Effectiveness of haemodialysis with high-flux membranes in the extracorporeal therapy of life-threatening acute lithium intoxication

Ramón Peces and Alfonso Pobes

Service of Nephrology, Hospital Central de Asturias, Oviedo, Spain

Sir,

Lithium carbonate is commonly prescribed for the treatment of bipolar (manic-depressive) disorders. However, because of its narrow therapeutic index an excessive elevation of serum lithium concentration, either during chronic maintenance therapy or after an acute overdose, can result in serious toxicity. In addition to supportive care, the established treatment of severe lithium toxicity is haemodialysis. Conventional haemodialysis can reduce the serum lithium concentration rapidly [14], but post-dialysis rebound elevations with recurrent toxicity have been documented. High-flux membranes should be capable of removing more lithium per hour of haemodialysis, but published values are not available. We report here a patient with life-threatening acute lithium intoxication complicated by renal failure who was treated successfully with haemodialysis. This is the first reported case describing the effects of high-efficiency dialysers on lithium pharmacokinetics.

Case.

A 29-year-old woman with a history of bipolar affective disorder attempted suicide. She was admitted to our hospital after being found unresponsive at home and approximately 20 h after ingesting 100, 400-mg lithium carbonate, sustained-release tablets (total 1083 mmol). At admission, the patient presented with stupor, gross tremor, and confusion. Blood pressure was 100/60 mmHg, heart rate was 120 bpm, and urine output was 15 ml/h. After repeated gastric lavages the initial serum lithium level was 5.83 mmol/l. Other laboratory data showed haematocrit 51%, haemoglobin 17.6 g/dl, WBC 42 000/mm3, platelets 300 000/mm3, urea 106 mg/dl, creatinine 5.7 mg/dl, sodium 132 mmol/l, potassium 7 mmol/l, bicarbonate 20 mmol/l. To reverse volume depletion and to lower the serum potassium level rapidly, 1000 ml of normal saline, 250 ml of 1/6 molar bicarbonate, and 1000 ml of 10% glucose with 45 IU of insulin were infused. Four hours after hospital admission, haemodialysis was instituted using a double-lumen femoral catheter, a high-efficiency dialyser made of 1.5 m2 cellulose triacetate membrane, a bicarbonate dialysate, a blood flow of 150 ml/min, and a dialysate flow of 500 ml/min. During 3 h of haemodialysis an ultrafiltrate volume of 1200 ml was replaced with saline. During and after haemodialysis, the patient's haemodynamic status remained stable and the urine output was maintained between 80 to 110 ml/h. The post-dialysis serum lithium level was 5.22 mmol/l. Twenty hours later the serum lithium level was 4.66 mmol/l and a second haemodialysis was performed using a 1.36 m2 high-flux polysulfone membrane, with a blood flow of 180 ml/min. During 4 h of haemodialysis an ultrafiltrate volume of 2000 ml was replaced with saline. The post-dialysis serum lithium level was 2.48 mmol/l. For the subsequent haemodialysis sessions, serum lithium concentrations dropped from 1.82 to 0.84, 1.02 to 0.50 mmol/l, after 6, and 4 h of haemodialysis, respectively. The haemodialysis treatment was discontinued when the serum lithium level was 0.50 mmol/l. Serum lithium concentrations were followed over several days after discontinuation of haemodialysis. Pre-dialysis and post-dialysis serum levels of lithium are given in Figure 1Go.



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Fig. 1. Lithium levels during the hospitalization. The timing of the haemodialysis (HD) procedure is indicated.

 
The serum lithium concentrations were used to calculate patient-specific pharmacokinetic parameters using standard equations. The rate constant of drug removal during haemodialysis and half-life were calculated using: K=1/time (C1/C2); T1/2=0.693/K, where ‘time’ denotes the change in time (hours) between the lithium serum samples ‘C1’ and ‘C2’ [1,3].

Forty-eight hours after admission the patient developed seizures and deep stupor and was intubated. She recovered consciousness slowly over the following 5 days and was extubated after 11 days. Her mental status and neurologic status returned to normal without permanent neurologic sequelae, and magnetic resonance imaging of the brain was unremarkable.

Discussion.

