Status Epilepticus Stan Bernbaum MD CCFP-EM May 31, 2001.

Status EpilepticusStatus Epilepticus

Stan Bernbaum MD CCFP-EMStan Bernbaum MD CCFP-EM

May 31, 2001May 31, 2001

Outline - Status Epilepticus (SE)Outline - Status Epilepticus (SE)

Case PresentationCase Presentation DefinitionsDefinitions EpidemiologyEpidemiology Clinical FeaturesClinical Features Causes / OutcomesCauses / Outcomes PathophysiologyPathophysiology Management *Management *

– GeneralGeneral– DrugsDrugs

CASECASE Patient BNW - 14 month femalePatient BNW - 14 month female

PMH: PMH: -Recurrent Grand Mal seizures since birth, -Recurrent Grand Mal seizures since birth, lasting up to 1 hourlasting up to 1 hour

-On meds: Carbamazepine, Topiramate, & Clobazam-On meds: Carbamazepine, Topiramate, & Clobazam-Family had detailed instructions from neurologist -Family had detailed instructions from neurologist

regarding management of her seizuresregarding management of her seizures

HX: HX: -Unwell all day- frequent vomiting, fever-Unwell all day- frequent vomiting, fever-Generalized tonic-clonic seizures began 1/2 hr ago-Generalized tonic-clonic seizures began 1/2 hr ago-Presents to ER at PLC by EMS-Presents to ER at PLC by EMS

having generalized convulsionshaving generalized convulsions

CASE - CASE - continuedcontinued

P/E: P/E:

--Generalized seizure activity, drooling, Generalized seizure activity, drooling, shallow respirations; being bagged by EMSshallow respirations; being bagged by EMS

-Pale, warm, diaphoretic-Pale, warm, diaphoretic

-VS: P 180, R 28, T 40.3, Sat 88%-VS: P 180, R 28, T 40.3, Sat 88%


Management:Management:AT HOMEAT HOME::

-Had been given -Had been given Lorazepam PRLorazepam PR 0.1 mg/kg by 0.1 mg/kg by fatherfather

-EMS repeated -EMS repeated Lorazepam PRLorazepam PR, and also gave , and also gave Midazolam IMMidazolam IM 0.2 mg/kg 0.2 mg/kg

-Glucometer by EMS - 7.2-Glucometer by EMS - 7.2-IV started just before arrival at hospital-IV started just before arrival at hospital


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


MANAGEMENT IN ER - MANAGEMENT IN ER - continuedcontinued::-Lorazepam 0.1 mg/kg repeat-Lorazepam 0.1 mg/kg repeat-consults - Peds PLC-consults - Peds PLC

- Ped Neurologist and ICU @ - Ped Neurologist and ICU @ ACHACH

-O2 sat still 100%-O2 sat still 100%-ordered Phenobarbital 20 mg/kg IV-ordered Phenobarbital 20 mg/kg IV......still seizing......still seizing


MANAGEMENT IN ER - MANAGEMENT IN ER - continuedcontinued::

-ABG: pH 7.01 -ABG: pH 7.01

pCO2 elevated pCO2 elevated

(other results not in chart) (other results not in chart)

-Thiopental 5 mg/kg-Thiopental 5 mg/kg

-Intubated (#5 uncuffed ET tube)-Intubated (#5 uncuffed ET tube)

...... seizure activity stopped....... seizure activity stopped.

-Phenobarbital given (from previous order)-Phenobarbital given (from previous order)


MANAGEMENT IN ER - MANAGEMENT IN ER - continuedcontinued::

repeat ABG: pH 7.4 pO2 359 sat 99repeat ABG: pH 7.4 pO2 359 sat 99

pCO2 18 HCO3 13 BE -9pCO2 18 HCO3 13 BE -9

Lactate 3.8 Gluc 8.3Lactate 3.8 Gluc 8.3

CBC OKCBC OK

Na 144 K 3.2 Cl 108 CO2 12Na 144 K 3.2 Cl 108 CO2 12

A Gap = 24A Gap = 24

-transferred to ACH ICU via transport team -transferred to ACH ICU via transport team

Severe Myoclonic Epilepsy in Severe Myoclonic Epilepsy in InfantsInfants

recognized as a syndrome in 1982recognized as a syndrome in 1982 features:features:

