Intravenous Valproate Dosing in Neonates

Abstract

The loading dosage of intravenous valproate required to achieve a desired serum concentration in neonates is not known. Two neonates with seizures received loading doses of intravenous valproate over 30 minutes. Serum valproate concentrations were measured 45 minutes and 3 hours after initiation of the infusion. Both neonates had received phenobarbital and phenytoin before the loading infusions. In the first patient, a loading dose of intravenous valproate of 10 mg/kg increased the 45-minute postinfusion serum valproate concentration to 41 microg/mL with a 3-hour postinfusion serum valproate concentration of 33 microg/mL. In the second patient, a loading dose of 25 mg/kg increased the 45-minute postinfusion serum valproic acid concentration to 100 microg/mL with a 3-hour postinfusion serum valproic acid concentration of 78 microg/mL. We found that each 1 mg/kg of intravenous valproate increased the 45-minute and 3-hour postinfusion serum valproic acid concentrations by approximately 4 microg/mL and 3 microg/mL, respectively. We suggest that these figures be used to calculate the desirable loading dose of intravenous valproate in neonates until larger studies are conducted. The volume of distribution and the serum clearance of valproate were approximately 0.245 L/kg and 25 mL/h/kg, respectively.

A Severe Valproate Overdose With Complete Recovery in a Newborn

“…3 Valproate-induced hyperammonemia does not appear to be related to liver failure as all reported patients with valproate-induced hyperammonemic encephalopathy had normal liver function tests (Tables 1 and 2). [1][2][3] Brain edema is a major complication of severe valproate intoxication. 7,9,12 Contrary to previously reported small children with fatal outcome, 3,12 our patient did not present cerebral edema and had a completely reversible hyperammonemic encephalopathy.…”

“…Even if valproate has demonstrated its efficacy in some cases of neonatal seizures, 1 it is almost constantly associated with a severe elevation of blood ammonium levels 1 –3 that prompts drug discontinuation in most cases (Table 1). 1,2 Because valproate is seldom used in newborns, overdose is extremely rare.…”

“…Even if valproate has demonstrated its efficacy in some cases of neonatal seizures, 1 it is almost constantly associated with a severe elevation of blood ammonium levels 1 –3 that prompts drug discontinuation in most cases (Table 1). 1,2 Because valproate is seldom used in newborns, overdose is extremely rare. In fact, there is only 1 report of a 26-day-old newborn that developed progressive hyperammonemia, cerebral edema, and diminished level of consciousness and had a fatal outcome after valproate overdose (Table 2).…”

“…Valproate can control seizures in some newborns 1 but, in this age group, it almost constantly elevates the blood ammonium levels, [1][2][3] and the risk of toxicity is uncertain. 4 Consequently, valproate is seldom used for neonatal seizures.…”

“…4 For this reason, while the clinical [4][5][6][7][8][9] and radiologic 10,11 consequences of valproate overdose have been extensively reported in adults and older children, they are largely unknown in the neonatal period. In fact, the literature on valproate intoxication in neonates is limited to a few cases of hyperammonemia in patients on therapeutic doses of valproate 1,2 and a single case report of valproate overdose with fatal outcome. 3 Here, we report the case of a newborn that developed a hyperammonemic encephalopathy after a severe valproate overdose.…”