We observed 2 cases of valproic acid overdose in which concentration-dependent prolongation of QT interval occurred. The most commonly reported adverse effects of toxic concentrations of valproic acid include cerebral edema, hyperammonemia and hepatotoxicity, but primary cardiovascular effects have not previously been reported. A 20-year-old woman developed prolongation of the corrected QT interval (QTc) following an overdose of 40 tablets of valproic acid 500 mg. There was no evidence of co-ingestion, electryolyte abnormalities or episodes of hypoxia. A 21-year-old man also developed prolongation of QTc following a suicide attempt with an unknown quantity of valproic acid. In both cases serial data on serum valproic acid concentrations and EKG’s enabled the relationship to QTc to be investigated. Analysis of concentration data demonstrated normal first order elimination of valproate with a half-life of 24 hours (normal 16 hours). The maximum concentration in the first case was 6000 µmol/L and in the second 5376 µmol/L (normal range 350 – 700 µmol/L). In the first case QTc was prolonged to 603 ms (normal 420 ms) and declined in relation to the falling valproic acid concentrations. The relationship followed a sigmoid concentration-response relationship shown in the Figure, with an EC50 for QTc effect of 1500 µmol/L. In the second case, QTC also declined as valproate was eliminated.

In these 2 patients, it appears that valproic acid affected the QTc. The sigmoidal response curve suggests the maximum response QTc to valproate is 600 ms, but over the therapeutic range of valproic acid concentrations, QTc would change by only 2%. Thus it would be neither evident nor of clinical importance in clinical therapy and only during overdose would concentrations be high enough to dangerously elevate QTc. It is reasonable to suggest that, as for tricyclic antidepressant overdoses, serial ECG’s should be obtained in cases of massive valproic acid overdose until
concentrations normalize.

DNC

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