Status Epilepticus

Stan Bernbaum MD CCFP-EM

May 31, 2001
Outline - Status Epilepticus (SE)
■ Case Presentation
■ Definitions
■ Epidemiology
■ Clinical Features
■ Causes / Outcomes
■ Pathophysiology
■ Management *
– General
– Drugs
 CASE
Patient BNW - 14 month female
PMH: -Recurrent Grand Mal seizures since birth,
lasting up to 1 hour
-On meds: Carbamazepine, Topiramate, & Clobazam
-Family had detailed instructions from neurologist
regarding management of her seizures

HX: -Unwell all day- frequent vomiting, fever

-Generalized tonic-clonic seizures began 1/2 hr ago
-Presents to ER at PLC by EMS
having generalized convulsions
 CASE - continued
P/E:
-Generalized seizure activity, drooling,
shallow respirations; being bagged by EMS
-Pale, warm, diaphoretic
-VS: P 180, R 28, T 40.3, Sat 88%
 CASE - continued
Management:
AT HOME:
-Had been given Lorazepam PR 0.1 mg/kg by
father
-EMS repeated Lorazepam PR, and also gave
Midazolam IM 0.2 mg/kg
-Glucometer by EMS - 7.2
-IV started just before arrival at hospital
 CASE - continued

MANAGEMENT IN EMERGENCY:
-Bagging --> O2 sat 100%
-Lorazepam 0.1 mg/kg IV
-Phenytoin 20 mg/kg IV over 20 min
-Acetaminophen 15 mg/kg supp
-pt exposed to help cool
-ABG, labs drawn
......still seizing
 CASE - continued

MANAGEMENT IN ER - continued:
-Lorazepam 0.1 mg/kg repeat
-consults - Peds PLC
- Ped Neurologist and ICU @ ACH
-O2 sat still 100%
-ordered Phenobarbital 20 mg/kg IV
......still seizing
 CASE - continued
MANAGEMENT IN ER - continued:
-ABG: pH 7.01
pCO2 elevated
(other results not in chart)
-Thiopental 5 mg/kg
-Intubated (#5 uncuffed ET tube)
...... seizure activity stopped.
-Phenobarbital given (from previous order)
 CASE - continued
MANAGEMENT IN ER - continued:
repeat ABG: pH 7.4 pO2 359 sat 99
pCO2 18 HCO3 13 BE -9
Lactate 3.8 Gluc 8.3
CBC OK
Na 144 K 3.2 Cl 108 CO2 12
A Gap = 24
-transferred to ACH ICU via transport team
 Severe Myoclonic Epilepsy in
Infants
■ recognized as a syndrome in 1982
■ features:
– family history of epilepsy or febrile convulsions
– seizures begin during first year of life
– very resistant to all treatment
– unknown etiology
– ataxia, pyramidal signs, & myoclonus develop
– psychomotor development retarded from 2nd year
– all have intellectual deficiency
Outline - Status Epilepticus (SE)
■ Case Presentation
■ Definitions
■ Epidemiology
■ Clinical Features
■ Causes / Outcomes
■ Pathophysiology
■ Management *
– General
– Drugs
 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
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 cont’d

■ 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
■ ABC’s (+ monitor / O2 / large IV’s)
■ START PHARMACOTHERAPY ASAP
■ Metabolic acidosis common - if severe, give
Bicarb
■ if intubating / ventilating - avoid long-
acting n-m blockers - masks sz activity
■ beware hyperthermia 2º 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 - AED’s, 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,
LFT’s, 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
 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
Lorazepam Diazepam
Duration of *12-24hr *< 1hr
action
Onset of 2-3min 1-3min
action
Sedation + ++
 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: Š 50 mg / min (Peds: Š1 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 NT’s
– 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 RCT’s
– 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