– family history of epilepsy or febrile convulsionsfamily history of epilepsy or febrile convulsions– seizures begin during first year of lifeseizures begin during first year of life– very resistant to all treatmentvery resistant to all treatment– unknown etiologyunknown etiology– ataxia, pyramidal signs, & myoclonus developataxia, pyramidal signs, & myoclonus develop– psychomotor development retarded from 2nd yearpsychomotor development retarded from 2nd year– all have intellectual deficiencyall have intellectual deficiency

Outline - Status Epilepticus (SE)Outline - Status Epilepticus (SE) Case PresentationCase Presentation DefinitionsDefinitions EpidemiologyEpidemiology Clinical FeaturesClinical Features Causes / OutcomesCauses / Outcomes PathophysiologyPathophysiology Management *Management *


Definition - Status EpilepticusDefinition - Status Epilepticus continuous or rapidly repeating seizurescontinuous or rapidly repeating seizures no consensus on exact definition - “abn prolonged”no consensus on exact definition - “abn prolonged”

– ““no recovery between attacks”no recovery between attacks”– ““20-30 min” --> injury to CNS neurons20-30 min” --> injury to CNS neurons– more practical definition: more practical definition: since isolated tonic - since isolated tonic -

clonic seizures rarely last > few minutes ... consider clonic seizures rarely last > few minutes ... consider Status if Status if sz > 5 min or 2 discrete sz with no sz > 5 min or 2 discrete sz with no regaining of consciousness betweenregaining of consciousness between

vs. vs. serialserial sz - close together - regained sz - close together - regained consciousness in betweenconsciousness in between

Epidemiology - SEEpidemiology - SE

life threateninglife threatening USA: -102,000 -152,000 cases / yearUSA: -102,000 -152,000 cases / year

- 52,000 deaths / year - 52,000 deaths / year of new cases of epilepsy, 12 -30%of new cases of epilepsy, 12 -30%

present in Status present in Status generalized Status is most common generalized Status is most common

form - and subject of this reviewform - and subject of this review

Clinical - Generalized SEClinical - Generalized SE

at onset - usu obvious tonic / clonicat onset - usu obvious tonic / clonic as continues often subtle - slight twitch of as continues often subtle - slight twitch of

face / extremities, nystagmoid eye face / extremities, nystagmoid eye movementsmovements

may be NO observable motor sz ***still may be NO observable motor sz ***still risk for CNS injury - assume still seizing if risk for CNS injury - assume still seizing if SE pt not wakingSE pt not waking

» need EEG to definitely dx - not uncommon need EEG to definitely dx - not uncommon in comatose hospital inpatientsin comatose hospital inpatients

Outcome of SEOutcome of SE

overall adult mortality overall adult mortality 20% 20% (>80 yr : (>80 yr : 50%50%))

– >90% mortality is d/t underlying disease>90% mortality is d/t underlying disease

– children - better outcomes - mortality children - better outcomes - mortality 2.5 %2.5 % increase risk future SE / chronic szincrease risk future SE / chronic sz worse outcome if prolonged / severe worse outcome if prolonged / severe

physiologic disturbancephysiologic disturbance outcome depends on cause - outcome depends on cause - acuteacute vs vs chronicchronic

Outcome of SE Outcome of SE continuedcontinued

AcuteAcute causes - difficult to control / higher causes - difficult to control / higher mortalitymortality– sepsis - esp CNSsepsis - esp CNS– CNS - infx, stroke, head trauma, neoplasmCNS - infx, stroke, head trauma, neoplasm– drug toxicitydrug toxicity– hypoxiahypoxia– metabolic encephalopathymetabolic encephalopathy

