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Evidence-Based Clinical Practice

Guidelines for the Management of
Pediatric Status Epilepticus

Clinical Practice Guidelines Committee

Al Khafji National Hospital
2020 Edition

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Background
Status epilepticus (SE) is a medical emergency associated with significant morbidity
and mortality. Most clinical and electrographic seizures last less than 5 minutes, and those
that last longer than 5 minutes do not stop spontaneously.
SE refers to either persistent generalised convulsive seizure activity (GCSE) that lasts
for at least 5 minutes or two or more discrete seizures between which there is incomplete
recovery of consciousness.
In a hospital setting, a more practical working definition of SE can be persistent
seizure
activity after sequential administration of appropriate doses of appropriate first- and
second-line antiepileptic drugs (AEDs).

TYPES
SE can be a primarily generalised SE (seizure starts as a generalised tonic–clonic
seizure), or a secondarily generalised SE (evolved from an initial partial seizure). Evaluation
and treatment of patients presenting with either type is same, although
diagnostic evaluation may vary.

 Non-convulsive status epilepticus: It is defined as persistent (e.g. >30 minute) change in

behaviour and or mental processes from baseline associated with continuous
epileptiform. EEG changes but without major motor signs. No universally accepted
definition yet exists but subtle motor signs (e.g. twitching, blinking) may be present. It
should be suspected in the following patients:
o Who have prolonged postictal period following control of status epilepticus
o Who have altered sensorium with subtle motor signs (twitching, blinking)
o Unexplained stupor or confusion in patients who are on multiple anti-convulsant.
It is essential that treating physician recognises this entity early and optimise the
treatment to prevent neurological and systemic sequelae.

 Refractory SE: is defined as SE that does not respond to the standard treatment
regimen, such as benzodiazepines (BDZ) and another AED. (Refractoriness is better
predicted with the response to AED rather than duration of SE.)

 Super refractory status epilepticus: Super refractory SE (SRSE) is defined as status

epilepticus that continues for 24 hours or more after the use of anaesthetic therapy,
including the cases in whom SE recurs on weaning of anaesthesia. It is a major cause of
mortality and morbidity and usually have a poor outcome.

AETIOLOGY
 In children, SE may be the first presentation of neurological illness.
 In children <2 years of age, more than 80% have either a febrile or an acute
symptomatic (identifiable) aetiology. Therefore, aetiology of SE in children should be
diagnosed and treated as early as possible.
 The causes of SE in children can be broadly grouped into acute and chronic
conditions.

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 ACUTE CONDITIONS CHRONIC CONDITIONS
 Prolonged febrile seizures (commonest cause)  Pre-existing epilepsy
 Acute CNS infections  Intracranial tumours
 Head trauma  Remote CNS pathology (stroke,
abscess, cortical dysplasia, etc.)
 Stroke/intracranial bleed
 Toxins/ingestion
 Metabolic disturbances (dyselectrolytaemia,
Hypoglycaemia, etc.)
 Drug issues (non-compliance with AED, toxicity,
withdrawal)
 Hypoxia, cardiac arrest
 Hypertensive encephalopathy
 Autoimmune disorders

 With ongoing increased brain electrical activity due to seizures, brain compensatory
mechanisms may initially prevent neuronal injury by increasing the cerebral blood
flow (and causing hypertension) to meet the increased cerebral oxygen and glucose
demand. However, brain compensation requires adequate airway, breathing and
circulatory support.
 For seizure episodes that last longer than 60 minutes, the normal compensatory
mechanisms begin to fail, causing complications related to both cerebral hypoxia and
direct neuronal death as well as systemic effects such as hypoxia, hypotension,
hypoperfusion and metabolic acidosis, hyperthermia, hyperkalaemia and
rhabdomyolysis (due to persistent muscle activity), and hypoglycaemia.

Scope and Purpose

I. PIPOH
a. Population: Pediatric Patient
b. Intervention: Clinical Management of the Condition
c. Target Profession Physicians and other healthcare providers
d. Outcomes Successful treatment and positive patient outcomes
e. Healthcare Setting Hospital Setting

II. Objectives:
a. Standardizing the management of a common clinical practice.
b. Improving clinical results and patient outcomes.
c. Improving Utilization by improving length of hospital stay, overall cost, etc.

Clinical Protocol
A. Diagnosis and Admission Criteria: Basic laboratory workup that needs to be done in all
patients presenting with SE includes the following:
 Bedside glucose stick test is required.

