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: – 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

 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

Outcome of SE

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

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

 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

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

Pathophysiology - SE

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

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

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  Definitions  Epidemiology  Clinical Features  Causes / Outcomes  Pathophysiology  Management * – General – Drugs

OUTLINE - Management of SE

 General approach  Anti - Epileptic Drugs: – 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

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 - 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 tonic-clonic – look for signs of underlying causes - trauma, infection, etc  LAB: gluc, lytes, creat, BUN, CBC, Ca, Mg, Phos, LFT’s, AED levels, ETOH / toxicology, PTT / INR -ABG

Management of SE

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: – Benzodiazepines – Phenytoin / Fosphenytoin – Barbiturates – Propofol – others / new possibilities

Drug Rx of SE

 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

 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

 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

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

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)

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)

Diazepam

 Dose: Peds .1-1.0 (.2-.5) mg/kg IV » Adults 10 - 20 mg (.2 mg/kg) IV  Duration of action: < 1 hr

Lorazepam vs. Diazepam

Duration of action Onset of action Sedation Lorazepam *12-24 hr 2-3 min + Diazepam *< 1 hr 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

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

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

 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

 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

 Negative considerations: – COST Approx 20x that of Phenytoin – CONFUSION equivalents” of ordering in “Phenytoin » 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

 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

Fosphenytoin

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

Barbiturates

 in use since 1912  general CNS depressant activity – 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  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

Phenobarbital

 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 – 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: – CV depression, hypotension, arrhythmias – resp depression, apnea

Thiopental

 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  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

Propofol

 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

Paraldehyde

 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: – 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

Ketamine in SE

 blocks NMDA receptors - this may protect brain from effects of excitatory NT’s – may be neuroprotective as well as antiepileptic  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

 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 – 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

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

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

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