» abn lytes, renal failureabn lytes, renal failure

Outcome of SE Outcome of SE continuedcontinued

ChronicChronic causes - usu better response to Rx causes - usu better response to Rx– known epilepsy - breakthrough sz +/- low known epilepsy - breakthrough sz +/- low

anticonvulsant levelsanticonvulsant levels– ETOH / drug abuse / withdrawalETOH / drug abuse / withdrawal– remote CNS process (eg brain surgery / CVA / remote CNS process (eg brain surgery / CVA /

trauma) --> SE after long latent periodtrauma) --> SE after long latent period

Pathophysiology - SEPathophysiology - SE

numerous mechanisms - poorly understoodnumerous mechanisms - poorly understood– failure of mechanisms that usu abort isolated szfailure of mechanisms that usu abort isolated sz– excess excitation or ineffective inhibitionexcess excitation or ineffective inhibition– there are excitatory and inhibitory receptors in the there are excitatory and inhibitory receptors in the

brain - activity is usually in balancebrain - activity is usually in balance

Pathophysiology - SE Pathophysiology - SE cont’dcont’d

GLUTAMATE = the major excitatory AA GLUTAMATE = the major excitatory AA neurotransmitter in brainneurotransmitter in brain– any factor which increases Glutamate activity any factor which increases Glutamate activity

can lead to seizurescan lead to seizures– e.g. 1987- mussels contaminated with Domoic e.g. 1987- mussels contaminated with Domoic

acid, a glutamate analog --> profound SE / acid, a glutamate analog --> profound SE / deathsdeaths

Pathophysiology - SE Pathophysiology - SE continuedcontinued

GABA = main inhibitory neurotransmitterGABA = main inhibitory neurotransmitter– GABA antagonists can cause SE - GABA antagonists can cause SE -

eg Penicillins, other antibioticseg Penicillins, other antibiotics– prolonged sz can desensitize GABA receptorsprolonged sz can desensitize GABA receptors


CNS damage can occur - mechanism:CNS damage can occur - mechanism:– uncontrolled neuronal firing -> excess glutamate uncontrolled neuronal firing -> excess glutamate

-> this sustained high influx of calcium ions into -> this sustained high influx of calcium ions into neurons leads to cell death (“excitotoxicity”) neurons leads to cell death (“excitotoxicity”)

– GABA released to counteract this, but GABA GABA released to counteract this, but GABA receptors eventually desensitizereceptors eventually desensitize

– these effects worsened if hyperthermia, hypoxia, or these effects worsened if hyperthermia, hypoxia, or hypotension hypotension


PHASE 1PHASE 1 (0-30 min) -- compensatory (0-30 min) -- compensatory mechanisms remain intactmechanisms remain intact– adrenaline or noradrenaline release ++adrenaline or noradrenaline release ++– increased CBF & metabolismincreased CBF & metabolism– hypertension, hyperpyrexiahypertension, hyperpyrexia– hyperventilation, tachycardiahyperventilation, tachycardia– lactic acidosislactic acidosis


PHASE 2PHASE 2 (>30 min) -- compensatory (>30 min) -- compensatory mechanisms failingmechanisms failing– cerebral autoregulation fails / cerebral edemacerebral autoregulation fails / cerebral edema– respiration depressedrespiration depressed– cardiac arrhythmiascardiac arrhythmias– hypotensionhypotension– hypoglycemia, hyponatremiahypoglycemia, hyponatremia– renal failure, rhabdomyolysis, hyperthermiarenal failure, rhabdomyolysis, hyperthermia– DICDIC

OUTLINE - Management of SEOUTLINE - Management of SE

General approachGeneral approach Anti - Epileptic Drugs:Anti - Epileptic Drugs:

– BenzodiazepinesBenzodiazepines– Phenytoin / FosphenytoinPhenytoin / Fosphenytoin– BarbituratesBarbiturates– PropofolPropofol– others / new possibilitiesothers / new possibilities

Management of SEManagement of SE

ABC’s (+ monitor / O2 / large IV’s)ABC’s (+ monitor / O2 / large IV’s) START PHARMACOTHERAPY ASAPSTART PHARMACOTHERAPY ASAP Metabolic acidosis common - if Metabolic acidosis common - if severesevere, give , give

Bicarb Bicarb if intubating / ventilating - avoid long-if intubating / ventilating - avoid long-

