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Status Epilepticus

               Time is brain!
          Kongkiat Kulkantrakorn, M.D.
                Associate Professor
Neurology division, Department of Internal Medicine
   Faculty of Medicine , Thammasat University


                                                      1
Status Epilepticus: Operational
                Definition

• Generalized, convulsive status
  epilepticus in adults and older children
  (>5 years old) refers to at least 5 min of
  – (a) continuous seizures        or
  – (b) two or discrete seizures between which there
    is incomplete recovery of consciousness



                                                  2
Types of Seizure Emergencies

• Convulsive status epilepticus (CSE)

• Nonconvulsive status epilepticus (NCSE)

• Acute repetitive seizures or clusters



                                            3
Generalized Convulsive Status
    Epilepticus (GCSE): Characteristics

•   Broad spectrum of clinical presentations
     –   Tonic-clonic motor activity
     –   Impaired consciousness
     –   Ictal discharges
•   Subtle GSCE
     –   Continuous subtle motor phenomena
     –   Generalized ictal discharges
     –   Profound coma
•   Other types
     –   Myoclonic
     –   Focal                                 4
Status epilepticus

• Incidence:
   – 27/100,000 in young adult
      » with 14% mortality rate
   – 86/100,000 in elderly
      » with 38% mortality rate
• Number of cases:
   – 65,000- 150,000 cases per year in USA


                                             5
Mortality in Status Epilepticus by Age Group
  Among 546 patients with status epilepticus in Richmond, Virginia,
  from 1982 to 1989.
    % Mortalitiy
               60

               50
               40

               30
               20

               10

                 0
                       0–1       2–4       5–9      10–19   20–39   40–59   60–79   80+
                                                     Age Group
                                                                                          6
DeLorenzo RJ, et al. Epilepsia. 1992;33(suppl 4):515-525.
Survival in Status Epilepticus by
  Duration of Seizure
  Survival curves for prolonged (solid line) and nonprolonged (dashed line)
  seizure duration. The data are presented as percent survival based on a
  30-day follow-up period.
  % Survival
              100

               90                                                       Length of Seizure
                                                                          >1 h
               80                                                         <1 h

               70

               60
                    0            5            10            15     20        25             30
                                                            Days
                                                                                                 7
DeLorenzo RJ, et al. Epilepsia. 1992;33(suppl 4):515-525.
Main causes of status epilepticus

•   Low AED level patients with epilepsy (34%)
•   Remote symptomatic causes (24%)
•   Cerebrovascular accidents (22%)
•   Anoxia or hypoxia (~10%)
•   Metabolic causes (~10%)
•   Alcohol and drug withdrawal (~10%)



                                                 8
9
Generalized convulsive status epilepticus after
        nontraumatic subarachnoid hemorrhage: the
                nationwide inpatient sample.
• Nationwide Inpatient Sample, a database of admissions to
  nonfederal United States hospitals between 1994 and 2002

• Among the 29,998 patients hospitalized with nontraumatic
  SAH, GCSE was reported to occur in 0.2% of patients (N = 73
  patients).

• GCSE risks: the youngest tertiale 49 years old or younger;
  OR ( 2.0-5.1), those with renal disease OR 4.8 ( 2.6-8.8),
  and those who did not undergo a neurosurgical procedure
  involving a craniotomy ; OR 2.2 (1.3-3.8).
                            Claassen J, et al. Neurosurgery 2007 ;61:60-4.   10
Generalized convulsive status epilepticus after
nontraumatic subarachnoid hemorrhage: the
        nationwide inpatient sample.
  • GCSE : higher in-hospital mortality (48% versus 33% of
    patients; OR 2.1 (1.3-3.4; P = 0.002) and longer (9 versus 7
    days; P = 0.016) and more expensive (US $39,677 versus
    US $26,686; P = 0.007) hospitalizations.

