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1212 SECTION 15: Toxicology Complications from profound muscle rigidity are responsible for most deaths in neuroleptic malignant syndrome. Prompt reduction in muscle rigidity can be expected to minimize the occurrence of compli cations such as rhabdomyolysis, renal failure, respiratory failure, dis seminated intravascular coagulation, and cardiovascular collapse. The role of specific pharmacotherapy is unclear ; no treatment has been shown to be superior to supportive care alone.27,37,38 Pharmacologic therapies described in case reports and series include dantrolene, bromocriptine, benzodiazepines, and amantadine. 39 Dantrolene is a direct-acting skeletal muscle relaxant that is primarily used for more severe cases of neuroleptic malignant syndrome in which the rigidity is pronounced. Dantrolene should not be used concurrently with calcium, because this increases the risk of cardiovascular collapse. Bromocriptine is a centrally acting dopamine agonist that can reduce fever and muscle rigidity in neuroleptic malignant syndrome and pos sibly shorten the duration. 40 This drug is only available in an oral preparation and may require administration by a nasogastric tube. Adverse side effects of hypotension, vomiting, and worsening of psychosis are limiting factors to the routine use of bromocriptine. 38 Amantadine is similar to bromocriptine in activity and only available in enteral form but is less likely to cause hypotension. Patients with neuroleptic malignant syndrome should be admitted to the intensive care unit for monitoring and treatment. Most patients recover in 2 to 14 days. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Lithium Anita Mudan David H. Jang INTRODUCTION Lithium is one of the most effective medications for the continuous treatment of bipolar disorder. It is particularly useful for the treatment of acute manic episodes and reduces rates of suicide associated with affective disorders. 1,2 Among agents used to treat depression, lithium is associated with high morbidity and mortality indices (events per 1000 exposures). PHARMACOLOGY Lithium is a simple ion with a complex mechanism of action that is not fully understood. It is postulated to involve primary monoamine neurotransmission, via a direct interaction between the lithium ion and cellular enzymes, influencing the secondary signaling pathways of dopamine, serotonin, and norepinephrine. 1,4 Lithium competes with other similar cations, including sodium, potassium, magnesium, and calcium, and displaces them from intracellular and extracellular sites. Interfer ence with sodium ions at the sodium channel and the sodium-potassium pump on the cell membrane is responsible for lithium’s adverse effect on myocardial electrical activity. Lithium inhibits arginine vasopressin, an effect that is responsible for polyuria and nephrogenic diabetes insipi dus seen during lithium therapy. Other pharmacologic effects include interference with the release and reuptake of norepinephrine at the nerve terminal site. Lithium may enhance serotonin release, particularly from the hippocampus, and has been implicated in serotonin syndrome when combined with other medications that alter serotonin metabolism. Lithium is handled by the kidney similar to sodium; anything that may CHAPTER increase sodium absorption, such as medications that reduce glomerular function, has the potential to contribute to lithium toxicity.