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  Blood glucose, complete blood count, blood culture, basic metabolic panel, calcium
(total and ionized), magnesium and AED levels (if the patient is known to be taking
AED) are also required.
 Lumbar puncture: Since acute CNS infection is a common cause of SE in young
children, most children should have the CSF sample collected. However, it should be
remembered that prolonged GCSE itself can induce fever and CSF pleocytosis,
making the diagnosis of meningitis/encephalitis difficult. In such cases, empirical
antimicrobials should be given till culture reports are available. Avoid LP in patients
who are unstable, viz. refractory SE or hemodynamic instability.
 Neuroimaging: Head CT scan (with contrast) is appropriate for most cases once they
have been stabilized. CT brain may help to rule out intracranial bleed (contrast not
required, especially in case of trauma), or suggest the diagnosis of stroke or CNS
infection. There is no preferred definite role of MRI for the diagnosis and
management of GCSE patients. Even though MRI can pick up an ischemic stroke
much before it becomes apparent on CT brain, MRI is much more time consuming
and should be deferred till the seizures are under control.
 EEG (electroencephalography) monitoring: EEG monitoring is not essential for the
acute diagnosis of SE. However, bedside continuous EEG (if possible, video EEG)
should be considered when the patient remains comatose after the termination of
generalized seizures. Use of neuromuscular agents makes the clinical/neurological
examination difficult. The patient is placed in a pharmacologically induced comatose
state (i.e. continuous infusion of AED for treatment of refractory SE).
 Other investigations that may be needed based on the clinical presentation and
condition of the patient includes renal function tests, liver function tests, serum
toxicology screen and investigations for inborn errors of metabolism.
B. Management/Treatment
 SE is a neurological and medical emergency. The longer the duration of the ongoing
seizures, greater would be the systemic effects. The principal goal of treatment is to
emergently stop both clinical and electrographic seizure activities.
 Initial stabilization of a patient who is actively seizuring involves the following:
o Ensuring adequate oxygenation and ventilation (ABC)
o Securing IV access and initiating pharmacological interventions
o Obtaining diagnostic studies
 Patient with ongoing SE should be intubated if airway or gas exchange is
compromised or elevated intracranial pressure (ICP) is suspected. Rapid sequence
intubation (RSI) is recommended.
Drugs Used for Control of SE
 Treatment of NCSE is the same as that for convulsive SE.
 Benzodiazepines
FIRST LINE AED:
 BDZ are the of treatment for control of seizures.
 Lorazepam: Of all BDZ available, lorazepam is the most preferred because it has a
small volume of distribution because of which the CNS levels remain constant for a
longer period of time. It can be given by either IV or IO route.
 Midazolam: When IV access is not available in a patient with SE, midazolam is
preferred as the initial drug as it can be given by alternate routes such as IM and
intra-nasal (in addition to IV/IO). It has a shorter duration of action when compared
to lorazepam. Midazolam infusion is used most often in patients with RSE. The

