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Gfh297 441.443

Nephrol Dial Transplant (2005) 20: 441–443doi:10.1093/ndt/gfh297 Treatment of baclofen overdose by haemodialysis: a pharmacokineticstudy Vin-Cent Wu1,2, Shuei-Liong Lin2, Shu-Meng Lin3 and Cheng-Chung Fang3 1Department of Internal Medicine, Far Eastern Memorial Hospital, 2Department of Internal Medicine and 3Departmentof Emergency Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei,Taiwan drowsy, her blood pressure was 199/60 mmHg and temperature 36.7C. Laboratory data showed haemo-globin 8.1 g/dl, WBC 4900/mm3, with a normaldifferential count and platelets 268 000/mm3. Serum sodium was 147.4 mmol/l, potassium 4.42 mmol/l,ammonia <1 mmol/l, sugar 107 mg/dl, urea 51 mmol/l Baclofen is currently used in the treatment of muscle and creatinine 8.26 mg/dl. The transaminases were spasticity, especially in patients with multiple sclerosis normal. A brain CT scan showed cortical atrophy or in patients with spinal or cerebral disorders.
and leukoaraiosis. Under the diagnosis of baclofen Baclofen is eliminated predominantly by the kidneys intoxication, she received emergency haemodialysis.
[1], putting patients with impaired renal function at The dialyser had ethylene vinyl alcohol copolymer resin particular risk for baclofen accumulation. Several filters with a surface area of 2.0 m2, and the blood flow investigators have suggested that haemodialyis is rate was at a constant 300 ml/h for 4 h without ultra- effective in the removal of baclofen [2], however the filtration. There was a complete recovery of conscious- pharmakokinetics of baclofen elimination during ness 8 h later. She received another haemodialysis haemodialysis remains unclear. We herein report session 30 h after admission. The patient was discharged a baclofen-associated encephalopathy, which was from the hospital 72 h later in good condition.
resolved by haemodialysis, and pharmacokinetic datais presented. To our knowledge, this is the first reportedcase of baclofen-related encephalopathy with pharma- cokinetic data during haemodialysis treatment.
Serum baclofen concentrations Blood samples were collected immediately after arrival, and at 4 (start of first haemodialysis), 5, 6, 7, 8 (end offirst haemodialysis), 30 (start of second haemodialysis), A 70-year-old woman with end-stage renal disease 32 and 34 h (the end of second haemodialysis) there- (ESRD) was treated by haemodialysis regularly for 14 after. Samples of serum were prepared according to the years. She was anuric and received adequate haemo- methods published in previous reports with minor dialysis at Kt/V 1.95. She presented with left leg modifications [3]. In brief, serum samples (1 ml) were soreness and was given 5 mg of oral baclofen three prepared by adding 200 ml of the internal standard times daily from the local clinic, receiving a cumulative [1 mg/ml of 3-amino-3-(4-chlorophenyl)-propionic acid] dose of 45 mg in 3 days. The patient became disor- and 20 ml of 85% ortho-phosphoric acid and then were iented, in a state of confusion and was referred to our loaded into Oasis HLB SPE columns (Waters) for hospital for evaluation. At admission, she was found extraction. Gas chromatography/mass spectrometryanalysis was performed on an Agilent 5890 gaschromatograph coupled with a 5973 mass selective Correspondence and offprint requests to: Dr Cheng-Chung Fang, detector and a 7683 injector. Quantitative analysis was Departments of Emergency Medicine, National Taiwan University carried out on the Agilent ChemStation. Calibrators Hospital, 7 Chung-Shan South Road, Taipei, Taiwan. Email:[email protected] were baclofen spiked serum samples at concentrations Nephrol Dial Transplant Vol. 20 No. 2 ß ERA–EDTA 2005; all rights reserved V.-C. Wu et al.
subjects, but increases in ESRD, and an accumulationphenomenon can occur [1]. Baclofen is moderatelylipophilic, 30% of the drug is protein bound, and canpenetrate the blood–brain barrier, entering the centralnervous Concentrations of baclofen in cerebral spinal fluid(CSF) have been described to be 8.4 times lower thanthose simultaneously present in plasma [5]. It has avolume of distribution of 0.83 l/kg in adult [7] and2.58 l/kg in children [8].
The therapeutic range of baclofen is 80–400 ng/ml in normal subjects [9], but the appropriate serum levelof baclofen in patients with severely impaired renalfunction remains unclear. Several authors have sug- Fig. 1. Changes of serum baclofen levels with time. (A) gested that patients with renal failure are more The first haemodialysis session. (B) second haemo- susceptible to baclofen toxicity [2]. This may explain dialysis session.
why our patient was comatose, although her plasmabaclofen concentrations were all within the therapeutic of 25, 50, 200 and 500 ng/ml. The serial serum range of normal subjects.
concentrations of baclofen after admission are shown Several observations of baclofen-associated encepha- in Figure 1.
lopathy have been reported in patients with ESRD [10].
Patients with severely impaired renal function generallydevelop baclofen intoxication soon after the initiation of therapy [2]. Altered consciousness has been the During dialysis, solute elimination occurs via the first- major manifestation in patients with severely impaired order kinetic process [4]. The distribution of a drug in a renal function. Other symptoms, such as respiratory dialysed, renal failure patient can be expressed by a depression muscular hypotonia and generalized hypor- one-compartment model [4]. As a result, baclofen eflexia have been observed in patients of baclofen plasma concentration (C) vs time profile may be intoxication with normal renal function [2]. Most described with the following equation: ESRD patients experienced marked improvement inclinical toxicity following haemodialysis, compared with patients who did not receive haemodialysis [2].
We measured the changes of baclofen serum concen- tration during haemodialysis and found that the serum Ke ¼ the total elimination rate constant; and t ¼ time baclofen eliminated up to 79% during the 4 h of the after admission.
haemodialysis session. Haemodialysis shortened the Furthermore, during dialysis, the total elimination baclofen half-life from 15.5 to 2.06 h in this patient.
constant rate (Ke) equals the non-renal removal rate Therefore, it is reasonable to suggest that haemodia- constant (Knr), plus the renal removal rate constant lysis should be used as a treatment modality in cases (Kr), plus the dialysis removal rate constant (Kd). Kr of baclofen intoxication with renal failure.
equals zero in this anuria patient, and Knr can be According to a previous report, patient conscious- calculated from the two samples collected before ness improved with several hours time lag after haemodialysis. Therefore, the Kd can be calculated by haemodialysis [2]. This delay may be due to the the given Ke and Knr. The pharmacokinetic data of redistribution of baclofen in crossing the blood–brain baclofen in this patient are Ke ¼ 0.336/h, Knr ¼ 0.045/h barrier [2]. This may explain longer central nervous and Kd ¼ 0.291/h; while the data of total elimination system depression despite reductions in serum drug half-life (t1/2) during haemodialysis is 2.06 h, 15.5 h for concentrations to negligible amounts. The conscious- non-renal t1/2.
ness improved after just one session of haemodialysis inthis patient, which was different from previous reportswhere two or more sessions were necessary [2]. Because there were no serum levels and other pharmacokineticdata in previous reports [2], it is difficult to compare the Baclofen is a b-( p-chlorophenyl) derivative of the effectiveness of haemodialysis in this report. In our neurotransmitter g-aminobutyric acid (GABA). This patient, early diagnosis, early start of haemodialysis centrally acting GABA agonist is prescribed as therapy and lower serum concentrations of baclofen may have for spasticity in the spinal cord region. Ingested resulted in the difference. The larger surface area of our baclofen is absorbed rapidly and completely, thereafter artificial kidney may be another possible cause.
69–85% are excreted without changes in urine and 15% In conclusion, it is necessary to reduce baclofen are metabolized by the liver to its inactive deaminated dosage in patients with renal disease and especially in ESRD patients. Haemodialysis is an appropriate [1,5]. The half-life is between 4.5 and 6.8 h in healthy treatment of baclofen intoxication in ESRD patients.
Baclofen elimination in haemodialysis The authors thank Dr Chun-Chen Yang for 4. Gibson TP, Matusik E, Nelson LD, Briggs WA. Artificial comments and criticism of this article. This study was supported by kidneys and clearance calculations. Clin Pharmacol Ther 1976; The Ta-Tung Kidney Foundation.
5. Faigle JW, Keberle H. The chemistry and kinetics of Lioresal.
Conflict of interest statement. None declared.
Postgrad Med J 1972; 48: [Suppl 5]: 9–13 6. Zieglgansberger W. Dorsal horn neuropharmacology: baclofen and morphine. Ann N Y Acad Sci 1988; 531: 150–156 7. Anderson P, Noher H, Swahn CG. Pharmacokinetics in baclofen overdose. J Toxicol Clin Toxicol 1984; 22: 11–20 1. Wuis EW, Dirks MJ, Termond EF, Vree TB, Van der Kleijn E.
8. Wiersma HE, van Boxtel CJ, Butter JJ, van Aalderen WM, Plasma and urinary excretion kinetics of oral baclofen in Omari T, Benninga MA. Pharmacokinetics of a single oral dose healthy subjects. Eur J Clin Pharmacol 1989; 37: 181–184 of baclofen in pediatric patients with gastroesophageal reflux 2. Chen KS, Bullard MJ, Chien YY, Lee SY. Baclofen toxicity disease. Ther Drug Monit 2003; 25: 93–98 9. Peces R, Navascues RA, Baltar J, Laures AS, Alvarez-Grande Pharmacother 1997; 31: 1315–1320 J. Baclofen neurotoxicity in chronic haemodialysis patients with 3. Flardh M, Jacobson BM. Sensitive method for the determina- hiccups. Nephrol Dial Transplant 1998; 13: 1896–1897 tion of baclofen in plasma by means of solid-phase extraction 10. Bassilios N, Launay-Vacher V, Mercadal L, Deray G. Baclofen neurotoxicity [correction of unerotoxicity] in a chronic haemo- J Chromatogr A 1999; 846: 169–173 dialysis patient. Nephrol Dial Transplant 2000; 15: 715–716 Received for publication: 27.12.03Accepted in revised form: 5.4.04


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HUMAN ENHANCEMENT? Ethical Reflections on Emerging Nanobio-technologies Report on an Expert Working Group on Converging Technologies for Human Functional Enhancement NanoBio-RAISE EC FP6 Science and Society Co-ordination Action by Donald Bruce Edinethics Ltd., 11/6 Dundonald Street, Edinburgh EH3 6RZ, Scotland, UK [email protected] with the Society, Religion and Technology Project, Church of Scotland