Status_Epilepticus.ppt

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Status_Epilepticus.ppt

  1. 1. Status EpilepticusStatus Epilepticus Stan Bernbaum MD CCFP-EMStan Bernbaum MD CCFP-EM May 31, 2001May 31, 2001
  2. 2. Outline - Status Epilepticus (SE)Outline - Status Epilepticus (SE) Case PresentationCase Presentation DefinitionsDefinitions EpidemiologyEpidemiology Clinical FeaturesClinical Features Causes / OutcomesCauses / Outcomes PathophysiologyPathophysiology Management *Management * – GeneralGeneral – DrugsDrugs
  3. 3. 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
  4. 4. 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%
  5. 5. CASE -CASE - continuedcontinued Management:Management: AT HOMEAT HOME:: -Had been given-Had been given Lorazepam PRLorazepam PR 0.1 mg/kg by0.1 mg/kg by fatherfather -EMS repeated-EMS repeated Lorazepam PRLorazepam PR, and also gave, and also gave Midazolam IMMidazolam IM 0.2 mg/kg0.2 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
  6. 6. CASE -CASE - continuedcontinued 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
  7. 7. CASE -CASE - continuedcontinued 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 @ ACH- Ped Neurologist and ICU @ ACH -O2 sat still 100%-O2 sat still 100% -ordered Phenobarbital 20 mg/kg IV-ordered Phenobarbital 20 mg/kg IV ......still seizing......still seizing
  8. 8. CASE -CASE - continuedcontinued MANAGEMENT IN ER -MANAGEMENT IN ER - continuedcontinued:: -ABG: pH 7.01-ABG: pH 7.01 pCO2 elevatedpCO2 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)
  9. 9. CASE -CASE - continuedcontinued 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
  10. 10. Severe Myoclonic Epilepsy inSevere 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
  11. 11. Outline - Status Epilepticus (SE)Outline - Status Epilepticus (SE) Case PresentationCase Presentation DefinitionsDefinitions EpidemiologyEpidemiology Clinical FeaturesClinical Features Causes / OutcomesCauses / Outcomes PathophysiologyPathophysiology Management *Management * – GeneralGeneral – DrugsDrugs
  12. 12. 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 ... considerclonic seizures rarely last > few minutes ... consider Status ifStatus if sz > 5 min or 2 discrete sz with nosz > 5 min or 2 discrete sz with no regaining of consciousness betweenregaining of consciousness between vs.vs. serialserial sz - close together - regainedsz - close together - regained consciousness in betweenconsciousness in between
  13. 13. Outline - Status Epilepticus (SE)Outline - Status Epilepticus (SE) Case PresentationCase Presentation DefinitionsDefinitions EpidemiologyEpidemiology Clinical FeaturesClinical Features Causes / OutcomesCauses / Outcomes PathophysiologyPathophysiology Management *Management * – GeneralGeneral – DrugsDrugs
  14. 14. 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 Statuspresent in Status generalized Status is most commongeneralized Status is most common form - and subject of this reviewform - and subject of this review
  15. 15. Outline - Status Epilepticus (SE)Outline - Status Epilepticus (SE) Case PresentationCase Presentation DefinitionsDefinitions EpidemiologyEpidemiology Clinical FeaturesClinical Features Causes / OutcomesCauses / Outcomes PathophysiologyPathophysiology Management *Management * – GeneralGeneral – DrugsDrugs
  16. 16. Clinical - Generalized SEClinical - Generalized SE at onset - usu obvious tonic / clonicat onset - usu obvious tonic / clonic as continues often subtle - slight twitch ofas continues often subtle - slight twitch of face / extremities, nystagmoid eyeface / extremities, nystagmoid eye movementsmovements may be NO observable motor sz ***stillmay be NO observable motor sz ***still risk for CNS injury - assume still seizing ifrisk for CNS injury - assume still seizing if SE pt not wakingSE pt not waking » need EEG to definitely dx - not uncommonneed EEG to definitely dx - not uncommon in comatose hospital inpatientsin comatose hospital inpatients
  17. 17. Outline - Status Epilepticus (SE)Outline - Status Epilepticus (SE) Case PresentationCase Presentation DefinitionsDefinitions EpidemiologyEpidemiology Clinical FeaturesClinical Features Causes / OutcomesCauses / Outcomes PathophysiologyPathophysiology Management *Management * – GeneralGeneral – DrugsDrugs
  18. 18. Outcome of SEOutcome of SE overall adult mortalityoverall 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 - mortalitychildren - better outcomes - mortality 2.5 %2.5 % increase risk future SE / chronic szincrease risk future SE / chronic sz worse outcome if prolonged / severeworse outcome if prolonged / severe physiologic disturbancephysiologic disturbance outcome depends on cause -outcome depends on cause - acuteacute vsvs chronicchronic
