Status EpilepticusDr. Waseem ChistiFellow Emergency Medicine

Outline - Status Epilepticus (SE)DefinitionsEpidemiologyClinical FeaturesCauses / OutcomesPathophysiologyManagement *GeneralDrugs

Definition - Status Epilepticuscontinuous or rapidly repeating seizuresno consensus on exact definition - abn prolongedno recovery between attacks20-30 min > injury to CNS neuronsmore 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 Lowenstein and colleagues have recommended revising the time frame of status epilepticus to 5 or more mins of seizure activity.

Epidemiology - SElife threateningUSA: -102,000 -152,000 cases / year - 52,000 deaths / yearof new cases of epilepsy, 12 -30% present in Statusgeneralized Status is most common form - and subject of this review

Clinical - Generalized SEat onset - usually obvious tonic / clonicas continues often subtle - slight twitch of face / extremities, nystagmoid eye movementsmay be NO observable motor sz, still risk for CNS injury - assume still seizing if SE pt not wakingneed EEG to definitely diagnose - not uncommon in comatose hospital inpatients

Outcome of SEoverall adult mortality 20% (>80 yr : 50%)>90% mortality is due to underlying diseasechildren - better outcomes - mortality 2.5 %increase risk future SE / chronic szworse outcome if prolonged / severe physiologic disturbanceoutcome depends on cause - acute vs chronic

Outcome of SE continuedAcute causes - difficult to control / higher mortalitysepsis - esp CNSCNS - infection, stroke, head trauma, neoplasmdrug toxicityhypoxiametabolic encephalopathy

Outcome of SE continuedChronic causes - usually better response to Rxknown epilepsy - breakthrough sz +/- low anticonvulsant levelsAlcohol / drug abuse / withdrawalremote CNS process (eg brain surgery / CVA / trauma) --> SE after long latent period

Pathophysiology - SEnumerous mechanisms - poorly understoodfailure of mechanisms that usu abort isolated szexcess excitation or ineffective inhibitionthere are excitatory and inhibitory receptors in the brain - activity is usually in balance

Pathophysiology - SE contdGLUTAMATE = the major excitatory AA neurotransmitter in brainany factor which increases Glutamate activity can lead to seizures

Pathophysiology - SE continuedGABA = main inhibitory neurotransmitterGABA antagonists can cause SE - eg Penicillins, other antibioticsprolonged sz can desensitize GABA receptors

Pathophysiology - SE continuedCNS 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 desensitizethese effects worsened if hyperthermia, hypoxia, or hypotension

Pathophysiology - SE continuedPHASE 1 (0-30 min) -- compensatory mechanisms remain intactadrenaline or noradrenaline release ++hypertension, hyperpyrexiahyperventilation, tachycardialactic acidosis

Pathophysiology - SE continuedPHASE 2 (>30 min) -- compensatory mechanisms failingcerebral autoregulation fails / cerebral edemarespiration depressedcardiac arrhythmiashypotensionhypoglycemia, hyponatremiarenal failure, rhabdomyolysis, hyperthermiaDIC

OUTLINE - Management of SEGeneral approachAnti - Epileptic Drugs:BenzodiazepinesPhenytoin / FosphenytoinBarbituratesPropofolothers / new possibilities

Management of SEABCs (+ monitor / O2 / large IVs)START PHARMACOTHERAPY ASAPMetabolic acidosis common - if severe, give Bicarb if intubating / ventilating - avoid long-acting n-m blockers - masks sz activitybeware hyperthermia

Management of SE continuedconsider underlying causes:infection (systemic / CNS)structural: trauma, CVA, IC bleedCNS malformationsmetabolic - hypoxia, abn electrolytes, hypoglycemiatoxic - alcohol, other drugsdrug withdrawal - AEDs, benzoscongenital - inborn errors of metabolism

Management of SE continuedHistory & Physical - do once Rx initiated events, trauma, meds, sz hx, alcohol, infections,P/E: Neuro - look for focal signs vs. generalized tonic-cloniclook for signs of underlying causes - trauma, infection, etcLAB: glucose, E.lytes, creat, BUN, CBC, Ca, Mg, Phos, LFTs, AED levels, ETOH / toxicology, PTT / INR -ABG

