Katherine Lemming.
Treatment of status epilepticus. Pediatr
Pharm. 2018;24(2).
https://med.virginia.edu/pediatrics/wp-content/uploads/sites/237/2018/03/Feb18_StatusEpilepticus_PedPharmaco_.pdf
Abstract
Status epilepticus is a serious and potentially
life-threatening medical emergency that requires prompt intervention. The
traditional definition of status epilepticus is any seizure lasting longer than
thirty minutes regardless of whether consciousness is impaired, or recurrent
seizures without an intervening period of consciousness between seizures. Clinically, the average seizure is less than two minutes; however, only 40% of
seizures that last 10 to 29 minutes cease without treatment. Given that status
epilepticus can be associated with significant morbidity and mortality, the
definition has been expanded to include prolonged seizures lasting longer than
five minutes in order to promote early and adequate intervention to reduce
complications.
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From the article
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.
Summary
Status epilepticus is a serious and potentially
life-threatening medical emergency that requires prompt intervention. In 2016,
the American Epilepsy Society released evidence-based guidelines and a
treatment algorithm for status epilepticus in adult and pediatric patients. The
treatment algorithm consisted of four phases laid out in a timeline format:
stabilization, initial therapy, second therapy, and third therapy. Following
stabilization, the initial therapy phase focuses on benzodiazepines as the
treatment of choice. For the remaining phases of therapy and treatment of
refractory seizures, there is a paucity of evidence to guide the optimal
approach. Reasonable agents to consider following first-line agents include
fosphenytoin, levetiracetam, valproic acid, or phenobarbital. For third-line
treatment, continuous sedative infusions of pentobarbital, midazolam or
propofol can be considered. Although not included in the guideline, ketamine
has emerged as another potential option for the treatment of refractory status
epilepticus. Further studies are necessary to evaluate the efficacy and safety
of these agents and determine their place in therapy.
https://www.medscape.com/viewarticle/894140_3
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