  19. 19. Outcome of SEOutcome of SE continuedcontinued AcuteAcute causes - difficult to control / highercauses - 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
  20. 20. Outcome of SEOutcome of SE continuedcontinued ChronicChronic causes - usu better response to Rxcauses - usu better response to Rx – known epilepsy - breakthrough sz +/- lowknown 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
  21. 21. Outline - Status Epilepticus (SE)Outline - Status Epilepticus (SE) Case PresentationCase Presentation DefinitionsDefinitions EpidemiologyEpidemiology Clinical FeaturesClinical Features Causes / OutcomesCauses / Outcomes PathophysiologyPathophysiology Management *Management * – GeneralGeneral – DrugsDrugs
  22. 22. 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 thethere are excitatory and inhibitory receptors in the brain - activity is usually in balancebrain - activity is usually in balance
  23. 23. Pathophysiology - SEPathophysiology - SE cont’dcont’d GLUTAMATE = the major excitatory AAGLUTAMATE = the major excitatory AA neurotransmitter in brainneurotransmitter in brain – any factor which increases Glutamate activityany factor which increases Glutamate activity can lead to seizurescan lead to seizures – e.g. 1987- mussels contaminated with Domoice.g. 1987- mussels contaminated with Domoic acid, a glutamate analog --> profound SE /acid, a glutamate analog --> profound SE / deathsdeaths
  24. 24. Pathophysiology - SEPathophysiology - 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
  25. 25. Pathophysiology - SEPathophysiology - SE continuedcontinued CNS damage can occur - mechanism:CNS damage can occur - mechanism: – uncontrolled neuronal firing -> excess glutamateuncontrolled 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 GABAGABA released to counteract this, but GABA receptors eventually desensitizereceptors eventually desensitize – these effects worsened if hyperthermia, hypoxia, orthese effects worsened if hyperthermia, hypoxia, or hypotensionhypotension
  26. 26. Pathophysiology - SEPathophysiology - SE continuedcontinued 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
  27. 27. Pathophysiology - SEPathophysiology - SE continuedcontinued 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
  28. 28. Outline - Status Epilepticus (SE)Outline - Status Epilepticus (SE) Case PresentationCase Presentation DefinitionsDefinitions EpidemiologyEpidemiology Clinical FeaturesClinical Features Causes / OutcomesCauses / Outcomes PathophysiologyPathophysiology Management *Management * – GeneralGeneral – DrugsDrugs
  29. 29. 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
  30. 30. 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 - ifMetabolic acidosis common - if severesevere, give, give BicarbBicarb 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
  31. 31. Management of SEManagement 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
  32. 32. Management of SEManagement of SE continuedcontinued 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. generalizedNeuro - 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
  33. 33. Management of SEManagement of SE continuedcontinued consider....consider.... – ThiamineThiamine – GlucoseGlucose – Pyridoxine 5 gm IV (70 mg/kg kids)Pyridoxine 5 gm IV (70 mg/kg kids) » reverses INH action inhibiting GABAreverses INH action inhibiting GABA synthesissynthesis » now recommended routinely by NYC Poisonnow recommended routinely by NYC Poison Control inControl in REFRACTORYREFRACTORY SE d/t frequencySE d/t frequency of INH ODof INH OD
  34. 34. 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
  35. 35. Drug Rx of SEDrug Rx of SE Starting Rx ASAP has been correlated withStarting Rx ASAP has been correlated with a better response rate to drug Rx, and lowera better response rate to drug Rx, and lower morbiditymorbidity – Lowenstein DH, Alldredge BKLowenstein 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; ? groupsbut - retrospective review; ? groups comparablecomparable
  36. 36. Drug Rx of SEDrug Rx of SE Ideal agent characteristics:Ideal agent characteristics: – easy to administereasy to administer – prompt onset, long-actingprompt onset, long-acting – 100% effective vs seizures100% effective vs seizures – no depression of cardio-resp function or mentalno depression of cardio-resp function or mental statusstatus – no other adverse effectsno other adverse effects
