Emergency Neurological Life Support:

Status Epilepticus

Karen Berger, PharmD11, Dionne E. Swor, DO2, and Craig Press, MD, PhD3
1
Department of Pharmacy, New York-Presbyterian Hospital/Weill Cornell Medical Center
2
Department of Neurology, Wake Forest Baptist Health, Winston Salem, NC
3
Department of Pediatrics-Neurology, University of Colorado, Aurora, CO

Abstract

Patients with prolonged or rapidly recurring convulsions lasting five minutes or more are
considered to be in status epilepticus (SE) and should receive immediate resuscitation. Although
there are few randomized clinical trials treating SE, available evidence and clinical experience
suggest that early and timely treatment of SE improves patient outcomes. The current approach to
the emergency treatment of SE emphasizes rapid initiation of adequately dosed first line therapy,
accelerated second line antiseizure drugs and induced coma with continuous infusion of
anesthetics when these fail, coupled with admission to a unit capable of neurological critical care
and electroencephalography (EEG) monitoring. This protocol will focus on the initial treatment of
SE and will also review subsequent steps in the protocol once the patient is hospitalized.

Keywords

status epilepticus, seizures, antiseizure drug (ASD), pharmacologic coma,

electroencephalography (EEG) monitoring, automated external defibrillator (AED)

1. Introduction

Each year in the United States (US), emergency departments (EDs) experience an average of one
million seizure-related visits based on International Classification of Diseases-9 coding. These
visits represent approximately 20% of ED visits for neurological problems and 1% of all ED
visits.1-3 Approximately 200,000 US patients per year have prolonged or rapidly recurring
convulsions lasting more than five minutes - the defining features of status epilepticus.

The 30-day mortality of patients with generalized convulsive SE ranges from 10-27%.4-9
Prolonged seizures are associated with higher mortality and worse clinical outcomes.8-12 Adverse
effects of SE include both indirect systemic problems arising from the convulsive state (e.g.,
impaired ventilation, aspiration, metabolic aberrations) and direct neuronal cellular injury from
excitotoxicity, causing both immediate neuronal loss and delayed cell death.

This module is meant to give a broad framework for the principles of diagnosis and emergent
management of SE, which can be adapted to reflect global and regional variations based on the
1
Karen Berger, PharmD
Email: karenberger7@gmail.com

1
local availability of diagnostic tools and treatments. Rapid control of seizures is fundamental to
the emergency treatment of SE (Figure 1). Earlier termination of SE reduces neuronal injury in
animal models of SE and is associated with improved clinical outcomes in human observational
studies. In experimental SE, benzodiazepines are more likely to terminate seizures when given
closer to seizure onset and decrease in effectiveness as seizure duration increases.

Figure 1
Caption: ENLS Status Epilepticus management protocol

The ENLS suggested algorithm for the initial management of SE is shown in Figure 1. For patients
with suspected SE, it is suggested that initial diagnostic steps be performed in parallel to, but not
delay treatment.

2
Fingerstick glucose should be checked as soon as possible as hypoglycemia is a rare, but rapidly
treatable cause of SE; however, benzodiazepine administration should not await a potential
diagnosis of hypoglycemia as this may lead to delays in therapy.13,14 Unless intravenous (IV)
access is already established, intramuscular (IM) midazolam should be immediately considered
(buccal or nasal midazolam, or rectal diazepam may be used as alternatives if needed).15 If IV or
IO access is already established, the IV or IO route should be preferentially used in adult patients.

Table 1. Status epilepticus checklist for the first hour

Checklist

 Fingerstick glucose

 Obtain IV access

 Pulse oximetry, BP monitor, supplemental O2 and fluid as needed, cardiac monitor

 Labs: Complete blood count, Basic metabolic panel, Calcium, Magnesium, HCG in females
of childbearing age

 Head CT

 Continuous EEG (if available); notify EEG tech if available (as soon as available unless
patient returns to pre-status epilepticus baseline)

 Consider rapid-response EEG with limited montage if continuous EEG is not available

The importance of rapid treatment of prolonged convulsions is reflected in the current definitions
of SE, requiring only five minutes of unrelenting seizure activity.16,17

The diagnostic workup of patients with SE is pursued concurrently with treatment and
stabilization, while ensuring that testing does not interfere with or delay control of seizures;
treatment comes first. The diagnostic evaluation begins in parallel with Emergent Initial Therapy
by ensuring airway, breathing, and hemodynamics are addressed. Evaluate for hypoglycemia,
hypoxia, and hemodynamic instability. Pregnancy status should be assessed in childbearing age
women to determine if preeclampsia is a potential cause of SE. Oxygen saturation and cardiac
monitoring should be initiated during this phase. A rapid focused neurological evaluation should
be performed including a description of ongoing convulsions, automatisms, focal deficits,
pupillary changes, and level of consciousness.

Once IV access is obtained, blood and serum laboratory evaluation typically include a complete
blood count, basic metabolic panel, pregnancy testing as applicable, and calcium and magnesium
determinations. Selected laboratory studies that may be useful in some patients include liver
enzymes, troponin, toxicology screen, lactate and blood gas determinations. Approximately two-
thirds of patients evaluated in the ED for SE have a history of a prior seizure, and many have either
discontinued or missed their medication or have subtherapeutic or supratherapeutic levels of

3
antiseizure drugs. Antiseizure drug levels for specific medications, such as
fosphenytoin/phenytoin, valproate, phenobarbital, and carbamazepine can be helpful to direct
management. ASD levels, if available, may be useful if medication nonadherence is suspected.

If a cardiac arrhythmia or myocardial injury is suspected, ECG should be performed when

possible. For patients with respiratory distress or hypoxia, supplemental oxygen should be
administered, and a chest X-ray performed. Consider potential toxidromes or medications that are
associated with seizures (Table 2).

Table 2: Toxidromes associated with seizures

Toxidrome Management

Isoniazid Treat with benzodiazepine followed by pyridoxine,

max dose 5 gm.