been implicated in serotonin syndrome when combined with other medications that alter serotonin metabolism. Lithium is handled by the kidney similar to sodium; anything that may CHAPTER increase sodium absorption, such as medications that reduce glomerular function, has the potential to contribute to lithium toxicity.  PHARMACOKINETICS After oral ingestion of therapeutic doses, lithium is rapidly and almost completely absorbed, although delayed absorption may occur with sustained-release products and after ingestion of a large number of tab lets. 6 Lithium is not bound to plasma proteins and has an initial volume of distribution between 0.6 and 0.9 L/kg. Ingestion of a single tablet of lithium carbonate 300 milligrams containing 8.12 mEq of lithium ion is expected to increase the lithium concentration by approximately 0.1 to 0.3 mEq/L (assuming a normal volume of distribution in a patient with a weight of 50 to 100 kg). Lithium exhibits a prolonged redistribution phase and tissue burden. Lithium distribution into and out of the brain is slower, resulting in neurologic effects that do not correlate with serum levels. The lithium concentrations in the brain and in the serum may differ by two- to threefold. 7 Continuation of toxic effects, even after hemodialysis, can be due to the drug’s slow movement out of the CNS and redistribution. Serum concentrations can serve as a marker of exposure but are poor predictors for severity of toxicity. Thus, clinical signs and symptoms provide a more accurate indicator of CNS lithium concentrations compared to serum concentrations. The elimination half-life after a single dose of lithium is about 18 to 24 hours in young adults and almost twice that in the elderly. 6 After continued therapy of longer than a year, the lithium elimination half-life increases, up to almost 60 hours in all ages. Lithium is not metabolized and is excreted unchanged, primarily in the urine. Like other cations of similar size, lithium is reabsorbed in the proximal tubule. The therapeutic index of lithium is narrow, and risk factors for the accumulation of lithium and the development of toxicity include NSAIDs, diuretics, angiotensinconverting enzyme inhibitors, advanced age, low-output heart failure, and states that result in decreased sodium intake such as GI loss. 1,5,8 CLINICAL FEATURES  TOXIC EFFECTS Lithium toxicity can be divided into three types: acute toxicity, chronic toxicity, and acute-on-chronic toxicity. 9-12 Acute ingestions of lithium produce findings similar to that of other metal salts, consisting primarily of GI symptoms of abdominal pain, nausea, vomiting, and diarrhea, which may result in significant volume depletion. The resulting hypovolemia decreases renal clear ance of lithium, further increasing serum concentration. Acute lithium overdoses present with more GI toxicity and less neurologic toxicity because of the slower accumulation into the brain after ingestion and distribution in body water. Patients with acute overdose may have markedly elevated serum concentrations that do not correlate well with either symptom severity or prognosis. As lithium distributes from the serum into the CNS, neurologic symptoms of confusion, seizures, and coma become apparent. Cardiac abnormalities such as hypotension, bradycardia, atrioventricular block, and ventricular dysrhythmias have been described but are very uncommon, and co-ingestions should be considered before attributing abnormalities solely to lithium toxicity. 13,14 Rare cases of adult respiratory distress syndrome have been associated with acute lithium toxicity. Lithium is a neurotoxin, and neurologic symptoms predominate in chronic toxicity.

described but are very uncommon, and co-ingestions should be considered before attributing abnormalities solely to lithium toxicity. 13,14 Rare cases of adult respiratory distress syndrome have been associated with acute lithium toxicity. Lithium is a neurotoxin, and neurologic symptoms predominate in chronic toxicity. Common symptoms include postural tremor (exaggerated physiologic tremor), muscle fasciculation, clonus, choreoathetoid movements, ataxia, muscle weakness, dysarthria, nystagmus, agitation, and lethargy. 1,16-19 Although most patients present with a slowing of cognitive function, cases of lithium toxicity presenting with mania or auditory, visual, or tactile hallucinations have been reported. As tox icity worsens, confusion, lethargy, stupor, seizures, and finally coma develop. Less common toxic effects include hyperthermia, hypothermia, peripheral neuropathy, and severe leukopenia. Recognizing chronic lithium toxicity is difficult because it predominantly causes neurologic Tintinalli_Sec15_p1187-1332.indd 1212 8/2/19 8:39 PM