  • CONCLUSION: GCSE rarely complicates SAH; however, it
    is associated with increased patient mortality, length of
    hospital stay, and cost. GCSE occurs more frequently in
    young patients, those with a history of renal disease, and
    patients who do not undergo a craniotomy

                                                                   11
Nonconvulsive electrographic seizures after
      traumatic brain injury result in a delayed,
      prolonged increase in intracranial pressure
                   and metabolic crisis.
• 20 moderate to severe TBI (Glasgow Coma Score 3-
  13) : continuous EEG and cerebral microdiablysis for 7
  days after injury.
• Ten patients had seizures , matched with control TBI.
  SE in 7 patients
• Using a within-subject design, post-traumatic seizures
  resulted in episodic increases in intracranial pressure
  (22.4 +/- 7 vs. 12.8 +/- 4.3 mm Hg; p < .001) and an
  episodic increase in lactate/pyruvate ratio (49.4 +/- 16
  vs. 23.8 +/- 7.6; p < .001) in the seizure group.

       •                                                        .
           Vespa PM, et al. Crit Care Med. 2007 Dec;35(12):2830-6   12
• Using a between-subjects comparison, the seizure group demonstrated a
  higher mean intracranial pressure (17.6 +/- 6.5 vs. 12.2 +/- 4.2 mm Hg; p
  < .001), a higher mean lactate/pyruvate ratio (38.6 +/- 18 vs. 27 +/- 9; p <
  .001) compared with nonseizure patients.

• The intracranial pressure and lactate/pyruvate ratio remained elevated
  beyond postinjury hour 100 in the seizure group but not the nonseizure
  group (p < .02).

• CONCLUSION: Post-traumatic seizures result in episodic as well as
  long-lasting increases in intracranial pressure and microdialysis
  lactate/pyruvate ratio. These data suggest that post-traumatic seizures
  represent a therapeutic target for patients with traumatic brain injury.
                                                                        13
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17
Management of Status Epilepticus:
General Principles
n   Medical emergency
n   Prolonged electrical seizure activity causes neuronal
    damage
n   EEG monitoring essential
n   Systemic factors exacerbate SE-induced neuronal damage
n   The longer the duration, the later the EEG stage, and
    the more subtle the motor manifestations, the harder SE
    is to stop
n   A predetermined Rx protocol more effective
                                                          18
Schematic Approach of
       Status Epilepticus


LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.   19
20
1. Assess and control airway
 2. Monitor vital signs ( including temperature )
 3. Conduct pulse oximetry and monitor
    cardiac function
 4. Perform rapid blood glucose assay
        Start intravenous infusion
      Administer thiamine ( 100 mg )
 and glucose ( 50 ml of 50 percent dextrose )
LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.   21
Investigation
•Antiepileptic drug level
•Septic work up
•CBC, UA
•Blood sugar
•BUN, Cr
•Liver function test
•Electrolyte
•Calcium, Magnesium,
Phosphorous
•Toxicology
•Lumbar puncture
•CT brain
•MRI brain                  22
Start anticonvulsant therapy
Take focused Hx and examine patient    Perform laboratory studies
Perform laboratory studies            Complete blood count
Known seizure disorder or other       Serum electrolytes and calcium
   illnesses ?                        Arterial - blood gas
Trauma ?                              Liver function
Focal neurologic signs ?              Renal function
Signs of medical illnesses ( e.g.,    Toxicology
   infection, hepatic or renal        Serum AEDs concentrations
   disease, substance abuse ) ?


          Undertake further work-up to define cause
              Manage other medical problems                            23
Schematic Approach of Status Epilepticus
Antiepileptic Drug Therapy



 •   Begin with Lorazepam 4mg
      • (0.1 mg/kg ) at 2 mg/min i.v.
 •   or Diazepam 10-20 mg
      • (0.3 mg/kg ) at 2 mg/min i.v.

 LowensteinD, Alldredge B. NEJM.1998; 338:970-976.
                                                     24
Seizures continuing at 5 min
Phenytoin (20 mg/kg IV at 50 mg/min) or
Fosphenytoin(20 mg/kg IV PE at 150 mg/min)

  Seizures continuing at 20 - 25 min
Phenytoin or Fosphenytoin
  (additional 5 - 10 mg/kg or 5 - 10 mg/kg PE)
LowensteinD, Alldredge B. NEJM.1998; 338:970-976.   25
Seizures continuing at 30 - 35 min
  Phenobarbital
  ( 20 mg/kg IV at 50 - 75 mg/min )
  Seizures continuing at 50 - 55 min
  Phenobarbital
  ( additional 5 - 10 mg/kg )
LowensteinD, Alldredge B. NEJM.1998; 338:970-976.   26
Seizures continuing at 60 - 65 min