Management of SE continuedconsider....ThiamineGlucosePyridoxine 5 gm IV (70 mg/kg kids)reverses INH action inhibiting GABA synthesisnow recommended routinely by NYC Poison Control in REFRACTORY SE d/t frequency of INH OD

OUTLINE - Management of SEGeneral approachAnti - Epileptic Drugs:BenzodiazepinesPhenytoin / FosphenytoinBarbituratesPropofolothers / new possibilities

Drug Rx of SEStarting Rx ASAP has been correlated with a better response rate to drug Rx, and lower morbidityLowenstein DH, Alldredge BK < 30 min - 80% stopped > 120 min - < 40% stopped but - retrospective review; ? groups comparable

Drug Rx of SEIdeal agent characteristics: easy to administer prompt onset, long-acting100% effective vs seizuresno depression of cardio-resp function or mental statusno other adverse effects

Drug Rx of SEExisting agents - adverse effects: Benzos / Bbts - decrease LOC / respirationDilantin / (Fosphenytoin) - infusion rate-related hypotension / dysrhythmiasDilantin / Bbts / (Fosphen) - slow onset d/t limited rate of administration

Drug Rx of SE1st - Benzodiazepines * Lorazepam, Diazepam 2nd - Phenytoin, Fosphenytoin3rd - Phenobarbital

Drug Rx - Refractory SEAnesthetic doses of:Midazolam (0.2 mg/kg slow IV bolus) - ->continuous IV infusion @ 0.4 - 6.0 mcg/kg/min OR .1 - 2.0 mg/kg/hrPropofol (1-2 mg/kg)Barbiturates (Thiopental, Phenobarbital, Pentobarbital)Inhalational anesthetics (Isoflurane)GA can suppress immune system -infection

Non - IV Rx of SEe.g. out of hospital -- often in childrenMidazolam IM (or Intranasal) .15-.3 mg/kgDiazepam Rectally .5 mg/kg (to 20 mg)Lorazepam SL(Paraldehyde rectally)

Lorazepam1st agent to useDose: 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 T1/2effects last 12 - 24 hrS/E: resp depression, hypotension, confusion, sedation (but less than diazepam)

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

Lorazepam vs. Diazepam

Lorazepam

Diazepam

Duration of action

*12-24 hr

*< 1 hr

Onset of action

2-3 min

1-3 min

Sedation

+

++

MidazolamDose: .2 mg/kg IV 5-10 mg IM 0.2 mg/kg IntranasalDose for refractory SE - continuous IV infusion @ 0.1 - 2.0 mg/kg/hr - titratedOnset: IV 2 - 3 min / other routes 15 minDuration: 1 - 4 hr

Phenytoin (Dilantin)still the standard 2nd IV Rx after Benzodose: 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, flushrate: 50 mg / min (Peds: 1 mg/kg/min)onset of action: 10 - 30 minduration of action: 12 - 24 hr

Phenytoin continuedS/E - (most avoided if slower administration)hypotensionarrhythmias - (must monitor)respiratory depressionvenous irritationextravasation -->tissue injury / necrosispurple glove syndrome: progressive limb edema, discoloration and pain 2-12 hr post IV admin

Fosphenytoina prodrug of Phenytoinit has no anticonvulsant action itself, but is rapidly converted to PhenytoinDosage: in Phenytoin Equivalents to attempt to avoid confusionMolecular wt = 1.5 x Phenytoin ... so 1.5 mg Fosphen --> 1 mg Phenytoincan safely give at 3x rate of Phenytoin, resulting in 2x amount of Phenytoin delivered

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

FosphenytoinNegative considerations:COST Approx 20x that of PhenytoinCONFUSION of ordering in Phenytoin equivalents can give IV at rate of 150 PE/min, which delivers 100 mg/min of Phenytoin750 mg Fosphen = 500 mg PE - One UK hospital expresses orders in both units ie 500 mg PE (750 mg Fosphen)