Tricyclic Antidepressants Evaluate for QRS widening on the ECG, treat with
sodium bicarbonate.

Theophylline Treat with benzodiazepines or barbiturates, consider

gastric lavage if patient has recently (<1 hr) ingested a
significant amount or a sustained release product,
administer activated charcoal, consider whole-bowel
irrigation.18

Cocaine/Sympathomimetics Treat with benzodiazepine.

Alcohol Withdraw Treat with accelerating doses of a benzodiazepine

and/or barbiturate

Organophosphates Treat with atropine, midazolam, and pralidoxime.

The need for neuroimaging should be individualized but is generally warranted in patients who do
not return to a normal level of consciousness, have new focal neurological findings, or have new
onset seizure without an otherwise obvious identifiable etiology. Non-contrast computed
tomography (CT) of the brain will identify most immediate threats and is the most typical initial
imaging study obtained in the ED. A lumbar puncture should be performed in febrile patients and,
when there is suspicion of central nervous system infection or subarachnoid hemorrhage, if there
are not any contraindications on the CT of the brain including space occupying lesion with mass
effect.

As noted in sections on hospital treatment below, EEG is necessary to identify non-convulsive

SE19 in patients who do not return to a normal level of consciousness. EEG may also guide therapy
in these patients and provide other diagnostic information. Ideally, EEG should be initiated within
one hour of suspected non-convulsive SE, however many hospitals do not have access to 24/7
EEG capabilities.20 Rapid response EEG with reduced montage may aid in quickly identifying

4
patients with non-convulsive SE in critical care settings where continuous EEG monitoring is not
available.21

Non-epileptic spells simulating SE (i.e., psychogenic nonepileptic seizures) may be difficult to

differentiate from SE. Indicators suggestive of non-epileptic spells include preserved
consciousness or purposeful movements, poorly coordinated thrashing, back arching, eyes held
shut, head rolling, and pelvic thrusting.

2. Emergent Initial Therapy: Prehospital Treatment

The initial minutes after seizure onset offer the best opportunity for termination of SE. Prehospital
management begins with immediate recognition of SE and emergent treatment with
benzodiazepines while assessing ABCs. Airway adjuncts and/or supplemental oxygen may be
needed. If present, hypoglycemia should be corrected with intravenous dextrose. In parallel,
benzodiazepines should be given emergently. Since emergency medical services (EMS) response
times are often 5 minutes or longer, patients found seizing upon EMS arrival may be considered
in status epilepticus. EMS delivery of benzodiazepines results in a higher rate of cessation of
seizures prior to arrival in the ED compared to placebo with a trend toward better outcomes.7 In
addition, IM administration of midazolam by EMS is superior to IV administration of lorazepam
in terminating SE.13 This has advantages as midazolam does not need refrigeration22,23 and the
administration of an IM drug is significantly easier and quicker than obtaining IV access.

Unless IV access is immediately available, initiate IM, PR, buccal or intranasal medications. In
adults or children over 40 kg, IM midazolam 10 mg or PR diazepam 20 mg may be administered;
in children 13-40 kg, the IM midazolam dose is 5 mg and in children <13 kg, the IM midazolam
dose is 0.2 mg/kg (although children <13 kg were excluded from the RAMPART trial).13 IV access
can then be attempted while evaluating the effectiveness of initial therapy. If not available,
consider a second dose of IM medication 5-10 minutes after the first dose if seizures persist.

When IV access is immediately available, consider lorazepam IV (adults, start 4 mg IV and repeat
up to the max weight-based total dose of 0.1 mg/kg; for children, 0.1 mg/kg IV up to a maximum
of 4 mg/dose). If lorazepam is not available in the area of practice, consider clonazepam 0.015
mg/kg IV (typically 1 mg IV) in adults or diazepam 0.15 mg/kg IV (up to 10 mg/dose). In one
study, patients did not benefit from prehospital add-on therapy with levetiracetam IV.24

Respiratory depression can occur both following SE and in untreated SE; therefore, prehospital
providers should be prepared to treat this irrespective of benzodiazepine use or dosing.
Benzodiazepine doses recommended for SE are higher than those used for many other indications;
however, the concern for respiratory depression should not prevent appropriate therapy. In fact,
rates of respiratory and circulatory complications were lower with both lorazepam and diazepam
as compared to placebo in the treatment of out-of-hospital status epilepticus7, as cardiorespiratory
compromise is frequently a consequence of seizure duration and loss of metabolic reserve. While
lorazepam is highly effective, it needs to be refrigerated or restocked frequently, raising logistical
challenges for EMS systems. Some may find that diazepam and midazolam are preferable
alternatives to stock.

5
3. Emergent Initial Therapy: Emergency Department

Early treatment of SE in the ED continues the care initiated by EMS. If IV access has not already
been obtained, it should be achieved upon arrival in the ED, and diagnostic studies should be
initiated in parallel with treatment as above.

In patients who continue to seize after initial benzodiazepine treatment, additional benzodiazepines
should be administered after 5-10 minutes. Therefore, initial ED therapy will typically include IV
benzodiazepines if initial EMS therapy has not succeeded. If the patient did not receive
benzodiazepines prior to ED arrival and is still seizing, initial dosing should include IV
benzodiazepines when IV access is immediately available. IM, PR, buccal, or intranasal
benzodiazepines should be administered in parallel with IV placement when IV access is not
available.

Benzodiazepines are frequently under-dosed because the labeled 4 mg initial (adult) dosing of
lorazepam for SE is greater than the initial dose used for most other indications.25 The same is true
in pediatric dosing. Initial treatment failure is therefore often a result of (1) using inadequate initial
doses of IV benzodiazepines due to fear of respiratory compromise, or (2) waiting too long to
repeat benzodiazepine doses and advance to second line agents.21,26,27

As fingerstick glucose testing is widely and rapidly available in emergency departments, empiric
administration of glucose is typically not warranted. However, for suspected or proven
hypoglycemia, intravenous dextrose should be emergently provided.