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

--> passive cooling --> passive cooling

Management of SE Management of SE continuedcontinued

consider underlying causes:consider underlying causes:– infection (systemic / CNS)infection (systemic / CNS)– structural: trauma, CVA, IC bleedstructural: trauma, CVA, IC bleed– CNS malformationsCNS malformations– metabolic - hypoxia, abn electrolytes, metabolic - hypoxia, abn electrolytes,

hypoglycemiahypoglycemia– toxic - alcohol, other drugstoxic - alcohol, other drugs– drug withdrawal - AED’s, benzosdrug withdrawal - AED’s, benzos– congenital - inborn errors of metabolismcongenital - inborn errors of metabolism


History & Physical - do once Rx initiatedHistory & Physical - do once Rx initiated Hx: Hx: events, trauma, meds, sz hx, ETOH, infxevents, trauma, meds, sz hx, ETOH, infx P/E: P/E: Neuro - look for focal signs vs. generalized Neuro - look for focal signs vs. generalized

tonic-clonictonic-clonic– look for signs of underlying causes - trauma, look for signs of underlying causes - trauma,

infection, etcinfection, etc LAB: LAB: gluc, lytes, creat, BUN, CBC, Ca, Mg, Phos, gluc, lytes, creat, BUN, CBC, Ca, Mg, Phos,

LFT’s, AED levels, ETOH / toxicology, PTT / INRLFT’s, AED levels, ETOH / toxicology, PTT / INR -ABG -ABG


consider....consider....

– ThiamineThiamine

– GlucoseGlucose

– Pyridoxine 5 gm IV (70 mg/kg kids)Pyridoxine 5 gm IV (70 mg/kg kids)» reverses INH action inhibiting GABA reverses INH action inhibiting GABA

synthesissynthesis» now recommended routinely by NYC Poison now recommended routinely by NYC Poison

Control in Control in REFRACTORYREFRACTORY SE d/t frequency SE d/t frequency of INH ODof INH OD

OUTLINE - Management of SEOUTLINE - Management of SE

General approachGeneral approach Anti - Epileptic Drugs:Anti - Epileptic Drugs:

– BenzodiazepinesBenzodiazepines– Phenytoin / FosphenytoinPhenytoin / Fosphenytoin– BarbituratesBarbiturates– PropofolPropofol– others / new possibilitiesothers / new possibilities

Drug Rx of SEDrug Rx of SE

Starting Rx ASAP has been correlated with Starting Rx ASAP has been correlated with a better response rate to drug Rx, and lower a better response rate to drug Rx, and lower morbiditymorbidity– Lowenstein DH, Alldredge BK Lowenstein DH, Alldredge BK

Neurology 1993 (43): 483-8Neurology 1993 (43): 483-8» < 30 min - 80% stopped< 30 min - 80% stopped» > 120 min - < 40% stopped > 120 min - < 40% stopped

but - retrospective review; ? but - retrospective review; ? groups groups comparablecomparable


Ideal agent characteristics: Ideal agent characteristics: – easy to administer easy to administer – prompt onset, long-actingprompt onset, long-acting– 100% effective vs seizures100% effective vs seizures– no depression of cardio-resp function or mental no depression of cardio-resp function or mental

statusstatus– no other adverse effectsno other adverse effects


Existing agents - adverse effects: Existing agents - adverse effects: – Benzos / Bbts - decrease LOC / respirationBenzos / Bbts - decrease LOC / respiration– Dilantin / (Fosphenytoin) - infusion rate-related Dilantin / (Fosphenytoin) - infusion rate-related

hypotension / dysrhythmiashypotension / dysrhythmias– Dilantin / Bbts / (Fosphen) - slow onset d/t Dilantin / Bbts / (Fosphen) - slow onset d/t

limited rate of administrationlimited rate of administration


1st - Benzodiazepines 1st - Benzodiazepines * * LorazepamLorazepam, Diazepam , Diazepam

2nd - Phenytoin, Fosphenytoin2nd - Phenytoin, Fosphenytoin 3rd - Phenobarbital3rd - Phenobarbital

Drug Rx - Drug Rx - RefractoryRefractory SE SE Anesthetic doses of:Anesthetic doses of:

– Midazolam (0.2 mg/kg slow IV bolus) - -Midazolam (0.2 mg/kg slow IV bolus) - ->continuous IV infusion @ .4 - 6.0 mcg/kg/min >continuous IV infusion @ .4 - 6.0 mcg/kg/min

