Transcript Status Epilepticus 2

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:
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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
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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
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Outcome of SE
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continued
Acute causes - difficult to control / higher
mortality
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sepsis - esp CNS
CNS - infx, stroke, head trauma, neoplasm
drug toxicity
hypoxia
metabolic encephalopathy
» abn lytes, renal failure
Outcome of SE
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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
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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
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continued
GABA = main inhibitory neurotransmitter
– GABA antagonists can cause SE eg Penicillins, other antibiotics
– prolonged sz can desensitize GABA receptors
Pathophysiology - SE
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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
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continued
PHASE 1 (0-30 min) -- compensatory
mechanisms remain intact
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adrenaline or noradrenaline release ++
increased CBF & metabolism
hypertension, hyperpyrexia
hyperventilation, tachycardia
lactic acidosis
Pathophysiology - SE
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continued
PHASE 2 (>30 min) -- compensatory
mechanisms failing
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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:
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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
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Management of SE
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continued
consider underlying causes:
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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
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tonic-clonic
– look for signs of underlying causes - trauma,
infection, etc
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LAB: gluc, lytes, creat, BUN, CBC, Ca, Mg, Phos,
LFT’s, AED levels, ETOH / toxicology, PTT / INR
-ABG
Management of SE
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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:
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Benzodiazepines
Phenytoin / Fosphenytoin
Barbiturates
Propofol
others / new possibilities
Drug Rx of SE
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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
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Ideal agent characteristics:
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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
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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
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Drug Rx - Refractory SE
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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
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e.g. out of hospital -- often in children
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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)
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Diazepam
Dose: Peds .1-1.0 (.2-.5) mg/kg IV
» Adults 10 - 20 mg (.2 mg/kg) IV
 Duration of action: < 1 hr
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Lorazepam vs. Diazepam
Duration of
action
Onset of
action
Sedation
Lorazepam
Diazepam
*12-24 hr
*< 1 hr
2-3 min
1-3 min
+
++
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
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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
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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
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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
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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
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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
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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
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Fosphenytoin
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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
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Despite giving more rapidly, not shown to
have more rapid onset of action
Barbiturates
in use since 1912
 general CNS depressant activity
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– 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
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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
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Phenobarbital
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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
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– 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:
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– CV depression, hypotension, arrhythmias
– resp depression, apnea
Thiopental
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Thiopental - negative aspects:
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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:
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– stimulates GABA receptors (like Benzos/Bbts)
– suppresses CNS metabolism
Propofol
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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
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Paraldehyde
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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:
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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
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Ketamine in SE
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blocks NMDA receptors - this may protect
brain from effects of excitatory NT’s
– may be neuroprotective as well as antiepileptic
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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
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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
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– 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
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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
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Consensus Guidelines
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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
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