Status Epilepticus

Muhammad Akbar
Department of Neurology
Hasanuddin University

Outline - Status Epilepticus (SE)

Definitions
Epidemiology
Clinical Features
Causes / Outcomes
Pathophysiology
Management *

General
Drugs

Status Epilepticus-Definition
1. Major motor (convulsive) status
Three(3) seizures uninterrupted by
consciousness or a single prolonged seizure greater
than 1/2 hour.
2. Spike wave stupor (Absence or Petit mal status) and
complex partial (psychomotor) status are prolonged
alterations of consciousness verified by EEG as
epileptic.

Definition - Status Epilepticus

continuous or rapidly repeating seizures

no consensus on exact definition - abn prolonged
no recovery between attacks
20-30 min --> injury to CNS neurons
more practical definition: since isolated tonic clonic seizures rarely last > few minutes ... consider
Status if sz > 5 min or 2 discrete sz with no
regaining of consciousness between

vs. serial sz - close together - regained

consciousness in between

Status epilepticus

It is a medical emergency requires prompt

and aggressive treatment

Therapy should be aimed at:

Rapid termination of status epilepticus
Prevention of seizure recurrence
Treatment of underlying cause

Outline - Status Epilepticus (SE)

Case Presentation
Definitions
Epidemiology
Clinical Features
Causes / Outcomes
Pathophysiology
Management *

General
Drugs

Epidemiology - SE
life threatening
USA: -102,000 -152,000 cases / year
- 52,000 deaths / year
of new cases of epilepsy, 12 -30%
present in Status
generalized Status is most common
form - and subject of this review

Outline - Status Epilepticus (SE)

Case Presentation
Definitions
Epidemiology
Clinical Features
Causes / Outcomes
Pathophysiology
Management *

General
Drugs

Clinical - Generalized SE
at onset - usu obvious tonic / clonic
as continues often subtle - slight twitch of
face / extremities, nystagmoid eye
movements
may be NO observable motor sz ***still
risk for CNS injury - assume still seizing if
SE pt not waking

need EEG to definitely dx - not uncommon

in comatose hospital inpatients

Outline - Status Epilepticus (SE)

Case Presentation
Definitions
Epidemiology
Clinical Features
Causes / Outcomes
Pathophysiology
Management *

General
Drugs

Outcome of SE
overall adult mortality 20% (>80 yr : 50%)
>90% mortality is d/t underlying disease
children - better outcomes - mortality 2.5 %
increase risk future SE / chronic sz
worse outcome if prolonged / severe
physiologic disturbance
outcome depends on cause - acute vs chronic

Outcome of SE

continued

Acute causes - difficult to control / higher

mortality

sepsis - esp CNS

CNS - infx, stroke, head trauma, neoplasm
drug toxicity
hypoxia
metabolic encephalopathy
abn lytes, renal failure

Outcome of SE

continued

Chronic causes - usu better response to Rx

known epilepsy - breakthrough sz +/- low
anticonvulsant levels
ETOH / drug abuse / withdrawal
remote CNS process (eg brain surgery / CVA /
trauma) --> SE after long latent period

Outline - Status Epilepticus (SE)

Case Presentation
Definitions
Epidemiology
Clinical Features
Causes / Outcomes
Pathophysiology
Management *

General
Drugs

Pathophysiology - SE

numerous mechanisms - poorly understood

failure of mechanisms that usu abort isolated sz
excess excitation or ineffective inhibition
there are excitatory and inhibitory receptors in the
brain - activity is usually in balance

Pathophysiology - SE contd

GLUTAMATE = the major excitatory AA

neurotransmitter in brain
any factor which increases Glutamate activity
can lead to seizures
e.g. 1987- mussels contaminated with Domoic
acid, a glutamate analog --> profound SE /
deaths

Pathophysiology - SE

continued

GABA = main inhibitory neurotransmitter

GABA antagonists can cause SE eg Penicillins, other antibiotics
prolonged sz can desensitize GABA receptors

