Status Epilepticus 2

8/8/2019 Status Epilepticus 2

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Status Epilepticus

Dr. Rehan Abdullah.

PGR. MU II


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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 noregaining of consciousness between

vs. serial sz - close together - regainedconsciousness in between


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Outline - Status Epilepticus (SE)

Case Presentation Definitions

Epidemiology

Clinical Features

Causes / Outcomes

Pathophysiology

Management *

General

Drugs


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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 commonform - and subject of this review


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Clinical - Generalized SE

at onset - usu obvious tonic / clonic

as continues often subtle - slight twitch offace / extremities, nystagmoid eyemovements

may be NO observable motor sz ***stillrisk for CNS injury - assume still seizing if SE

pt not waking need EEG to definitely dx - not uncommon

in comatose hospital inpatients


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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 continued

Acute causes - difficult to control / highermortality

sepsis - esp CNS CNS - infx, stroke, head trauma, neoplasm

drug toxicity

hypoxia metabolic encephalopathy

abn lytes, renal failure


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Outcome of SE continued

Chronic causes - usu better response to Rx

known epilepsy - breakthrough sz +/- lowanticonvulsant levels

ETOH / drug abuse / withdrawal

remote CNS process (eg brain surgery / CVA /trauma) --> SE after long latent period


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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 thebrain - activity is usually in balance


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Pathophysiology - SE contd

GLUTAMATE = the major excitatory AAneurotransmitter in brain

any factor which increases Glutamate activity canlead to seizures

e.g. 1987- mussels contaminated with Domoicacid, a glutamate analog --> profound SE / deaths


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Pathophysiology - SE continued

GABA = main inhibitory neurotransmitter

GABA antagonists can cause SE -eg Penicillins, other antibiotics

prolonged sz can desensitize GABA receptors


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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


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PHASE 1 (0-30 min) -- compensatorymechanisms remain intact

adrenaline or noradrenaline release ++

increased Cerebral blood flow & metabolism

hypertension, hyperpyrexia

hyperventilation, tachycardia

lactic acidosis


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PHASE 2 (>30 min) -- compensatorymechanisms failing

cerebral autoregulation fails / cerebral edema

respiration depressed

cardiac arrhythmias

hypotension

hypoglycemia, hyponatremia renal failure, rhabdomyolysis, hyperthermia

DIC


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OUTLINE - Management of SE

General approach

Anti - Epileptic Drugs:

Benzodiazepines Phenytoin / Fosphenytoin

Barbiturates

Propofol

others / new possibilities


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Management of SE

ABCs (+ monitor / O2 / large IVs)

START PHARMACOTHERAPY ASAP

Metabolic acidosis common - if severe, giveBicarb

if intubating / ventilating - avoid long-acting

n-m blockers - masks sz activity beware hyperthermia 2 sz - in 30-80%

--> passive cooling


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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


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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. generalizedtonic-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


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Management of SE continued consider....

Thiamine

Glucose

Pyridoxine 5 gm IV (70 mg/kg kids)

reverses INH action inhibiting GABAsynthesis

now recommended routinely by NYC PoisonControl in REFRACTORY SE d/t frequency ofINHOD


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OUTLINE - Management of SE

General approach

Anti - Epileptic Drugs:

Benzodiazepines Phenytoin / Fosphenytoin

Barbiturates

Propofol

others / new possibilities


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Drug Rx of SE

Starting Rx as soon as possible has beencorrelated 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% stoppedbut - retrospective review; ? groups

comparable


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Drug Rx of SE

Ideal agent characteristics:

easy to administer

prompt onset, long-acting 100% effective vs seizures

no depression of cardio-resp function ormental status

no other adverse effects


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Drug Rx of SE

Existing agents - adverse effects:

Benzos / Bbts - decrease LOC / respiration

Dilantin / (Fosphenytoin) - infusion rate-relatedhypotension / dysrhythmias

Dilantin / Bbts / (Fosphen) - slow onset d/t limitedrate of administration


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Drug Rx of SE

1st - Benzodiazepines

* Lorazepam, Diazepam

2nd - Phenytoin, Fosphenytoin 3rd - Phenobarbital


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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


