1 Department of Nephrology, 3 Department of Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), 2 Institute of Pharmacology and Toxicology, University Leipzig, Leipzig, Germany
Sir,
The application of the alkylating agent ifosfamide (IFO) in combination with other chemotherapeutics plays an important role in the treatment of solid tumours and lymphoma in the oncology. However, the therapeutic use is limited because of the nephrotoxicity and neurotoxicity of IFO and its metabolites. An IFO dose of 12 g/m2/cycle causes myelosuppressive effects and an increased infection rate. Irreversible renal failure was obtained following cumulative doses of 26 g/m2/cycle IFO; however, acute nephrotubular damage has been frequently observed in cumulative doses of 15 g/m2/ cycle IFO [13].
In case of IFO intoxication, therapeutic approaches are the application of methylene blue in IFO-associated encephalopathy [4] and haemodialysis [5]. In vitro experiments suggest that haemodialysis might be an effective detoxification method, since IFO concentrations were decreased by 87%, those of 4-hydroxyifosfamide by 36%, and those of chloroacetaldehyde by 77% [6]. The aim of our investigation was to evaluate the potentially additional effect of haemoperfusion when combined with haemodialysis in IFO intoxication.
Case.
In a 38-years-old male patient suffering a relapse of non-Hodgkin lymphoma (enlargement of lymph nodes in the neck and in the thoracic and abdominal cavities), the schedule of a planned new oncological chemotherapy was determined on the basis of body surface area (1.83 m2) with 9.1 g IFO over 24 h, etoposide 183 mg, and carboplatin 576 mg over 60 min per day, all for 3 consecutive days.
There were no problems on day 1. However on day 2 a technical failure led to the application of 9.1 g IFO in 1 h instead of being administered over 24 h. When the overdosage was detected, approximately 1 h after the end of the IFO infusion, the patient already showed clinical symptoms (slight confusion and muscle weakness). Vital parameters such as blood pressure, heart rate, and blood gas analysis were in the normal range. Immediately after the detection of overdosage, detoxification by means of haemoperfusion (charcoal cartridge Adsorba 300 C, Gambro, contents 300 g active carbon) combined with haemodialysis (haemodialyser F 6, Fresenius Medical Care), was initiated.
During the following detoxification procedure (4 h) we observed no aggravation of clinical symptoms. Haemoperfusion combined with haemodialysis reduced the serum concentrations of IFO by 84% (T=0 h, 206.3 µg/ml; T=4 h, 32.9 µg/ml), of carboxy-IFO by 61% (T=0 h, 9 µg/ml; T=4 h, 3.5 µg/ml), of 2-dechloroethyl-IFO by 45% (T=0 h, 4.2 µg/ml; T=4 h, 2.3 µg/ml), and of 3-dechloroethyl-IFO by 52% (T=0 h, 14.9 µg/ml; T=4 h, 7.2 µg/ml). The elimination effect of haemoperfusion was the binding of at least 678 mg IFO, 19.1 mg carboxy-IFO, 18 mg 2-dechloroethyl-IFO, and 50.9 mg 3-dechloroethyl-IFO on the whole charcoal cartridge. IFO and its metabolites were measured in serum and in 250 mg active carbon by gas chromatography and high-pressure liquid chromatography-linked spectroscopy respectively.
In relation to the applied IFO dose (9.1 g) and its elimination (84%=7.6 g) the detoxification effect of IFO by haemoperfusion was at least 9% (0.68 g).
During the further course renal function was regularly controlled by measuring serum creatinine and urea as well as diuresis and creatinine clearance. Four days after intoxication, an impairment of renal function (creatinine clearance 46 ml/min) with mild tubular proteinuria (protein 230 mg/l, albumin 31 mg/l, alpha1-microglobulin 41.4 mg/l, beta2-microglobulin 16 mg/l) and increased activity of beta-NAG (34.9 IU/l) in urine was detected. After 10 days, renal function recovered (creatinine clearance 139 ml/min) and proteinuria was no longer demonstrable. Serum creatinine (61106 µmol/l), serum urea (4.110.7 mmol/l) and diuresis (3.35.4 l/day) were unchanged during this time.
Comments.
Thus the combination of haemoperfusion and haemodialysis was a very effective detoxification method in this patient with IFO intoxication, because elimination of IFO was acceptable and neurotoxic and nephrotoxic damage was reversible. Several authors [5,6] have already established haemodialysis as an efficient detoxification method, but so far haemoperfusion as an additional method has not been examined. Although our results shows only a low haemoperfusion effect, we recommend haemoperfusion combined with haemodialysis in IFO intoxication. Finally, in cases of intoxication all effective detoxification methods available should be used.
References