Pathophysiology - SE

continued

CNS damage can occur - mechanism:

uncontrolled neuronal firing -> excess glutamate
-> this sustained high influx of calcium ions into
neurons leads to cell death (excitotoxicity)
GABA released to counteract this, but GABA
receptors eventually desensitize
these effects worsened if hyperthermia, hypoxia, or
hypotension

Pathophysiology - SE

continued

PHASE 1 (0-30 min) -- compensatory

mechanisms remain intact

adrenaline or noradrenaline release ++

increased CBF & metabolism
hypertension, hyperpyrexia
hyperventilation, tachycardia
lactic acidosis

Pathophysiology - SE

continued

PHASE 2 (>30 min) -- compensatory

mechanisms failing

cerebral autoregulation fails / cerebral edema

respiration depressed
cardiac arrhythmias
hypotension
hypoglycemia, hyponatremia
renal failure, rhabdomyolysis, hyperthermia
DIC

Outline - Status Epilepticus (SE)

Case Presentation
Definitions
Epidemiology
Clinical Features
Causes / Outcomes
Pathophysiology
Management *

General
Drugs

OUTLINE - Management of SE
General approach
Anti - Epileptic Drugs:

Benzodiazepines
Phenytoin / Fosphenytoin
Barbiturates
Propofol
others / new possibilities

Management of SE
ABCs (+ monitor / O2 / large IVs)
START PHARMACOTHERAPY ASAP
Metabolic acidosis common - if severe, give
Bicarb
if intubating / ventilating - avoid longacting n-m blockers - masks sz activity
beware hyperthermia 2 sz - in 30-80%
--> passive cooling

Management of SE

continued

consider underlying causes:

infection (systemic / CNS)

structural: trauma, CVA, IC bleed
CNS malformations
metabolic - hypoxia, abn electrolytes,
hypoglycemia
toxic - alcohol, other drugs
drug withdrawal - AEDs, benzos
congenital - inborn errors of metabolism

Management of SE

continued

History & Physical - do once Rx initiated

Hx: events, trauma, meds, sz hx, ETOH, infx
P/E: Neuro - look for focal signs vs. generalized

tonic-clonic
look for signs of underlying causes - trauma,
infection, etc

LAB: gluc, lytes, creat, BUN, CBC, Ca, Mg, Phos,

LFTs, AED levels, ETOH / toxicology, PTT / INR
-ABG

Management of SE

continued

consider....
Thiamine
Glucose
Pyridoxine 5 gm IV (70 mg/kg kids)
reverses INH action inhibiting GABA
synthesis
now recommended routinely by NYC Poison
Control in REFRACTORY SE d/t frequency
of INH OD

OUTLINE - Management of SE
General approach
Anti - Epileptic Drugs:

Benzodiazepines
Phenytoin / Fosphenytoin
Barbiturates
Propofol
others / new possibilities

Drug Rx of SE

Starting Rx ASAP has been correlated with

a better response rate to drug Rx, and lower
morbidity
Lowenstein DH, Alldredge BK
Neurology 1993 (43): 483-8
< 30 min - 80% stopped
> 120 min - < 40% stopped
but - retrospective review; ? groups
comparable

Drug Rx of SE

Ideal agent characteristics:

easy to administer
prompt onset, long-acting
100% effective vs seizures
no depression of cardio-resp function or mental
status
no other adverse effects

Status Epilepticus - Treatment

Immediate treatment
1. Secure IV line draw blood for analysis (including
anticonvulsant levels).
2. Push 50 cc of 50% Dextrose i.v.,
100mg thiamine i.v.
3. Monitor vital signs.
4. Examine patient.
5. Protect airway, tongue, head, never leave patient
alone
6. Intubate all patients if first line drugs fail.

