Third Therapy Phase: 40–60 Minutes and Refractory Seizures
The third therapy phase begins when the duration of seizure reaches 40 minutes. There is no clear evidence or consensus to guide selection of anticonvulsant at this point during status epilepticus. In addition to repeating the second-line therapy options, continuous infusions of midazolam, pentobarbital, or propofol may be considered. A patient's condition is considered refractory when seizures continue despite initial treatment with a first- and second-line drug or the seizure duration has been greater than 1 hour, or there is a need for general anesthesia. Although not specifically mentioned in the AES guideline, ketamine has emerged as a potential option for refractory status epilepticus.
Similar to other benzodiazepines, midazolam works via the GABAA receptors. The typical dose used for a midazolam continuous infusion is a loading dose of 0.15 to 0.2 mg/kg followed by a rate of 0.06 to 0.12 mg/kg/hour titrated until seizure activity ceases. Pentobarbital works via GABAA receptors, similar to phenobarbital. When used for the treatment of refractory seizures, the dose of pentobarbital is a loading dose of 5 mg/kg followed by a maintenance infusion of 1 mg/kg/hour (up to 3 mg/kg/hour). The most common adverse events related to pentobarbital infusions are CNS depression and profound hypotension necessitating initiation of a vasopressor, such as norepinephrine. Propylene glycol, the vehicle for pentobarbital, can be associated with cardiotoxic effects leading to sinus tachycardia, myocardial depression, and cardiac arrest.
Although not specifically known, propofol is thought to work through stimulation of GABAA receptors and inhibition of NMDA receptors. The dose of propofol when used as a continuous infusion is a loading dose of 1 to 2 mg/kg followed by a rate of 20 mcg/kg/minute titrating to desired effect. The most common adverse events are CNS depression and hypotension.
Similarly, ketamine is a NMDA receptor antagonist that reduces glutamatergic activity. The dose of ketamine for continuous infusion is a starting rate of 10 mcg/kg/minute titrating to desired effect with a maximum infusion rate of 100 mcg/kg/minute. The most common adverse events are tachycardia, increased secretions, and emergence reaction.
Available Pediatric Literature
There are no randomized, controlled trials comparing agents for the third therapy phase or for the treatment of refractory seizures. Kim and colleagues evaluated the safety and efficacy of IV levetiracetam for the treatment of refractory status epilepticus in the pediatric population. A total of 14 patients were included in the retrospective analysis. Treatment success was defined as the complete cessation of the seizure activity. The standard protocol for the treatment of status epilepticus used benzodiazepines as initial therapy followed by phenobarbital, phenytoin, and/or valproic acid. If the seizure activity continued, levetiracetam was considered. The dose for IV levetiracetam was 20 to 30 mg/kg. Seizure termination occurred in 6 (43%) of the 14 patients with no immediate adverse events. The authors concluded that levetiracetam should be considered a safe and effective treatment option.
Barberio and colleagues conducted a retrospective chart review to describe the dosing regimens and outcomes in children who received continuous pentobarbital therapy for refractory status epilepticus. Thirty patients were included in the analysis. All patients achieved some period of burst suppression after initiation of pentobarbital with 33% achieving sustained burst suppression without relapse. The most common adverse event documented was hypotension requiring intervention, with 50% requiring fluid boluses and 93% requiring vasoactive support.
Gaspard and colleagues conducted a multicenter retrospective analysis to examine patterns of use, as well as efficacy and safety of intravenous ketamine for the treatment of refractory status epilepticus. A total of 60 episodes were included in the analysis, involving 46 adults and 12 children. Response was defined as "likely" if permanent control of status epilepticus occurred within 24 hours of initiation and if ketamine was the last drug added. "Possible" response was defined as permanent control of status epilepticus within 24 h of initiation when ketamine was not the last drug added. Ketamine was introduced after a median 9 days of status epilepticus. The dosing of ketamine included a median loading dose of 1.5 mg/kg (maximum 5 mg/kg) followed by a median continuous infusion of 2.75 mg/kg/hour (maximum 10 mg/kg/hour). Permanent control of status epilepticus was likely or possibly attributed to ketamine in 32% of episodes. Discontinuation due to possible adverse events occurred in five patients. The authors concluded that ketamine appeared to be safe and moderately effective for treatment of refractory status epilepticus; however, further prospective studies are necessary.
Currently, there is a multicenter, randomized, controlled, open-label study being conducted in Italy to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory status epilepticus in children. The primary outcome is the resolution of status epilepticus up to 24 hours after withdrawal of therapy. The trial registration number is NCT02431663 and expected completion of the study was April 2016. As of publication of this article, no study results have been published.
Pediatr Pharm. 2018;24(2) © 2018 University of Virginia