status epilepticus
TRANSCRIPT
Status Epilepticus
Time is brain!
Kongkiat Kulkantrakorn, M.D.
Associate Professor
Neurology division, Department of Internal Medicine
Faculty of Medicine , Thammasat University
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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
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Types of Seizure Emergencies
• Convulsive status epilepticus (CSE)
• Nonconvulsive status epilepticus (NCSE)
• Acute repetitive seizures or clusters
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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
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
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Mortality in Status Epilepticus by Age Group
Among 546 patients with status epilepticus in Richmond, Virginia,
from 1982 to 1989.
% Mortalitiy
0
10
20
30
40
50
60
0–1 2–4 5–9 10–19 20–39 40–59 60–79 80+
Age Group
DeLorenzo RJ, e t al. Epilepsia. 1992;33(suppl 4):515-525.
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Length of Seizure
>1 h
<1 h
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 a30-day follow-up period.
Days
DeLorenzo RJ, e t al. Epilepsia. 1992;33(suppl 4):515-525.
% Survival
60
70
80
90
100
0 5 10 15 20 25 30
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%)
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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).
10Claassen J, et al. Neurosurgery 2007 ;61:60-4.
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
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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.
12• Vespa PM, et al. Crit Care Med. 2007 Dec;35(12):2830-6.
• 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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Management of Status Epilepticus:
General Principles
n Medical emergency
n Prolonged electrical seizure activity causes neuronaldamage
n EEG monitoring essential
n Systemic factors exacerbate SE-induced neuronal damage
n The longer the duration, the later the EEG stage, andthe more subtle the motor manifestations, the harder SEis to stop
n A predetermined Rx protocol more effective
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Schematic Approach ofStatus Epilepticus
LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.
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1. Assess and control airway2. Monitor vital signs ( including temperature )3. Conduct pulse oximetry and monitor cardiac function4. Perform rapid blood glucose assay
Start intravenous infusionAdminister thiamine ( 100 mg )
and glucose ( 50 ml of 50 percent dextrose )LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.
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
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Start anticonvulsant therapy
Take focused Hx and examine patient
Perform laboratory studies
Known seizure disorder or other
illnesses ?
Trauma ?
Focal neurologic signs ?
Signs of medical illnesses ( e.g.,
infection, hepatic or renal
disease, substance abuse ) ?
Perform laboratory studies
Complete blood count
Serum electrolytes and calcium
Arterial - blood gas
Liver function
Renal function
Toxicology
Serum AEDs concentrations
Undertake further work-up to define cause
Manage other medical problems
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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.
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Seizures continuing at 5 minPhenytoin (20 mg/kg IV at 50 mg/min) or Fosphenytoin(20 mg/kg IV PE at 150 mg/min)
Seizures continuing at 20 - 25 minPhenytoin or Fosphenytoin
(additional 5 - 10 mg/kg or 5 - 10 mg/kg PE)LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.
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Seizures continuing at 30 - 35 minPhenobarbital( 20 mg/kg IV at 50 - 75 mg/min )Seizures continuing at 50 - 55 minPhenobarbital( additional 5 - 10 mg/kg )
LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.
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Seizures continuing at 60 - 65 min
Anesthesia with IV midazolam ,pentobarbital or propofol
LowensteinD, Alldredge B. NEJM. 1998; 338:970-976.
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 reviewComparison 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
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Pharmacology of AED
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DiazepamPeak 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
PhenobarbitalPeak 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
PhenytoinPeak 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
All Fosphenyoin dosing is expressed in phenytoin equivalents (PE)
(1mg PE Fosphenytoin = 1 mg IV phenytoin)
Fosphenytoin
Phenytoin
Phenytoin vs Fosphenytoin
Phenytoin
Water, TRIS
Fosphenytoin
Propylene glycol & ethanolVehicle
8.6 - 9
150 mg PE/min
Saline, dextrose
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50 mg/min
No
pH
Maximum
infusion rate
Admixtures
Fosphenytoin IV administration-events at maximum dose and rate
Perc
enta
ge o
f patients
Nystagmus Dizziness Pruritus Ataxia Somnolence Hypotension Headache
IV Fosphenytoin (n=90)
IV Phenytoin (n=22)
Summary—Fosphenytoin benefits(rapid administration)
• Rapidly and completely converted to phenytoinafter 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
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•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%
• 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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AED Dosage/Rate of Infusion
Phenytoin
(Dilantin®)
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
recommended; Dilute in NS or LR, DO NOT MIX WITH DEXTROSE, do not
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
Fosphenytoin
(Cereneu®)
Status epilepticus: Loading Dose: 15-20 mg PE/kg IV
Non-emergent: Loading Dose: 10-20 mg PE/kg IV or IM; MD: 4-6 mg PE/kg/day IV
or IM
Infusion Rate: Should not exceed 150 mg PE/minute
Valproic acid
(Depakine®)
Loading : 15-20/kg
No Loading Dose; 1000-2500 mg/day in 1-3 divided doses
Admin over 60 min (<= 20 mg/min); rapid infusion over 5-10 min as 1.5-3
mg/kg/min
Levetiracetam
(Keppra®)
>16 y/o. No loading dose. 1000 mg/day (500 MG BID). Dose can be increased by
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%
and infuse over 15 minutes
Admixture and Administration of Injectable AEDs
Special group of status epilepticus
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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
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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
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Status epilepticus
Timing is everything
Save the brain!
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