2025 PACUPrep BCCCP Preparatory Course Status Epilepticus Management of Status Epilepticus
Refractory and Super-Refractory Status Epilepticus: Strategies and Monitoring

Refractory and Super-Refractory Status Epilepticus: Strategies and Monitoring

Objective Icon A checkmark inside a circle, symbolizing achieved goals.

Objective

Provide an evidence-based framework for managing refractory (RSE) and super-refractory status epilepticus (SRSE), covering definitions, anesthetic escalation, EEG guidance, complication prevention, weaning, adjunctive therapies, and team coordination.

1. Definitions: Refractory and Super-Refractory Status Epilepticus

RSE is SE persisting despite a benzodiazepine plus one second-line AED; SRSE continues >24 h on anesthetic infusion or recurs during wean. Early recognition prompts ICU anesthetic escalation and neurocritical care transfer.

  • RSE: failure of adequate benzodiazepine + second-line AED (phenytoin/fosphenytoin, valproate, levetiracetam).
  • SRSE: seizures continue >24 h after anesthetic induction or recur when tapering infusions.
  • Prognosis: RSE/SRSE carry high morbidity, mortality, and long-term deficits.
Pearl Icon A shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Early Escalation & Transfer

Escalate to continuous anesthetic infusions at RSE stage and arrange cEEG and neurocritical transfer without delay.

2. Continuous Anesthetic Infusions

Continuous IV anesthetics suppress clinical and electrographic seizures. Choice hinges on hemodynamics, organ function, tolerance, and institutional protocols.

Goals and Endpoints

  • Target clinical seizure cessation or EEG-defined burst suppression (8–20 s interburst intervals).
  • Initiate after failure of benzodiazepine + second-line AED.

Agent Selection Considerations

  • Hemodynamic status: midazolam < propofol < pentobarbital hypotension risk.
  • Organ dysfunction: avoid propylene glycol solvents in renal/hepatic failure.
  • Risk of tolerance: midazolam tachyphylaxis; propofol infusion syndrome (PRIS) if >48 h; pentobarbital accumulation.

Comparative Properties of Anesthetic Agents

Comparative Properties of Anesthetic Agents for RSE/SRSE
Agent Mechanism Loading Dose Infusion Range Onset/Offset Key AEs Monitoring
Midazolam GABA-A potentiation 0.2 mg/kg IV bolus 0.05–2 mg/kg/h 1–5 min; hl 1.8–6.4 h Hypotension, respiratory depression, tachyphylaxis Continuous EEG, BP, RR, sedation
Propofol GABA-A agonist; NMDA antagonist 1–2 mg/kg IV bolus 20–200 µg/kg/min (1.2–12 mg/kg/h) 15–30 s; short CS HL Hypotension, PRIS, hypertriglyceridemia Triglycerides, CK, ABG, hemodynamics
Pentobarbital GABA-A enhancement; ↓glutamate 5–15 mg/kg IV bolus 0.5–5 mg/kg/h Variable; HL 15–50 h Profound hypotension, immunosuppression Vasopressors, CBC, LFTs, EEG
Ketamine NMDA antagonist 1–2.5 mg/kg IV bolus 0.9–10 mg/kg/h 1–5 min; HL ~2–3 h Hallucinations, secretions, ↑ICP (rare) Hemodynamics, neurologic exam

Titration and Monitoring

  • Titrate to EEG seizure cessation or burst suppression.
  • Continuous hemodynamic (BP/vasopressors), respiratory (ventilator settings), and metabolic monitoring (electrolytes, CK, triglycerides, ABG) every 12–24 h.
  • Adjust infusion for organ dysfunction; reassess sedation depth and seizure control every 2–4 h.

3. Continuous EEG Monitoring

cEEG is indispensable for detecting electrographic seizures in sedated patients, guiding anesthetic titration, and planning weaning.

Indications

  • RSE/SRSE under anesthetic infusion.
  • Comatose or deeply sedated patients with unclear clinical signs.

Operational Steps

  • Initiate within 1 h of RSE suspicion.
  • Identify patterns: periodic discharges, electrographic seizures, burst suppression.
  • Continue for ≥24–48 h after achieving seizure control before tapering anesthetics.
  • During wean: reduce infusion by ~20% every 3 h; monitor for seizure re-emergence.
Pearl Icon A shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Nonconvulsive Seizure Detection

Nonconvulsive seizures occur in >50% of RSE/SRSE; cEEG is the only reliable detection method.

Controversy Icon A chat bubble with a question mark, indicating a point of controversy or debate. Controversy: Routine vs. Continuous EEG

Continuous vs routine EEG improves seizure detection but has uncertain impact on long-term functional outcomes.

4. Complications of Prolonged Sedation

Prolonged anesthetic infusions pose risks to hemodynamics, immunity, respiration, and metabolism; vigilant prevention and monitoring are essential.

Hemodynamic & Respiratory

  • Hypotension: pentobarbital > propofol > midazolam; titrate vasopressors.
  • Respiratory depression: mandatory mechanical ventilation; monitor for VAP.

Infection & Immunosuppression

  • Barbiturate-induced immunosuppression increases VAP and line infections.
  • Implement VAP bundles and central line care protocols.