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 advantages of midazolam as a continuous infusion in the management of RSE are
that it has a rapid onset of action, it has a short half-life, it is stable in aqueous
solution, the metabolites of midazolam clear very rapidly from the circulation, and it
has a lower incidence of cardiovascular and respiratory depression when compared
to other drugs used for RSE (viz. high-dose phenobarbitone and thiopentone).
SECOND LINE AED:
 Phenytoin and Fosphenytoin: These drugs are used for the long-term control of
seizures and to prevent recurrence (after the seizures have been controlled with
BDZ).
 Phenytoin: Limitation of phenytoin is the rate at which it can be given (maximum 50
mg/min; at 25 mg/min in patients with underlying cardiovascular disease) because it
slows the recovery of voltage-activated sodium channel and can lead to prolongation
of QT interval and arrhythmias. Hypotension secondary to phenytoin infusion occurs
primarily due to the propylene glycol diluent. Phenytoin is extremely toxic to
vascular walls (pH 12 to maintain its solubility) and hence should be given slowly
through a large vein (cannot be given IM). In addition, as phenytoin is a highly
protein-bound drug, hypalbuminaemia can lead to an increased level of free
phenytoin and cause toxicity. Hence, a lower loading dose of phenytoin should be
used in patients with decreased serum albumin level (therapeutic phenytoin level =
15–25 mg/dL). Phenytoin level correction for hypalbuminaemia can be done by the
formula given below:
o Corrected serum phenytoin level = measured phenytoin level/(0.2 ×
measured albumin level) + 0.1
 Fosphenytoin: It is a prodrug of phenytoin with an added phosphoryl group that
makes it water soluble at a lower pH (8.6–9); it can also be given by IM route.
Without propylene glycol, it can be given at a rate faster than phenytoin and has less
chances of causing hypotension. Conversion half-life of fosphenytoin to phenytoin is
8–15 minutes. For simplicity and ease of calculation, dose of fosphenytoin is
calculated in phenytoin equivalents (PE). 1.5 mg fosphenytoin = 1 mg phenytoin
 Valproate Sodium valproate is now available as an IV preparation and can be used in
the emergency management of SE after the first-line treatment has failed to break
the seizure cycle. Valproate has an excellent safety profile as compared to other
AEDs used for SE. It is useful in cases where BDZ use is limited by hypotension and
where there is a known hypersensitivity to phenytoin, or status resulting from non-
compliance in patients on valproic acid. It is best avoided in patients with hepatitis or
any other cause of liver dysfunction. Loading dose should be reduced if the patient is
already on other hepatic enzyme-inducing medications such as antitubercular
therapy and paracetamol.
 Levetiracetam: Levetiracetam is rapidly emerging as an effective second-line drug in
the management of SE refractory to phenytoin. It has an excellent safety profile,
especially with respect to its cardiorespiratory profile and interaction with other
medications. It can be used in the presence of liver dysfunction, but dose should be
decreased in renal failure (excreted by kidneys).
RD
3 line of AED:
 Phenobarbitone is useful in control of seizures that are unresponsive to phenytoin
and is used commonly for the control of neonatal seizures. Availability of other AEDs
that have a better safety profile, such as valproate and levetiracetam, has decreased
the use of phenobarbitone as a second-line agent in the management of SE. Use of

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 phenobarbitone is limited by its potential to cause profound respiratory depression
and hypotension (due to its vasodilatory and cardio depressant effects); this effect
may be compounded with the concomitant use of BDZ. Neonates and infants <18
months of age with persistent seizures who fail to respond to AEDs (including
phenobarbitone) should be given pyridoxine. In refractory SE, multiple doses of
phenobarbitone can be given (irrespective of serum levels) with the sole aim to
interrupt the seizure cycle. Such patients have to be intubated as respiratory
depression and airway compromise is very likely with high-dose barbiturates, and
invasive arterial blood pressure monitoring should be done.
 Thiopentone infusion provides general anaesthesia that is reserved only for those
patients with RSE who fail to respond to midazolam infusion and high-dose
phenobarbitone. It has a strong antiepileptic activity and is considered to be
neuroprotective agent and has zero order kinetics which may lead to prolonged half-
life. Thiopentone infusion is titrated to achieve burst suppression on a continuous
bedside EEG. However, caution is recommended while using thiopentone infusion as
it causes significant hypotension due to vasodilatation (fluids and
inotropes/vasopressors may be needed), and it has negative inotropic and
immunosuppressive effect.
 Propofol is another barbiturate that has been found to be useful in RSE as it provides
an almost immediate suppression of seizure activity after an IV bolus. However,
infusions longer than 48 hours can be associated with “propofol infusion syndrome”
that manifests with hypotension, hyperlipidaemia, metabolic acidosis,
rhabdomyolysis and renal failure.

MANAGEMENT OF REFRACTORY STATUS EPILEPTICUS

 RSE is associated with acute, severe and potentially fatal underlying aetiologies such
as encephalitis, massive stroke, or rapidly progressive primary brain tumours, and
may be accompanied by severe impairment of consciousness.
 RSE requires the use of anaesthetic agents given as infusion. Commonly used
anaesthetic drugs include infusions of midazolam, thiopentone, or propofol.
 Occasionally, bolus doses of phenobarbitone have also been used to achieve very
high drug levels.
 The target end-point of anaesthesia is to achieve the level of “burst suppression”.
Drug dosing is typically set at a level which intends to produce burst suppression
with inter-burst intervals of 2–30 seconds.
 Once achieved, slowly weaning from anaesthesia is strongly recommended with a
goal to reduce the infusion rate by 25% during the first 12 hours of the weaning
phase.
 Additional anticonvulsants, depending on the aetiology of the seizures, if not added
can be added. The drug interactions among various anticonvulsants should be
considered and if possible, drug levels should be measured periodically.