    Anesthesia with IV midazolam ,
    pentobarbital or propofol

LowensteinD, Alldredge B. NEJM.1998; 338:970-976.
                                                    27
EFNS guideline on the management of
        status epilepticus in adults.
• The preferred treatment pathway for generalised
  convulsive status epilepticus (GCSE) is
• Intravenous (i.v.) administration of 4-8 mg lorazepam
  or 10 mg diazepam directly followed by 18 mg/kg
  phenytoin.
• If seizures continue more than 10 min after first
  injection, another 4 mg lorazepam or 10 mg diazepam
  is recommended.
        Eur J Neurol. 2009 Dec 30. [Epub ahead of print]
EFNS guideline on the management of
         status epilepticus in adults.
• The initial therapy of non-convulsive SE depends on type
  and cause. Complex partial SE is initially treated in the
  same manner as GCSE.
• However, if it turns out to be refractory, further non-
  anaesthetising i.v. substances such levetiracetam,
  phenobarbital or valproic acid should be given instead of
  anaesthetics.
• In subtle SE, in refractory GCSE is treated by anaesthetic
  doses of barbiturates, midazolam or propofol; the
  anaesthetics are titrated against an electroencephalogram
  burst suppression pattern for at least 24 h. Most patients,
  i.v. anaesthesia is required.
          Eur J Neurol. 2009 Dec 30. [Epub ahead of print]
Evidence based review
            Comparison of 2 drugs

• Benzodiazepine:
  – no difference among lorazepam, diazepam, midazolam
• Hydantoin:
  – Fosphenytoin: less pain and phlebitis at injection side
  – Faster infusion rate in fos-PHT with 10-15 min
    dephosphorylation
     » Save 19 min on 150mg/kg vs 50 mg/kg in 70 kg patient
     » Advantage: displace PHT form albumin binding site in
       chronic PHT treatment, rapidly increase free PHT

                                                         30
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35
36
Pharmacology of AED




                      37
Diazepam
    Peak brain levels in 5 minutes by IV
Dosage              : I.V. : 0.15-0.25 mg/kg.
IV rate             : No faster than 5 mg/min
Effective level     : more than 0.2-0.8 mcg/dl
Time to stop Sz : 1 - 3 minutes
Effective duration : 15-30 minutes
Half-life           : 30 hr, rapid redistribution to fat/muscle
Volume of distribution : 1-2 L/kg
Advantage           : rapid action, can be given rectally
Disadvantages : hypotension, respiratory depression
Phenobarbital
    Peak brain levels in 20-60 minutes by IV
Dosage           : I.V. : 20 mg/kg.
IV rate           : No faster than 100 mg/min
Effective level : more than 20 mcg/dl
Time to stop Sz : 20 - 30 minutes, 60-70% effective
Effective duration : > 24 hours
Half-life         : 4-6 days
Volume of distribution : 0.7 L/kg
Advantage        : Long lasting therapeutic effort
Disadvantages : Hypotension, Respiration depression
   Sensorial depression, Consider intubation when used
   after diazepam administration
Phenytoin
    Peak brain levels in 15 minutes by IV
Dosage               : I.V. : 20 mg/kg.
IV rate              : No faster than 50 mg/min
Effective level      : more than 25-35 mcg/dl
Time to stop Sz : 10 - 30 min
Effective duration : > 24 hr, 50% effective after failing BDZ
Half-life            : varies, around 24 hours
Volume of distribution : 0.5-0.8 L/kg
Advantage           : No sedation, less respiratory depression
Disadvantages       : hypotension, cardiac arrhythmia
   need ECG monitoring, purple glove syndrome, cannot mix
   with glucose
Fosphenytoin
             Fosphenytoin




                                  Phenytoin




All Fosphenyoin dosing is expressed in phenytoin
                equivalents (PE)
 (1mg PE Fosphenytoin = 1 mg IV phenytoin)
Phenytoin vs Fosphenytoin


                         Phenytoin           Fosphenytoin
Vehicle         Propylene glycol & ethanol   Water, TRIS

pH              12                           8.6 - 9

Maximum
infusion rate   50 mg/min                    150 mg PE/min

Admixtures      No                           Saline, dextrose
Fosphenytoin IV administration-events at maximum
                  dose and rate