s, confusion, lethargy, stupor, seizures, and finally coma develop. Less common toxic effects include hyperthermia, hypothermia, peripheral neuropathy, and severe leukopenia. Recognizing chronic lithium toxicity is difficult because it predominantly causes neurologic Tintinalli_Sec15_p1187-1332.indd 1212 8/2/19 8:39 PM CHAPTER 181: Lithium 1213 concentrating ability (simultaneous serum and urine sodium, creatinine, and osmolality). In acute overdose, additional tests may be useful (see Chapter 176, “General Management of Poisoned Patients”). TREATMENT Initial stabilization of the patient’s condition includes protection of the airway and provision of respiratory and hemodynamic support. Estab lish IV access, initiate cardiac rhythm monitoring, and obtain an ECG. Information regarding the lithium formulation can aid in further treat ment, such as immediate- versus sustained-release tablets, doses, and quantity of ingestion. Subsequent treatment depends on clinical severity (Table 181-2). GI decontamination has a limited role in lithium toxicity. Activated charcoal does not readily bind with lithium. Gastric lavage has no role in most cases of lithium overdose because the sustained-release preparations are often too large to fit through the lavage tubes and the immediate-release preparations are too rapidly absorbed in the GI tract. Whole-bowel irrigation with polyethylene glycol solution at 2 L/h is the only method of GI decontamination that has shown some efficacy in removing lithium in the setting of acute ingestion of the sustainedrelease formulation provided there is no evidence of airway compromise or intestinal obstruction. The critical principle of lithium poisoning treatment is assessment of volume status and restoration of intravascular volume. IV administration of normal saline is required in nearly all patients with significant toxicity because of sodium and volume deficits. 12,37 Typical adult dosing is an IV bolus of normal saline 20 mL/kg, followed by continuous infusion at 1.5 to 2 times the maintenance rate. Volume repletion reestablishes normal renal elimination kinetics of lithium. Diuretic-induced diuresis does not enhance lithium elimination, and in fact, loop and thiazide diuretics promote water loss, which is followed by lithium retention. Lithium is amenable to extracorporeal removal. 1,12 Consensus recommendations from the Extracorporeal Treatment in Poisoning Workgroup are to use extracorporeal treatment, such as dialysis, for severe lithium toxicity (coma, seizures, life-threatening dysrhythmias) or a serum lithium level >4.0 mEq/L (>4 mmol/L) in the presence of renal insufficiency. 38 Intermittent hemodialysis is the preferred modality, with continuous renal replacement being an acceptable alternative. 38 The goal of hemodialysis is to reduce the total body burden of lithium, but because the molecule is primarily intracellular and slowly diffuses across the cell membrane, removal of extracellular lithium through intermittent hemodialysis results in redistribution from the intracellular to extracellular compartments, causing a postdialysis rebound increase in serum lithium concentrations. Therefore, it is essential to monitor serum lithium levels for up to 8 hours after hemodialysis, and if symp toms recur or serum levels rise significantly, consider repeat hemodialysis. Peritoneal dialysis is no longer recommended because the clearance rates are approximately the same as through normal renal clearance with potential for complications such as bowel perforation. Treat seizures with IV benzodiazepines, such as lorazepam, because phenytoin is ineffective in controlling drug-induced seizures. Consultation with a medical toxicologist is recommended for patients with seri ous toxicity.