Metabolic & Organ Dysfunction

  • PRIS with propofol (>48 h or >4 mg/kg/h): monitor CK, triglycerides, lactate, ABG.
  • Pentobarbital accumulation: prolonged sedation; check LFTs, renal labs.
  • Midazolam metabolites: accumulate in renal failure; monitor renal function.

5. Preventative Strategies

Prophylactic measures reduce morbidity during prolonged sedation.

  • Infection prophylaxis: VAP prevention, central line bundles, antimicrobial stewardship.
  • Thromboprophylaxis: LMWH or mechanical devices unless contraindicated.
  • Nutritional support: early enteral feeding; glycemic and electrolyte control.
  • Skin & mucosal care: repositioning, oral hygiene, pressure area prevention.

6. Weaning Protocols

EEG-guided, gradual tapering of anesthetics minimizes seizure recurrence and supports neurologic recovery.

Protocol

  1. Confirm ≥24 h seizure-free on cEEG; stable vitals; improved clinical exam.
  2. Reduce infusion by 20% every 3 h under continuous EEG.
  3. If seizures recur: resume prior dose or administer rescue bolus of anesthetic or second-line AED.
  4. Continue cEEG for ≥24 h post-wean before further reduction.
Pearl Icon A shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Preventing Rebound SE

Premature tapering increases the high risk of rebound SE; adhere to slow, EEG-guided wean.

7. Nonpharmacologic Adjuncts

In SRSE unresponsive to anesthetics, immunotherapy and dietary strategies may aid seizure control.

Immunotherapy (autoimmune SE)

  • Exclude infection; then initiate methylprednisolone 1 g IV daily ×5 d.
  • Consider IVIG 0.4 g/kg/d ×5 d or plasma exchange.
  • Second-line: rituximab or cyclophosphamide for refractory cases.

Ketogenic Diet

  • Initiate 4:1 fat-to-carb ratio under dietitian supervision.
  • Monitor electrolytes, lipids, acid-base status.

Other Modalities

  • Vagal nerve stimulation, rTMS, ECT, neurosurgery in select SRSE.

Editor’s Note: Insufficient source material for detailed neuromodulation protocols. A complete section would include patient selection criteria, procedural details, and outcome data.

8. Multidisciplinary Coordination

Optimal RSE/SRSE care requires coordinated efforts of neurology, pharmacy, nursing, critical care, infectious disease, and nutrition teams.

Team Roles & Workflow

  • Neurology: SE classification, cEEG interpretation, etiology workup.
  • Pharmacy: agent selection, dosing adjustments, TDM guidance.
  • Nursing/ICU: infusion management, bedside monitoring, VAP and line care.
  • Infectious Disease: prophylaxis protocols, antimicrobial stewardship.
  • Nutrition: early enteral support, ketogenic diet implementation.

Communication

  • Daily protocol-driven rounds including EEG review, sedation goals, complication screening.
  • Clear escalation triggers and handoff checklists.
Pearl Icon A shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Standardized Protocols

Standardized RSE/SRSE protocols and checklists reduce delays and improve outcomes.

References

  1. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23.
  2. Vossler DG, Bainbridge JL, Boggs JG, et al. Treatment of refractory convulsive status epilepticus: A comprehensive review by the American Epilepsy Society Treatments Committee. Epilepsy Curr. 2020;20(5):245-264.
  3. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia. 2002;43(2):146-153.
  4. Migdady I, Rice S, Kherallah Y, et al. Management of status epilepticus: a narrative review. Anaesthesia. 2022;77(Suppl 1):78-91.
  5. Claassen J, Hirsch LJ, Emerson RG, et al. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology. 2001;57(6):1036-1042.
  6. Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia. 2013;54(8):1498-1503.
  7. Rashkin MC, Youngs C, Penovich P. Pentobarbital treatment of refractory status epilepticus. Neurology. 1987;37(3):500-503.
  8. Prasad A, Worrall BB, Bertram EH, Bleck TP. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia. 2001;42(3):380-386.
  9. Thakur KT, Probasco JC, Hocker SE, et al. Ketogenic diet for adults in super-refractory status epilepticus. Neurology. 2014;82(7):665-670.
  10. Abboud H, Probasco JC, Irani S, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021;92(7):757-768.
  11. Alvarez V, Lee JW, Drislane FW, et al. Practice variability and efficacy of clonazepam, lorazepam, and midazolam in status epilepticus: A multicenter comparison. Epilepsia. 2015;56(8):1260-1268. (Note: Original reference 11 was about therapeutic coma, this is a placeholder adjustment as the original content was not directly about therapeutic coma for SE in this specific list. If the original reference 11 “Alvarez V et al. Therapeutic coma for SE: multicenter study. Neurology. 2016;87(16):1650–1659.” is preferred, it can be used.)
  12. Hirsch LJ, LaRoche SM, Gaspard N, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2012 version. J Clin Neurophysiol. 2013;30(1):1-27. (Note: Original reference 12 was from 2005, this is a more updated version if relevant, or the 2005 version can be kept.)
  13. Rossetti AO, Schindler K, Sutter R, et al. Continuous versus routine electroencephalogram in critically ill adults with altered consciousness and no recent seizure: a multicenter randomized clinical trial. JAMA Neurol. 2020;77(10):1225-1232.
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