Fosphenytoinconfusion:case report 25 yo female given infusion of Phenytoin (mistaken for Fosphenytoin) at 150 mg/minbradycardia to 34BP dropped to 45/0asystoleoops.resuscitated with CPR ( x 15 min), intubation, atropine, isoproterenol

Fosphenytoin

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

Fosphenytoinminor S/E similar to Phenytoin (since is converted to Phenytoin):nystagmus, dizziness, headache, somnolence, ataxia; MORE pruritus & paraesthesias, esp in groin area - responds to BenadrylDespite giving more rapidly, not shown to have more rapid onset of action

Barbituratesin use since 1912general CNS depressant activityraise threshold of most neuronal pathways to direct and indirect stimulationat high levels, slows EEG --> burst suppression and ultimately electrocortical silencemechanism of action not clearly definedS/E: resp depression, hypotension

PhenobarbitalDose: 20 mg/kg IV (range 10-40 mg/kg) -usu maximum 1 gmMaximum rate: 100 mg/minonset of action: 10 - 20 minduration of action: 1 - 3 days

PhenobarbitalIV Phenobarb in Refractory SE:as effective as Diazepam plus Phenytoin, but S/E more pronouncedbecause 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)

PentobarbitalDose: 5 - 12 mg/kgRate: 5 - 20 mg/minonce SE resolved -maintenance: 1-10 mg/kg/hr

ThiopentalDose: 2-5 mg/kg IVrapid onset: 30 - 60 secshort duration: 20 - 30 minS/E: CV depression, hypotension, arrhythmias resp depression, apnea

ThiopentalThiopental - negative aspects:accumulates in fatty tissuesan active metabolite - Pentobarbital long recovery time after infusionhemodynamic instability

PropofolDose: 1-2 (3-5) mg/kgRate: 5-10 mg/min (1-15 mg/kg/hr)Onset: 2-4 minHalf-life: 30-60 mindoes not accumulate --> rapid recoveryMechanism:stimulates GABA receptors (like Benzos/Bbts)suppresses CNS metabolism

Propofolstudy 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

PropofolAdvantages over Barbituratesless hypotensionmore rapid onset of actionrapid eliminationPro-convulsant effect - is now thought to be myoclonus, unlikely a significant problem

Paraldehydean old agent, but has uses:when no IV - rapid IM or PR absorptioneffective vs ETOH withdrawal seizures / SEDose: .1 - .15 ml/kghas fallen out of favor because:smells very bad - an aromatic aldehydedegrades easily, which increases toxicitydecomposes plastic syringes & tubing < 2 minsignificant toxicity - other agents safer

Possible new drugs for StatusLidocaine - some positive trialsValproate - IV form available15-20 mg/kg IV. Not studied yet in SEGabapentin / Vigabatrin / LamotrigineFelbamate - blocks NMDA receptorsKetamine - blocks NMDA receptors

Consensus GuidelinesRx of Status Ep. in Childrenby the Status Epilepticus Working Party - Britain 2000based on literature search of Ped SE papers in English ; >1100 found, though only 2 were pediatric RCTsthey admit these are more practice-based than evidence-based

Consensus Guidelines:if IV Access1. Lorazepam 0.1 mg/kg (over 30-60 sec)2. Lorazepam - repeat3. Phenytoin 18 mg/kg (over 20 min)OR Phenobarbital 20 mg/kg (over 10 min) if already on PhenytoinAND Paraldehyde rectally 0.4 ml/kg in same volume olive oil4. RSI - Thiopental induction 4 mg/kg

Consensus Guidelines:if NO IV Access1. Diazepam 0.5 mg/kg rectally2. Paraldehyde 0.4 ml/kg rectallystart intraosseous if still no IVthen follow IV algorithm4. RSI using Thiopental3. Phenytoin / Phenobarb; plus Paraldehyde rectally

Take-Home points - Statusbetter outcome if sz stopped earlierLorazepam - best 1st line RxFosphenytoin - 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