R) extended-release oral tablets, 2009; Prod Info Lithium Carbonate extended-release oral tablets, 2005).

B) LITHIUM CITRATE

1) BIPOLAR DISORDER

a) SOLUTION: The recommended dose is 5 mL (8 mEq of lithium) orally 3 to 4 times daily or 10 mL (16 mEq of lithium) orally 3 times daily (Prod Info lithium citrate oral solution, 2009).

7.2.2)

A) LITHIUM CARBONATE

1) BIPOLAR DISORDER

a) EXTENDED-RELEASE TABLETS: 12 YEARS OF AGE AND OLDER: The recommended dose is 900 to 1800 mg/day orally in 2 to 4 divided doses (Prod Info lithium carbonate oral tablets, capsules, 2009; Prod Info LITHOBID(R) extended-release oral tablets, 2009; Prod Info Lithium Carbonate extended-release oral tablets, 2005).
b) IMMEDIATE-RELEASE AND CAPSULES: 12 YEARS OF AGE AND OLDER: maintenance, 300 mg orally 3 to 4 times daily; desired serum lithium levels ranging between 0.6 to 1.2 mEq/L (Prod Info lithium carbonate oral tablets, capsules, 2009)
c) YOUNGER THAN 12 YEARS OF AGE: Safety and effectiveness have not been established (Prod Info lithium carbonate oral tablets, capsules, 2009; Prod Info LITHOBID(R) extended-release oral tablets, 2009; Prod Info Lithium Carbonate extended-release oral tablets, 2005).

B) LITHIUM CITRATE

1) BIPOLAR DISORDER

a) SOLUTION, 12 YEARS AND OLDER: The recommended dose is 5 mL (8 mEq of lithium) orally 3 to 4 times daily or 10 mL (16 mEq of lithium) orally 3 times daily (Prod Info lithium citrate oral solution, 2009).
b) YOUNGER THAN 12 YEARS OF AGE: Safety and effectiveness have not been established (Prod Info lithium citrate oral solution, 2009).

Minimum Lethal Exposure

1) A 65-year-old woman with acute on chronic lithium toxicity (8.5 milliequivalents/liter) developed renal failure 48 hours after ingestion. Hemodialysis was initiated.

a) She eventually succumbed to intractable hypotension and ventricular fibrillation with electromechanical dissociation at 4.5 days postingestion (Rose et al, 1988).

Maximum Tolerated Exposure

1) Mild to moderate toxic reactions may occur at 1.2 to 2.5 mEq/L in chronic intoxications (Chen et al, 2004)
2) In one study, it was observed that in patients with chronic lithium intoxication, the frequency of severe symptoms was higher than in acute intoxication. Chronic lithium intoxication was described as those patients treated with lithium without any change in their regular dosage; the median maintenance dose was 900 mg/day (range 600 to 1600 mg/day) (Chen et al, 2004).
3) It was found that patients with chronic intoxication and lithium levels of 1.2 mEq/L to 2.5 mEq/L or greater (therapeutic 0.6 to 1.2 mEq/L) were more likely to develop severe symptoms of intoxication versus only one patient who developed severe symptoms following an acute intoxication with a serum lithium level of greater than 2.5 mEq/L. Patients with an acute intoxication can develop high serum levels with limited distribution to the brain (which can be delayed up to 24 hours), and therefore less severe CNS effects. Conversely, in patients on chronic therapy the serum lithium level is closer to steady state and correlates better with brain lithium levels (Chen et al, 2004).

