Unrecognized delayed toxic lithium peak concentration in an acute poisoning with sustained release lithium product.

Abstract: A 32-year-old female with a history of bipolar disorder was admitted after taking approximately 16 g of an extended-release lithium carbonate formulation in an attempted suicide. Five hours after consumption, the lithium serum level was 3.2 mEq/L. Fourteen hours after consumption, the lithium level was 5.1 mEq/L and the patient was asymptomatic. Due to a level >4 mEq/L, the patient was transferred to a renal medicine service for hemodialysis. The lithium concentration 6 hours after the hemodialysis was 2.54 mEq/L. Thirty seven hours after the consumption (15 hours after hemodialysis), lithium levels increased up to 6.09 mEq/L. A second hemodialysis session was performed, which successfully reduced the serum lithium concentration to 1.86 mEq/L. Lithium levels 85 hours after the consumption were 0.61 mEq/L and the patient was transferred to the Psychiatry Department. Unrecognized delayed toxic peak lithium concentration may appear in an acute poisoning with a sustained release lithium product. Therefore, patients presenting with acute intoxication with extended release formulations should be managed with caution, and continued drug monitoring is suggested.

Key Words: lithium, dialysis, sustained-release lithium formulation, overdose, delayed peak concentration

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Lithium is the drug of choice for the treatment of recurrent bipolar illness. (1) The combination of the increased use of lithium and its extremely narrow therapeutic window (0.6-1.2 mEq/L) enhances the potential for increased toxicity. As a guideline, a level of 1.5 mEq/L or higher is considered toxic. Although there is no "clear-cut relationship" between the serum lithium level and the severity of symptoms, it is believed that symptoms and signs of mild poisoning (1.5-2.5 mEq/L) include marked tremor, nausea, diarrhea, blurred vision, vertigo, confusion, ataxia, fatigue, apathy and hyperreflexia. With levels higher than 3.5 mEq/L, patients may experience more severe neurologic complications such as seizures, coma, cardiac dysrrhythmia, renal failure and permanent neurologic impairment. (2) The most efficient method for removing lithium is hemodialysis. The severity of lithium toxicity depends on the length of exposure, peak serum concentrations, lithium preparations and the rate of elimination. Consumption of sustained-release preparations of lithium carbonate may result in delayed onset of toxicity. (3) Therefore, it may be difficult to determine the appearance of peak serum concentration when there is an acute lithium overdose with an extended-release preparation. (4) We report a delayed peak lithium concentration (>6 mEq/L) after intentional lithium poisoning with sustained-release lithium tablets.

Case Report

A 32-year-old female with a history of bipolar disorder, cocaine and alcohol abuse was brought to the emergency room. About 4 hours before admission, the patient took an intentional overdose of 16 g of an extended-release lithium carbonate formulation. She was on treatment with clorazepate 50 mg p.o. three times daily, clomipramine 50 mg p.o. two times daily, lorazepam p.o. 5 mg/d and amitriptyline 25 mg p.o. two times daily. Initial treatment included gut decontamination with a single dose of activated charcoal. Toxicological screening was negative for benzodiazepines, cocaine, barbiturates, morphine, methadone, amphetamines, tetrahydrocannabinol and tricyclic antidepressants. Temperature was below 37[degrees]C, pulse rate was 64 beats/min and blood pressure was 130/60 mm Hg. The rest of the physical examination was unremarkable. Initial laboratory values were sodium 139 mmol/L, potassium 4 mmol/L, hemoglobin 12.5g/dL, white cell count 12 [10.sup.3]/uL, platelets 291 [10.sup.3]/uL and glucose, creatinine, iron, and serum liver enzymes were normal. Thorax x-ray and echocardiogram were both normal. Five hours after consumption, the serum lithium level was 3.2 mEq/L, higher than the therapeutic range (0.6-1.2 mEq/L). Treatment with IV furosemide 40 mg three times daily and 250 mL/h of NaCl 0.9% were started. A second lithium value was taken 14 hours after the consumption; it showed a serum level of 5.1 mEq/L with a serum creatinine and sodium concentration within normal values. Due to the level greater than 4 mEq/L, the patient was transferred to a renal medicine service for hemodialysis. The lithium concentration 6 hours after the hemodialysis was 2.54 mEq/L. Treatment with IV furosemide 40 mg t.i.d. continued and saline intake was reduced up to 150 mL/h. Due to the patient's good physical condition she began to take oral liquids 24 hours after the admission and oral diet 8 hours later. Thirty-seven hours after the consumption, the lithium levels increased up to 6.09 mEq/L. A second hemodialysis session was performed, which successfully reduced the serum lithium concentration up to 1.86 mEq/L with a serum creatinine and sodium concentration within normal values. Lithium levels 85 hours after the consumption were 0.61 mEq/L (Fig.) and patient was transferred to the Psychiatry Department. Blood samples were collected in a yellow top tube without lithium heparin.