Status Epilepticus - Definite Treatment

Non-specific
Correct electrolyte imbalance - acidosis lowers
seizure threshold, treat with bicarbonate if pH<7.1
Lower fever
Antibiotics/ LP if indicated
If neurologic exam dictates, treatment of
underlying cause may proceed concurrently with
drug therapy, e.g., neurosurgical decompression.
Hypotension maintain BP

Status Epilepticus-Definitive Treatment

a.

Diazepam - 10mg IV push over 30-60 seconds

repeat after 10-15mins upto 30mg (5mg/min)
Repeat after 2-4hrs. 100mg/day
i.Good results, easy to administer. (fast acting,
short lasting)
ii. If two doses fail to stop status, then further
doses probably won't work either.
iii. Side effects -- hypotension, bradycardia,
respiratory depression, cardiac arrest, depresses
mental status.

OR
Lorazepam - 4 mg IV push (2mg/min) may
be repeated.
i. Fast acting, medium lasting.
ii. Respiratory depression only in the
extubated patient.

Status Epilepticus-Definite Treatment

b. Phenytoin - 12-20mg/kg IV (slow IV push)

(50mg/min) fast and long acting.
i. Presently used concomitantly with a
benzodiazepine
ii. Its pH is 12, all i.v. fluids are pH 4-6. Do not
add to dextrose drip as it preciptiates.
iii. Monitor BP and ECG

d. IV Valproate - 25 mg/kg IV push, may

repeat.
i. Generally not used because of lack of
experience. Good results in both major
motor and absence status.
ii. fast acting, long acting.
iii. Far less side effects than Diazepam
and dilantin especially in unstable cardiac
status, hypotension, hepatic failure etc.

Status Epilepticus - Definite Treatment

Other drugs that can be used:
IV Midazolam, IM fosphenytoin
IM paraldehyde
In children and when venous access
unavailable, rectal diazepam, lorazepam,
midazolam or paraldehyde.
IV thiopentone, IV lignocaine, IV propofol.
Neuro muscular blocking agents

Drug Rx of SE

Existing agents - adverse effects:

Benzos / Bbts - decrease LOC / respiration
Dilantin / (Fosphenytoin) - infusion rate-related
hypotension / dysrhythmias
Dilantin / Bbts / (Fosphen) - slow onset d/t
limited rate of administration

Drug Rx of SE
1st - Benzodiazepines
* Lorazepam, Diazepam
2nd - Phenytoin, Fosphenytoin
3rd - Phenobarbital

Drug Rx - Refractory SE

Anesthetic doses of:

Midazolam (0.2 mg/kg slow IV bolus) ->continuous IV infusion @ .4 - 6.0 mcg/kg/min
OR .1 - 2.0 mg/kg/hr
Propofol (1-2 mg/kg)
Barbiturates (Thiopental, Phenobarbital,
Pentobarbital)
Inhalational anesthetics (Isoflurane)

GA can suppress immune system -->infection

Non - IV Rx of SE

e.g. out of hospital -- often in children

Midazolam IM (or Intranasal) .15-.3 mg/kg

Diazepam Rectally .5 mg/kg (to 20 mg)
Lorazepam SL
(Paraldehyde rectally)

Lorazepam
1st agent to use
Dose: Adults 4 -10 mg (.1 mg/kg) IV
Peds .05 - .1 mg/kg (to 4 mg) IV
less lipid soluble than Diazepam --> smaller
volume of distribution / longer T1/2
effects last 12 - 24 hr
S/E: resp depression, hypotension, confusion,
sedation (but less than diazepam)

Diazepam
Dose: Peds .1-1.0 (.2-.5) mg/kg IV
Adults 10 - 20 mg (.2 mg/kg) IV
Duration of action: < 1 hr

Lorazepam vs. Diazepam

Durationof
action
Onsetof
action
Sedation

Lorazepam

Diazepam

*1224hr

*<1hr

23min

13min

++

Midazolam
Dose: .2 mg/kg IV
5-10 mg IM
0.2 mg/kg Intranasal
Dose for refractory SE - continuous IV
infusion @ .1 - 2.0 mg/kg/hr - titrated
Onset: IV 2 - 3 min / other routes 15 min
Duration: 1 - 4 hr