1) Serum lithium concentration of a 32-year-old asymptomatic woman peaked at 6.09 mEq/L 37 hours after ingesting approximately 16 g of an extended-release lithium carbonate formulation. She underwent two sessions of hemodialysis which resulted in the decline of serum lithium concentration to 0.61 mEq/L 85 hours post-ingestion (Borras-Blasco et al, 2007).
2) A 28-year-old man survived an acute ingestion with a lithium level of 10 mEq/L (Kondziela, 1984).
3) A 46-year-old male survived a severe poisoning with a serum lithium level of 14.6 millimoles/liter (Perrier et al, 1991).
4) A patient survived after ingesting 22.5 g of lithium carbonate. The blood serum concentration reached 8.2 mmol/L but was successfully reduced to 3.4 mg/L within 22 hours by diureses (Baselt & Cravey, 1995).
5) Full recovery was reported after a 39-year-old man ingested 210 lithium carbonate tablets (400 mg each) following a suicide attempt. At 40 hours post-ingestion, the lithium serum level was 5.89 mmol/L. Following treatment with hemodialysis and 6 days after admission, he was discharged with lithium level at 0.2 mmol/L (Kerbusch et al, 2002).
6) De Haro et al (2002) observed 306 cases of lithium intoxication between January 1991 and December 2000, of which 190 were suicide attempts. The most frequent signs of intoxication included; drowsiness (76%), muscle rigidity (21%), tremor (16%), and coma (15%). The average lithium blood level was 2.35 mmol/L (average ingested quantities 25 tablets). Fifteen treated patients developed renal failure; the average lithium blood level was 2.1 mmol/L (De Haro et al, 2002).
7) CASE REPORT - A 51-year-old woman developed nausea and headache after ingesting 50 slow-release lithium carbonate tablets (450 mg each) in a suicide attempt. Thirteen hours after ingestion, her serum lithium level was 10.6 mmol/L; level fell to 5.8 mmol/L 24 hours post-ingestion. Headache gradually resolved with time (Nagappan et al, 2002).

1) A 6-year-old developed lithium toxicity with neurological symptoms after 6 months of 40 milligrams/kilogram/day. The lithium level was 5.15 millimoles/liter (FitzSimons & Keane, 1981).
2) The accidental ingestion of lithium (average, 2 pills) in 13 children resulted only in drowsiness (De Haro et al, 2002).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) Therapeutic level is 0.6 to 1.2 mEq/L.

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) Toxic levels are close to therapeutic levels. Therapeutic level is 0.6 to 1.2 mEq/L.
b) CHRONIC TOXICITY

1) Mild to moderate toxic reactions may occur at 1.2 to 2.5 mEq/L in chronic intoxications (Chen et al, 2004)
2) In one study, it was observed that in patients with chronic lithium intoxication, the frequency of severe symptoms was higher than in acute intoxication. Chronic lithium intoxication was described as those patients treated with lithium without any change in their regular dosage; the median maintenance dose was 900 mg/day (range 600 to 1600 mg/day) (Chen et al, 2004).
3) It was found that patients with chronic intoxication and lithium levels of 1.2 mEq/L to 2.5 mEq/L or greater (therapeutic 0.6 to 1.2 mEq/L) were more likely to develop severe symptoms of intoxication versus only one patient who developed severe symptoms following an acute intoxication with a serum lithium level of greater than 2.5 mEq/L. Patients with an acute intoxication can develop high serum levels with limited distribution to the brain (which can be delayed up to 24 hours). Conversely, in patients on chronic therapy the serum lithium level is closer to steady state and correlates better with brain lithium levels (Chen et al, 2004).
4) Since lithium clears from the plasma much faster than from the brain, patients with chronic lithium toxicity may still have neurological toxicity when lithium levels have fallen into or below the therapeutic range (Spinewine et al, 2005).
5) The table below describes the typical signs and symptoms of lithium intoxication associated with blood levels (Hall et al, 1979).

BLOOD LEVEL	TYPICAL SIGNS AND SYMPTOMS
1.5 mEq/L	Nausea, vomiting, diarrhea
2 mEq/L	Polyuria, increasing confusion, blackouts, slurred speech, dizziness, muscular weakness, drowsiness, fasciculations, vertigo, increased deep tendon reflexes, blurred vision, transient scotomas
2.5 mEq/L	Urinary and fecal incontinence, choreoathetoid movements, myoclonic twitches, myoclonic movements of entire limb, increasing restlessness followed by stupor and coma
3 mEq/L	Cardiac arrhythmias, epileptiform seizures
4 mEq/L	Peripheral vascular collapse, hypotension

c) ACUTE TOXICITY

1) Toxicity does NOT necessarily correspond with serum levels in an acute lithium overdose and any of the signs and symptoms may occur first (Gadallah et al, 1988; Hall et al, 1979). Patients with levels of up to 6.8 mEq/L after acute ingestion have developed minor toxicity, with no sequelae (Gadallah et al, 1988). In a more recent study, most patients with an acute lithium intoxication and serum levels of greater than 2.0 mEq/L developed only mild symptoms (Chen et al, 2004). Patients with an acute intoxication can develop high serum levels with limited distribution to the brain (which can be delayed up to 24 hours) (Chen et al, 2004).
2) A 28-year-old man survived an acute ingestion with a lithium level of 10 milliequivalents/liter (Kondziela, 1984).
3) A 46-year-old male survived a severe poisoning with a serum lithium level of 14.6 millimoles/liter (Perrier et al, 1991).
4) Serum lithium concentration of a 32-year-old asymptomatic woman peaked at 6.09 mEq/L 37 hours after ingesting approximately 16 g of an extended-release lithium carbonate formulation. She underwent two sessions of hemodialysis which resulted in the decline of serum lithium concentration to 0.61 mEq/L 85 hours post-ingestion (Borras-Blasco et al, 2007).