                                                                                     IV Fosphenytoin (n=90)
                                                                                      IV Phenytoin (n=22)
Percentage of patients




                         Nystagmus   Dizziness   Pruritus   Ataxia   Somnolence   Hypotension   Headache
Summary—Fosphenytoin benefits
            (rapid administration)

• Rapidly and completely converted to phenytoin
  after IV and IM dosing

• Completely converted regardless of dose, rate, or
  route

• Bioequivalent to phenytoin when infused at 150
  mg PE/min

• Therapeutic phenytoin levels rapidly achieved
 — Within 7 minutes with IV infusion at 150 mg PE/min
 — Within 30 minutes with IM injection
Summary—Fosphenytoin benefits
               (tolerability)

• Better tolerated at injection site than IV phenytoin

• Improved flexibility of IM administration

• CNS adverse events similar to phenytoin

• Transient paresthesia and pruritus with IV infusion

• Fewer reductions in IV rates and site changes than IV

  phenytoin

• IV loading dose-special populations
Recommended doses and rates
47
•32 cases diagnosed as SE with VPAiv treatment; 12 and 20 patients
received VPAiv as the first- and second-line therapy, (15-20 mg/kg).
•SE ceased in 7/12 patients (75%) and in 7/20 (35%) patients
•Hypotension and leucocytosis associated with death
•Mortality 54.8%




                                                                       48
Status epilepticus
Status epilepticus
• Thirty-two patients (15 female) were treated with i.v. LEV for SE
  (median age 71 years).
• SE was generalized convulsive in five, nonconvulsive in 20, and
  simple focal in seven patients.
• Etiology was acute 13 times and remote symptomatic 16 times;
  three SE were of unknown etiology.
• Therapy was initiated within a median time of 3 h and
• LEV i.v. was applied within a median time of 6 h. Median LEV
  bolus was 2,000 mg; median total dose on day 1 was 3500 mg
• Benzodiazepines plus i.v. LEV terminated SE in 23 patients without
  application of additional anticonvulsants, 10 within 30 min.
• LEV could not terminate SE in seven patients.
52
53
Admixture and Administration of
             Injectable AEDs
    AED                               Dosage/Rate of Infusion
                Loading Dose: 15-20 mg/kg; up to 25 mg/kg has been used clinically.
                Maintenance Dose: 300 mg/day or 5-6 mg/kg/day in 3 divided doses,IM not
 Phenytoin      recommended; Dilute in NS or LR, DO NOT MIX WITH DEXTROSE, do not
 (Dilantin®)    refrigerate, use within 4 hrs. Use inline 0.22-5 micron filter
                Infusion Rate: Should not exceed 50 mg/min; elderly/debilitated should not exceed
                20 mg/min
                Status epilepticus: Loading Dose: 15-20 mg PE/kg IV
Fosphenytoin    Non-emergent: Loading Dose: 10-20 mg PE/kg IV or IM; MD: 4-6 mg PE/kg/day IV
 (Cereneu®)     or IM
                Infusion Rate: Should not exceed 150 mg PE/minute
                Loading : 15-20/kg
Valproic acid   No Loading Dose; 1000-2500 mg/day in 1-3 divided doses
(Depakine®)     Admin over 60 min (<= 20 mg/min); rapid infusion over 5-10 min as 1.5-3
                mg/kg/min
                >16 y/o. No loading dose. 1000 mg/day (500 MG BID). Dose can be increased by
Levetiracetam   1000 mg/day ever 2 weeks up to a maximum dose of 3000 mg/day
                Rate: Dilute in 100ml of normal saline (NS), lactated ringers (LR) or dextrose 5%
  (Keppra®)
                and infuse over 15 minutes
Special group of status epilepticus




                                      55
SE in children
• Young children: More febrile seizures and acute
  causes, infection in etiology than older children
• Generalized SE, less NCSE
• Similar treatment protocol as in adult
• May use IV or rectal diazepam or buccal
  /intranasal midazolam as initial treatment
• Should not use valproate if below 2 years old or
  propofol
• Midazolam IV infusion in refractory cases

                                                  56
Relationship between depth of coma (x-axis), prognosis (x-axis),
degree of structural brain damage (red y-axis) and epileptic brain dysfunction (blue y-axis) due to status epilepticus.
Refractory Status epilepticus

• Definition: failure to stop after 2 drugs

• Slow taper of continuous infusion at least over 24 hours
  after seizure control

• Possible benefit of more intensity of burst suppression

• Recurrence: 25% in acute or remote symptomatic and
  idiopathic cases

• Role of neuroprotection ???
                                                             58
59
60
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62
Status epilepticus

Timing is everything
  Save the brain!


                         63

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Status epilepticus

  • 1. Status Epilepticus Time is brain! Kongkiat Kulkantrakorn, M.D. Associate Professor Neurology division, Department of Internal Medicine Faculty of Medicine , Thammasat University 1
  • 2. Status Epilepticus: Operational Definition • Generalized, convulsive status epilepticus in adults and older children (>5 years old) refers to at least 5 min of – (a) continuous seizures or – (b) two or discrete seizures between which there is incomplete recovery of consciousness 2
  • 3. Types of Seizure Emergencies • Convulsive status epilepticus (CSE) • Nonconvulsive status epilepticus (NCSE) • Acute repetitive seizures or clusters 3
  • 4. Generalized Convulsive Status Epilepticus (GCSE): Characteristics • Broad spectrum of clinical presentations – Tonic-clonic motor activity – Impaired consciousness – Ictal discharges • Subtle GSCE – Continuous subtle motor phenomena – Generalized ictal discharges – Profound coma • Other types – Myoclonic – Focal 4
  • 5. Status epilepticus • Incidence: – 27/100,000 in young adult » with 14% mortality rate – 86/100,000 in elderly » with 38% mortality rate • Number of cases: – 65,000- 150,000 cases per year in USA 5
  • 6. Mortality in Status Epilepticus by Age Group Among 546 patients with status epilepticus in Richmond, Virginia, from 1982 to 1989. % Mortalitiy 60 50 40 30 20 10 0 0–1 2–4 5–9 10–19 20–39 40–59 60–79 80+ Age Group 6 DeLorenzo RJ, et al. Epilepsia. 1992;33(suppl 4):515-525.
  • 7. Survival in Status Epilepticus by Duration of Seizure Survival curves for prolonged (solid line) and nonprolonged (dashed line) seizure duration. The data are presented as percent survival based on a 30-day follow-up period. % Survival 100 90 Length of Seizure >1 h 80 <1 h 70 60 0 5 10 15 20 25 30 Days 7 DeLorenzo RJ, et al. Epilepsia. 1992;33(suppl 4):515-525.
  • 8. Main causes of status epilepticus • Low AED level patients with epilepsy (34%) • Remote symptomatic causes (24%) • Cerebrovascular accidents (22%) • Anoxia or hypoxia (~10%) • Metabolic causes (~10%) • Alcohol and drug withdrawal (~10%) 8
  • 9. 9
  • 10. Generalized convulsive status epilepticus after nontraumatic subarachnoid hemorrhage: the nationwide inpatient sample. • Nationwide Inpatient Sample, a database of admissions to nonfederal United States hospitals between 1994 and 2002 • Among the 29,998 patients hospitalized with nontraumatic SAH, GCSE was reported to occur in 0.2% of patients (N = 73 patients). • GCSE risks: the youngest tertiale 49 years old or younger; OR ( 2.0-5.1), those with renal disease OR 4.8 ( 2.6-8.8), and those who did not undergo a neurosurgical procedure involving a craniotomy ; OR 2.2 (1.3-3.8). Claassen J, et al. Neurosurgery 2007 ;61:60-4. 10
  • 11. Generalized convulsive status epilepticus after nontraumatic subarachnoid hemorrhage: the nationwide inpatient sample. • GCSE : higher in-hospital mortality (48% versus 33% of patients; OR 2.1 (1.3-3.4; P = 0.002) and longer (9 versus 7 days; P = 0.016) and more expensive (US $39,677 versus US $26,686; P = 0.007) hospitalizations. • CONCLUSION: GCSE rarely complicates SAH; however, it is associated with increased patient mortality, length of hospital stay, and cost. GCSE occurs more frequently in young patients, those with a history of renal disease, and patients who do not undergo a craniotomy 11