  37. 37. Drug Rx of SEDrug Rx of SE Existing agents - adverse effects:Existing agents - adverse effects: – Benzos / Bbts - decrease LOC / respirationBenzos / Bbts - decrease LOC / respiration – Dilantin / (Fosphenytoin) - infusion rate-relatedDilantin / (Fosphenytoin) - infusion rate-related hypotension / dysrhythmiashypotension / dysrhythmias – Dilantin / Bbts / (Fosphen) - slow onset d/tDilantin / Bbts / (Fosphen) - slow onset d/t limited rate of administrationlimited rate of administration
  38. 38. Drug Rx of SEDrug Rx of SE 1st - Benzodiazepines1st - Benzodiazepines ** LorazepamLorazepam, Diazepam, Diazepam 2nd - Phenytoin, Fosphenytoin2nd - Phenytoin, Fosphenytoin 3rd - Phenobarbital3rd - Phenobarbital
  39. 39. Drug Rx -Drug Rx - RefractoryRefractory SESE 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
  40. 40. 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)
  41. 41. LorazepamLorazepam 1st agent to use1st agent to use Dose: Adults 4 -10 mg (.1 mg/kg) IVDose: Adults 4 -10 mg (.1 mg/kg) IV Peds .05 - .1 mg/kg (to 4 mg) IVPeds .05 - .1 mg/kg (to 4 mg) IV less lipid soluble than Diazepam --> smallerless lipid soluble than Diazepam --> smaller volume of distribution / longer T1/2volume 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)
  42. 42. 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
  43. 43. Lorazepam vs. DiazepamLorazepam vs. Diazepam Lorazepam Diazepam Duration of action *12-24 hr *< 1 hr Onset of action 2-3 min 1-3 min Sedation + ++
  44. 44. MidazolamMidazolam Dose: .2 mg/kg IVDose: .2 mg/kg IV 5-10 mg IM5-10 mg IM 0.2 mg/kg Intranasal0.2 mg/kg Intranasal Dose for refractory SE - continuous IVDose 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
  45. 45. 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 inIV solution is highly alkaline - dissolved in propylene glycol, alcohol, and NaOHpropylene 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
  46. 46. PhenytoinPhenytoin 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 limbprogressive limb edema, discoloration and pain 2-12 hr post IV adminedema, discoloration and pain 2-12 hr post IV admin
  47. 47. FosphenytoinFosphenytoin a prodrug of Phenytoina prodrug of Phenytoin – it has no anticonvulsant action itself, but isit has no anticonvulsant action itself, but is rapidly converted to Phenytoinrapidly converted to Phenytoin – Dosage: in “Phenytoin Equivalents” to attemptDosage: in “Phenytoin Equivalents” to attempt to avoid confusionto avoid confusion – Molecular wt = 1.5 x Phenytoin ... soMolecular wt = 1.5 x Phenytoin ... so 1.5 mg Fosphen --> 1 mg Phenytoin1.5 mg 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
  48. 48. FosphenytoinFosphenytoin Advantages over Phenytoin:Advantages over Phenytoin: – pH 8pH 8 (vs Phenytoin(vs Phenytoin pH 12pH 12)) – does not require solvent (Phenytoin is dissolved indoes 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 fasterIV: - less potential for irritation - can give faster - no risk of tissue necrosis if goes- no risk of tissue necrosis if goes interstitialinterstitial - does not precipitate in IV- does not precipitate in IV solutionssolutions – lower risk of hypotension and dysrhythmiaslower risk of hypotension and dysrhythmias
  49. 49. FosphenytoinFosphenytoin Negative considerations:Negative considerations: – COSTCOST Approx 20x that of PhenytoinApprox 20x that of Phenytoin – CONFUSIONCONFUSION of ordering in “Phenytoinof ordering in “Phenytoin equivalents”equivalents” » can give IV at rate of 150 PE/min, whichcan 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 PE750 mg Fosphen = 500 mg PE - One UK hospital expresses orders in both- One UK hospital expresses orders in both units ie “500 mg PE (750 mgunits ie “500 mg PE (750 mg Fosphen)”Fosphen)”
  50. 50. FosphenytoinFosphenytoin confusion:confusion: – case reportcase 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 mg/min(mistaken for Fosphenytoin) at 150 mg/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
  51. 51. FosphenytoinFosphenytoin – NOTES -NOTES - both Fosphen (Cerebyx) and Dilantin areboth Fosphen (Cerebyx) and Dilantin are marketed by Parke-Davismarketed by Parke-Davis Fosphen was developed to solve problemsFosphen was developed to solve problems associated with parenteral Phenytoin, andassociated with parenteral Phenytoin, and eventually replace iteventually replace it P-D have stopped making IV Dilantin - butP-D have stopped making IV Dilantin - but generic IV Phenytoin still availablegeneric IV Phenytoin still available
