Refractory Status Epilepticus

Neurocritical Care
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Sep 13, 2021
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Refractory Status Epilepticus


  • Refractory status epilepticus (RSE)
    • Patients who do not respond to standard treatment regimens for SE
    • RSE is considered
      • when patients fail first line therapy which is sufficient dose of benzodiazepines and
      • at least one AED as second line therapy, irrespective of time
    • 26.6% to 36.6% of patients with SE fail to respond to administration of first-line agents
      • Out of all patients who fail first-line agents, 23-48% of the patients fail second line-agents and termed as RSE
  • Super-refractory status epilepticus (SRSE)
    • SRSE is considered when SE continues for 24 hours or more after the use of 3rd line therapies or anesthetic therapy (continuous IV infusions)
      • includes cases that recur on weaning of the anesthetic agent
    • SRSE occurs in 22% of patients with SE

Treatment of Refractory Status Epilepticus (RSE)

  • There is no clear evidence, according to AES protocol, to guide therapy in RSE
  • Estimates of the frequency of RSE in patients with SE have ranged from 9% to 40%
  • Treatment for RSE should be carried out with continuous EEG monitoring
  • Treatment should be started immediately
  • Main decision lies between repeating bolus of urgent control AED or to immediately initiate additional agents

General Measures

  • Adequate ventilatory and hemodynamic support
  • Intubation
  • Monitoring with continuous electroencephalography(EEG)
  • Continuous pulse oximetry
  • Blood pressure monitoring, often with an arterial catheter
  • Vasopressors should be available at the bedside

Specific Drug Therapy

The primary drugs used for refractory status epilepticus are
  • Midazolam
  • Propofol
  • Ketamine

Table 1 Specific Drug Therapies

Following are RSE dosing recommendations; initial doses and continuous infusion (CI) dosing recommendations-titrated to EEG
Drug Therapies
Adverse Effects
•Initial dose: 0.2 mg/kg; administer at an infusion rate of 2 mg/min •CI: 0.05-2 mg/kg/hr •Breakthrough status epilepticus (SE): 0.1-0.2 mg/kg bolus, increase CI rate by 0.05-0.1 mg/kg/hr every 3-4 hours
•Tachyphylaxis occurs after prolonged use •Active metabolite, renally eliminated, rapid redistribution (short duration) •Does not contain propylene glycol
•Respiratory depression •Hypotension
•Initial dose: start at 20 mcg/kg/min, with 1-2 mg/kg loading dose •CI: 30-200 mcg/kg/min •Breakthrough SE: Increase CI rate by 5-10 mcg/kg/min every 5 min or 1 mg/kg bolus plus CI titration
•When administering high doses (>80 mcg/kg/min) for extended periods of time (i.e. >48h) •Peds: with doses >65 mcg/kg/min; contraindicated in young children •Requires mechanical ventilation •Must adjust daily caloric intake (1.1 kcal/ml)
•Hypotension (especially with loading dose in critically ill patients) •Respiratory depression •Cardiac failure •Rhabdomyolysis •Metabolic acidosis •Renal failure (propofol related infusion syndrome)
•Initial dose: 1-2 mg/kg IV slow push •CI: 0.5-7.5 mg/kg/hr •Titrate by 0.5 mg/kg/hr every 10 minutes
•Maximal effect in 1 minute •Hepatic metabolism to active metabolite norketamine •Favorable hemodynamic effects •Minimal respiratory effects
•Agitation with auditory and visual hallucinations •Conscious vivid dreams •Increased intracranial pressure •Tachyarrhythmias •Hypersalivation

Management of Super-Refractory Status Epilepticus (MGH SRSE Protocol)

  • Repeat burst suppression for 24-48 hours
  • Add other AEDs like carbamazepine or topiramate
  • IV magnesium (bolus 4g, then infuse 2-6 g/hr)
  • Pentobarbital
    • Initial dose: 5-15 mg/kg, may give additional 5-10 mg/kg; administer at an infusion rate ≤50 mg/min
    • CI: 0.5-5 mg/kg/h
    • Breakthrough SE: 5 mg/kg bolus, increase CI by 0.5-1 mg/kg/h every 12 h
  • Ketamine (a propofol sparing agent)
    • See Above in RSE protocol Table 1
  • IV pyridoxine 200 mg/day
  • Thiopental
    • Initial dose: 2-7 mg/kg, administer at an infusion rate ≤50 mg/min
    • CI: 0.5-5 mg/kg/h
    • Breakthrough SE: 1-2 mg/kg bolus, increase CI rate by 0.5-1 mg/kg/h every 12h
    • Adverse effects
      • Hypotension
      • Respiratory depression
      • Cardiac depression
    • Considerations
      • Requires mechanical ventilation

Box 1: Alternative Therapy Options for Super-Refractory Status Epilepticus

Alternative Therapy Options for Super-Refractory Status Epilepticus
  • Brivacetam
  • Brexanolone
  • Immunomodulatory agents
  • Inhalation anesthetics
  • Clobazam
  • Therapeutic hypothermia
  • Pryidoxine
  • Ketogenic Diet
  • Electoconvulsive therapy
  • Deep brain stimulation
  • Surgical intervention
  • Transcranial magnetic stimulation
  • Vagal nerve stimulation
  • Magnesium

