Second Therapy Phase: 20–40 Minutes
The second therapy phase begins when a benzodiazepine fails to terminate seizures or approximately 20 minutes after the onset of the seizure. Reasonable options in therapy to consider at this point include IV forms of fosphenytoin, valproic acid, and levetiracetam. If these agents are unavailable, phenobarbital can be considered.
Fosphenytoin is a pro-drug of phenytoin which is converted to phenytoin by phosphatases in the liver and red blood cells. Fosphenytoin works by binding to voltage-gated sodium channels leading to stabilization of neuronal membranes and decreased seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses. Fosphenytoin is preferred over phenytoin due to differences in the formulation which allow for a faster rate of administration and reduced incidence of adverse events (e.g., phlebitis, hypotension). The dose of IV fosphenytoin is 20 mg Phenytoin Equivalents (PE) per kg (maximum single dose: 1500 mg PE).
Valproic acid has a similar mechanism of action to fosphenytoin, binding to voltage-gated sodium channels leading to a prolonged recovery phase. It also causes increased availability of GABA to brain neurons or may enhance the action of GABA and mimic its action at postsynaptic receptor site. The usual dose of IV valproic acid in the setting of status epilepticus is 40 mg/kg/dose (maximum single dose: 3000 mg). The most common adverse events associated with valproic acid administration include central nervous system (CNS) depression and hepatic dysfunction.
Levetiracetam binds selectively to the synaptic vesicular protein SV2A; however, the function of this protein is unknown. The presumed mechanism of action is through modifications in the production of GABA and glutamate. Most institutions currently use a levetiracetam dose ranging from 20 to 60 mg/kg for the initial management of status epilepticus, with a maximum single dose of 3000 mg. There have been relatively few serious adverse events associated with the administration of levetiracetam.
Phenobarbital binds to GABAA receptors increasing the time the chloride channel is open leading to membrane hyperpolarization and inhibition of action potentials. The recommended dose for phenobarbital in this setting is 15 to 20 mg/kg, with a maximum single dose of 1000 mg. Rapid IV administration, greater than 30 mg/minute in children and 60 mg/minute in adults, should be avoided due to risk of severe respiratory depression, hypertension, or vasodilation with hypotension. The most common adverse event related to phenobarbital administration is CNS depression.
Available Pediatric Literature
Limited clinical trials have evaluated the use of second-line therapy agents for the treatment of status epilepticus. Agarwal and colleagues compared the efficacy of phenytoin and valproate in patients with benzodiazepine-refractory seizures. Patients were randomized to receive IV phenytoin 20 mg/kg or IV valproate 20 mg/kg with both groups receiving initial therapy with a single dose of IV diazepam 0.2 mg/kg. Successful treatment was defined as cessation of all motor or electroencephalogram seizure activity within 20 minutes following the beginning of the drug infusion. A total of 100 patients were included in the study, matched for age and sex. Of those, 22 patients in the valproate group and 16 in the phenytoin group were less than 18 years of age. The overall efficacy was similar between valproic acid and phenytoin (88% vs 84%) in patients whose seizures did not respond initially to diazepam. There was not a statistically significant difference in the total number of adverse events between the two groups. The authors concluded valproate is as effective as phenytoin for the treatment of benzodiazepine-refractory seizures.
Pediatr Pharm. 2018;24(2) © 2018 University of Virginia