OR .1 - 2.0 mg/kg/hrOR .1 - 2.0 mg/kg/hr– Propofol (1-2 mg/kg)Propofol (1-2 mg/kg)– Barbiturates (Thiopental, Phenobarbital, Barbiturates (Thiopental, Phenobarbital,

Pentobarbital)Pentobarbital)– Inhalational anesthetics (Isoflurane)Inhalational anesthetics (Isoflurane)

GA can suppress immune system -->infectionGA can suppress immune system -->infection

Non - IV Rx of SENon - IV Rx of SE

e.g. out of hospital -- often in childrene.g. out of hospital -- often in children– Midazolam IM (or Intranasal) .15-.3 mg/kgMidazolam IM (or Intranasal) .15-.3 mg/kg– Diazepam Rectally .5 mg/kg (to 20 mg)Diazepam Rectally .5 mg/kg (to 20 mg)– Lorazepam SLLorazepam SL– (Paraldehyde rectally)(Paraldehyde rectally)

LorazepamLorazepam 1st agent to use1st agent to use Dose: Adults 4 -10 mg (.1 mg/kg) IV Dose: Adults 4 -10 mg (.1 mg/kg) IV

Peds .05 - .1 mg/kg (to 4 mg) IV Peds .05 - .1 mg/kg (to 4 mg) IV less lipid soluble than Diazepam --> smaller less lipid soluble than Diazepam --> smaller

volume of distribution / longer T1/2 volume of distribution / longer T1/2

– effects last 12 - 24 hreffects last 12 - 24 hr S/E: resp depression, hypotension, confusion, S/E: resp depression, hypotension, confusion,

sedation (but less than diazepam) sedation (but less than diazepam)

DiazepamDiazepam

Dose: Peds .1-1.0 (.2-.5) mg/kg IVDose: Peds .1-1.0 (.2-.5) mg/kg IV

» Adults 10 - 20 mg (.2 mg/kg) IVAdults 10 - 20 mg (.2 mg/kg) IV Duration of action: < 1 hrDuration of action: < 1 hr

Lorazepam vs. DiazepamLorazepam vs. Diazepam

Lorazepam Diazepam

Duration ofaction

*12-24 hr *< 1 hr

Onset ofaction

2-3 min 1-3 min

Sedation + ++

MidazolamMidazolam

Dose: .2 mg/kg IV Dose: .2 mg/kg IV 5-10 mg IM 5-10 mg IM

0.2 mg/kg Intranasal 0.2 mg/kg Intranasal Dose for refractory SE - continuous IV Dose for refractory SE - continuous IV

infusion @ .1 - 2.0 mg/kg/hr - titratedinfusion @ .1 - 2.0 mg/kg/hr - titrated Onset: IV 2 - 3 min / other routes 15 minOnset: IV 2 - 3 min / other routes 15 min Duration: 1 - 4 hrDuration: 1 - 4 hr

Phenytoin (Dilantin)Phenytoin (Dilantin) still the standard 2nd IV Rx after Benzostill the standard 2nd IV Rx after Benzo dose: 18 - dose: 18 - 2020 mg/kg (better than “1 gram”) mg/kg (better than “1 gram”) IV solution is highly alkaline - dissolved in IV solution is highly alkaline - dissolved in

propylene glycol, alcohol, and NaOH propylene glycol, alcohol, and NaOH - pH is - pH is 1212-give in large vein, dilute N/S, flush-give in large vein, dilute N/S, flush

rate: Š 50 mg / min (Peds: Š1 mg/kg/min)rate: Š 50 mg / min (Peds: Š1 mg/kg/min) onset of action: 10 - 30 minonset of action: 10 - 30 min duration of action: 12 - 24 hrduration of action: 12 - 24 hr

Phenytoin Phenytoin continuedcontinued

S/E - (most avoided if slower administration)S/E - (most avoided if slower administration)

– hypotensionhypotension

– arrhythmias - (must monitor)arrhythmias - (must monitor)

– respiratory depressionrespiratory depression

– venous irritationvenous irritation

– extravasation -->tissue injury / necrosisextravasation -->tissue injury / necrosis– ““purple glove syndrome”: purple glove syndrome”: progressive limb progressive limb

edema, discoloration and pain 2-12 hr post IV adminedema, discoloration and pain 2-12 hr post IV admin

