Tuesday, May 17, 2016

Intravenous levetiracetam versus valproate for treatment of status epilepticus

Rana İşgüder, Orkide Güzel, Gökhan Ceylan, Ünsal Yılmaz, Hasan Ağın.  A Comparison of Intravenous Levetiracetam and Valproate for the Treatment of Refractory Status Epilepticus in Children.  Journal of Child Neurology.  Published online.


Because of the lack of studies comparing the efficacy and safety of levetiracetam and valproate before the induction of general anesthesia in the treatment of convulsive refractory status epilepticus in children, we aimed to compare the effectiveness of these antiepileptic drugs in patients with convulsive status epilepticus admitted to the Pediatric Intensive Care Unit between 2011 and 2014. Forty-six (59%) of the 78 patients received levetiracetam, and 32 (41%) received valproate for the treatment of refractory status epilepticus. The response rate was not significantly different between the 2 groups. Although no adverse event was noted in patients who received levetiracetam,  (12.5%) patients in the valproate group experienced liver dysfunction (P = .025). According to our results, levetiracetam and valproate may be used in the treatment of refractory status epilepticus before the induction of general anesthesia. Levetiracetam appears as effective as valproate, and also safer.

From the paper:

Median duration of status epilepticus was 75 minutes (interquartile range 110, min 60 to max 720). Of the patients, 46 (59%) received levetiracetam, and 32 (41%) received valproate for the treatment of refractory status epilepticus. According to our hospital’s protocol, a loading dose of 20 mg/kg levetiracetam or 20 mg/kg valproate was administered to patients. Status epilepticus was terminated in 56 (71.8%) patients during the period of valproate or levetiracetam treatment. In the remainder, midazolam or pentobarbital infusion were administered. Of all patients, 6 (7.7%) died before termination of seizure...

Although no adverse event was noted in patients who received levetiracetam, 4 (12.5%) patients in the valproate group experienced liver dysfunction (P = .025). Alanine aminotransferase and aspartate aminotransferase levels had increased up to 4 times in 3 cases and up to 5 times in one case but returned to normal levels after discontinuation of valproate therapy. Patients who were unresponsive to levetiracetam or valproate therapy were intubated, and coma induction therapy was started. There was no statistically significant difference between the 2 groups in terms of mortality rate and duration of pediatric intensive care unit stays...

Mortality in pediatric refractory status epilepticus ranges from 13% to 30%, and 50% of survivors have neurologic sequelae. Refractory status epilepticus is typically treated by induction of pharmacological coma. Aggressive treatment is associated with a rapid seizure control and improved outcomes.47 However, general anesthetic medications such as thiopental and its metabolite pentobarbital are associated with more serious side effects like respiratory depression or hypotension.

Propofol is used rarely in children, as it is associated with the risk of developing “propofol infusion syndrome (PRIS),” which is characterized by metabolic acidosis, rhabdomyolysis, and renal and cardiac failure.  Because of these serious adverse effects, other second-line anticonvulsant medications including valproate and levetiracetam are being increasingly used before anesthesia induction in the refractory status epilepticus.  This approach has also been accepted in our hospital and implemented in our daily practice .

Valproate is an antiepileptic drug used effectively in status epilepticus and refractory status epilepticus. It has a wide spectrum with multiple acting mechanisms, including modulating Na and Ca channel or inhibition of γ-aminobutyric acid transmission. However, it is associated with a high risk of hepatotoxicity in children who are younger than 2 years, those using multiple antiepileptic drugs, and those with certain inborn errors of metabolism. In our study, 12.5% of patients who received valproate developed liver dysfunction, which resolved after discontinuation of medication.

Levetiracetam have multiple sites of action including calcium channels, glutamate receptors, and GABA modulation. In the recent years, animal studies have reported that levetiracetam was highly effective in status epilepticus treatment and had a neuroprotective effect. Refractory status epilepticus is often associated with systemic disorders, such as coagulopathy, liver failure, and hypotension, that could be complicated by traditional anticonvulsants. Levetiracetam may be a safe option as it is not metabolized by the liver, has low protein binding, is renally excreted, and exhibits limited drug-drug interactions.8 Many studies have recently reported that levetiracetam might be an effective and safe option for the treatment of pediatric status epilepticus. Accordingly, levetiracetam was preferred in 59% of children with refractory status epilepticus admitted to our pediatric intensive care unit, and 78.3% of them responded to the therapy without any adverse effects.

In a study comparing the effect of levetiracetam and valproate in adults for the treatment of refractory status epilepticus before anesthesia induction, no difference was observed between groups in regard to efficacy, side effects, duration of status epilepticus, need for intubation, duration of stay in the intensive care unit, and mortality rate.

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