Seizure

Status Epilepticus

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Status Epilepticus, Seizure Emergency Management

  • Epidemiology
  1. Prevalence: 152,000 cases per year in United States
  2. Age (Bimodal distribution)
    1. Adults: Highest Incidence after age 60 years
    2. Children: Highest Incidence under age 1 year
  • Definition
  1. Diagnostic criteria (2015)
    1. Single unremitting Seizure lasting >5 minutes OR
    2. Frequent clinical Seizures without inter-ictal return to baseline lasting longer than 5 minutes
    3. Trinka (2015) Epilepsia 56(10): 1515-23 [PubMed]
  2. Older classical diagnostic criteria (deprecated, do not use)
    1. Continuous Seizure activity longer than 30 minutes or
    2. Two or more sequential Seizures
      1. No recovery of consciousness between Seizures
  • Pathophysiology
  1. Excessive excitation (excess glutamate)
  2. Ineffective inhibition (inadequate GABA)
    1. GABA aminobutyric receptors are also targeted by Benzodiazepines, Propofol
  3. With prolonged Seizures
    1. GABA receptors (inhibitory) decrease on cell surface (Seizure becomes refractory)
    2. NMDA receptors (excitatory) increase on cell surface
  • Types
  1. Convulsive Status Epilepticus
    1. Rhythmic jerking and generalized tonic clonic activity with Altered Mental Status
  2. NonConvulsive Status Epilepticus
    1. Electrographic (EEG) Seizure activity without clinical Seizure activity
  3. Refractory Status Epilepticus
    1. Persistent clinical or EEG Seizure activity despite 2 antiepileptic agents
    2. Affects 10-40% of children with Status Epilepticus
  • Causes
  1. See Seizure Causes
  2. Poor Medication Compliance with low anticonvulsant drug levels
  3. Alcohol Withdrawal
  4. Drug Overdose (e.g. INH Overdose)
  5. Toxin Ingestion
  6. Intracranial Infection
    1. Meningitis
    2. Encephalitis
  7. Cerebral Neoplasm
  8. Metabolic disorder
    1. Electrolyte disturbance (especially Sodium, calcium and phosphorus)
    2. Inborn Errors of Metabolism
    3. Vitamin B6 Deficiency
  • Differential Diagnosis
  • Signs
  1. See definition above
  2. Witnessed persistent Seizure
  3. Consciousness not regained within 5 minutes of Seizure
  4. Signs may be subtle (e.g. tonic Eye Deviation)
  • Labs
  1. Bedside Glucose
  2. Serum Electrolytes (e.g. Basic Metabolic panel with additional labs)
    1. Serum Sodium
    2. Serum Calcium
    3. Serum Phosphorus
    4. Serum Magnesium
    5. Renal Function tests (Serum Creatinine and Blood Urea Nitrogen)
  3. Hepatic panel
  4. Venous Blood Gas
  5. Antiepileptic drug levels
  6. Urine Tox Screen
  7. Complete Blood Count
  • Diagnostics
  • Indicated for refractory Status Epilepticus
  • Management
  • Initial
  1. See ABC Management
  2. Control airway
    1. Nasal Airway
    2. Consider intubation
  3. Obtain IV Access with Normal Saline to keep open
  4. Administer Supplemental Oxygen
  5. Treat reversible causes (see below)
  6. Monitor Vital Signs closely
    1. Especially Temperature
    2. Telemetry
    3. Electrocardiogram
  • Management
  • Reversible Causes
  1. DONT Mnemonic (Dextrose, Oxygen, Naloxone, Thiamine)
  2. Treat Hypoglycemia if present (based on bedside Glucose - consider if Glucose <80 mg/dl)
    1. Neonate: 0.5 mg/kg (5 ml/kg) D10W
    2. Child: 0.5 mg/kg (2 ml/kg) D25W
    3. Adult: 50 ml IV of D50W
  3. Consider Thiamine in Alcoholism or nutritional deficiency
    1. Thiamine 100 mg IV or IM
  4. Infants under age 2 years (empiric for Autosomal RecessivePyridoxine dependent Seizures)
    1. Pyridoxine 10-15 mg/kg up to 100 mg IV
  5. Severe Hyponatremia (typically in infant <3 months mistakenly fed free water)
    1. Hypertonic Saline 5-10 cc/kg 3% saline over 10 minutes
  • Management
  • Protocol
  1. Precautions
    1. Ensure ABC Management and reversible cause management (e.g. Hypoglycemia) as above
    2. Goal of Status Epilepticus management is definitive Seizure control within 60 minutes of onset
    3. Post-ictal period and Somnolence may persist longer than typical 30 minutes following Status Epilepticus