Phenytoin (Dilantin)
still the standard 2nd IV Rx after Benzo
dose: 18 - 20 mg/kg (better than 1 gram)
IV solution is highly alkaline - dissolved in
propylene glycol, alcohol, and NaOH
- pH is 12
-give in large vein, dilute N/S, flush
rate: 50 mg / min (Peds: 1 mg/kg/min)
onset of action: 10 - 30 min
duration of action: 12 - 24 hr

Phenytoin

continued

S/E - (most avoided if slower administration)

hypotension
arrhythmias - (must monitor)
respiratory depression
venous irritation
extravasation -->tissue injury / necrosis
purple glove syndrome: progressive limb
edema, discoloration and pain 2-12 hr post IV admin

Fosphenytoin

a prodrug of Phenytoin
it has no anticonvulsant action itself, but is
rapidly converted to Phenytoin
Dosage: in Phenytoin Equivalents to attempt
to avoid confusion
Molecular wt = 1.5 x Phenytoin ... so
1.5 mg Fosphen --> 1 mg Phenytoin
can safely give at 3x rate of Phenytoin,
resulting in 2x amount of Phenytoin delivered

Fosphenytoin

Advantages over Phenytoin:

pH 8 (vs Phenytoin pH 12)
does not require solvent (Phenytoin is dissolved in
propylene glycol)
can give IM when no IV access
IV: - less potential for irritation - can give faster
- no risk of tissue necrosis if goes
interstitial
- does not precipitate in IV
solutions
lower risk of hypotension and dysrhythmias

Fosphenytoin

Negative considerations:
COST Approx 20x that of Phenytoin
CONFUSION of ordering in Phenytoin
equivalents
can give IV at rate of 150 PE/min, which
delivers 100 mg/min of Phenytoin
750 mg Fosphen = 500 mg PE
- One
UK hospital expresses orders in both
units ie 500 mg PE (750 mg Fosphen)

Fosphenytoin

confusion:
case report (Epilepsia 42(2): 288, 2001)
- 25 yo female given infusion of Phenytoin
(mistaken for Fosphenytoin) at 150 mg/min
bradycardia to 34
BP dropped to 45/0
asystole
oops.
resuscitated with CPR ( x 15 min),
intubation, atropine, isoproterenol

Fosphenytoin
NOTES both Fosphen (Cerebyx) and Dilantin are
marketed by Parke-Davis
Fosphen was developed to solve problems
associated with parenteral Phenytoin, and
eventually replace it
P-D have stopped making IV Dilantin - but
generic IV Phenytoin still available

Fosphenytoin

minor S/E similar to Phenytoin (since is

converted to Phenytoin):
nystagmus, dizziness, headache, somnolence,
ataxia;
MORE pruritus & paraesthesias, esp in groin
area - responds to Benadryl

Despite giving more rapidly, not shown to

have more rapid onset of action

Barbiturates
in use since 1912
general CNS depressant activity

raise threshold of most neuronal pathways to

direct and indirect stimulation
at high levels, slows EEG --> burst suppression
and ultimately electrocortical silence
mechanism of action not clearly defined

S/E: resp depression, hypotension

Phenobarbital
Dose: 20 mg/kg IV (range 10-40 mg/kg)
-usu maximum 1 gm
Maximum rate: 100 mg/min
onset of action: 10 - 20 min
duration of action: 1 - 3 days

Phenobarbital

IV Phenobarb in Refractory SE:

as effective as Diazepam plus Phenytoin, but
S/E more pronounced
because of profound hypotension & respiratory
depression, patient will likely need intubation
& ventilation at this point;
(and will need ICU admission and continuous
EEG monitoring if SE persists)

Pentobarbital
Dose: 5 - 12 mg/kg
Rate: 5 - 20 mg/min

once SE resolved -maintenance: 1-10 mg/kg/hr

Thiopental
Dose: 2-5 mg/kg IV
rapid onset: 30 - 60 sec
short duration: 20 - 30 min
S/E:

CV depression, hypotension, arrhythmias

resp depression, apnea

Thiopental

Thiopental - negative aspects:

accumulates in fatty tissues

an active metabolite - Pentobarbital
long recovery time after infusion
hemodynamic instability

Propofol
Dose: 1-2 (3-5) mg/kg
Rate: 5-10 mg/min (1-15 mg/kg/hr)
Onset: 2-4 min
Half-life: 30-60 min
does not accumulate --> rapid recovery
Mechanism:

stimulates GABA receptors (like Benzos/Bbts)

suppresses CNS metabolism

Propofol

study in rodent model of refractory SE

(Ann Neurol 2001; 49: 260-63 M. Holtkamp)
* showed effective resolution of refractory SE
using Propofol at sub-anesthetic doses (50 mg/kg
intraperitoneally) in 5 / 5 animals given that dose
* Diazepam effective in 3 / 4 animals at similarly
high dose

Propofol
Advantages over Barbiturates
less hypotension
more rapid onset of action
rapid elimination
Pro-convulsant effect - is now thought to
be myoclonus, unlikely a significant
problem

Paraldehyde

an old agent, but has uses:

when no IV - rapid IM or PR absorption
effective vs ETOH withdrawal seizures / SE

Dose: .1 - .15 ml/kg

has fallen out of favor because:

smells very bad - an aromatic aldehyde

degrades easily, which increases toxicity
decomposes plastic syringes & tubing < 2 min
significant toxicity - other agents safer

Possible new drugs for Status

Lidocaine - some positive trials
Valproate - IV form available
15-20 mg/kg IV. Not studied yet in SE
Gabapentin / Vigabatrin / Lamotrigine
Felbamate - blocks NMDA receptors
Ketamine - blocks NMDA receptors

Ketamine in SE

blocks NMDA receptors - this may protect

brain from effects of excitatory NTs
may be neuroprotective as well as antiepileptic

some animal studies have demonstrated

control of refractory SE with Ketamine:
Ketamine Controls Prolonged SE DJBorris Epilepsy Research 42 (2000): 117-22
more efffective than Phenobarb in LATE SE
(>60 min); not as effective in EARLY SE

Ketamine in SE

has NOT been studied in SE in the

Emergency setting

Consensus Guidelines
Rx of Status Ep. in Children
by the Status Epilepticus Working Party Britain 2000
based on literature search of Ped SE papers
in English ; >1100 found, though only 2
were pediatric RCTs

they admit these are more practice-based than

evidence-based

Consensus Guidelines:
if IV Access
1. Lorazepam 0.1 mg/kg (over 30-60 sec)
2. Lorazepam - repeat
3. Phenytoin 18 mg/kg (over 20 min)
OR Phenobarbital 20 mg/kg (over 10
min) if already on Phenytoin
AND Paraldehyde rectally 0.4 ml/kg in
same volume olive oil
4. RSI - Thiopental induction 4 mg/kg

Consensus Guidelines:
if NO IV Access
1. Diazepam 0.5 mg/kg rectally
2. Paraldehyde 0.4 ml/kg rectally
start intraosseous if still no IV
then follow IV algorithm
4. RSI using Thiopental
3. Phenytoin / Phenobarb; plus Paraldehyde
rectally

Consensus Guidelines

Suggestions for future:

compare rectal with buccal midazolam
compare IV Fosphenytoin with IV Phenytoin
for refractory SE, after algorithm, consider
midazolam infusion
inhalational anesthetic e.g. Isoflurane

Take-Home points - Status

better outcome if sz stopped earlier
Lorazepam - best 1st line Rx
Fosphenytoin - surpasses Phenytoin for SE,
and for any patient with altered mental
status who would otherwise need IV
Phenytoin - hopefully more available soon
Propofol - advantages over barbiturates for
resistant SE

Thank You

71

TERIMA KASIH