FosphenytoinFosphenytoin

a prodrug of Phenytoina prodrug of Phenytoin– it has no anticonvulsant action itself, but is it has no anticonvulsant action itself, but is

rapidly converted to Phenytoinrapidly converted to Phenytoin– Dosage: in “Phenytoin Equivalents” to attempt Dosage: in “Phenytoin Equivalents” to attempt

to avoid confusionto avoid confusion– Molecular wt = 1.5 x Phenytoin ... so Molecular wt = 1.5 x Phenytoin ... so 1.5 1.5

mg Fosphen --> 1 mg Phenytoinmg Fosphen --> 1 mg Phenytoin– can safely give at 3x rate of Phenytoin, can safely give at 3x rate of Phenytoin,

resulting in 2x amount of Phenytoin deliveredresulting in 2x amount of Phenytoin delivered


Advantages over Phenytoin:Advantages over Phenytoin:– pH 8pH 8 (vs Phenytoin (vs Phenytoin pH 12pH 12) ) – does not require solvent (Phenytoin is dissolved in does not require solvent (Phenytoin is dissolved in

propylene glycol)propylene glycol)» can give IM when no IV accesscan give IM when no IV access» IV: - less potential for irritation - can give faster IV: - less potential for irritation - can give faster

- no risk of tissue necrosis if - no risk of tissue necrosis if goes interstitial goes interstitial - does not - does not precipitate in IV solutionsprecipitate in IV solutions

– lower risk of hypotension and dysrhythmiaslower risk of hypotension and dysrhythmias


Negative considerations:Negative considerations:– COSTCOST Approx 20x that of Phenytoin Approx 20x that of Phenytoin– CONFUSIONCONFUSION of ordering in “Phenytoin of ordering in “Phenytoin

equivalents”equivalents”» can give IV at rate of 150 PE/min, which can give IV at rate of 150 PE/min, which

delivers 100 mg/min of Phenytoindelivers 100 mg/min of Phenytoin» 750 mg Fosphen = 500 mg PE 750 mg Fosphen = 500 mg PE - One - One

UK hospital expresses orders in both UK hospital expresses orders in both units ie “500 mg PE (750 mg Fosphen)” units ie “500 mg PE (750 mg Fosphen)”

FosphenytoinFosphenytoin confusion:confusion:

– case report case report (Epilepsia 42(2): 288, 2001)(Epilepsia 42(2): 288, 2001)- 25 yo female given infusion of - 25 yo female given infusion of

PhenytoinPhenytoin (mistaken for Fosphenytoin) at 150 (mistaken for Fosphenytoin) at 150 mg/minmg/min» bradycardia to 34bradycardia to 34» BP dropped to 45/0BP dropped to 45/0» asystoleasystole» oops.oops.» resuscitated with CPR ( x 15 min), resuscitated with CPR ( x 15 min),

intubation, atropine, isoproterenolintubation, atropine, isoproterenol


– NOTES -NOTES - both Fosphen (Cerebyx) and Dilantin are both Fosphen (Cerebyx) and Dilantin are

marketed by Parke-Davismarketed by Parke-Davis Fosphen was developed to solve problems Fosphen was developed to solve problems

associated with parenteral Phenytoin, and associated with parenteral Phenytoin, and eventually replace iteventually replace it

P-D have stopped making IV Dilantin - but P-D have stopped making IV Dilantin - but generic IV Phenytoin still availablegeneric IV Phenytoin still available


minor S/E similar to Phenytoin (since is minor S/E similar to Phenytoin (since is converted to Phenytoin):converted to Phenytoin):– nystagmus, dizziness, headache, somnolence, nystagmus, dizziness, headache, somnolence,

ataxia; ataxia; – MORE pruritus & paraesthesias, esp in groin MORE pruritus & paraesthesias, esp in groin

area - responds to Benadrylarea - responds to Benadryl Despite giving more rapidly, not shown to Despite giving more rapidly, not shown to

have more rapid onset of actionhave more rapid onset of action

BarbituratesBarbiturates

in use since 1912in use since 1912 general CNS depressant activitygeneral CNS depressant activity

