Therapeutic approaches in the management of oral cyclosporine A intoxication.

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Although cyclosporine A (CsA) is widely used in transplantation to prevent allograft rejection and graft-versus-host disease, limited experience exists in the management of patients receiving an acute overdose of CsA. Oral overdoses seem to be of minor hazard compared with parenteral intoxication (1). Here we report a renal transplant patient who underwent whole blood exchange (WBE) after enteral intoxication with CsA, followed by continuous hemofiltration. A 68-year-old man who underwent renal transplantation because of bilateral end-stage kidney disease of unknown origin received a 100-fold oral overdose of CsA (50 mL instead of 0.5 mL). Renal parameters were within the normal range. Overdose was detected within 2 hr. Although CsA is poorly absorbed from the gut, plasma levels exceeded 1500 ng/mL and detoxification therapy was started to prevent further renal complications. First, intensive gastric lavage was performed followed by endoscopic fluid suction from the duodenum and instillation of cholestyramine (4,000 mg/bag; Quantalan, Bristol-Myers Squibb, Epernon, France). Plasma levels of CsA were almost unchanged (1100 ng/mL) 8 hr after detoxification management had been started. CsA is predominantly distributed through the tissues, but 60% of CsA in blood is red blood cell associated, 10% is leukocyte associated, and 30% is bound to plasma lipoproteins. Therefore, we decided to perform WBE. For WBE, a portable cell separator (MCS 3p; Haemonetics, Braintree, MA) was used. Because of acute renal failure, continuous hemofiltration (Prisma Set, Hospal, Cobe Lakewood) with a filtration rate of 2,000 mL per hour was applied 2 hr after WBE. WBE had no immediate effect on serum CsA levels, which measured 1,100 ng/mL before and 1,110 ng/mL after WBE. Levels were 1,022 ng/mL and 1,237 ng/mL in the depleted red blood cell fraction and plasma fraction, respectively. However, CsA plasma levels rapidly decreased after starting the hemofiltration. Plasma levels declined to 802 ng/L within 2 hr and continuously decreased during hemofiltration to 159 ng/mL after 72 hr. Because of persisting anuria, hemofiltration was continued for another 5 days and was stopped when the patient produced 910 mL of urine. Serum creatinine levels increased from 114 μmol/L to a maximum of 194 μmol/L and normalized within 11 days (83 μmol/L). No impairment of liver function occurred. The patient recovered and was dismissed from intensive care 10 days after CsA intoxication. He was discharged from the hospital 1 month later. There is no definite treatment for CsA intoxication. Until now, only symptomatic treatment of intoxication has been possible (2). In the case of oral intoxication, detoxification management by forced emesis or gastric lavage is recommended to minimize enteral absorption (1). In addition an attempt was made to eliminate CsA from our patient’s blood in adjunct to the prevention of gastroenteric resorption because of high risk for renal failure. CsA is not dialyzable and therapeutic plasma exchange is not established (2), because the protein binding capacity of CsA is too low (30%) (3). In two cases with neonatal CsA intoxication, WBE was applied with different outcomes. In one case, the CsA level was reduced by 30% (1). The almost unchanged CsA levels after WBE (Fig. 1) may possibly be a result of further gastroenteric resorption or a result of redistribution from the tissues. The decrease of CsA levels after onset of hemofiltration would at first suggest therapeutic benefit, but when compared with the mean elimination half-life of CsA, its effect is doubtful (Fig. 1). Figure 1: Time course of CsA levels (filled circles) after WBE (no apparent effect) and during hemofiltration (HF). Open triangles, estimated plasma CsA levels based on the half-life of CsA (T1/2=27 hr). As the two curves overlap, HF does not seem to enhance CsA elimination.Thus, hemofiltration should remain restricted to patients with renal impairment or should be used for symptomatic treatment of renal sequelae. In summary, gastric lavage, cholestyramine installation, and fluid suction are possibly helpful to reduce absorption of CsA after oral intoxication. WBE and hemofiltration are probably not useful. Gerda C. Leitner Michael Hiesmayr Paul Hoecker Bernd Jilma