Lithium Poisoning

Lithium Poisoning

Kent R. Olson

Thanjira Jiranantakan

Lithium was introduced in the nineteenth century for the treatment of gout. Apparently, toxicity was rarely encountered because of low recommended doses. In the 1940s, lithium chloride was briefly marketed as a salt substitute, but was withdrawn after several cases of serious intoxication and death resulted from its use. In 1949, its antimanic properties were reported, and lithium has found increasingly wide psychiatric use since its approval by the U.S. Food and Drug Administration in 1970 [1,2].

In patients with mania, lithium reduces hyperactivity, irritability, pressured speech, assaultive behavior, and sleeplessness. These effects may require several days of therapy, during which time alternate medications are used. Lithium is very effective in reducing the recurrence of episodes of manic–depressive bipolar disorder and is used to treat some patients with unipolar depression and schizophrenia. It induces neutrophilia (up to 1.5 to 2.0 times the normal leukocyte counts) by enhanced production of G-CSF (granulocyte colony-stimulating factor) and stimulation of pluripotential stem cell production. Lithium has been used to treat a variety of causes of neutropenia [1,3,4].

Lithium is available in conventional tablets or capsules containing 300 mg (8.12 mEq) of lithium carbonate or in sustained-release preparations containing 450 mg (12.18 mEq) of lithium carbonate. Liquid solutions of lithium citrate containing 8 mEq per 5 mL are also available [3].


Lithium is the lightest alkali metal, occupying the same column in the periodic table as sodium and potassium, elements with which it shares some properties. However, it has no known normal physiologic role. The exact mechanisms of its therapeutic and toxic effects remain to be determined. Lithium affects ion transport and cell membrane potential by competing
with sodium and potassium and possibly other cations. However, unlike sodium and potassium, lithium does not produce a large distribution gradient and, therefore, cannot maintain a significant membrane potential. It is believed to enhance serotonin and acetylcholine effects, resulting in an indirect effect on the central nervous system (CNS). In addition, its inhibitory effects on second messengers, such as inositol phosphates, may reduce neuronal responsiveness to some neurotransmitters [1].

Lithium is readily absorbed from the gastrointestinal tract. The bioavailability of conventional tablets and capsules and the liquid solution is 95% to 100%; bioavailability is not affected by food. Normally, absorption is complete within 1 to 6 hours; peak levels are reached in 2 to 4 hours [1,3]. Sustained-release preparations are less predictably absorbed (60% to 90%), and peak levels may be delayed by more than 4 to 12 hours [3]. Overdose has resulted in delayed peak levels or secondary peak levels as long as 148 hours after ingestion [5]. In one case, esophagoscopy at 84 hours revealed a 5- to 6-cm tablet and hair bezoar in the stomach [6].

Lithium initially occupies an apparent volume of distribution of 0.3 to 0.4 L per kg (approximately that of intracellular water), but further distribution into various intracellular tissue compartments occurs during 6 to 10 hours, with the final volume of distribution being 0.7 to 1.0 L per kg. This explains why initial serum lithium levels may be very high, with few or no signs of toxicity. After a single dose, the equilibrium serum lithium concentration can be expected to increase by 1.0 to 1.5 mEq per L for each 1.0 mEq of lithium per kilogram of body weight. Steady-state tissue levels are achieved after 3 to 4 days of the therapy. Tissue distribution is uneven; whereas the cerebrospinal fluid lithium concentration is only 40% to 60% that of plasma, the saliva concentration may be two to three times greater than that of plasma. Lithium is not bound to serum proteins and freely crosses the placenta [1,3].

Lithium is not metabolized. More than 95% of absorbed lithium is excreted by the kidneys, with 4% to 5% eliminated in sweat and 1% in the feces. It is also excreted in breast milk. Eighty percent of renally filtered lithium is reabsorbed in the proximal tubule against a concentration gradient that does not distinguish lithium from sodium. Sodium depletion can result in as much as a 50% increase in lithium reabsorption. The usual renal clearance is 10 to 40 mL per minute, but it may be 10 to 15 mL per minute or less in the elderly and in patients with renal dysfunction or dehydration [3,7,8]. However, lithium excretion rate may be different in different types of renal failure. Some study demonstrated increased fractional excretion of lithium in patients with prerenal failure, but decreased fractional excretion in acute tubular necrosis (ATN) renal failure [9]. The elimination half-life averages 20 to 24 hours; in patients with chronic intoxication, it may be as long as 47.6 hours [10]. The very slow terminal elimination phase may last up to 10 to 14 days because of gradual lithium release from tissue storage sites such as a bone and the brain [1].