Lithium is a small ion with virtually no protein binding; hence its volume of distribution is very low, thereby allowing dialysis to be particularly effective as an adjunct mechanism of lithium removal. The occurrence of toxicity is related to the serum concentration of lithium. Mild toxicity appears at levels up to 2.5 mmol/l, severe toxicity is seen at levels of 2.5 to 3.5 mmol/l, and life-threatening effects are manifest at levels above 3.5 mmol/l. The highest lithium serum level following acute intoxication, 9.6 mmol/l, was reported by Jaeger et al. [1] and the patient survived. Initial serum levels between 5 and 6 mmol/l have been reported by others [2]. Although haemodialysis markedly decreases lithium half-life, at the end of session there is typically a significant rebound in serum levels as lithium diffuses out of cells [3]. This has been interpreted as reflecting a slower equilibrium across the cell membrane than across the dialyser membrane. This rebound also may be a result of delayed gastrointestinal absorption of extended-release tablets of lithium. Acetate haemodialysis also may partially contribute to lithium rebound [2]. By promoting intracellular lithium accumulation, acetate would reduce net cellular efflux of lithium. Acetate diffuses into cells as acetic acid, inducing intracellular acidosis and activating the sodium–hydrogen antiporter. Protons are transported out of the cell while lithium substituting for sodium is transported into the cell. After the acetate is metabolized, lithium exiting from the cell would increase the extracellular lithium level. Consequently, conventional haemodialysis has to be performed over extended time periods and/or repeated frequently.

Because of a longer treatment time, continuous renal replacement therapy would offer the major advantage of a sustained and more complete removal of intracellular lithium, thus avoiding post-dialysis rebound [57]. However, a rebound increase in lithium concentration after cessation of continuous arteriovenous hemodiafiltration has been reported [5]. In addition, continuous therapies do not reduce lithium levels as quickly as haemodialysis and are often limited by the need for close surveillance and prolonged anticoagulation, which can lead to bleeding complications. They may be particularly useful for patients with chronic poisoning (or acute on chronic intoxication) in whom intracellular lithium accumulation poses a substantial risk for permanent sequelae [6].

Our patient presented with a severe degree of intoxication, based on the amount of drug ingested, the initial serum lithium level, the impairment of renal function, the severity of neurologic symptoms, and systemic manifestations. She developed acute renal failure probably as a result of volume depletion since it was rapidly reversible by haemodialysis and infusion therapy. In addition, consecutive haemodialysis sessions and improvement of renal function allowed a rapid decrease in serum lithium levels without haemodynamic instability or rebound elevations in lithium concentration. The effectiveness of the procedure in this case can be attributed to the use of high-efficiency dialysers.

In a recent report describing the effect of conventional haemodialysis on the pharmacokinetic of lithium, the rate constant of drug removal and the half-life were 0.26 h-1 and 2.6 h, respectively [3]. In our case with high-flux haemodialysis membranes, the elimination rate constant ranged from 0.36 to 0.51 h-1 and the half-life from 1.36 to 1.91 h, respectively. The elimination rate constant in our patient was 5–7 times greater during haemodialysis than after haemodialysis (only renal excretion). During the procedure, the serum half-life values were 1.86, 1.47, 1.91, and 1.36 h. The serum half-life increased to 12.37, 10.17, and 9.65 h after the procedure while only receiving forced diuresis.

There are several reasons to suggest that haemodialysis as implemented in this case is preferable to continuous therapies in the treatment of acute lithium intoxication. Haemodialysis offers the advantage of more rapid removal of lithium. In addition, haemodialysis removes uraemic toxins and corrects fluid, electrolyte and acid–base abnormalities, when present. Finally, the lactate-based alkalinizing agent used in continuous therapies also may reduce net cellular efflux of lithium (such as acetate). In this context, the use of a bicarbonate- containing dialysate may prevent intracellular acidification, the subsequent activation of the sodium–hydrogen antiporter and ultimately, the intracellular accumulation of lithium [2].

We conclude from the above data, that modern haemodialysis using bicarbonate dialysate and highly permeable dialysis membranes should be recommended as the therapy of choice for severe acute lithium intoxication. It should be performed in any patient who presents with coma, convulsions, respiratory failure, deteriorating mental status, and especially if renal function is compromised. Using this technique, the elimination rate of lithium was found to be greater than previously reported with haemodialysis.

References

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