Status Epilepticus Stan Bernbaum MD CCFPEM May 31

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

Outline - Status Epilepticus (SE) Case Presentation n Definitions n Epidemiology n Clinical Features n Causes / Outcomes n Pathophysiology n Management * n – 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 --> O 2 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 -O 2 sat still 100% -ordered Phenobarbital 20 mg/kg IV. . . still seizing

CASE - continued MANAGEMENT IN ER - continued: -ABG: p. H 7. 01 p. CO 2 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: p. H 7. 4 p. O 2 359 sat 99 p. CO 2 18 HCO 3 13 BE -9 Lactate 3. 8 Gluc 8. 3 CBC OK Na 144 K 3. 2 Cl 108 CO 2 12 A Gap = 24 -transferred to ACH ICU via transport team

Severe Myoclonic Epilepsy in Infants recognized as a syndrome in 1982 n features: n – 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 2 nd year – all have intellectual deficiency

Outline - Status Epilepticus (SE) Case Presentation n Definitions n Epidemiology n Clinical Features n Causes / Outcomes n Pathophysiology n Management * n – General – Drugs

Definition - Status Epilepticus n n n 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 n Definitions n Epidemiology n Clinical Features n Causes / Outcomes n Pathophysiology n Management * n – General – Drugs

Epidemiology - SE life threatening n USA: -102, 000 -152, 000 cases / year - 52, 000 deaths / year n of new cases of epilepsy, 12 -30% present in Status n generalized Status is most common form - and subject of this review n

Outline - Status Epilepticus (SE) Case Presentation n Definitions n Epidemiology n Clinical Features n Causes / Outcomes n Pathophysiology n Management * n – General – Drugs

Clinical - Generalized SE at onset - usu obvious tonic / clonic n as continues often subtle - slight twitch of face / extremities, nystagmoid eye movements n may be NO observable motor sz ***still risk for CNS injury - assume still seizing if SE pt not waking n » need EEG to definitely dx - not uncommon in comatose hospital inpatients

Outline - Status Epilepticus (SE) Case Presentation n Definitions n Epidemiology n Clinical Features n Causes / Outcomes n Pathophysiology n Management * n – 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 % n increase risk future SE / chronic sz n worse outcome if prolonged / severe physiologic disturbance n outcome depends on cause - acute vs chronic n

Outcome of SE n 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 n 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 n Definitions n Epidemiology n Clinical Features n Causes / Outcomes n Pathophysiology n Management * n – General – Drugs

Pathophysiology - SE n 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 n 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 n continued GABA = main inhibitory neurotransmitter – GABA antagonists can cause SE eg Penicillins, other antibiotics – prolonged sz can desensitize GABA receptors

Pathophysiology - SE n 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 n 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 n 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 n Definitions n Epidemiology n Clinical Features n Causes / Outcomes n Pathophysiology n Management * n – General – Drugs

OUTLINE - Management of SE General approach n Anti - Epileptic Drugs: n – Benzodiazepines – Phenytoin / Fosphenytoin – Barbiturates – Propofol – others / new possibilities

Management of SE ABC’s (+ monitor / O 2 / large IV’s) n START PHARMACOTHERAPY ASAP n Metabolic acidosis common - if severe, give Bicarb n if intubating / ventilating - avoid long-acting n-m blockers - masks sz activity n beware hyperthermia 2º sz - in 30 -80% --> passive cooling n

Management of SE n 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 n Hx: events, trauma, meds, sz hx, ETOH, infx n P/E: Neuro - look for focal signs vs. generalized n tonic-clonic – look for signs of underlying causes - trauma, infection, etc n LAB: gluc, lytes, creat, BUN, CBC, Ca, Mg, Phos, LFT’s, AED levels, ETOH / toxicology, PTT / INR -ABG

Management of SE n 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 n Anti - Epileptic Drugs: n – Benzodiazepines – Phenytoin / Fosphenytoin – Barbiturates – Propofol – others / new possibilities

Drug Rx of SE n 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 n 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 n 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 1 st - Benzodiazepines n * Lorazepam, Diazepam n 2 nd - Phenytoin, Fosphenytoin n 3 rd - Phenobarbital n

Drug Rx - Refractory SE n 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) n GA can suppress immune system -->infection