– raise threshold of most neuronal pathways to raise threshold of most neuronal pathways to direct and indirect stimulationdirect and indirect stimulation

– at high levels, slows EEG --> burst suppression at high levels, slows EEG --> burst suppression and ultimately electrocortical silenceand ultimately electrocortical silence

– mechanism of action not clearly definedmechanism of action not clearly defined S/E: resp depression, hypotensionS/E: resp depression, hypotension

PhenobarbitalPhenobarbital

Dose: 20 mg/kg IV (range 10-40 mg/kg) Dose: 20 mg/kg IV (range 10-40 mg/kg) -usu maximum 1 gm-usu maximum 1 gm

Maximum rate: 100 mg/minMaximum rate: 100 mg/min onset of action: 10 - 20 minonset of action: 10 - 20 min duration of action: 1 - 3 daysduration of action: 1 - 3 days

PhenobarbitalPhenobarbital

IV Phenobarb in Refractory SE:IV Phenobarb in Refractory SE:– as effective as Diazepam plus Phenytoin, but as effective as Diazepam plus Phenytoin, but

S/E more pronouncedS/E more pronounced– because of profound hypotension & respiratory because of profound hypotension & respiratory

depression, patient will likely need intubation depression, patient will likely need intubation & ventilation at this point; & ventilation at this point; (and will need ICU admission and continuous (and will need ICU admission and continuous EEG monitoring if SE persists)EEG monitoring if SE persists)

PentobarbitalPentobarbital

Dose: 5 - 12 mg/kgDose: 5 - 12 mg/kg Rate: 5 - 20 mg/minRate: 5 - 20 mg/min

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

ThiopentalThiopental

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

– CV depression, hypotension, arrhythmias CV depression, hypotension, arrhythmias – resp depression, apnearesp depression, apnea

ThiopentalThiopental

Thiopental - negative aspects:Thiopental - negative aspects:– accumulates in fatty tissuesaccumulates in fatty tissues– an active metabolite - Pentobarbital an active metabolite - Pentobarbital – long recovery time after infusionlong recovery time after infusion– hemodynamic instabilityhemodynamic instability

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

– stimulates GABA receptors (like Benzos/Bbts)stimulates GABA receptors (like Benzos/Bbts)– suppresses CNS metabolismsuppresses CNS metabolism

PropofolPropofol

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

* showed effective resolution of refractory SE * showed effective resolution of refractory SE using Propofol at sub-anesthetic doses (50 mg/kg using Propofol at sub-anesthetic doses (50 mg/kg intraperitoneally) in 5 / 5 animals given that dose intraperitoneally) in 5 / 5 animals given that dose

* Diazepam effective in 3 / 4 animals at similarly * Diazepam effective in 3 / 4 animals at similarly high dosehigh dose

PropofolPropofol

Advantages over BarbituratesAdvantages over Barbiturates

– less hypotensionless hypotension

– more rapid onset of actionmore rapid onset of action

– rapid eliminationrapid elimination ““Pro-convulsant effect” - is now thought to Pro-convulsant effect” - is now thought to

be myoclonus, unlikely a significant be myoclonus, unlikely a significant problemproblem

ParaldehydeParaldehyde an old agent, but has uses:an old agent, but has uses:

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

Dose: .1 - .15 ml/kgDose: .1 - .15 ml/kg has fallen out of favor because:has fallen out of favor because:

– smells very bad - an aromatic aldehydesmells very bad - an aromatic aldehyde– degrades easily, which increases toxicitydegrades easily, which increases toxicity– decomposes plastic syringes & tubing < 2 mindecomposes plastic syringes & tubing < 2 min– significant toxicity - other agents safersignificant toxicity - other agents safer

Possible new drugs for StatusPossible new drugs for Status

Lidocaine - some positive trialsLidocaine - some positive trials Valproate - IV form availableValproate - IV form available

»15-20 mg/kg IV. Not studied yet in SE15-20 mg/kg IV. Not studied yet in SE Gabapentin / Vigabatrin / LamotrigineGabapentin / Vigabatrin / Lamotrigine Felbamate - blocks NMDA receptorsFelbamate - blocks NMDA receptors Ketamine - blocks NMDA receptorsKetamine - blocks NMDA receptors