Therapeutic serum lithium concentrations are usually considered to be 0.80 to 1.25 mEq per L; prophylaxis against recurrent manic–depressive illness may be achieved with levels of 0.75 to 1.00 mEq per L. Drug levels should be drawn at least 10 to 12 hours after the last dose to allow for complete tissue distribution. Onset of therapeutic effects usually requires 5 to 21 days after initiation of daily drug administration. Therapeutic levels are achieved by administration of 600 to 1,200 mg of lithium carbonate (16 to 32 mEq of lithium) per day. Careful monitoring of lithium levels is essential because of its low toxic-to-therapeutic ratio [3].

Lithium intoxication primarily involves the CNS and kidneys, although a variety of other organ systems are also affected (Table 138.1). Lithium intoxication may follow an acute overdose or result from chronic accumulation because of either an increase in dosage or a decrease in lithium elimination by the kidneys. Most serious toxicity occurs in patients with chronic intoxication, especially in older patients and patients with renal insufficiency [11].

Table 138.1 Common Features of Lithium Intoxication

Feature Number Percentage of total
Confusion 19a 68
Agitation 17 61
Drowsiness 16a 57
Mutism 5 18
Coma (grades III–IV) 1 4
Convulsions 4 14
Hyperreflexia 22 79
Increased tone 16 57
Ankle clonus 4 14
Extensor plantar responses 3 11
Tremor 18 64
Ataxia 14 50
Dysarthria 10 36
Myoclonus 7 25
Vomiting 7 25
Diarrhea 4 14
Acute diabetes insipidus 3 11
Acute renal failure 2 7
aExcludes one patient who also took temazepam in overdose.
Reprinted from Dyson EH, Simpson D, Prescott LF, et al: Self-poisoning and therapeutic intoxication with lithium. Hum Toxicol 6:326, 1987, with permission.

Acute ingestion of at least 1 mEq per kg (40 mg per kg of lithium carbonate) in a person not previously taking lithium would be required to produce a potentially toxic serum lithium level. The acute toxic dose in a patient already taking lithium (“acute-on-chronic” overdose) depends on the prior lithium level (due to tissue soaking). The dose required to produce chronic intoxication depends on the individual’s rate of renal elimination of lithium.

Clinical Manifestations

Signs and symptoms of mild lithium intoxication include nausea, vomiting, lethargy, fatigue, memory impairment, and fine tremor. Moderate signs and symptoms of toxicity include confusion, agitation, delirium, coarse tremor, hyperreflexia, hypertension, tachycardia, dysarthria, nystagmus, ataxia, muscle fasciculations, extrapyramidal syndromes, and choreoathetoid movements. Patients with severe toxicity may also exhibit bradycardia, complete heart block, Brugada syndrome, coma, seizures, nonconvulsive status epilepticus, hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, and hypotension [12,13,14,15]. Permanent sequelae include choreoathetosis, tardive dystonia, tremor, peripheral neuropathy, scanning speech, dysarthria, muscle rigidity, cognitive deficits, nystagmus, and ataxia [16,17,18,19,20].

Neurotoxic effects of lithium usually develop gradually and may become progressively severe over several days. Neurologic manifestations may worsen even as serum lithium levels are falling and may persist for days to weeks after cessation of the therapy, in part because of slow movement of lithium into and out of intracellular brain sites and possibly brain damage, such as demyelination caused by lithium [19].

Cardiovascular manifestations are nonspecific. The electrocardiogram changes are often similar to those seen with hypokalemia and may result from displacement of intracellular
potassium by lithium; U waves and flattened, biphasic, or inverted T waves can be seen with therapeutic doses and mild overdoses. Sinus and junctional bradycardia, sinoatrial and first- degree AV block, and QRS and QTc interval prolongation may be seen with severe intoxication [20,21]. Life-threatening dysrhythmias are rare. Patients with complete heart block during lithium treatment have been reported [12,13]. This lithium-associated cardiac toxicity is more common in patients older than 65 years with baseline EKG abnormalities, conduction abnormalities, use of renal toxic medication, and concomitant use of AV nodal–blocking agents [13]. Brugada syndrome precipitated by lithium has been reported [14]. Pulse and blood pressure abnormalities may be seen in moderate or severe poisoning, but they are usually not pronounced. Hypotension is more often due to dehydration, which can be a cause and a complication of lithium intoxication, than direct cardiotoxicity [20,21].

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Sep 5, 2016 | Posted by in CRITICAL CARE | Comments Off on Lithium Poisoning
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