Clinical Features of Lithium Toxicity

Patients with lithium toxicity present with a variety of clinical manifestations (Box 180-2). Neurologic symptoms are predominant.²⁷ Central nervous system symptoms often develop gradually, starting initially with confusion and progressing to impaired consciousness, coma,^27,86 and occasionally death.⁸⁷ Cerebellar manifestations are often prominent and can include dysarthria,⁸⁸ truncal ataxia, broad-based ataxic gait, nystagmus, and varying degrees of incoordination. Other central nervous system manifestations of lithium intoxication are seizures^86–90 and involvement of the basal ganglia, as suggested by choreiform movements^48,91,92 and Parkinson’s disease–like movements.⁹³

Gastrointestinal side effects of lithium therapy include gastric irritation, epigastric bloating, abdominal pain, nausea, vomiting, and diarrhea.⁹⁴ Although these are common findings, gastrointestinal complaints are not prominent manifestations of lithium intoxication.²⁷

Electrocardiographic changes are frequently associated with lithium therapy.⁹⁴ Lithium intoxication can be associated with transient ST-segment depression or inverted T waves in leads V_4-6.²⁷ Although electrocardiographic changes are common, cardiac symptoms are rarely manifestations of lithium intoxication. Sinus node dysfunction has been reported to be a consequence of lithium intoxication leading to syncope.^95,96

Polyuria and polydipsia are frequent side effects of lithium therapy; they are estimated to occur in 20% to 70% of patients.³ The concentrating defect may develop not only in patients who are overtly toxic but also in those with therapeutic levels.³ Polyuria may lead to volume depletion and decrease the fractional excretion of lithium. The mechanisms responsible for lithium-induced polyuria were summarized by Singer³; they include primary polydipsia, central diabetes insipidus, and nephrogenic diabetes insipidus.

Other less common manifestations of lithium intoxication are hyperthermia,⁹⁷ hypothermia,⁹⁸ peripheral neuropathy,^99,100 myopathy,¹⁰¹ and severe leukopenia.¹⁰²

Treatment

The initial management of lithium intoxication is determined by the degree of intoxication (serum level), a history of acute versus chronic lithium exposure, the clinical symptoms, and the adequacy of renal function.¹⁰³ As noted in Table 180-2, patients present with a variety of clinical manifestations, from chronic lithium therapy to acute overdose. Those who appear to have severe impairment of consciousness require airway protection and admission to an intensive care unit. Activated charcoal is an ineffective gastrointestinal decontaminant in lithium overdose because it does not absorb strongly ionized chemicals. In contrast, polyethylene glycol (CoLyte, GoLYTELY) has been shown to be effective in acute lithium intoxication.¹⁰⁴ Sodium polystyrene sulphonate has been used only in cases of chronic stable lithium toxicity with serum levels of no more than 2.3 mEq/L.¹⁰⁵

Volume status should be assessed because significant volume depletion can occur as a result of urinary concentrating defects. Many of these patients have volume-responsive decreases in renal function.²⁷ Therefore, fluid resuscitation is critical in the initial management. Administration of large volumes of isotonic saline should be done carefully because severe hypernatremia has been associated with such fluid management.^{27,42,92,106,107} After fluid resuscitation, efforts to enhance lithium removal are the next step. Various modalities for lithium removal are listed in Table 180-3. The efficacy of each modality in removing lithium can be assessed by comparing lithium clearance values. Because there are no controlled studies of lithium clearance during intoxication, the following data on lithium clearance rely heavily on case reports.

TABLE 180-3 Lithium Removal

In normal individuals, renal lithium clearance is about 10 to 40 mL/min.^38–40 Hansen and Amdisen²⁷ reported that renal lithium clearance is 0.9 to 18.4 mL/min in patients with lithium intoxication. Of the 23 patients studied by these authors, only 5 had normal renal function (i.e., creatinine clearance > 78 mL/min). Therefore, in patients with lithium intoxication, the ability to remove lithium by renal excretion can be limited by poor renal function.