Non - IV Rx of SE n 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 1 st agent to use n Dose: Adults 4 -10 mg (. 1 mg/kg) IV Peds. 05 -. 1 mg/kg (to 4 mg) IV n less lipid soluble than Diazepam --> smaller volume of distribution / longer T 1/2 – effects last 12 - 24 hr n S/E: resp depression, hypotension, confusion, sedation (but less than diazepam) n

Diazepam Dose: Peds. 1 -1. 0 (. 2 -. 5) mg/kg IV » Adults 10 - 20 mg (. 2 mg/kg) IV n Duration of action: < 1 hr n

Lorazepam vs. Diazepam

Midazolam Dose: . 2 mg/kg IV 5 -10 mg IM 0. 2 mg/kg Intranasal n Dose for refractory SE - continuous IV infusion @. 1 - 2. 0 mg/kg/hr - titrated n Onset: IV 2 - 3 min / other routes 15 min n Duration: 1 - 4 hr n

Phenytoin (Dilantin) still the standard 2 nd IV Rx after Benzo n dose: 18 - 20 mg/kg (better than “ 1 gram”) n IV solution is highly alkaline - dissolved in propylene glycol, alcohol, and Na. OH - p. H is 12 -give in large vein, dilute N/S, flush n rate: Š 50 mg / min (Peds: Š 1 mg/kg/min) n onset of action: 10 - 30 min n duration of action: 12 - 24 hr n

Phenytoin n 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 n 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 3 x rate of Phenytoin, resulting in 2 x amount of Phenytoin delivered

Fosphenytoin n Advantages over Phenytoin: – p. H 8 (vs Phenytoin p. H 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 n Negative considerations: – COST Approx 20 x 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 n 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 n Fosphen was developed to solve problems associated with parenteral Phenytoin, and eventually replace it n P-D have stopped making IV Dilantin - but generic IV Phenytoin still available n

Fosphenytoin n 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 n Despite giving more rapidly, not shown to have more rapid onset of action

Barbiturates in use since 1912 n general CNS depressant activity n – 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 n S/E: resp depression, hypotension

Phenobarbital Dose: 20 mg/kg IV (range 10 -40 mg/kg) -usu maximum 1 gm n Maximum rate: 100 mg/min n onset of action: 10 - 20 min n duration of action: 1 - 3 days n

Phenobarbital n 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 n Rate: 5 - 20 mg/min n – once SE resolved -maintenance: 1 -10 mg/kg/hr

Thiopental Dose: 2 -5 mg/kg IV n rapid onset: 30 - 60 sec n short duration: 20 - 30 min n S/E: n – CV depression, hypotension, arrhythmias – resp depression, apnea

Thiopental n 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 n Rate: 5 -10 mg/min (1 -15 mg/kg/hr) n Onset: 2 -4 min n Half-life: 30 -60 min n does not accumulate --> rapid recovery n Mechanism: n – stimulates GABA receptors (like Benzos/Bbts) – suppresses CNS metabolism

Propofol n n n 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 n “Pro-convulsant effect” - is now thought to be myoclonus, unlikely a significant problem n

Paraldehyde n 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 n has fallen out of favor because: n – 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 n Valproate - IV form available » 15 -20 mg/kg IV. Not studied yet in SE n Gabapentin / Vigabatrin / Lamotrigine n Felbamate - blocks NMDA receptors n Ketamine - blocks NMDA receptors n

Ketamine in SE n blocks NMDA receptors - this may protect brain from effects of excitatory NT’s – may be neuroprotective as well as antiepileptic n 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 n 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 n based on literature search of Ped SE papers in English ; >1100 found, though only 2 were pediatric RCT’s n – 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) n 2. Lorazepam - repeat n 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 n 4. RSI - Thiopental induction 4 mg/kg n

Consensus Guidelines: if NO IV Access 1. Diazepam 0. 5 mg/kg rectally n 2. Paraldehyde 0. 4 ml/kg rectally n start intraosseous if still no IV n then follow IV algorithm – 4. RSI using Thiopental – 3. Phenytoin / Phenobarb; plus Paraldehyde rectally n

Consensus Guidelines n 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 n Lorazepam - best 1 st line Rx n Fosphenytoin - surpasses Phenytoin for SE, and for any patient with altered mental status who would otherwise need IV Phenytoin - hopefully more available soon n Propofol - advantages over barbiturates for resistant SE n