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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)


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Lorazepam

1st agent to use

Dose: Adults 4 -10 mg (.1 mg/kg) IVPeds .05 - .1 mg/kg (to 4 mg) IV

less lipid soluble than Diazepam --> smallervolume 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

Lorazepam Diazepam

Duration of

action

*12-24 hr *< 1 hr

Onset ofaction

2-3 min 1-3 min

Sedation + ++


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Midazolam

Dose: .2 mg/kg IV5-10 mg IM 0.2mg/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: 50 mg / min (Peds: 1 mg/kg/min) onset of action: 10 - 30 min

duration of action: 12 - 24 hr


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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


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Fosphenytoin

a prodrug of Phenytoin

it has no anticonvulsant action itself, but israpidly converted to Phenytoin

Dosage: in Phenytoin Equivalents to attemptto 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


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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


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Fosphenytoin

Negative considerations:

COST Approx 20x that of Phenytoin

CONFUSION of ordering in Phenytoinequivalents

can give IV at rate of 150 PE/min, whichdelivers 100 mg/min of Phenytoin

750 mg Fosphen = 500 mg PE -One UK hospital expresses orders in bothunits ie 500 mg PE (750 mg Fosphen)


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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


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Fosphenytoin

NOTES -

both Fosphen (Cerebyx) and Dilantin aremarketed by Parke-Davis

Fosphen was developed to solve problemsassociated with parenteral Phenytoin, andeventually replace it

P-D have stopped making IV Dilantin - butgeneric IV Phenytoin still available


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Fosphenytoin

minor S/E similar to Phenytoin (since isconverted to Phenytoin):

nystagmus, dizziness, headache, somnolence,ataxia;

MORE pruritus & paraesthesias, esp in groin area -responds to Benadryl

Despite giving more rapidly, not shown tohave more rapid onset of action


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Barbiturates

in use since 1912

general CNS depressant activity

raise threshold of most neuronal pathways todirect and indirect stimulation

at high levels, slows EEG --> burst suppressionand ultimately electrocortical silence

mechanism of action not clearly defined

S/E: resp depression, hypotension


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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

IV Phenobarb in Refractory SE:

as effective as Diazepam plus Phenytoin, but S/Emore pronounced

because of profound hypotension & respiratorydepression, patient will likely need intubation &ventilation at this point; (and willneed ICU admission and continuous EEGmonitoring if SE persists)


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Pentobarbital

Dose: 5 - 12 mg/kg

Rate: 5 - 20 mg/min

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


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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


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Thiopental

Thiopental - negative aspects:

accumulates in fatty tissues

an active metabolite - Pentobarbital

long recovery time after infusion

hemodynamic instability


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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


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Propofol

study in rodent model of refractory SE (AnnNeurol 2001; 49: 260-63 M. Holtkamp)

* showed effective resolution of refractory SE using

Propofol at sub-anesthetic doses (50 mg/kgintraperitoneally) in 5 / 5 animals given that dose

* Diazepam effective in 3 / 4 animals at similarly highdose


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Propofol

Advantages over Barbiturates

less hypotension

more rapid onset of action rapid elimination

Pro-convulsant effect - is now thought tobe myoclonus, unlikely a significantproblem


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Paraldehyde an old agent, but has uses:

when no IV - rapid IM or PR absorption

effective vs ETOHwithdrawal 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


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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 blocks NMDA receptors - this may protect

brain from effects of excitatory NTs

may be neuroprotective as well as antiepileptic

some animal studies have demonstratedcontrol 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


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Ketamine in SE

has NOT been studied in SE in the Emergencysetting


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Consensus GuidelinesRx of Status Ep. in Children

by the Status Epilepticus Working Party -Britain 2000

based on literature search of Ped SE papersin English ; >1100 found, though only 2were pediatric RCTs

they admit these are more practice-based thanevidence-based


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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 insame 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 Paraldehyderectally


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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


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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 mentalstatus who would otherwise need IVPhenytoin - hopefully more available soon

Propofol - advantages over barbiturates forresistant SE

Status Epilepticus 2

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