ame as through normal renal clearance with potential for complications such as bowel perforation. Treat seizures with IV benzodiazepines, such as lorazepam, because phenytoin is ineffective in controlling drug-induced seizures. Consultation with a medical toxicologist is recommended for patients with seri ous toxicity. TABLE 181-1 Clinical Features of Lithium Toxicity Category Features Mild Nausea, vomiting, fatigue, lethargy, fine tremor Moderate Confusion, agitation, dysarthria, ataxia, hypertonia, hyperreflexia, nystagmus, muscular weakness Severe Coma, seizures, myoclonus, hyperthermia, ventricular dysrhythmias, atrioventricular block, cardiovascular collapse symptoms that are indistinguishable from organic causes of delirium, and symptoms do not reliably correlate with serum levels. 11,17,20,21 Most patients recover from chronic toxicity as the body burden of lithium decreases. The syndrome of irreversible lithium-effectuated neurotoxicity describes the persistent neurologic dysfunction caused by lithium that persists for >2 months after cessation of the drug in patients without prior neurologic illness. Cerebellar dysfunction is the key find ing with syndrome of irreversible lithium-effectuated neurotoxicity, manifested by truncal ataxia, unsteady gait, tremor of the hands and head, scanning speech, and diffuse incoordination. Acute-on-chronic toxicity results from a disruption in the balance of serum lithium concentrations in patients with a stable body burden from chronic therapy, most often precipitated by decreases in glomerular filtration or intravascular volume depletion or when a patient inten tionally or unintentionally ingests an increased amount of lithium. 16 The resulting lithium load in the presence of already saturated tissue leads to toxicity, with clinical symptoms mimicking both acute (GI symptoms) and chronic (neurologic symptoms) toxicity (Table 181-1).  ADVERSE EFFECTS OF CHRONIC THERAPY Adverse effects during therapeutic lithium use are common, occurring in up to 90% of treated patients. The most frequent adverse effects include fine postural hand tremor, fatigue, polyuria due to loss of urinary concentration ability, hypothyroidism, and hyperparathy roidism with hypercalcemia. 23-25 Worsening of a baseline tremor and development of ataxia or dysarthria are important signs of developing toxicity and may signal a need to decrease the dose of lithium. Lithium is a common cause of drug-induced nephrogenic diabetes insipidus, which is prevalent in up to 40% of patients receiving longterm lithium treatment. 26,27 The decreased urinary concentrating ability is usually compensated in patients by increased thirst. The ability of the distal nephron to acidify the urine can be impaired, causing an incom plete distal renal tubular acidosis without acidemia. Long-term lithium treatment can lead to a progressive nephropathy, with a mild reduction in glomerular filtration 25,28 and approximately a 1% absolute risk of requiring renal replacement therapy. 28-30 Maintaining serum lithium levels <0.8 mEq/L (0.8 mmol/L) may reduce long-term renal damage.31 ECG abnormalities commonly reported with lithium use include QT interval prolongation, T-wave flattening or inversion, and significant bradycardia. 32 Hypothyroidism is the most prevalent endocrine dysfunction, occurring at a rate almost six times that in the general populace.25,33 Hyperparathyroidism and hypercalcemia are frequently reported and can be associated with stimulation of hyperplasia or adenomas. DIAGNOSIS The patient’s history, symptoms, and signs should guide therapy, as opposed to a lithium concentration, which primarily serves as a marker of an exposure.

the general populace.25,33 Hyperparathyroidism and hypercalcemia are frequently reported and can be associated with stimulation of hyperplasia or adenomas. DIAGNOSIS The patient’s history, symptoms, and signs should guide therapy, as opposed to a lithium concentration, which primarily serves as a marker of an exposure. 12 Blood samples should be sent in lithium-free tubes because the use of lithiated heparin tubes can lead to falsely posi tive results up to 4 mEq/L (4 mmol/L). 32 Therapeutic lithium levels are considered to be 0.6 to 1.2 mEq/L (0.6 to 1.2 mmol/L), and most patients manifesting toxic effects have levels >2 mEq/L (>2 mmol/L). Additional tests to obtain if acute toxicity is suspected include a CBC where leukocytosis can be seen and a metabolic panel to evaluate kidney function. In chronic toxicity, consider assessing thyroid function (thyroid-stimulating hormone and thyroid hormone levels) and renal TABLE 181-2 Management of Lithium Toxicity IV saline infusion Used in essentially all patients with toxicity Reestablishes euvolemia and normal lithium renal elimination Whole-bowel irrigation Used in awake patients who ingest sustained-release lithium preparations Hemodialysis Used for patients with severe toxicity Also used for patients with renal failure, patients who cannot tolerate IV saline infusion, and patients with high elevated serum lithium levels (>4.0 mEq/L in any type of overdose and >2.5 mEq/L in chronic toxicity) IV benzodiazepines Used for seizures seen in severe toxicity Tintinalli_Sec15_p1187-1332.indd 1213 8/2/19 8:39 PM