Peds Status Epilepticus

Background

Incidence
● In the neonatal to first year of life
~135-150 incidents per 100,000
● Overall pediatric incidence estimated to
be 5-15 per 100,000
● In over 75% of cases status epilepticus
may be the first seizure of life
○ Only have a 30% risk of a later
diagnosis of epilepsy

What is a seizure?
● A result of disordered, synchronous, and
rhythmic firing of a population of brain
neurons
● Clinical manifestations depend on the
site of focus, the degree of irritability of
the surrounding area of the brain, and on
the intensity of the impulse
● During a seizure, the brain uses more
energy than it can manufacture and so prolonged seizures can lead to cell death

What causes seizures in children?

● Low anti-seizure medication levels
● Electrolyte imbalances
○ Hyponatremia
○ Hypocalcemia
○ Hypomagnesemia
● Hypoglycemia
● CNS infections/Fever
● Ingestion
○ Alcohol withdrawal
○ Cyclic antidepressants
○ Cocaine and other stimulants
○ Diphenhydramine and other antihistamines
○ Theophylline
● Head injury

Status Epilepticus Defined

1. Seizure lasting more than 5 minutes
a. Majority of seizures are brief, once a seizure lasts more than 5 minutes it’s likely to be prolonged
2. 2 or more sequential seizures without full recovery of consciousness between seizures

Presentation of Status Epilepticus

● Convulsive: repeated generalized tonic-clonic seizures with persistent postictal depression of neurologic
 function between seizures
● Nonconvulsive: produce a continuous or fluctuating “epileptic twilight” state
● Repeated partial seizures manifested as focal motor signs, focal sensory symptoms, or focal impairment of
function
NOTE: the type of seizure does not affect choice of treatment

Management of Status Epilepticus

Notes Regarding Treatment

● Several studies have described associations between status epilepticus management delays and more
prolonged seizures and lower anti-seizure medication responsiveness
○ GABA receptors are internalized

Stabilization Phase (0-5 minutes)

● Stabilize patients (ABCs)
● Time seizure from onset
● Monitor vital signs
● Initiate ECG monitoring
● Finger stick glucose
● Attempt IV access and collect electrolytes, hematology, toxicology screen, anticonvulsant drug levels

Initial Therapy Phase (5-20 minutes)

● First Line
○ Lorazepam IV (0.1 mg/kg/dose; repeat once in 5-10 minutes if needed) - max 4 mg per dose
○ Diazepam IV (0.15-0.2 mg/kg/dose; repeat once in 5 minutes if needed) - max 10 mg per dose
○ Midazolam IM (10 mg for >40 kg and 5 mg for 13-40 kg; single dose)
● Alternative Agents
○ Midazolam intranasal (0.2 mg/kg)
○ Diazepam PR (0.2-0.5 mg/kg) - max 20 mg

Second Therapy Phase (20-40 minutes)

● Fosphenytoin OR phenytoin IV (20 mg PE/kg) - max 1,500 mg PE
● Levetiracetam IV (20-60 mg/kg) - max 4,500 mg/dose
● Phenobarbital IV (15-20 mg/kg) - max 1,000mg/dose
● Valproic acid IV (20-40 mg/kg) - max 3000mg/dose

Third Therapy Phase AKA Refractory (40-60 minutes)

● Definition: seizures persist after adequate doses of initial benzodiazepine followed by a second appropriate
anti-seizure medication - no specific time that must elapse
● Malignant refractory status epilepticus: refractory status epilepticus may last many weeks or months
despite treatment with multiple medications
● Agents
○ Try any urgent control anti-seizure medications that haven’t been tried
○ Midazolam
■ Loading dose of 0.2 mg/kg then 0.05-2 mg/kg hour titrated as needed to achieve clinical or
electrographic seizure suppression
○ Pentobarbital
■ Loading dose of 5-15 mg/kg followed by an infusion at 0.5-5 mg/kg/hour titrated as needed
to achieve seizure suppression or EEG burst-suppression
○ Anesthetics
 ■ Hypotension concerns
○ Propofol
■ Usually require higher doses for extended period of time (>4 mg/kg/hour) - increased risk for
propofol-related infusion syndrome
● PRIS = unexplained metabolic acidosis, arrhythmias, acute renal failure,
rhabdomyolysis, hyperkalemia, cardiovascular collapse