  52. 52. FosphenytoinFosphenytoin minor S/E similar to Phenytoin (since isminor 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 groinMORE pruritus & paraesthesias, esp in groin area - responds to Benadrylarea - responds to Benadryl Despite giving more rapidly, not shown toDespite giving more rapidly, not shown to have more rapid onset of actionhave more rapid onset of action
  53. 53. BarbituratesBarbiturates in use since 1912in use since 1912 general CNS depressant activitygeneral CNS depressant activity – raise threshold of most neuronal pathways toraise threshold of most neuronal pathways to direct and indirect stimulationdirect and indirect stimulation – at high levels, slows EEG --> burst suppressionat 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
  54. 54. 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
  55. 55. PhenobarbitalPhenobarbital IV Phenobarb in Refractory SE:IV Phenobarb in Refractory SE: – as effective as Diazepam plus Phenytoin, butas effective as Diazepam plus Phenytoin, but S/E more pronouncedS/E more pronounced – because of profound hypotension & respiratorybecause of profound hypotension & respiratory depression, patient will likely need intubationdepression, 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)
  56. 56. 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/hronce SE resolved -maintenance: 1-10 mg/kg/hr
  57. 57. 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, arrhythmiasCV depression, hypotension, arrhythmias – resp depression, apnearesp depression, apnea
  58. 58. ThiopentalThiopental Thiopental - negative aspects:Thiopental - negative aspects: – accumulates in fatty tissuesaccumulates in fatty tissues – an active metabolite - Pentobarbitalan active metabolite - Pentobarbital – long recovery time after infusionlong recovery time after infusion – hemodynamic instabilityhemodynamic instability
  59. 59. 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
  60. 60. PropofolPropofol study in rodent model of refractory SEstudy in rodent model of refractory SE (Ann Neurol 2001; 49: 260-63 M. Holtkamp)(Ann 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/kgusing Propofol at sub-anesthetic doses (50 mg/kg intraperitoneally) in 5 / 5 animals given that doseintraperitoneally) 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
  61. 61. 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 toPro-convulsant effect” - is now thought to be myoclonus, unlikely a significantbe myoclonus, unlikely a significant problemproblem
  62. 62. 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
  63. 63. 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
  64. 64. Ketamine in SEKetamine in SE blocks NMDA receptors - this may protectblocks 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 demonstratedsome animal studies have demonstrated control of refractory SE with Ketamine:control of refractory SE with Ketamine: Ketamine Controls Prolonged SE -Ketamine Controls Prolonged SE - DJBorrisDJBorris Epilepsy Research 42 (2000): 117-22Epilepsy Research 42 (2000): 117-22 – more efffective than Phenobarb inmore efffective than Phenobarb in LATELATE SESE (>60 min); not as effective in EARLY SE(>60 min); not as effective in EARLY SE
  65. 65. Ketamine in SEKetamine in SE has NOT been studied in SE in thehas NOT been studied in SE in the Emergency settingEmergency setting
  66. 66. Consensus GuidelinesConsensus Guidelines Rx 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 papersbased on literature search of Ped SE papers in English ; >1100 found, though only 2in English ; >1100 found, though only 2 were pediatric RCT’swere pediatric RCT’s – they admit these are more practice-based thanthey admit these are more practice-based than evidence-basedevidence-based
  67. 67. 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 10Phenobarbital 20 mg/kg (“over 10 min”) if already on Phenytoinmin”) if already on Phenytoin »ANDAND Paraldehyde rectally 0.4 ml/kg inParaldehyde 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
  68. 68. Consensus Guidelines:Consensus Guidelines: ifif NONO IV AccessIV 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 Paraldehyde3. Phenytoin / Phenobarb; plus Paraldehyde rectallyrectally
  69. 69. 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 infusionmidazolam infusion » inhalational anesthetic e.g. Isofluraneinhalational anesthetic e.g. Isoflurane
  70. 70. 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 mentaland for any patient with altered mental status who would otherwise need IVstatus 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

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