Because 80% of lithium is reabsorbed in the proximal tubule, factors that decrease proximal lithium reabsorption can increase lithium clearance, enabling enhanced lithium removal during states of intoxication. Because sodium balance alters the clearance of lithium,^49–51108 forced diuresis with isotonic saline has been used as a treatment of lithium intoxication. Because consistent therapeutic benefits have not been achieved with forced diuresis^27,109 and because of the potential for hypernatremia, forced diuresis is not recommended for severe lithium intoxication.^27,35 However, if lithium clearance is impaired as a result of volume contraction, administration of isotonic saline may increase lithium clearance transiently.

The effects of various agents on the clearance of lithium have been studied in humans challenged with a single dose of lithium.³⁸ Whereas water loading, furosemide, thiazide diuretics, ethacrynic acid, ammonium chloride, and spironolactone did not increase clearance of lithium, sodium bicarbonate, acetazolamide, urea, and aminophylline were effective. Clinical studies employing these agents for lithium removal during intoxication have not been reported.

Peritoneal dialysis is another means of lithium removal. Wilson and coworkers,¹¹⁰ using 2-L exchanges per hour, attained clearances of 13 to 15 mL/min. Similar results were achieved by O’Connor and Gleeson,¹⁰⁹ who reported lithium clearances of 9 mL/min with frequent 2-L exchanges. Although peritoneal dialysis is no more efficient in removing lithium than forced diuresis, it avoids problems associated with intravenous administration of large volumes of isotonic saline.

Conventional hemodialysis remains the mainstay of therapy in severe lithium intoxication.¹¹¹ The decision to use hemodialysis (or other extracorporeal therapies) should be made by the nephrologist in consultation with the intensivist and not be expected to come from the poison control centers, because specific factors other than serum lithium levels are not always evident to staff at the local poison control center.¹¹²

Lithium is one of the most readily dialyzable toxins because of its small atomic weight and negligible protein binding. Several reports indicate lithium clearances between 70 and 170 mL/min with hemodialysis.^27,113,114 Because lithium clearance is almost proportional to blood flow, increasing the blood flow to more than 300 mL/min can further enhance clearance. Table 180-3 compares lithium clearance by various modalities, showing the superiority of hemodialysis to other traditional methods.

The duration of hemodialysis should be guided by serial measurements of serum lithium levels. When levels approach therapeutic range, dialysis may be terminated; however, subsequent hemodialysis may be necessary because serum levels may rise after termination of hemodialysis.^27,103,114 This rebound effect occurs as a result of continued absorption of lithium from the gastrointestinal tract, delayed release from long-acting preparations, and redistribution of lithium from intracellular stores.¹⁰³ Although serum lithium clearance has been reported to range from 70 to 170 mL/min,^110,113 the extraction or clearance of lithium from intracellular stores, as reflected by red blood cell clearance, is only 10 to 13 mL/min.¹¹³ This slower extraction of lithium from intracellular stores contributes to the rebound effect.

Continuous renal replacement therapy (e.g., continuous arteriovenous hemodiafiltration, continuous venovenous hemofiltration) has been used either as an alternative to conventional hemodialysis or in addition to conventional hemodialysis.^{111,115–119} The combination of conventional hemodialysis followed by continuous renal replacement therapy is very useful for preventing the rebound phenomenon.^{103,111,116,117}

Box 180-3 summarizes the management of lithium intoxication. Initially, the degree of consciousness and volume status should be assessed. The airway should be protected if necessary, and isotonic saline should be administered for volume repletion. After these critical maneuvers, management should focus on lithium removal. The method of lithium removal is determined by the degree of elevation of the serum lithium concentration, severity of symptoms, and duration of intoxication. Although each patient should be evaluated individually, rough guidelines with rational therapeutic options can be derived from knowledge of the pharmacokinetics of lithium removal. For those patients with minimal symptoms, normal renal function, and mild elevation of serum lithium levels (<2.5 mEq/L), intravenous hydration may be adequate. Urinary electrolytes should be evaluated as a guide to the type of replacement fluid used. This approach avoids hypernatremia, which commonly occurs with forced diuresis. For severe lithium intoxication, hemodialysis is clearly superior to other modalities. Peritoneal dialysis or continuous arteriovenous hemofiltration may be used if hemodialysis is unavailable.

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