4. Urgent Control Therapy

If SE continues after 10-20 minutes of two adequate doses of benzodiazepines, and no correctable
underlying etiology is found during this time, the next step will typically be a second line agent.
The best choice of second line antiseizure drugs for established SE is heavily debated, with the
most used agents being phenytoin/fosphenytoin, valproate sodium, and levetiracetam.
Consideration of other medical problems including renal failure, liver disease and hemodynamic
status when choosing a second line agent. A recent prospective randomized double blind clinical
trial evaluating the efficacy of fosphenytoin, levetiracetam, and valproate found no significant
difference in the rate of seizure cessation among these drugs.28

Phenytoin is administered as 20 mg/kg IV (maximum rate of 50 mg/min) or 20 mg PE/kg of

fosphenytoin (maximum rate of 150 mg PE/min).29-31 Fosphenytoin is a water-soluble prodrug that
is converted to phenytoin by plasma esterases. Thus, while IV fosphenytoin can be administered
faster than IV phenytoin, it has the same time to effect on seizures, as it must be converted to
phenytoin, which takes about 15 min. Fosphenytoin can also be administered IM if IV access is
lost or has yet to be established. In addition, fosphenytoin is compatible with many intravenous
fluids making administration easier. Phenytoin and fosphenytoin are FDA-labeled for the
treatment of SE in adults. They act at the sodium channel rather than the gamma-aminobutyric
acid (GABA) receptor, and therefore represent a rational choice for treating patients whose
seizures do not terminate with the benzodiazepine GABA agonists. Bradycardia and hypotension

6
may occur at high infusion rates, especially in the elderly or those with significant cardiac disease.
Hypotension is more profound with IV phenytoin due to its co-formulation with propylene glycol.

Valproate 40 mg/kg is given intravenously over 10 minutes, with an additional 20 mg/kg given 10
minutes after the loading dose if the patient is still seizing. Although adverse events were not
statistically significantly different in the randomized study, sodium valproate probably has fewer
cardiopulmonary side effects than phenytoin and may be preferred in patients with hypotension or
respiratory distress. Phenytoin, fosphenytoin, and valproic acid are listed as hazardous medications
according to the National Institute for Occupational Safety and Health (NIOSH) list and may
require special handling per institutional guidelines.32

Levetiracetam is often used as a second line agent to treat SE and can be given as a 60 mg/kg dose
up to a maximum dose of 4500 mg infused over 10-15 minutes.28,33 Alternatively, a bolus of 1-3 g
can be administered as an undiluted intravenous push over 2-5 minutes and may be faster than
waiting for preparation of in IV piggyback dose.34-38

IV phenobarbital is also FDA labeled for the treatment of SE in adults and children and remains a
reasonable option, but it is now less commonly chosen in adults unless other agents are
contraindicated or unavailable. Phenobarbital 20 mg/kg IV is administered at a rate of 50–100
mg/min. An additional 5–10 mg/kg may be given after 10 minutes, if the patient is still seizing.

If seizures have stopped and the patient has awakened, loading doses of antiseizure medications
with longer half-lives should be initiated and can be given either intravenously or orally.

Second line antiseizure drugs may be less effective, and may sometimes be contraindicated, for
urgent treatment in patients with SE that is secondary to intoxications or poisonings. SE known to
result from isoniazid or organophosphates should preferentially be treated with specific antidotes.
Cardiac effects of tricyclic antidepressant poisoning may be exacerbated by attempting to prevent
seizures with some second line antiseizure drugs.

5. Treatment of Refractory SE

Management of SE requires the use of the first and second line antiseizure drugs described above.39
If the seizures have not stopped despite emergent and urgent drug therapy, SE is considered
refractory. Intubation and drug-induced coma are recommended in these circumstances.

It is not necessary, and is usually not advisable, to delay advanced therapy with repeated trials of
alternative second tier antiseizure drugs.39 30 minutes is usually adequate to determine if the
above-described conventional approach is successful. Early administration of continuous infusion
anesthetics (within 48 hours) has been associated with a shorter duration of refractory SE and
better outcomes at last follow-up. However, early administration was not associated with improved
mortality or refractory status epilepticus termination.40

Endotracheal intubation is necessary to allow induction of coma and should be quickly performed
in refractory SE (RSE). Because pharmacologic paralysis performed for purposes of intubation
and mechanical ventilation will mask ongoing convulsions, it is necessary to use a short-acting

7
neuromuscular blocker and pursue continuous EEG monitoring. If continuous EEG monitoring is
not available, the patient should be emergently transferred to another facility where advanced
monitoring is available.

The agents most commonly used to induce a general anesthetic state of coma are continuous
infusions of midazolam or propofol.41-44 IV midazolam infusions should be preceded by a loading
dose of 0.2 mg/kg at 2 mg/min, with repeated boluses of 0.2–0.4 mg/kg every five minutes until
the seizures stop, up to a maximum loading dose of 2 mg/kg. A continuous infusion should then
be started at 0.05–2 mg/kg/hour. It is important to clarify the units in the electronic medical record
order entry and infusion pumps since dosing for status should be in “mg/kg/hour” as compared to
sedation dosing of “mg/hour” to avoid any potential dosing errors. IV propofol infusions usually
include a loading dose of 1–2 mg/kg IV over 3–5 minutes, with repeated boluses of the same
amount every 3–5 minutes until the seizures stop. The propofol infusion should then be maintained
at a rate of 30–200 mcg/kg/min. An alternative agent may be selected when propofol doses are
greater than 80 mcg/kg/min to reduce the risk of propofol infusion syndrome (PRIS) and
hypotension.