  • 12. Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis. • 20 moderate to severe TBI (Glasgow Coma Score 3- 13) : continuous EEG and cerebral microdiablysis for 7 days after injury. • Ten patients had seizures , matched with control TBI. SE in 7 patients • Using a within-subject design, post-traumatic seizures resulted in episodic increases in intracranial pressure (22.4 +/- 7 vs. 12.8 +/- 4.3 mm Hg; p < .001) and an episodic increase in lactate/pyruvate ratio (49.4 +/- 16 vs. 23.8 +/- 7.6; p < .001) in the seizure group. • . Vespa PM, et al. Crit Care Med. 2007 Dec;35(12):2830-6 12
  • 13. • Using a between-subjects comparison, the seizure group demonstrated a higher mean intracranial pressure (17.6 +/- 6.5 vs. 12.2 +/- 4.2 mm Hg; p < .001), a higher mean lactate/pyruvate ratio (38.6 +/- 18 vs. 27 +/- 9; p < .001) compared with nonseizure patients. • The intracranial pressure and lactate/pyruvate ratio remained elevated beyond postinjury hour 100 in the seizure group but not the nonseizure group (p < .02). • CONCLUSION: Post-traumatic seizures result in episodic as well as long-lasting increases in intracranial pressure and microdialysis lactate/pyruvate ratio. These data suggest that post-traumatic seizures represent a therapeutic target for patients with traumatic brain injury. 13
  • 14. 14
  • 15. 15
  • 16. 16
  • 17. 17
  • 18. Management of Status Epilepticus: General Principles n Medical emergency n Prolonged electrical seizure activity causes neuronal damage n EEG monitoring essential n Systemic factors exacerbate SE-induced neuronal damage n The longer the duration, the later the EEG stage, and the more subtle the motor manifestations, the harder SE is to stop n A predetermined Rx protocol more effective 18
  • 19. Schematic Approach of Status Epilepticus LowensteinD, Alldredge B. NEJM. 1998; 338:970-976. 19
  • 20. 20
  • 21. 1. Assess and control airway 2. Monitor vital signs ( including temperature ) 3. Conduct pulse oximetry and monitor cardiac function 4. Perform rapid blood glucose assay Start intravenous infusion Administer thiamine ( 100 mg ) and glucose ( 50 ml of 50 percent dextrose ) LowensteinD, Alldredge B. NEJM. 1998; 338:970-976. 21
  • 22. Investigation •Antiepileptic drug level •Septic work up •CBC, UA •Blood sugar •BUN, Cr •Liver function test •Electrolyte •Calcium, Magnesium, Phosphorous •Toxicology •Lumbar puncture •CT brain •MRI brain 22
  • 23. Start anticonvulsant therapy Take focused Hx and examine patient Perform laboratory studies Perform laboratory studies Complete blood count Known seizure disorder or other Serum electrolytes and calcium illnesses ? Arterial - blood gas Trauma ? Liver function Focal neurologic signs ? Renal function Signs of medical illnesses ( e.g., Toxicology infection, hepatic or renal Serum AEDs concentrations disease, substance abuse ) ? Undertake further work-up to define cause Manage other medical problems 23
  • 24. Schematic Approach of Status Epilepticus Antiepileptic Drug Therapy • Begin with Lorazepam 4mg • (0.1 mg/kg ) at 2 mg/min i.v. • or Diazepam 10-20 mg • (0.3 mg/kg ) at 2 mg/min i.v. LowensteinD, Alldredge B. NEJM.1998; 338:970-976. 24
  • 25. Seizures continuing at 5 min Phenytoin (20 mg/kg IV at 50 mg/min) or Fosphenytoin(20 mg/kg IV PE at 150 mg/min) Seizures continuing at 20 - 25 min Phenytoin or Fosphenytoin (additional 5 - 10 mg/kg or 5 - 10 mg/kg PE) LowensteinD, Alldredge B. NEJM.1998; 338:970-976. 25
  • 26. Seizures continuing at 30 - 35 min Phenobarbital ( 20 mg/kg IV at 50 - 75 mg/min ) Seizures continuing at 50 - 55 min Phenobarbital ( additional 5 - 10 mg/kg ) LowensteinD, Alldredge B. NEJM.1998; 338:970-976. 26
  • 27. Seizures continuing at 60 - 65 min Anesthesia with IV midazolam , pentobarbital or propofol LowensteinD, Alldredge B. NEJM.1998; 338:970-976. 27