MANAGEMENT OF SUPER REFRACTORY STATUS EPILEPTICUS

The management options for SRSE are limited and are mostly either experimental or lack
evidence. Nevertheless, since it is a medical emergency, so all efforts must be made to
control the seizures. The treatment approach is of three-pronged strategy. These are as
follows:

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 1. The primary objective of the treatment is to control seizures with the intent of
preventing occurrence of the initial excitotoxicity.
2. The secondary objective being neuroprotection and prevention of brain damage.
3. The third and final objective is the need to avoid or treat the systemic complications
caused by the prolonged unconsciousness and anaesthesia.
4. The various management options are described next which can be added to ongoing
anaesthetic armamentarium. These lack strong evidence but are used as measures
to break the seizure cycle. The most effective drug should be chosen, and as the
duration of SRSE increases, it is best to avoid drugs with the GABAergic mechanism.

The options currently available include the following:

 Ketamine infusion: It is a useful adjuvant in the treatment of SRSE, especially in the
late stages when medications that rely on GABA enhancement are ineffective. It is
given as a bolus: 0.5–4.5 mg/kg, followed by infusion ranging from 2 to 5 mg/kg/hr.
It has a two-fold advantage over other conventional anaesthetics as primarily it is
potentially neuroprotective through its n-methyl-d-aspartate (NMDA) antagonist
action, and secondarily, it does not cause systemic hypotension attributable to the
fact that it is not a cardiac depressant.
 Magnesium infusion: Intravenous magnesium has its distinctive role in the
management of SRSE and is commonly administered even in the absence of
evidence of deficiency. Dose is usually 25–50 mg/kg/dose.
 Other drugs: Drugs such as Lignocaine infusion and intravenous Paraldehyde have
been used and reported in literature. Drugs such as Verapamil have also been used
but these are documented in isolated case reports.
 Inhalational anaesthetics: Inhalational anaesthetics such as isoflurane (0.8–2% end-
tidal concentration) and declarant (8–10% end-tidal concentration) have been used
and shown some success in few cases. The major impending factor for their use is
the need for an anaesthesia workstation and vaporiser. A vaporiser that can be
integrated into the respiratory circuit, between the Y-piece and the patient, known
as the anaesthetic conserving device (AnaConDa), has been effectively used to
administer inhalational agents in the intensive care unit.
 Immunotherapy: The use of immunotherapy has been interesting development in
recent years even when immunological cause is not evident for SRSE. The rationale is
that there was the possibility of an overt immunologic disease in these subjects. The
discovery of the anti-NMDA-receptor antibodies leading to SRSE is a proof that
antibodies may play a part in the pathogenesis of SRSE. The other alternative
therapy in such scenarios is high-dose methyl-prednisolone (1 g/day), followed by
one or two courses of intravenous immunoglobulins (IVIG). In the presence of a
positive response, long-term therapy with steroids, IVIG, cyclophosphamide, or
rituximab is continued.
 CHAPTER

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Pathway

GCSE diagnosed Assessment of ABCs, consideration of need for

Lorazepam 0.1 mg/kg (maximum dose 4mg) RSI. Check glucose and give dextrose of
3.1
Or Midazolam 0.15mg/kg (maximum 3 doses) <60mg/dl. Monitor vital signs, ECG and SPO2

First line therapy If seizures terminated with BDZ, begin Phenytoin

Lorazepam 0.1 mg/kg
OR
SE CONTINUES
Midazolam 0.15mg/kg
Phenytoin or fosphenytoin
(20mg/kg PE)
GCSE continues, patient now
Considered to be in refractory SE.
Neurology consult and bedside EEG planned.
pressure monitoring necessary to titrate
Phenobarbitone 20mg/kg; can
repeat 10/kg if seizures persist
OR
Midazolam 0.2 mg/kg bolus followed
by infusion0.05-2.0mg/kg/hr
OR
Propofol 3-5 mg/kg followed by
infusion 0.05-2.0 mg/kg/hr
OR
Thiopentone 4mg/kg followed
by infusion 1-4 mg/kg/hr
20mg/kg or Fosphenytoin 30mg/kg (20mg/kg PE)
(1.5mg fosphenytoin = 1mg phenytoin)
Consider IV Valproic acid
20mg/kg at this time
OR
Levetiracetam 20mg/kg
By now, patient considered to be in
refractory SE (RSE)
All drugs used for RSE can cause
hypotension; invasive hemodynamic
fluid/ vasoactive support.
Intubate and secure airway to prevent
aspiration.
For RSE therapy, continue
pharmacological coma after the last
seizure with EEG goal of burst
suppression.

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