Sedatives and anesthetics used for treatment of SE have a number of side effects and will
frequently be associated with dose dependent hypotension requiring IV vasopressor support.41
Hypotension may be seen with higher doses of both midazolam and propofol, however, midazolam
is preferable in hemodynamically unstable patients.41 Prolonged use of propofol at higher doses is
associated with the rare-but-often-fatal propofol infusion syndrome (PRIS). PRIS is characterized
by rhabdomyolysis, metabolic acidosis, and cardiac and renal failure.45 Pentobarbital at a loading
dose of 5 mg/kg followed by a maintenance infusion of 1-3 mg/kg may be used more frequently
in children with refractory SE because of this adverse effect with propofol.

The use of ketamine infusion as a third line agent may be an effective adjuvant therapy for the
treatment of refractory and super-refractory SE.18,46,47 Ketamine acts as an NMDA receptor
antagonist and offers a different mechanism of action than propofol and midazolam. Ketamine
infusions should be preceded by a loading dose of 1-2 mg/kg IV followed by a continuous infusion
of 0.5-10 mg/kg/hour.

Another IV anti-seizure medication may be added before a continuous infusion anesthetic for
patients with refractory SE who cannot or should not be intubated (i.e., patient with advanced
directives against intubation).18,45,48,49 Alternate IV anti-seizure medication, such as lacosamide
and brivaracetam may be useful therapeutic options in refractory SE.18,50,51

In the ED, sedative IV agents will usually be titrated to the cessation of clinical manifestations of
convulsive or subtle SE. When continuous EEG monitoring is available, the administration rate
can be titrated to the desired electroencephalographic findings, ranging from suppression of
seizures to burst suppression or a completely suppressed background. Few data are available to
identify the optimal treatment level of suppression.18

It is appropriate to continue second line antiseizure medications to attain therapeutic serum levels
during the treatment of refractory SE, as these are needed to prevent seizure recurrence.

8
 Expeditious admission to an intensive care unit with a dedicated neurointensivist, with continuous
EEG monitoring, is strongly recommended for RSE.

Table 3. Emergent Initial Therapy

If no IV available:

Midazolam IM 10 mg
Adults and children >40 kg
If not available, Diazepam PR 20 mg
Midazolam buccal 0.2-0.5 mg/kg, maximum dose 10 mg (or age based: 6m-11m 2.5mg, 1y-4y
5mg, 5y-9y 5mg, >10 y 10mg)

Midazolam intranasal 0.2 mg/kg, maximum dose 10 mg

Children
Midazolam IM 0.2 mg/kg; 10 mg if >40 kg; 5 mg if 13-40 kg

If not available, diazepam PR 0.5 mg/kg if 1-5yo, 0.3 mg/kg if 6-11yo, 0.2 mg/kg if >11yo

If no IV available and seizures continue, repeat x1 after 3-5 minutes

If IV available:

Lorazepam IV 0.1 mg/kg (up to 4 mg per dose)

All patients
If initial dose (whether prehospital or ED) is not effective, repeat x1 after 3-5 minutes

Table 4. Urgent Control Therapy

Adults and Fosphenytoin IV 20 mg PE/kg

Children Valproate IV 40 mg/kg

Levetiracetam IV 60 mg/kg (max dose 4500 mg)

Phenobarbital IV 20 mg/kg

Neonates Phenobarbital IV 20 mg/kg

Fosphenytoin IV 20 mg PE/kg

Levetiracetam IV 40-60 mg/kg (max dose 4500 mg)

9
 Table 5. Refractory SE
Adult Midazolam, 0.2 mg/kg
If seizures continue for another 5 min, repeat dose at 0.2 mg/kg and start infusion of 0.1 mg/kg/h
If seizures continue for another 5 min, repeat dose at 0.2 mg/kg and increase infusion to 0.2 mg/kg/h
Propofol, 1-2 mg/kg and start infusion at 20 mcg/kg/min (range 30-200 mcg/kg/min)
Phenobarbital 20 mg/kg, infuse no faster than 60 mg/min (adults) or 30 mg/min (children) or 1 mg/kg/min
Ketamine, 1-2 mg/kg and start infusion at 0.5 mg/kg/hr (range 0.5-10 mg/kg/h)
Children Midazolam, 0.1-0.2 mg/kg, start infusion 0.1-0.4 mg/kg/hr and titrate to lowest effective dose up to 1 mg/kg/hr
Phenobarbital 20 mg/kg, infuse no faster than 1 mg/kg/min
Ketamine, 1-2 mg/kg and start infusion at 0.5 mg/kg/hr (range 0.5-10 mg/kg/h)

6. Pediatric Considerations

Etiologies of SE in infants, children and adolescents include those encountered in adults:

meningoencephalitis, trauma, stroke, hypoxemia, toxidrome, hypoglycemia and other electrolyte
or metabolic disturbance, and new onset epilepsy.52 Particular to pediatrics are febrile seizures (30-
50% pediatric SE) and underlying genetic or metabolic disorders, especially in the infant and
younger child.53 Hyponatremic seizures related to improper mixing of formula or the
administration of free water to neonates are not uncommon. In the first weeks of life, infants with
hypoparathyroidism and hypocalcemia can present with tetany or seizures. Abusive head trauma
in infants and young children frequently presents with seizures, and a history of trauma is rarely
disclosed. Patients with underlying structural brain abnormalities, particularly if they are
associated with abnormal neurodevelopment, are at higher risk to develop epilepsy, and may
present with SE. This includes acutely antecedent or remote brain injury. Brain tumors are the
most common solid tumor of childhood and can cause seizures, especially if there is associated
spontaneous hemorrhage. Neonatal SE is most often focal or multifocal and rarely generalized.
Seizures in neonates are often subclinical and may instead present as altered mental status with
tremor, extensor or flexor posturing, apnea, eye deviation and stereotypic automatisms such as
tongue thrusting and lip smacking.54 These movements do not respond to stimulation.

In pediatrics, antiseizure drugs are similar to those in adults, and early dosing of benzodiazepines
is essential.55 Importantly, the IV midazolam formulation can be given via IM, intranasal, or buccal
routes, which is preferable to delaying treatment while obtaining IV access. Intranasal midazolam
and IM midazolam are likely the most effective non-intravenous medications for SE.56 The recent
ESETT trial included children ≥2 years of age and found no difference between the efficacy of IV
levetiracetam 60 mg/kg, IV fosphenytoin 20 mg PE/kg or IV valproate 40 mg/kg all administered
over 10 minutes as second line agents after adequate dosing with benzodiazepines.28 Additional
recent studies have demonstrated similar effects of phenytoin 20mg/kg and levetiracetam 40mg/kg
in treating pediatric SE.57

10
In pediatrics, antiseizure drugs are similar to those in adults, and early dosing of benzodiazepines
is essential.55 Importantly, the IV midazolam formulation can be given via IM, intranasal, or buccal
routes, which is preferable to delaying treatment while obtaining IV access. Intranasal midazolam
and IM midazolam are likely the most effective non-intravenous medications for SE.56 The recent
ESETT trial included children ≥2 years of age and found no difference between the efficacy of IV
levetiracetam 60 mg/kg, IV fosphenytoin 20 mg PE/kg or IV valproate 40 mg/kg all administered
over 10 minutes as second line agents after adequate dosing with benzodiazepines.28 Additional
recent studies have demonstrated similar effects of phenytoin 20mg/kg and levetiracetam 40mg/kg
in treating pediatric SE.57

Throughout resuscitation, vigilance to ABCs and cardiopulmonary support is paramount, but

preparations should be made for intubation if second-line drugs fail. Practice varies between
institutions, and some will trial a second second-line drug if the first fails, but third-line continuous
intravenous infusions in children with refractory SE should not be delayed, as doing so may
unnecessarily prolong SE and contribute to refractory SE. The risks of poor outcome and mortality
increase with SE duration. High-dose midazolam infusion or pentobarbital are generally preferred
over propofol in children because of concerns regarding PRIS, though propofol use during inter-
hospital transport may be requested depending on patient’s age and diagnosis.40,59 Similar to adults,
ketamine is also being used more frequently in children to treat refractory status epilepticus and
may be considered.60,61

Prior knowledge of facility capabilities and identification of a center with expertise caring for
neurocritically-ill children is important, as children are at risk for etiologies that may require
pediatric multi-subspecialty care. Children with prolonged coma or postictal state, and those
requiring intubation for SE, require EEG evaluation to rule out transition to non-convulsive SE,
ongoing SE under paralysis, or titrate a third-line agent to suppress cortical electrical activity.
Consultation with a pediatric intensivist or neurologist can be helpful in identifying additional
measures that may be taken beyond the generally efficacious resuscitation outlined previously, in
choosing a second- or third-line agent or titrating high-dose benzodiazepines or barbiturates and
managing the invasive mechanical ventilation and blood pressure support typically required. If the
child has a history of refractory epilepsy and is cared for by an epileptologist at a tertiary or
quaternary pediatric center, they may have specific insight into what has worked for this child’s
seizures previously.

7. Nursing Considerations

Initial nursing care begins immediately at seizure onset. Safety is a primary focus of nursing care
in the patient with seizures. Safety measures include placing the patient in lateral recumbent
position, keeping the head of the bed elevated, padding the side rails of the bed and having suction
supplies available at bedside. It is important not to restrain patients or insert anything into the
patient’s mouth as this can cause further injury.62 Supplemental oxygen should be applied if the
patient becomes hypoxic. Vigilant monitoring of vital signs should be maintained so that instability
can be treated to prevent secondary injury.

11
Concurrent with initial resuscitation, the nursing staff should obtain an initial neurologic
examination that includes a baseline level of consciousness, pupillary evaluation, and assessment
for any focal deficits. It is important to monitor and document the type of seizure activity including
precipitating factors, the description of the seizure including sensory, motor and behavioral
activities and the length of the seizure activity.62 The nursing staff should be prepared to obtain IV
access and administer antiseizure medications and continuous infusion anesthetics promptly at the
direction of the provider team.

Nursing knowledge of medications and anticipation of potential diagnostics and procedures can
save precious time in the care of the seizing patient. Nursing should ensure adequate IV access for
administration of medications, monitor for response and the patient’s ability to protect the airway
and prompt completion of ordered diagnostics to determine etiology of seizures. The role of the
nurse includes ensuring diagnostics proceed in parallel with treatment, including laboratory
testing, facilitating EEG testing and neuroimaging as needed.
Nursing report between the ED and inpatient teams is imperative and communication should
include a description of the type and duration of seizures, medications given, pending medications
that need to be given, positive or negative response to medications already given, respiratory and
hemodynamic status and what tests still need to be obtained.

8. Patient Transport

Medications, especially continuous infusions, should be continued during transport. Prescribers

should ensure that patients do not miss doses of scheduled antiseizure drugs if they are scheduled
for a prolonged procedure or even during transport to and during neuroimaging. Communication
to the transport provider should clarify that doses should not be decreased or stopped. If possible,
transport should be avoided until the patient is clinically stable as this may require disconnecting
the patient from EEG and potentially missing nonconvulsive seizures. Vasopressors may be
needed during transport if the patient’s blood pressure is fluctuating or if continuous infusion
anesthetics were recently bolused or initiated.

9. Pregnancy

Status epilepticus during pregnancy is a rare occurrence that carries a significant risk to both the
mother and the fetus necessitating prompt diagnosis and treatment. The etiology of SE during
pregnancy is varied, with eclampsia as the most common cause followed by underlying epilepsy,
posterior reversible encephalopathy syndrome (PRES), reversible vasoconstriction syndrome
(RCVS), venous sinus thrombosis, subarachnoid hemorrhage, stroke, encephalitis, tumor, and
metabolic derangement.63

There are no guidelines for the treatment of SE during pregnancy. The general consensus is to
follow the standard SE treatment algorithm with special considerations regarding the underlying
etiology of SE and the teratogenicity of particular anti-seizure drugs. Benzodiazepines remain the
first line agent for SE during pregnancy except for eclampsia, for which the first-line treatment is
intravenous magnesium sulfate. Many second-line anti-seizure drugs are associated with increased
risk of teratogenicity and should be used with caution particularly during the first trimester of
pregnancy. Valproate exposure carries the highest risk of major congenital malformations

12
followed by phenobarbital and phenytoin.64 Newer anti-seizure drugs such as lamotrigine and
levetiracetam have the lowest risk of congenital malformations.65

Pharmacokinetics of anti-seizure drugs are altered in pregnancy, including increased volume of

distribution, changes in absorption, elevated renal excretion, and induction of hepatic
metabolism.61 These changes can result in reduced serum concentrations of anti-seizure drugs and
necessitate frequent drug level checks in order to assure appropriate therapeutic dosing.

10. Communication

When communicating to an accepting or referring physician about an SE patient, consider

including the key elements listed in Table 5 and relaying them to all relevant healthcare providers
who are caring for the patient (i.e., accepting physician, resident/advanced practice provider, nurse,
pharmacist). The nursing report should also include these key elements.

Table 6 Status Epilepticus communication regarding assessment and referral

 Clinical presentation

 Duration of status epilepticus

 Relevant past medical history/past surgical history

 Relevant labs, including anticonvulsant levels if drawn

 Prior medications, medications given so far (and outcomes ie; seizures resolved after drug X, no

effect from drug Y)

 Neurological examination

 Brain imaging/lumbar puncture/other results (if available)

Clinical Pearls

Clinical Pearls: Management

• Early, aggressive management of patients with SE is imperative.
Delay of therapy reduces the likelihood of seizure termination.
● Benzodiazepines are frequently underdosed for initial therapy, and
should be dosed aggressively in SE.
● Continuous EEG is recommended for the management of ongoing
SE and should be assessed frequently to monitor treatment effects;
the optimal goal (seizure termination vs. burst suppression vs.
complete suppression) is unknown at this time.
● Diagnostic workup should proceed in parallel with initial and urgent
treatment and should continue until a source of seizures is identified.

13
Clinical Pearls: Medication
● Benzodiazepines such as lorazepam IV or midazolam IM (if no IV
access) are first-line treatment agents for SE.
● Fosphenytoin is the prodrug of phenytoin; it can be administered
more rapidly than phenytoin, is compatible in more solutions, is not
formulated with propylene glycol, and can be administered IM.
● Fosphenytoin, levetiracetam, and valproic acid have comparable
rates of seizure cessation in patients with SE who have failed a
benzodiazepine (<50%).
● Antiseizure medication levels should be monitored frequently
(typically daily during active SE) and titrated to the higher end of
normal; free levels should be assessed if available (i.e., phenytoin
and valproic acid); antiseizure levels for medications the patient
was known to be taking (or prescribed) should be checked at
presentation to assess for nonadherence or subtherapeutic levels.
• Drug/tube feed interactions, renal and hepatic dysfunction, and
medication-adverse event profile should be considered when
initiating and up-titrating antiseizure drugs.

14
Starred References
**4 (Treiman, et al): This is one of the few randomized controlled trials conducted in SE. It
established benzodiazepines as first line therapy. It also demonstrated that seizure termination
efficacy diminishes with each additional agent.
**7 (Alldredge, et al): This study demonstrated the efficacy of benzodiazepines in the treatment
of SE. In addition, the study provided useful information about the side effects of
benzodiazepines in SE, particularly that there were actually more respiratory and circulatory
complications in the placebo group over both lorazepam and diazepam.
**15 (Silbergleit, et al): This study compared midazolam IM to lorazepam IV. The results
established IM midazolam as a non-inferior first line treatment option for SE.
*20 (Brophy, et al): These are the NCS guidelines for the management of status epileptics. They
provide an in-depth overview of the diagnosis and treatment of SE.
*41 (Claassen, et al): This was a systematic analysis comparing the most commonly used
continuous infusion anesthetics, midazolam, propofol, and pentobarbital. This review provides a
comparison of agent safety and efficacy in RSE and super refractory SE.
**28 (Kapur J, et al): This was a randomized clinical trial that compared IV fosphenytoin, IV
valproic acid, and IV levetiracetam for status epilepticus in adults and pediatrics. There was no
difference in efficacy between the three treatment arms.
*58 (Sharpe C, et al). This was a randomized, multicenter trial comparing levetiracetam (40-60
mg/kg) and phenobarbital (20-40 mg/kg) as first line treatment for neonatal seizures of any
cause. The 24-hour seizure cessation rate was higher with phenobarbital than with
levetiracetam.
References
1. Pallin DJ, Goldstein JN, Moussally JS, Pelletier AJ, Green AR, Camargo CA, Jr. Seizure
visits in US emergency departments: epidemiology and potential disparities in care. Int J
Emerg Med. 2008;1(2):97-105.
2. Farhidvash F, Singh P, Abou-Khalil B, Arain A. Patients visiting the emergency room for
seizures: insurance status and clinic follow-up. Seizure. 2009;18(9):644-647.
3. Pitts SR, Niska RW, Xu J, Burt CW. National Hospital Ambulatory Medical Care
Survey: 2006 emergency department summary. Natl Health Stat Report. 2008(7):1-38.
4. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for
generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus
Cooperative Study Group. N Engl J Med. 1998;339(12):792-798.
5. Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA. Short-term
mortality after a first episode of status epilepticus. Epilepsia. 1997;38(12):1344-1349.
6. Towne AR, Pellock JM, Ko D, DeLorenzo RJ. Determinants of mortality in status
epilepticus. Epilepsia. 1994;35(1):27-34.
7. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and
placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med.
2001;345(9):631-637.
8. Legriel S, Azoulay E, Resche-Rigon M, et al. Functional outcome after convulsive status
epilepticus. Crit Care Med. 2010;38(12):2295-2303.
9. Legriel S, Mourvillier B, Bele N, et al. Outcomes in 140 critically ill patients with status
epilepticus. Intensive Care Med. 2008;34(3):476-480.

15
10. Claassen J, Hirsch LJ, Emerson RG, Bates JE, Thompson TB, Mayer SA. Continuous
EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus.
Neurology. 2001;57(6):1036-1042.
11. Rossetti AO, Hurwitz S, Logroscino G, Bromfield EB. Prognosis of status epilepticus:
role of aetiology, age, and consciousness impairment at presentation. J Neurol Neurosurg
Psychiatry. 2006;77(5):611-615.
12. Scholtes FB, Renier WO, Meinardi H. Generalized convulsive status epilepticus: causes,
therapy, and outcome in 346 patients. Epilepsia. 1994;35(5):1104-1112.
13. Remick K, Redgate C, Ostermayer D, Kaji AH, Gausche-Hill M. Prehospital Glucose
Testing for Children with Seizures: A Proposed Change in Management. Prehosp Emerg
Care. 2017;21(2):216-221.
14. Beskind DL, Rhodes SM, Stolz U, et al. When should you test for and treat
hypoglycemia in prehospital seizure patients? Prehosp Emerg Care. 2014;18(3):433-441.
15. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy
for prehospital status epilepticus. N Engl J Med. 2012;366(7):591-600.
16. Lowenstein DH. Status epilepticus: an overview of the clinical problem. Epilepsia.
1999;40 Suppl 1:S3-8; discussion S21-22.
17. Lowenstein DH. Status epilepticus. West J Med. 1998;168(4):263.
18. Hymel G. Theophylline Toxicity. Emedicine. 2016.
https://emedicine.medscape.com/article/818847-treatment.
19. DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. Persistent nonconvulsive status
epilepticus after the control of convulsive status epilepticus. Epilepsia. 1998;39(8):833-
840.
20. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of
status epilepticus. Neurocrit Care. 2012;17(1):3-23.
21. Vespa PM, Olson DM, John S, et al. Evaluating the Clinical Impact of Rapid Response
Electroencephalography: The DECIDE Multicenter Prospective Observational Clinical
Study. Crit Care Med. 2020;48(9):1249-1257.
22. McMullan JT, Jones E, Barnhart B, et al. Degradation of benzodiazepines after 120 days
of EMS deployment. Prehosp Emerg Care. 2014;18(3):368-374.
23. McMullan JT, Pinnawin A, Jones E, et al. The 60-day temperature-dependent
degradation of midazolam and Lorazepam in the prehospital environment. Prehosp
Emerg Care. 2013;17(1):1-7.
24. Navarro V, Dagron C, Elie C, et al. Prehospital treatment with levetiracetam plus
clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a
randomised, double-blind, phase 3 trial. Lancet Neurol. 2016;15(1):47-55.
25. Sathe AG, Tillman H, Coles LD, et al. Underdosing of Benzodiazepines in Patients With
Status Epilepticus Enrolled in Established Status Epilepticus Treatment Trial. Acad
Emerg Med. 2019;26(8):940-943.
26. Rao SK, Mahulikar A, Ibrahim M, Shah A, Seraji-Bozorgzad N, Mohamed W.
Inadequate benzodiazepine dosing may result in progression to refractory and non-
convulsive status epilepticus. Epileptic Disord. 2018;20(4):265-269.
27. Chin RF, Verhulst L, Neville BG, Peters MJ, Scott RC. Inappropriate emergency
management of status epilepticus in children contributes to need for intensive care. J
Neurol Neurosurg Psychiatry. 2004;75(11):1584-1588.

16
28. Kapur J, Elm J, Chamberlain JM, et al. Randomized Trial of Three Anticonvulsant
Medications for Status Epilepticus. N Engl J Med. 2019;381(22):2103-2113.
29. Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N. Randomized study of
intravenous valproate and phenytoin in status epilepticus. Seizure. 2007;16(6):527-532.
30. Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot
study. Neurology. 2006;67(2):340-342.
31. Shaner DM, McCurdy SA, Herring MO, Gabor AJ. Treatment of status epilepticus: a
prospective comparison of diazepam and phenytoin versus phenobarbital and optional
phenytoin. Neurology. 1988;38(2):202-207.
32. Connor TH MB, DeBord DG, Trout DB, O’Callaghan JP. NIOSH list of antineoplastic
and other hazardous drugs in healthcare settings. In: U.S. Department of Health and
Human Services CfDCaP, National Institute for Occupational Safety and Health, ed.
DHHS (NIOSH) Publication Number 2016-161 (Supersedes 2014-138)2016.
33. Berning S, Boesebeck F, van Baalen A, Kellinghaus C. Intravenous levetiracetam as
treatment for status epilepticus. J Neurol. 2009;256(10):1634-1642.
34. Ramael S, Daoust A, Otoul C, et al. Levetiracetam intravenous infusion: a randomized,
placebo-controlled safety and pharmacokinetic study. Epilepsia. 2006;47(7):1128-1135.
35. Lyttle MD, Rainford NEA, Gamble C, et al. Levetiracetam versus phenytoin for second-
line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-
label, randomised trial. Lancet. 2019;393(10186):2125-2134.
36. Morgan O, Medenwald B. Safety and Tolerability of Rapid Administration Undiluted
Levetiracetam. Neurocrit Care. 2020;32(1):131-134.
37. Uges JW, van Huizen MD, Engelsman J, et al. Safety and pharmacokinetics of
intravenous levetiracetam infusion as add-on in status epilepticus. Epilepsia.
2009;50(3):415-421.
38. Wheless JW, Clarke D, Hovinga CA, et al. Rapid infusion of a loading dose of
intravenous levetiracetam with minimal dilution: a safety study. J Child Neurol.
2009;24(8):946-951.
39. Marawar R, Basha M, Mahulikar A, Desai A, Suchdev K, Shah A. Updates in Refractory
Status Epilepticus. Crit Care Res Pract. 2018;2018:9768949.
40. Madzar D, Reindl C, Giede-Jeppe A, et al. Impact of timing of continuous intravenous
anesthetic drug treatment on outcome in refractory status epilepticus. Crit Care.
2018;22(1):317.
41. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus
with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia.
2002;43(2):146-153.
42. Iyer VN, Hoel R, Rabinstein AA. Propofol infusion syndrome in patients with refractory
status epilepticus: an 11-year clinical experience. Crit Care Med. 2009;37(12):3024-
3030.
43. Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still
more questions than answers. Lancet Neurol. 2011;10(10):922-930.
44. Rossetti AO, Milligan TA, Vulliemoz S, Michaelides C, Bertschi M, Lee JW. A
randomized trial for the treatment of refractory status epilepticus. Neurocrit Care.
2011;14(1):4-10.
45. Tripathi M, Vibha D, Choudhary N, et al. Management of refractory status epilepticus at
a tertiary care centre in a developing country. Seizure. 2010;19(2):109-111.