  • 28. EFNS guideline on the management of status epilepticus in adults. • The preferred treatment pathway for generalised convulsive status epilepticus (GCSE) is • Intravenous (i.v.) administration of 4-8 mg lorazepam or 10 mg diazepam directly followed by 18 mg/kg phenytoin. • If seizures continue more than 10 min after first injection, another 4 mg lorazepam or 10 mg diazepam is recommended. Eur J Neurol. 2009 Dec 30. [Epub ahead of print]
  • 29. EFNS guideline on the management of status epilepticus in adults. • The initial therapy of non-convulsive SE depends on type and cause. Complex partial SE is initially treated in the same manner as GCSE. • However, if it turns out to be refractory, further non- anaesthetising i.v. substances such levetiracetam, phenobarbital or valproic acid should be given instead of anaesthetics. • In subtle SE, in refractory GCSE is treated by anaesthetic doses of barbiturates, midazolam or propofol; the anaesthetics are titrated against an electroencephalogram burst suppression pattern for at least 24 h. Most patients, i.v. anaesthesia is required. Eur J Neurol. 2009 Dec 30. [Epub ahead of print]
  • 30. Evidence based review Comparison of 2 drugs • Benzodiazepine: – no difference among lorazepam, diazepam, midazolam • Hydantoin: – Fosphenytoin: less pain and phlebitis at injection side – Faster infusion rate in fos-PHT with 10-15 min dephosphorylation » Save 19 min on 150mg/kg vs 50 mg/kg in 70 kg patient » Advantage: displace PHT form albumin binding site in chronic PHT treatment, rapidly increase free PHT 30
  • 31. 31
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  • 36. 36
  • 38. Diazepam Peak brain levels in 5 minutes by IV Dosage : I.V. : 0.15-0.25 mg/kg. IV rate : No faster than 5 mg/min Effective level : more than 0.2-0.8 mcg/dl Time to stop Sz : 1 - 3 minutes Effective duration : 15-30 minutes Half-life : 30 hr, rapid redistribution to fat/muscle Volume of distribution : 1-2 L/kg Advantage : rapid action, can be given rectally Disadvantages : hypotension, respiratory depression
  • 39. Phenobarbital Peak brain levels in 20-60 minutes by IV Dosage : I.V. : 20 mg/kg. IV rate : No faster than 100 mg/min Effective level : more than 20 mcg/dl Time to stop Sz : 20 - 30 minutes, 60-70% effective Effective duration : > 24 hours Half-life : 4-6 days Volume of distribution : 0.7 L/kg Advantage : Long lasting therapeutic effort Disadvantages : Hypotension, Respiration depression Sensorial depression, Consider intubation when used after diazepam administration
  • 40. Phenytoin Peak brain levels in 15 minutes by IV Dosage : I.V. : 20 mg/kg. IV rate : No faster than 50 mg/min Effective level : more than 25-35 mcg/dl Time to stop Sz : 10 - 30 min Effective duration : > 24 hr, 50% effective after failing BDZ Half-life : varies, around 24 hours Volume of distribution : 0.5-0.8 L/kg Advantage : No sedation, less respiratory depression Disadvantages : hypotension, cardiac arrhythmia need ECG monitoring, purple glove syndrome, cannot mix with glucose
  • 41. Fosphenytoin Fosphenytoin Phenytoin All Fosphenyoin dosing is expressed in phenytoin equivalents (PE) (1mg PE Fosphenytoin = 1 mg IV phenytoin)
  • 42. Phenytoin vs Fosphenytoin Phenytoin Fosphenytoin Vehicle Propylene glycol & ethanol Water, TRIS pH 12 8.6 - 9 Maximum infusion rate 50 mg/min 150 mg PE/min Admixtures No Saline, dextrose
  • 43. Fosphenytoin IV administration-events at maximum dose and rate IV Fosphenytoin (n=90) IV Phenytoin (n=22) Percentage of patients Nystagmus Dizziness Pruritus Ataxia Somnolence Hypotension Headache
  • 44. Summary—Fosphenytoin benefits (rapid administration) • Rapidly and completely converted to phenytoin after IV and IM dosing • Completely converted regardless of dose, rate, or route • Bioequivalent to phenytoin when infused at 150 mg PE/min • Therapeutic phenytoin levels rapidly achieved — Within 7 minutes with IV infusion at 150 mg PE/min — Within 30 minutes with IM injection
