Related Experiment Videos
Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticus
C A Hovinga1, M F Chicella, D F Rose
1Pediatric Pharmacotherapy, The University of Tennessee, Memphis 38163, USA.
Insights
Intravenous valproate (VPA) dosing in pediatric status epilepticus requires adjustments for hepatic induction. Higher VPA clearance rates were observed in children on concurrent anticonvulsants, necessitating tailored maintenance infusions for optimal therapeutic concentrations.
Area of Science:
- Pediatric pharmacology
- Clinical pharmacokinetics
- Neurology
Background:
- Status epilepticus (SE) is a neurological emergency requiring prompt treatment.
- Intravenous valproate (VPA) is an effective anticonvulsant, but its pharmacokinetics in pediatric SE, especially with concurrent anticonvulsant use, require further elucidation.
Observation:
- Pharmacokinetic parameters of intravenous VPA were evaluated in two children with generalized convulsive status epilepticus (GCSE) and one with nonconvulsive status epilepticus (NCSE).
- Patients receiving concurrent anticonvulsants exhibited VPA clearance rates 2.5 times higher than those on oral anticonvulsant polytherapy.
- Unbound VPA fractions were significantly elevated (48.3% and 66%) in patients with hepatic induction.
Findings:
- A 20 mg/kg loading dose of intravenous VPA is estimated to achieve concentrations of approximately 75 mg/L.
- Maintenance infusion rates should be adjusted based on hepatic induction status: 1 mg/kg/h for noninduced, 2 mg/kg/h for polyanticonvulsant therapy, and 4 mg/kg/h for high-dose pentobarbital.
- Volume of distribution and elimination half-life were comparable to existing pediatric data.
Implications:
- These findings provide crucial dosing guidance for intravenous VPA in pediatric SE, particularly for patients with hepatic enzyme induction.
- Optimized loading and maintenance doses can improve therapeutic efficacy and patient outcomes.
- Further research into VPA pharmacokinetics in diverse pediatric populations is warranted.
Objective:
To report the pharmacokinetics of intravenous valproate (VPA) in children with generalized convulsive status epilepticus (GCSE) or nonconvulsive status epilepticus (NCSE). To provide loading and maintenance dosing for patients with hepatic induction secondary to concurrent anticonvulsants.
Case Summary:
Two patients (10 y, 34 mo) with GCSE refractory to benzodiazepines, phenobarbital, phenytoin, and pentobarbital received intravenous VPA. Apparent volume of distribution (Vd) following a 20 mg/kg loading dose was 0.29 L/kg. Maintenance infusions of 4-6 mg/kg/h produced steady-state total concentrations of 66 mg/L and 92.4 mg/L (unbound concentration 44.6 mg/L). Clearance ranged from 63-66 mL/h/kg. An eight-year-old with NCSE received intravenous VPA (13.4 mg/kg load followed by 9 mg/kg every 8 h). Total and unbound steady-state VPA concentrations were 32.9 mg/L and 21.2 mg/L, respectively. Elimination half-life was eight hours.
Discussion:
We constructed a pharmacokinetic simulation using VPA parameters from children receiving mono- or polyanticonvulsants. Our Vd and elimination half-life rates were comparable with published pediatric values. Patients on hepatic inducers had clearance rates 2.5 times those of children receiving oral anticonvulsant polytherapy. Unbound fractions (48.3% and 66%) were significantly higher than normal.
Conclusions:
A 20 mg/kg loading dose should produce a concentration after the bolus dose of approximately 75 mg/L. Initial infusion should consider hepatic induction (noninduced = 1 mg/kg/h, polyanticonvulsant therapy = 2 mg/kg/h, and high-dose pentobarbital = 4 mg/kg/h). Adjustments should be based on response and serum concentrations.