17
46. Alkhachroum A, Der-Nigoghossian CA, Mathews E, et al. Ketamine to treat super-
refractory status epilepticus. Neurology. 2020;95(16):e2286-e2294.
47. Rosati A, De Masi S, Guerrini R. Ketamine for Refractory Status Epilepticus: A
Systematic Review. CNS Drugs. 2018;32(11):997-1009.
48. Limdi NA, Shimpi AV, Faught E, Gomez CR, Burneo JG. Efficacy of rapid IV
administration of valproic acid for status epilepticus. Neurology. 2005;64(2):353-355.
49. Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable patients with
status epilepticus. Neurology. 2000;55(5):722-724.
50. Brigo F, Lattanzi S, Nardone R, Trinka E. Intravenous Brivaracetam in the Treatment of
Status Epilepticus: A Systematic Review. CNS Drugs. 2019;33(8):771-781.
51. Strzelczyk A, Zollner JP, Willems LM, et al. Lacosamide in status epilepticus:
Systematic review of current evidence. Epilepsia. 2017;58(6):933-950.
52. Bennett KS VOC. Chapter 63: Status Epilepticus. In: Rogers’ Textbook of Pediatric
Intensive Care, 5th ed. Philadelphia: Wolters Kluwer; 2016:990-1008.
53. Singh RK, Stephens S, Berl MM, et al. Prospective study of new-onset seizures
presenting as status epilepticus in childhood. Neurology. 2010;74(8):636-642.
54. Glass HC, Shellhaas RA, Wusthoff CJ, et al. Contemporary Profile of Seizures in
Neonates: A Prospective Cohort Study. J Pediatr. 2016;174:98-103 e101.
55. Au CC, Branco RG, Tasker RC. Management protocols for status epilepticus in the
pediatric emergency room: systematic review article. J Pediatr (Rio J). 2017;93 Suppl
1:84-94.
56. Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Efficacy of nonvenous
medications for acute convulsive seizures: A network meta-analysis. Neurology.
2015;85(21):1859-1868.
57. Dalziel SR, Borland ML, Furyk J, et al. Levetiracetam versus phenytoin for second-line
treatment of convulsive status epilepticus in children (ConSEPT): an open-label,
multicentre, randomised controlled trial. Lancet. 2019;393(10186):2135-2145.
58. Sharpe C, Reiner GE, Davis SL, et al. Levetiracetam Versus Phenobarbital for Neonatal
Seizures: A Randomized Controlled Trial. Pediatrics. 2020;145(6).
59. Tasker RC, Goodkin HP, Sanchez Fernandez I, et al. Refractory Status Epilepticus in
Children: Intention to Treat With Continuous Infusions of Midazolam and Pentobarbital.
Pediatr Crit Care Med. 2016;17(10):968-975.
60. Keros S, Buraniqi E, Alex B, et al. Increasing Ketamine Use for Refractory Status
Epilepticus in US Pediatric Hospitals. J Child Neurol. 2017;32(7):638-646.
61. Rosati A, L'Erario M, Ilvento L, et al. Efficacy and safety of ketamine in refractory status
epilepticus in children. Neurology. 2012;79(24):2355-2358.
62. Lawson T, Yeager S. Status Epilepticus in Adults: A Review of Diagnosis and
Treatment. Crit Care Nurse. 2016;36(2):62-73.
63. Rajiv KR, Radhakrishnan A. Status epilepticus in pregnancy - Can we frame a uniform
treatment protocol? Epilepsy Behav. 2019;101(Pt B):106376.
64. Tomson T, Battino D, Bromley R, et al. Global Survey of Guidelines for the Management
of Epilepsy in Pregnancy: A report from the International League Against Epilepsy Task
Force on Women and Pregnancy. Epilepsia Open. 2020;5(3):366-370.
65. Veroniki AA, Cogo E, Rios P, et al. Comparative safety of anti-epileptic drugs during
pregnancy: a systematic review and network meta-analysis of congenital malformations
and prenatal outcomes. BMC Med. 2017;15(1):95.

18
Acknowledgements
The authors are grateful for the contributions and insights provided by the authors of prior
versions, including: Joshua N. Goldstein, MD, PhD: AM Iqbal O’Meara, MD: Sarah Peacock,
DNP, APRN, ACNP-BC; Rob Silbergleit, MD; Jan Claassen, MD, PhD; and James J. Riviello,
Jr., MD. The authors are also grateful for the contributions and insight provided by the following
reviewers: Jason McMullan, MD; Natalie Gofman, Pharm.D., BCPS, BCCCP; and Pedro Kurtz,
MD, PhD.

19
20
21