  • 45. Summary—Fosphenytoin benefits (tolerability) • Better tolerated at injection site than IV phenytoin • Improved flexibility of IM administration • CNS adverse events similar to phenytoin • Transient paresthesia and pruritus with IV infusion • Fewer reductions in IV rates and site changes than IV phenytoin • IV loading dose-special populations
  • 47. 47
  • 48. •32 cases diagnosed as SE with VPAiv treatment; 12 and 20 patients received VPAiv as the first- and second-line therapy, (15-20 mg/kg). •SE ceased in 7/12 patients (75%) and in 7/20 (35%) patients •Hypotension and leucocytosis associated with death •Mortality 54.8% 48
  • 51. • Thirty-two patients (15 female) were treated with i.v. LEV for SE (median age 71 years). • SE was generalized convulsive in five, nonconvulsive in 20, and simple focal in seven patients. • Etiology was acute 13 times and remote symptomatic 16 times; three SE were of unknown etiology. • Therapy was initiated within a median time of 3 h and • LEV i.v. was applied within a median time of 6 h. Median LEV bolus was 2,000 mg; median total dose on day 1 was 3500 mg • Benzodiazepines plus i.v. LEV terminated SE in 23 patients without application of additional anticonvulsants, 10 within 30 min. • LEV could not terminate SE in seven patients.
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  • 54. Admixture and Administration of Injectable AEDs AED Dosage/Rate of Infusion Loading Dose: 15-20 mg/kg; up to 25 mg/kg has been used clinically. Maintenance Dose: 300 mg/day or 5-6 mg/kg/day in 3 divided doses,IM not Phenytoin recommended; Dilute in NS or LR, DO NOT MIX WITH DEXTROSE, do not (Dilantin®) refrigerate, use within 4 hrs. Use inline 0.22-5 micron filter Infusion Rate: Should not exceed 50 mg/min; elderly/debilitated should not exceed 20 mg/min Status epilepticus: Loading Dose: 15-20 mg PE/kg IV Fosphenytoin Non-emergent: Loading Dose: 10-20 mg PE/kg IV or IM; MD: 4-6 mg PE/kg/day IV (Cereneu®) or IM Infusion Rate: Should not exceed 150 mg PE/minute Loading : 15-20/kg Valproic acid No Loading Dose; 1000-2500 mg/day in 1-3 divided doses (Depakine®) Admin over 60 min (<= 20 mg/min); rapid infusion over 5-10 min as 1.5-3 mg/kg/min >16 y/o. No loading dose. 1000 mg/day (500 MG BID). Dose can be increased by Levetiracetam 1000 mg/day ever 2 weeks up to a maximum dose of 3000 mg/day Rate: Dilute in 100ml of normal saline (NS), lactated ringers (LR) or dextrose 5% (Keppra®) and infuse over 15 minutes
  • 55. Special group of status epilepticus 55
  • 56. SE in children • Young children: More febrile seizures and acute causes, infection in etiology than older children • Generalized SE, less NCSE • Similar treatment protocol as in adult • May use IV or rectal diazepam or buccal /intranasal midazolam as initial treatment • Should not use valproate if below 2 years old or propofol • Midazolam IV infusion in refractory cases 56
  • 57. Relationship between depth of coma (x-axis), prognosis (x-axis), degree of structural brain damage (red y-axis) and epileptic brain dysfunction (blue y-axis) due to status epilepticus.
  • 58. Refractory Status epilepticus • Definition: failure to stop after 2 drugs • Slow taper of continuous infusion at least over 24 hours after seizure control • Possible benefit of more intensity of burst suppression • Recurrence: 25% in acute or remote symptomatic and idiopathic cases • Role of neuroprotection ??? 58
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  • 63. Status epilepticus Timing is everything Save the brain! 63