d) FATAL

1) Levels of greater than 3 to 4 mEq/L can be fatal in patients with chronic lithium toxicity.
2) Postmortem lithium concentrations after the death of a 47-year-old were: Blood: 1.93 mEq/L; Bile: 15.7 mEq/L; Brain: 1.41 mEq/kg; Liver: 1.35 mEq/kg and, Kidney: 2.07 mEq/kg (Winek et al, 1980).

e) RBC LEVELS

1) Martin et al (1991) suggested that early in an acute lithium overdose, RBC lithium levels may be more useful than serum lithium levels to predict toxicity (Martin et al, 1991; Harvey, 1992).
2) Lithium clearance from plasma during hemodialysis was greater than from RBC's. The slower decline in RBC lithium levels more closely correlated with the patient's condition.

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 236 mg/kg -- effected sleep patterns; hyper activity; loss of muscle coordination ((RTECS, 2000))

B) LD50- (SUBCUTANEOUS)MOUSE:

1) 413 mg/kg ((RTECS, 2000))

C) LD50- (INTRAPERITONEAL)RAT:

1) 156 mg/kg -- activity and respiratory depression; effected gastrointestinal system ((RTECS, 2000))

D) LD50- (ORAL)RAT:

1) 0.71 g/kg ((RTECS, 2000))
2) 525 mg/kg -- activity and respiratory depression; effected gastrointestinal system ((RTECS, 2000))

E) LD50- (SUBCUTANEOUS)RAT:

1) 434 mg/kg -- altered ability to secrete tears and hair; respiratory depression ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

1) A monovalent cation, chemically similar to Na+ and K+, its mechanism of action is thought to be 1. imperfect substitution for other cations in ionic processes and 2. alteration of the critical microenvironment required for humoral or metabolic processes.
2) By these mechanisms in the CNS, lithium affects nerve excitation, synaptic transmission, and neuronal metabolism.
3) The neurotoxic effects seen with lithium are presumed to be due to cell membrane conductivity and changes in synaptic transmission (Chang et al, 1990).

1) Because naloxone produced an abatement of these hallucinations, an interaction of lithium with opioid receptors was proposed (Sandyk & Gillman, 1985).

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

242)

243)

244)

245)

246)

247)

248)

249)

250)

251)

252)

253)

254)

255)

256)

257)

258)

259)

260)

261)

262)

263)

264)

265)

266)

267)

268)

269)

270)

271)

272)

273)

274)

275)

276)

277)

278)

279)

280)

281)

282)

283)

284)

285)

286)

287)

288)

289)

290)

291)

292)

293)

294)

295)

296)

297)

298)

299)

300)

301)

302)

303)

304)

305)

306)

307)

308)

309)

310)

311)

312)

313)

314)

315)

316)

317)

318)

319)

320)

321)

322)

323)

324)

325)

326)

327)

328)

329)

330)

331)

332)

333)

334)

335)

336)

337)

338)

339)

340)

341)

342)

343)

344)

345)

346)

347)

348)

349)

350)

351)

352)

353)

354)

355)

356)

357)

358)

359)

360)

361)

362)

363)

364)

365)

366)

367)

368)

369)

370)

371)

372)

373)

374)

375)

376)

377)

378)

379)

380)

381)

382)

383)

384)

385)

386)

387)

388)

389)

390)

391)

392)

393)

394)

395)

396)

397)

398)

399)

400)

401)

402)

403)

404)

405)

406)

407)

408)

409)

410)

411)

412)

413)

414)

415)

416)

417)

418)

419)

420)

421)

422)

423)

424)

425)

426)

427)

428)

429)

430)

431)

432)

433)

434)

435)

436)

437)

438)

439)

440)

441)

442)

443)

444)

445)

446)

447)

448)

449)

450)

451)

452)

453)

454)

455)

456)

457)

458)

459)

460)

FeedBack

LITHIUM SALTS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography