Extracorporeal elimination in acute valproic acid poisoning.
BACKGROUND
Valproic acid (VPA) is an antiepileptic drug that is now used for a variety of neurological and psychiatric indications. Clinical manifestations of severe VPA poisoning include central nervous system depression, hypotension, electrolyte and acid-base disturbances, and hyperammonemia. Although extracorporeal methods have been used to enhance VPA elimination, the indications for and effectiveness of these methods have not been fully characterized.


METHODS
A systematic literature search was performed, which identified 31 reports of the use of extracorporeal elimination in VPA poisoning.


RESULTS
VPA has a low molecular weight of 144 Da and a low volume of distribution, but at therapeutic concentrations, it is highly protein bound (85-95%). Protein-binding studies during hemodialysis demonstrate that at high VPA concentrations protein binding is saturated, allowing substantial clearance of the free VPA fraction. Case reports consistently show that during hemodialysis the elimination half-life of VPA can be reduced to around 2 h and the enhanced VPA clearance is often associated with improvement clinically. Hemoperfusion also enhances VPA elimination, but its effectiveness may be limited by column saturation. "In-series" hemodialysis and hemoperfusion have been used, but the combination offers little benefit over hemodialysis alone. Continuous renal replacement techniques are increasingly being used although continuous venovenous hemofiltration and continuous venovenous hemodiafiltration do not appear to be as effective as hemodialysis. No controlled trials are available comparing clinical outcomes with or without extracorporeal elimination in VPA poisoning. Novel techniques such as slow low-efficiency dialysis with filtration and supplementation of the dialysate with albumin are being evaluated.


METHODS
Extracorporeal methods of elimination should be considered in patients with features of severe VPA poisoning (coma or hemodynamic compromise) and plasma VPA concentration >850 mg/L (coma is more likely to be present at concentrations >850 mg/L), particularly if severe hyperammonemia and electrolyte and acid-base disturbances are present.


CONCLUSIONS
Based on limited anecdotal evidence, hemodialysis appears to be the extracorporeal method of choice to enhance VPA elimination in acute poisoning. Controlled, randomized trials are required to better characterize the effect of extracorporeal treatment on clinical outcome.
Thanacoody
Ruben H K
RH
National Poisons Information Service (Newcastle Unit), Regional Drugs and Therapeutics Centre, School of Clinical and Laboratory Sciences, University of Newcastle, Newcastle upon Tyne, UK. ruben.thanacoody@nuth.nhs.uk
D000208:Acute Disease; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000506:poisoning*; D016206:Databases, Bibliographic; D062787:Drug Overdose; D006207:Half-Life; D006464:Hemoperfusion / Q000379:methods*; D006801:Humans; D011041:Poisoning / Q000209:etiology / Q000628:therapy*; D011485:Protein Binding; D006435:Renal Dialysis / Q000379:methods*; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000506:poisoning*
D000927:Anticonvulsants; D014635:Valproic Acid