Ketamine in SEKetamine in SE blocks NMDA receptors - this may protect blocks NMDA receptors - this may protect

brain from effects of excitatory NT’sbrain from effects of excitatory NT’s– may be neuroprotective as well as antiepilepticmay be neuroprotective as well as antiepileptic

some animal studies have demonstrated some animal studies have demonstrated control of refractory SE with Ketamine:control of refractory SE with Ketamine:

Ketamine Controls Prolonged SE - DJBorrisKetamine Controls Prolonged SE - DJBorris Epilepsy Research 42 (2000): 117-22Epilepsy Research 42 (2000): 117-22

– more efffective than Phenobarb in more efffective than Phenobarb in LATELATE SE SE (>60 min); not as effective in EARLY SE(>60 min); not as effective in EARLY SE

Ketamine in SEKetamine in SE

has NOT been studied in SE in the has NOT been studied in SE in the Emergency settingEmergency setting

Consensus GuidelinesConsensus GuidelinesRx of Status Ep. in ChildrenRx of Status Ep. in Children

by the Status Epilepticus Working Party - by the Status Epilepticus Working Party - Britain 2000Britain 2000

based on literature search of Ped SE papers based on literature search of Ped SE papers in English ; >1100 found, though only 2 in English ; >1100 found, though only 2 were pediatric RCT’swere pediatric RCT’s– they admit these are more practice-based than they admit these are more practice-based than

evidence-basedevidence-based

Consensus Guidelines:Consensus Guidelines:if IV Accessif IV Access

1. Lorazepam 0.1 mg/kg (over 30-60 sec)1. Lorazepam 0.1 mg/kg (over 30-60 sec) 2. Lorazepam - repeat2. Lorazepam - repeat 3. Phenytoin 18 mg/kg (“over 20 min”)3. Phenytoin 18 mg/kg (“over 20 min”)

»OROR Phenobarbital 20 mg/kg (“over 10 Phenobarbital 20 mg/kg (“over 10 min”) if already on Phenytoinmin”) if already on Phenytoin

»ANDAND Paraldehyde rectally 0.4 ml/kg in Paraldehyde rectally 0.4 ml/kg in same volume olive oilsame volume olive oil

4. RSI - Thiopental induction 4 mg/kg4. RSI - Thiopental induction 4 mg/kg

Consensus Guidelines:Consensus Guidelines:if if NONO IV Access IV Access

1. Diazepam 0.5 mg/kg rectally1. Diazepam 0.5 mg/kg rectally 2. Paraldehyde 0.4 ml/kg rectally2. Paraldehyde 0.4 ml/kg rectally start intraosseous if still no IVstart intraosseous if still no IV then follow IV algorithmthen follow IV algorithm

– 4. RSI using Thiopental4. RSI using Thiopental

– 3. Phenytoin / Phenobarb; plus Paraldehyde 3. Phenytoin / Phenobarb; plus Paraldehyde rectallyrectally

Consensus GuidelinesConsensus Guidelines

Suggestions for future:Suggestions for future:– compare rectal with buccal midazolamcompare rectal with buccal midazolam– compare IV Fosphenytoin with IV Phenytoincompare IV Fosphenytoin with IV Phenytoin– for refractory SE, after algorithm, considerfor refractory SE, after algorithm, consider

» midazolam infusion midazolam infusion » inhalational anesthetic e.g. Isofluraneinhalational anesthetic e.g. Isoflurane

Take-Home points - StatusTake-Home points - Status better outcome if sz stopped earlierbetter outcome if sz stopped earlier LorazepamLorazepam - best 1st line Rx - best 1st line Rx FosphenytoinFosphenytoin - - surpasses Phenytoin for SE, surpasses Phenytoin for SE,

and for any patient with altered mental and for any patient with altered mental status who would otherwise need IV status who would otherwise need IV Phenytoin - hopefully more available soonPhenytoin - hopefully more available soon

PropofolPropofol - advantages over barbiturates for - advantages over barbiturates for resistant SEresistant SE

Status Epilepticus Stan Bernbaum MD CCFP-EM May 31, 2001.

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Transcript of Status Epilepticus Stan Bernbaum MD CCFP-EM May 31, 2001.