Alternative Therapy Options

  • Brivaracetam
    • 10-30 fold higher affinity than levetiracetam
    • Initial dose range between 50-400 mg/day
    • Titrated to daily dose of 100-400 mg
  • Brexanolone
    • Initial dose: 286.6 μg/kg for 1 hour
    • CI: 86-156 μg/kg/h for four days
  • Immune modulation
    • Methylprednisolone 1 g IV qd x 3-5 days
    • IVIG 0.4 g/kg/day x 5 days
    • Plasma exchange every other day x 5-7 days
  • Isoflurane
    • MAC ranging from 0.5-5.0%
    • Seizure control was seen in 43 out of 47 patients
    • Seizure activity often returned upon discontinuation
  • Emergency neurosurgery
    • Suggested that patients who fail three courses of cerebral suppressant therapy for 2 weeks be considered for surgical treatment
    • Preferred for intractable partial SE with focal electrographic changes
  • Ketogenic diet
    • 4:1 ratio of fat (g) to protein plus carbohydrates (g)
    • Studies show improvements and cessation of seizures in 1-2 weeks
    • Benefits
      • Easy to start, maintain, and monitor in the ICU
      • Synergism with other AEDs
      • Minimal side effects
  • Electroconvulsive therapy
    • There is evidence that cases of SRSE may benefit from ECT
    • ECT consisted of a 504-mC (≈99.4 J)
    • Improvement in seizures in 5 out of 8 patients
    • Need for further research
  • Transcranial magnetic stimulation
    • Had dismal results in epilepsy, although recent promising reports of use in epilepsia partialis continua have been published.
  • Vagal nerve stimulation
    • Four published cases reporting benefit from VNS
  • Therapeutic hypothermia
    • Review of studies include a total of 40 patients
    • Target temperature of 33 degree Celsius, sustained for a median 48 hours
    • 62.5% patients displayed seizure cessation
    • 15% had seizure reduction
    • 22.5% had failure of treatment


The outcome of refractory status epilepticus is often poor
  • Prognosis for RSE treated with prolonged courses of pentobarbital, propofol, or midazolam is poor
  • Outcome of new-onset RSE by Gaspard et al.
    • Retrospective review of patients with RSE etiology within 48 hours of admission
The most important prognostic factors are
  • Age
  • Etiology
  • Medical comorbidities


  • Ranging from 19 to 60 percent
  • In-hospital mortality rate is 38 percent
  • From a systemic review on 61 studies by Neligan et al.
    • RSE: Pooled mortality was at 17.3%
  • Case mortality rate in patients with RSE was recorded as 38% by Sutter et al.

Further Reading

  • Gaspard, Nicolas et al. “New-onset refractory status epilepticus: Etiology, clinical features, and outcome.” Neurology vol. 85,18 (2015): 1604-13. doi:10.1212/WNL.0000000000001940
  • Rossetti, Andrea O et al. “A randomized trial for the treatment of refractory status epilepticus.” Neurocritical care vol. 14,1 (2011): 4-10. doi:10.1007/s12028-010-9445-z


  • Dubey, D., Kalita, J., & Misra, U. K. (2017). Status epilepticus: Refractory and super-refractory. Neurology India, 65(7), 12.
  • Shaner DM, McCurdy SA, Herring MO, Gabor AJ. Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology 1988; 38: 202–07
  • Mayer, S. A., Claassen, J., Lokin, J., Mendelsohn, F., Dennis, L. J., & Fitzsimmons, B. F. (2002). Refractory status epilepticus: frequency, risk factors, and impact on outcome. Archives of neurology, 59(2), 205-210.
  • Strzelczyk, A., Steinig, I., Willems, L. M., Reif, P. S., Senft, C., Voss, M., ... & Rosenow, F. (2017). Treatment of refractory and super-refractory status epilepticus with brivaracetam: a cohort study from two German university hospitals. Epilepsy & Behavior, 70, 177-181.
  • Rosenthal, E. S., Claassen, J., Wainwright, M. S., Husain, A. M., Vaitkevicius, H., Raines, S., ... & Kanes, S. J. (2017). Brexanolone as adjunctive therapy in super‐refractory status epilepticus. Annals of neurology, 82(3), 342-352.
  • Zeiler, F. A., Zeiler, K. J., Teitelbaum, J., Gillman, L. M., & West, M. (2015). Therapeutic hypothermia for refractory status epilepticus. Canadian Journal of Neurological Sciences, 42(4), 221-229.
  • Ma, X., Liporace, J., O'Connor, M. J., & Sperling, M. R. (2001). Neurosurgical treatment of medically intractable status epilepticus. Epilepsy research, 46(1), 33-38.
  • McDonald, T. J., & Cervenka, M. C. (2017). Ketogenic diets for adults with highly refractory epilepsy. Epilepsy currents, 17(6), 346-350.
  • Ahmed, J., Metrick, M., Gilbert, A., Glasson, A., Singh, R., Ambrous, W., ... & Bobel, K. (2018). Electroconvulsive therapy for super refractory status epilepticus. The journal of ECT, 34(1), e5-e9.
  • Shorvon, S., & Ferlisi, M. (2011). The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain, 134(10), 2802-2818.
  • Hesdorffer, D. C., Logroscino, G., Cascino, G. D., & Hauser, W. A. (2007). Recurrence of afebrile status epilepticus in a population-based study in Rochester, Minnesota. Neurology, 69(1), 73-78.
  • Donaire, A., Carreno, M., Gomez, B., Fossas, P., Bargalló, N., Agudo, R., ... & Obach, V. (2006). Cortical laminar necrosis related to prolonged focal status epilepticus. Journal of Neurology, Neurosurgery & Psychiatry, 77(1), 104-106.
  • Gaspard, N., Foreman, B. P., Alvarez, V., Kang, C. C., Probasco, J. C., Jongeling, A. C., ... & Gerard, E. E. (2015). New-onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology, 85(18), 1604-1613.
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