1

PHARMACOTHERAPY
OF STATUS EPILEPTICS

By: Bezie K. (B.Pharm, MSc)

Email: beza.kebede21@gmail.com/beziekebede@mtu.edu.et
 Learning objectives
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At the end of this session, you will be able to:

➢ Define status epileptics(SE)

➢ Differentiate between SE and epilepsy

➢ Identify etiology of SE

➢ Know patient clinical presentation

➢ Design treatment protocol

➢ Validate patient treatment response

 Introduction
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 Status epilepticus (SE) is a common neurologic

emergency that is associated with brain damage
and death.
 Any seizure lasting longer than 5 minutes whether or not
consciousness is impaired or
◼ recurrent seizures without an intervening period of
consciousness between seizures.
 Introduction
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 Pharmacoresistance and mortality significantly increase

with prolonged seizure duration.
 Therefore, aggressive treatment of seizures lasting 5
minutes or more is strongly recommended.
 SE can present in several forms
◼ GCSE and NCSE
 NCSE occurs in 25% of those with SE
 An electroencephalogram (EEG) is the most important
diagnostic and management tool.
 Epidemiology
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 The worldwide and United States incidence ranges

between 1.2 to 5 million and 100,000 to 152,000
cases each year, respectively
 GCSE has no predilection for gender or socioeconomic
status but does occur more frequently in nonwhites across
all ages.
 Most GCSE occurs in individuals with no history of
epilepsy
 however, approximately 5% of adults and 10% to 25%
of children with epilepsy will develop GCSE.
 The incidence of GCSE is highest in those younger than 1
year of age and in those older than 60 years of age.
 Etiology
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 anticonvulsant withdrawal
 metabolic disorder
 concurrent illness
 progression of a preexisting neurologic disease.
 Alcohol withdrawals
 Low level of AED in the plasma
 Trauma
 CNS tumor
 Etiology
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 There are major differences in etiologies for pediatric

and adult patients
 younger than 1 year of age.
◼ Acute encephalopathy
◼ metabolic disorders
 In young children
◼ the cause is often a nonspecific illness such as fever and/or a viral
illness.
 Adults:
◼ cerebrovascular disease
◼ rapid anticonvulsant withdrawal,
◼ and low anticonvulsant serum concentrations
 Pathophysiology
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 Most of what is known has focused on gated ion

channels.
 GCSE is largely caused by glutamate acting on
postsynaptic N-methyl-D-aspartate (NMDA) and ε-
amino-3-hydroxy-5-methyl-isoxazole-4- propionate
(AMPA)/kainate receptors.
 During GCSE, glutamate activation of the NMDA and
AMPA receptors causes opening of the gated calcium
and sodium channels, which lead to neuronal
depolarization.
 Pathophysiology
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 Two distinct and predictable phases

 Phase I occurs during the first 30 minutes of seizure
activity
◼ increases plasma epinephrine, norepinephrine, and
steroid concentrations
◼ lactic acid release
◼ rhabdomyolysis with secondary hyperkalemia and
acute tubular necrosis can occur
◼ increase in salivation and tracheal and pulmonary
secretions can cause aspiration pneumonia.


 Pathophysiology
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phase II immediately
 the EEG ictal discharge and clonic motor activity
become continuous, and the patient begins to decompensate
 The patient become hypotensive
 Auto-regulation of cerebral blood flow becomes dependent on
mean arterial pressure and begins to fail.
 There continues to be an excessive consumption of oxygen and
glucose
 however, compensatory mechanisms are no longer
able to meet demands.
 Hyperthermia and respiratory deterioration with hypoxia and
ventilatory failure, metabolic acidosis, hyperkalemia,
hyponatremia, and azotemia, may develop
 Mortality and morbidity
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 Prolonged, severe muscle contractions and CNS

dysfunction from uncontrolled seizure discharges result
in
 hyperthermia, cardio-respiratory collapse,
myoglobinuria, renal failure, and neurologic damage.
 Even in the absence of convulsive muscle movements,
neurologic damage can occur from excessive electrical
activity and the resultant alterations in brain
metabolism.
 Mortality and morbidity
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 When seizure activity persists longer than approximately

30 minutes, failure of mechanisms that regulate cerebral
blood flow is more likely
 this failure accompanies dramatic increases in brain
metabolism and demand for glucose and oxygen.
 Failure to meet the metabolic demands of brain
tissue results in accumulation of lactate and cell death.
 Peripherally, lactate accumulates and serum glucose and
electrolytes are altered.
 Mortality in adults with SE is approximately
20%
 Mortality and morbidity
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 After 30 minutes of seizure activity, the body often fails

to compensate for increased metabolic demands,
and cardiovascular collapse can occur.
 For these reasons, SE is considered a medical
emergency that requires immediate treatment to prevent
or lessen both systemic and neurologic damage.
 Long term consequences
 cognitive impairment, memory loss, and worsening of seizure
disorders
◼ younger children, the elderly, and those with preexisting epilepsy
 Clinical presentation
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 altered consciousness that ranges from obtunded to