    4. Following Benzodiazepines
      1. No evidence in 2014 to suggest one antiepileptic is better than another (e.g. Keppra, Valproic Acid)
      2. (2014) Ann Emerg Med 63(4): 437-47 [PubMed]
  2. First: Benzodiazepines (choose one)
    1. Precaution
      1. Do not underdose (give full dose early to have best chance to terminate Seizure)
      2. IV Lorazepam and IV Diazepam have equivalent efficacy in Status Epilepticus
      3. Midazolam IM, intranasal or buccal may be more effective than Diazepam IV or rectal
      4. Benzodiazepine effectiveness decreases (and respiratory depression increases) with each subsequent dose
      5. Neonatal Seizure
        1. Call pharmacy at presentation to have phenobarbital available in case Benzodiazepines fail
    2. Lorazepam (Ativan)
      1. IV: 0.1 mg/kg IV (<2 mg/minute) up to 4 mg
      2. Rectal: 0.1 mg/kg up to 4 mg
      3. May repeat once in 5-10 minutes
      4. Avoid more than 2 doses in children due to risk of respiratory depression
      5. Phamacokinetics: Onset in 2-3 minutes with duration of action 12-24 hours
      6. Avoid IM Lorazepam (unreliable in Status Epilepticus)
    3. Diazepam (Valium)
      1. IV or IM: 0.1 to 0.3 mg/kg IV up to 8-10 mg/dose maximum (may repeat once in 5 minutes)
      2. Rectal: 0.5 mg/kg per Rectum up to maximum of 20 mg
        1. Instill via lubricated Feeding Tube inserted 4-5 cm into the Rectum OR
        2. Via tuberculin syringe (without needle) intra-rectally
        3. Hold buttocks closed after instilling medication
      3. Pharmacokinetics: Onset in 1-3 minutes with duration of action 5-15 minutes
        1. Must be immediately followed with longer acting anticonvulsant (e.g. Fosphenytoin) due to short duration
      4. Efficacy
        1. Diazepam is as effective as Lorazepam in Status Epilepticus
          1. Chamberlain (2014) JAMA 311(16): 1652-60
        2. Diazepam IM dosing is as effective as IV dosing
          1. Silbergleit (2012) N Engl J Med 366:591-600 [PubMed]
    4. Midazolam (Versed)
      1. Alternative agent when longer acting Benzodiazepines not available or without IV Access (e.g. Ambulance)
        1. Lorazepam and Diazepam are preferred if available
      2. IV: 0.15 mg/kg up to 4 mg (then infused IV at 1 mcg/kg/min and titrated every 5 min as needed) up to 10 mg
      3. IM: 0.2 mg/kg of the IV formulation up to 10 mg
        1. Weight 13-40 kg: 5 mg IM
        2. Weight >40 kg: 10 mg IM
      4. Rectal: 0.25 to 0.5 mg/kg
        1. May be delivered via tuberculin syringe (without needle) intra-rectally
      5. Intranasal: 0.2 to 0.4 mg/kg up to 10 mg of the IV formulation (best delivered via atomizer)
      6. Buccal mucosa: 0.5 mg/kg of the IV formulation
  3. Next (if refractory after 5 minutes): Choose one
    1. If Neonatal Seizure skip to phenobarbital below (due to higher efficacy in this age group)
    2. Not effective in Alcohol Withdrawal (continue with Benzodiazepines)
    3. Pharmacokinetics: Both agents have onset within 10-30 minutes with a duration of action of 12-24 hours
    4. Fosphenytoin (Cerebyx)
      1. Dose: 20 mg/kg IV or IM (at 3 mg/kg/min up to 150 mg/min) up to 1500 mg maximum
        1. Deliver slowly over 7 minutes
      2. Preferred over Phenytoin
        1. Fosphenytoin can be infused with dextrose
        2. Fosphenytoin has lower risk of arrhythmia (due to no Ethylene Glycol in base)
        3. Fosphenytoin may be given IM or delivered a faster IV rate (not tissue toxic)
          1. However onset of activity is similar to that with Phenytoin
          2. Fosphenytoin is converted to active Phenytoin form
    5. Phenytoin (Dilantin) - Fosphenytoin is preferred instead (see above)
      1. Dose: 20 mg/kg IV (at 1 mg/kg/min up to 50 mg/min) up to to 1500 mg maximum
        1. Deliver very slowly over 20 minutes
      2. May repeat once with Phenytoin 5-10 mg/kg IV
      3. Maintenance with Phenytoin 50 mg/min
    6. Levetiracetam (Keppra)
