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Valproic acid efficacy, toxicity, and pharmacokinetics in neonates with intractable seizures
1Moses H. Cone Memorial Hospital, Greensboro, NC 27401.
Insights
Valproic acid (VPA) effectively controlled prolonged seizures in 83% of neonates unresponsive to other treatments. In some cases, VPA monotherapy achieved seizure control, though hyperammonemia was a noted side effect.
Area of Science:
- Neonatal Neurology
- Pharmacology
Background:
- Prolonged, intractable seizures in neonates pose significant treatment challenges.
- Standard anticonvulsant therapies often prove insufficient for refractory neonatal seizures.
Purpose of the Study:
- To evaluate the efficacy and safety of valproic acid (VPA) in treating prolonged, intractable seizures in neonates.
- To assess VPA pharmacokinetics in this patient population.
Main Methods:
- Retrospective analysis of six neonates with intractable seizures treated with VPA.
- Patients had failed maximum doses of phenobarbital and often multiple other anticonvulsants.
- Pharmacokinetic parameters for total and unbound VPA were measured.
Main Results:
- Seizure control was achieved in 5 out of 6 (83%) neonates.
- VPA monotherapy was successful in 4 cases after withdrawal of other anticonvulsants.
- Hyperammonemia led to VPA discontinuation in 3 patients.
- Detailed VPA pharmacokinetic data (volume of distribution, clearance, half-life) for total and unbound VPA were documented.
Conclusions:
- Valproic acid demonstrates significant efficacy in managing intractable neonatal seizures, even after failure of other treatments.
- VPA monotherapy can be a viable option for seizure control in neonates.
- VPA-induced hyperammonemia is a critical adverse event requiring monitoring in neonates.
Abstract:
Six neonates with prolonged, intractable seizures were treated with valproic acid (VPA). Each patient had received maximum doses of phenobarbital (greater than 40 micrograms/ml), and five patients received at least two additional anticonvulsants, without success. Seizure activity was controlled in five of six (83%) cases. In four cases, all other anticonvulsants could be withdrawn, and seizures were controlled on VPA monotherapy. VPA was discontinued in three patients because of VPA-induced hyperammonemia. VPA pharmacokinetic measurements were as follows: for total VPA, volume of distribution (V) = 0.40 l/kg (range, 0.36 to 0.47 l/kg), serum clearance (Cl) = 14.4 ml/h/kg (5.5 to 18.2 ml/h/kg), half-life (T1/2) = 26.4 hours (8.6 to 48.5); for unbound VPA, V = 2.02 l/kg (1.14 to 2.44 l/kg), Cl = 108.9 ml/h/kg (42.0 to 252.0 ml/h/kg). T1/2 = 17.6 hours (6.7 to 34.2). VPA free fraction ranged from 11.3 to 31.6% (mean, 19.2%).