Discussion

Initial treatment of acute lithium poisoning involves emesis or gastric lavage to remove undissolved pills. Activated charcoal does not bind lithium effectively. (5) However, it is prescribed to absorb other coadministered drugs that may have been in the possession of patients with psychiatric disorders. Volume status should be assessed and isotonic saline administered as indicated. Forced diuresis appears to have been successful in some instances, but unsatisfactory in others. Dialysis is recommended to increase lithium elimination in acute intoxication of this drug. Meanwhile, lithium is a low-molecular mass monovalent cation that is not metabolized or protein-bound, ideally suitable for removal by hemodialysis. (6) Even if the patient is asymptomatic, dialysis may be prescribed if the lithium level is 4 mEq/L or higher at least 6 hours after the consumption. (7) Dialysis is also recommended in case of serious clinical signs and patients with a neuropsychiatric abnormality or renal impairment. Redistribution between lithium from peripheral tissues into the central compartment or from release of lithium from bone stores can result in a rebound effect in the lithium concentration 6 to 8 hours after cessation of hemodialysis. (8) Lithium levels should be reduced 6 to 8 hours after the last hemodialysis to monitor the expected rebound effect. (9,11)

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Peak lithium concentrations are typically attained in 2 hours, when the drug is formulated in regular release product. After the intake of a sustained-release lithium formula, peak concentrations appear in approximately 4 to 12 hours. (12-14) In our patient, 14 hours after the consumption, lithium concentration was 5.1 mEq/L with a serum creatinine and sodium concentration within normal values. Hemodialysis was performed and lithium serum levels declined 6 hours later. Twenty-four hours after the admission, the patient began to take oral liquids, and 8 hours later, an oral diet was instituted. Thirty-seven hours after the admission, with no decline in renal function or changes in fluid status, a delayed toxic peak lithium concentration of 6.09 mEq/L was noticed. Therefore, a possible correlation was noted between the increase in lithium plasma concentration and the administration of oral intake in our patient. In the literature, delayed peak concentrations after acute lithium poisoning have been described. (3,15,16) This phenomenon could be explained by a delayed excretion of lithium due to renal impairment, a delayed gastrointestinal absorption where concomitant ingestion of anticholinergic drugs may decrease gastrointestinal motility, a possible "rebound effect" after the hemodialysis, or because the sustained-release lithium products form an aggregate in the gastrointestinal tract. In this case, the patient's renal function was normal, and no other drugs were ingested, which explains the delayed lithium excretion. The possibility of a lab error was discarded; meanwhile, blood samples were collected in a yellow top tube without lithium heparin. A possible "rebound effect" after the hemodyalisis cannot be ensured, although this effect normally appears 6 to 8 hours after the hemodialysis.

Friedberg et al presented two cases of delayed absorption of lithium after intentional overdose. In one patient, the lithium peak concentration was achieved after 33 hours and a second peak occurred at 148 hours, after initiation of enteral tube feedings. The second patient, who ingested 98 g of lithium, received periodic hemodialysis sessions to decrease serum lithium concentrations. The patient was given fluids via nasogastric tube three times during hemodialysis. Each was temporally associated with an increase in serum lithium concentration, despite concurrent hemodialysis. The authors concluded that the quantity of lithium absorption in each patient after instillation of fluid directly into the gastrointestinal tract implies an intestinal drug depot. (3)

Dupuis et al reported the case of a delayed peak lithium concentration after an overdose of extended-release lithium tablets. When the patient was admitted, the lithium plasma level was 1.4 mEq/L. Significant enteral intake was initiated 27 hours after presentation, and the lithium concentration 5 hours later increased to 3.2 mEq/L. A second lithium peak concentration of 5.0 mEq/L was noted 40 hours after admission. Two hemodialysis sessions lasting 4 hours each were performed and eighty-eight hours after presentation, the lithium concentration had decreased to 1.5 mEq/L. The authors concluded that the delayed peak lithium concentrations could be associated with a delayed absorption of a large fraction of aggregate-formed lithium in the gastrointestinal tract, although the presence of a lithium aggregate or pharmacobezoar was not investigated. (15)

In our patient, there was a temporal correlation between the time course of the delayed peak concentrations and the oral liquid intake, which could explain the increase in lithium serum levels. (14) This phenomenon could be explained by the presence of a gastrointestinal drug reservoir, where insoluble aggregates may be formed. (3,15,17,18) In our patient, any studies were performed to detect the presence of a lithium aggregate into the gastrointestinal tract. In the literature, the delayed peak lithium concentration was associated with direct instillation of fluids or feedings into the gastrointestinal tract via a nasogastric tube. (3,15)

Conclusion

We report a case of a minimally symptomatic acute poisoning with an extended-release lithium formulation. In this case, an unrecognized delayed toxic peak lithium concentration was detected 37 hours after overdose with this formula. Therefore, patients presenting with acute intoxication with extended release formulations should be managed with caution. Continued drug monitoring is advisable after an acute ingestion with a sustained-release lithium product.

References

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15. Dupuis RE, Cooper AA, Rosamond LJ, et al. Multiple delayed peak lithium concentrations following acute intoxication with an extended-release product. Ann Pharmacother 1996;30:356-360.

16. Borras-Blasco J, Murcia Lopez A, Romero Crespo I, et al. [Acute intoxication with sustained-release lithium carbonate tablets. A propos of a case.] Farm Hosp 2005;29:140-143.

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Joaquin Borras-Blasco, PharmD, PhD, Ana Esther Sirvent, MD, Andres Navarro-Ruiz, PharmD, Ana Murcia-Lopez, PharmD, Isabel Romero-Crespo, PharmD, and Ricardo Enriquez, MD, PhD

From the Pharmacy Department, Hospital de Sagunto, Sagunto, Spain and Pharmacy Department and Nephrology Department and Pharmacy Service, Hospital General Universitario de Elche, Elche, Spain.

Reprint requests to Joaquin Borras-Blasco, Pharmacy Department, Hospital de Sagunto, Avda Ramon y Cajal s/n, Sagunto 46520 (Valencia) Spain. Email: [e-mail]

Accepted August 1, 2006.

RELATED ARTICLE: Key Points

* Delayed peak lithium concentrations (>6 mEq/L) may occur after an overdose of extended-release lithium tablets.

* Continued drug monitoring is advisable after an acute ingestion with a sustained-release lithium product.