      1. Dosing recommended in Status Epilepticus is higher
        1. Dose: 60 mg/kg IV (up to 4500 mg/dose) for single dose
      2. Typical dosing
        1. Load: 20-30 mg/kg IV at 5 mg/kg/min (may give additional second 20 mg/kg IV dose)
        2. Maximum: 3000 mg (or 80 mg/kg/day)
      3. IV formulation is not FDA approved in children
      4. Limited data in Status Epilepticus
    7. Valproic Acid (Depakote)
      1. Dosing recommended in Status Epilepticus is higher
        1. Dose: 40 mg/kg IV (up to 3000 mg/dose)
      2. Typical dosing
        1. Load: 20 mg/kg IV over 1 to 5 minutes
        2. Maintain: 5 mg/kg/hour
      3. Less sedation, respiratory depression, and cardiovascular effects than any of the other agents
      4. Risk of hepatotoxicity
      5. Risk of hyperammonemia (avoid in age under 2 years, especially if inborn error of metabolism)
  4. Next (if refractory after 30 minutes)
    1. Phenobarbital (less commonly used in 2014 - used if second line options not available)
      1. Dose: 20 mg/kg IV
        1. May repeat once with Phenobarbital 5-10 mg/kg IV
        2. Maximal infusion rate: 0.5 to 1 mg/kg/minute up to 50 mg/min
      2. Pharmacokinetics: Onset within 10-20 minutes and duration of 1-3 days
      3. Be prepared to ventilate patient
  5. Next (if refractory after 60 minutes)
    1. Preparation
      1. Requires full life support (coma state)
        1. Intubate and ventilate
        2. Rapid Sequence Intubation
          1. Consider Pentobarbital, Benzodiazepines, Ketamine or Propofol for induction agent
      2. Foley Catheter
      3. Electroencephalogram (EEG)
        1. Dosages below titrated based on EEG
        2. Infusion slowed every 4-6 hours to check EEG status
      4. Follow Temperature closely
        1. Treat hyperthermia with rectal Acetaminophen 15 mg/kg up to 650-1000 mg every 6 hours
      5. Pressor support
        1. Often required for next set of medictions
    2. Choose one medication
      1. Pentobarbital (Nembutal)
        1. Load: 5 mg/kg IV (up to 15 mg/kg, coma dose)
        2. Maintain: 0.5 to 1 mg/kg/hour (up to 5 mg/kg/hour)
        3. Anticipate myocardial depression with secondary reduced Cardiac Output and Hypotension
      2. Midazolam (Versed)
        1. Load: 0.2 mg/kg IV
        2. Maintain: 1 mcg/kg/min
        3. Titrate: Increase by 1 mcg/kg/min every 15 minutes until burst suppression (up to 0.75 to 10 mg/hour)
        4. Anticipate respiratory depression
      3. Propofol (Diprivan)
        1. Load: 1 to 2 mg/kg IV
        2. Maintain: 2-10 mg/kg/hour if Propofol loading dose aborted the Seizure
        3. Anticipate apnea and Hypotension with rapid infusion
        4. Risk of Propofol Infusion Syndrome (esp. children) with catastrophic outcomes with use >48 hours
          1. Do not use Propofol for extended time, especially in children
      4. Ketamine (alternative agent, Pentobarbital, Midazolam, Propofol are preferred)
        1. Antagonizes NMDA receptors and AMPA receptors
        2. Dose: 1.5 to 2 mg/kg
        3. If Ketamine aborts Seizure, then start Propofol maintenance at dose as above
        4. Case reports of neurotoxicity in adults
  • Prognosis
  1. Mortality
    1. Overall: 22%
    2. Children: 3%
    3. Adults: 26%
    4. Elderly: 38%
    5. DeLorenzo (1996) Neurology 46:1026-35 [PubMed]
  2. Morbidity
    1. High Incidence of neurologic sequelae
  • Complications
  1. Anoxic brain injury
  2. Death
  3. Rhabdomyolysis (after 30-60 minutes of Seizure)
  • References
  1. Fuchs and Yamamoto (2012) APLS, Jones and Bartlett, Burlington, p. 191-7
  2. Lu, Claudius and Behar in Herbert (2013) EM:Rap 13(12): 12-3
  3. Nocera, Valente, Amanullah (2018) Crit Dec Emerg Med 32(11): 3-9
  4. (1993) JAMA 270:854-9 [PubMed]
  5. Abend (2008) Pediatr Neurol 38(6): 277-390 [PubMed]
  6. Glauser (2016) Epilepsy Currents 16(1): 48-61 [PubMed]
  7. Hanhan (2001) Pediatr Clin North Am 48(3): 1-12 [PubMed]
  8. Lowenstein (1998) N Engl J Med 338:970-6 [PubMed]
  9. Sirven (2003) Am Fam Physician 68(3):469-76 [PubMed]