marked lethargy and somnolence with pronounced eyes
open unresponsiveness and waxy rigidity.
 muscle contractions, extensor or flexor posturing, and
spasms.
 Hypothermia or fever
 Incontinence
 Clinical seizures may or may not be apparent
 Diagnosis
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 Observation
 physical examination
 The nature and duration of the seizure but a diagnosis
of GCSE should not be made until a clinician has
observed a seizure.
 Laboratory tests are essential
 RFT, LFT, electrolyte
 Diagnostic test
 MRI, EEG, CT, Radiograph
16
Treatment
What is expected from the treatment?
 immediate termination of all clinical and electrical
seizure activity
 no clinically significant adverse effects

 Avoid recurrent seizure activity.

The long-term outcomes involves

 minimizing or avoiding

 pharmacoresistant epilepsy
 the development of neurologic sequelae that significantly
impact quality of life
 Treatment
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Non pharmacologic
 Vital signs should be assessed

 adequate and protected airway should be established

 ventilation should be maintained, and oxygen should be

administered.
 Frequent arterial blood gas determinations should assess for
metabolic acidosis
 which should be treated with sodium bicarbonate if the pH is less than 7.2
 Assisted ventilation should be used to correct
respiratory acidosis.
 Hyperthermia, if present, should be aggressively
treated (e.g., rectal acetaminophen, cooling blanket).
 Treatment
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Pharmacologic
 When a seizure does not stop within 5 minutes, or

when doubt exists regarding the diagnosis, patients

should be treated as if they have GCSE
 The benzodiazepines, hydantoins, and barbiturates

are the most commonly used classes of anticonvulsants

for the initial treatment of GCSE.
 Treatment
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 Treatment
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Benzodiazepines
 benzodiazepines are effective initial therapy in most
patients and should be administered as soon as
possible.
 Generally, one or two IV doses will terminate seizures
within 2 to 3 minutes.
 which BZD?

 Diazepam is extremely lipophilic

 Treatment
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Phenytoin
 A hydantoin is the second-line agent in GCSE that is
◼ unresponsive to the benzodiazepines or
◼ seizures that recur after successful treatment with a
benzodiazepine
 it is effective in terminating seizures in 40% to 91%
of patients
 it can be inferior to lorazepam, phenobarbital, or
diazepam plus phenytoin at stopping GCSE within
20 minutes of their infusion
 Treatment
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 less respiratory depression and sedation than the

benzodiazepines or phenobarbital
 Injectable phenytoin should be diluted to less than or
equal to 5 mg/mL in normal saline.
 Microcrystals will precipitate if it is mixed in a
glucose-containing solution.
 Rate of infusion should be controlled
 A reduction in the loading dose is recommended for
elderly patients and a larger loading dose is required
in obese individuals.
 If the patient is priorly on phenytoin?
 Treatment
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 it can take up to 60 minutes before the

pharmacodynamic effect is apparent
 Phenytoin has an alkaline pH, which may cause pain
and burning during infusion
 phlebitis can occur with chronic infusion, and tissue
necrosis is likely on infiltration.
 Treatment
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Fosphenytoin
 Fosphenytoin, a water-soluble phosphate ester, has no

known pharmacologic activity.

 It is converted rapidly (7 to 15 minutes) and

completely (100%) to phenytoin by blood and tissue

phosphatases after IV and IM dosing.
 It does not contain propylene glycol and is compatible
with most common IV fluids.
 Treatment
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 a loading dose should not be given IM unless IV

access is impossible.
 the desired serum concentration range is the same as
that for phenytoin
 blood should not be obtained for at least 2 hours
after IV and 4 hours after IM administration.
 Treatment
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Phenobarbital
 Phenobarbital has biphasic distribution into body
organs.
 During phase I, the drug distributes into highly vascular
organs, but does not distribute into the brain.
 With the exception of fat, phenobarbital distributes
throughout the body during phase II
 Although the highest brain concentrations occur 12 to 60
minutes after an IV dose, seizures are controlled within
minutes of the loading dose.
 phenobarbital be given after a benzodiazepine plus
phenytoin has failed.
 Treatment
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 When necessary, larger loading doses (30 mg/kg)

have been used in neonates without adverse effects.
 If the initial loading dose does not stop the seizures
within 20 to 30 minutes, an additional 10 to 20 mg/kg
can be given. If seizures continue, a third 10 mg/kg
load can be given.
 Once GCSE is controlled, the maintenance dose should
be started within 12 to 24 hours.
 Although injectable phenobarbital contains propylene
glycol, it can be given more rapidly than phenytoin.
 It can be given IM, but its rate of absorption is too slow
to be effective.
 Treatment
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How do we treat
special population?
Refractory GCSE?
 Treatment
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 Treatment
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 Evaluation of therapeutic outcome
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 Success
 Initial

 Ultimate

 vital signs should be monitored

 Infusion site should be assessed
 EEG should be done