Overview of Medications

Benzodiazepines
● Mechanism of Action
○ Binds to an allosteric regulatory site on the GABAA receptor, increases duration of Cl
channel-opening events (enhances GABA inhibitory signaling)
● Time to onset
○ Diazepam
■ IV: 1-3 minutes
■ Rectal: 2-10 minutes
○ Midazolam
■ IM: within 5 minutes
○ Lorazepam
■ IV: within 10 minutes
● Duration
○ Diazepam: 15-30m minutes
○ Midazolam IM: up to 6 hours
○ Midazolam inhalation: 20 minutes
○ Lorazepam IV: ~2 hours
● Side effects
○ Sedation
○ Drowsiness
○ Motor impairment
○ ICU setting - delirium
● Pearls
○ Lorazepam is stored in the refrigerator
○ No difference in respiratory depression between midazolam, lorazepam, and diazepam by aunty
route

Valproic Acid
● Mechanism of Action
○ Inhibits Na and Ca channels
○ Increases GABA levels by stimulating glutamic acid decarboxylase or inhibiting GAT-1 or GABA-T
● Side Effects/Monitoring
○ Hepatotoxicity
○ Thrombocytopenia
○ Drug interactions: can increase levels of lamotrigine, phenobarbital, phenytoin
○ Therapeutic trough
■ Generally 50-100 mcg/mL but correlation to response not well documented - toxicity may
occur at levels 100-150 mcg/mL

Levetiracetam
 ● Mechanism of Action
○ Binds the synaptic vesicular protein SV2A and thus interferes with synaptic vesicle release and
neurotransmission; also appears to interfere with calcium entry
● Side Effects/Monitoring
○ Hyperactivity
● Pearls
○ Minimal drug interactions

Fosphenytoin
● Mechanism of Action
○ Binds and stabilizes the inactivated state of sodium channels - decreases neuron firing rate
● Side Effects/Monitoring
○ Hypotension
○ Extravasation - leading to purple glove syndrome (edema, pain and bluish discoloration of the skin
which can lead to tissue necrosis)
○ Nystagmus
○ Strong CYP inducer
○ Trough serum concentrations
■ Total phenytoin neonates: 8-15 mcg/mL
■ Total phenytoin 1 month and older: 10-20 mcg/mL
● 5-10 may be effective but <5 mcg/mL are not likely to be affective
■ Keep in mind that babies have low albumin levels and phenytoin binds to albumin
● Pearls
○ Do not infuse >150 mg PE/minute - can lead to hypotension and cardiac arrhythmias
○ Fosphenytoin is better tolerated than phenytoin

Phenobarbital
● Mechanism of Action
○ Binds to an allosteric regulatory site on the GABAA receptor, increases duration of Cl
channel-opening events (enhances GABA inhibitory signaling)
● Side Effects/Monitoring
○ Hypotension
○ Respiratory depression
○ Strong CYP inducer
○ Trough serum concentrations
■ A clear correlation to therapeutic response has not been demonstrated
● Pearls
○ Most commonly used in NICU due to the amount of studies available

Personal Takeaways From Studies

● Several studies have shown that there is no difference in the efficacy between the 3 first-line
benzodiazepines (and their routes) for the treatment of status epilepticus - and adverse effects
○ Some have shown that buccal midazolam may be superior to rectal diazepam but several other
studies have found that opposite conclusion
○ Controversy between faster onset between intranasal midazolam and IV diazepam
○ Intranasal midazolam has shown to be superior/faster onset to rectal diazepam
■ Concern with outpatient administration?
● IV valproic acid has been shown to have a higher efficacy than phenytoin
● IV valproic acid had no difference in outcomes when compared to phenobarb - valproic acid did have very
clinically significant adverse effects