Introduction

Hard prerequisite for every agent below: a secured airway + mechanical ventilation + continuous EEG + ICU, with vasopressors immediately available. These are anesthetic doses far higher than ICU sedation; they cause apnea and hypotension. Adult dosing only (not validated for pediatrics); not for post-arrest myoclonic status or epilepsia partialis continua. Teaches the approach, use your institution's SE order set.
Before you call it refractory: confirm adequate first-line benzodiazepine dosing (lorazepam 0.1 mg/kg IV, max 4 mg/dose, repeat once; or IM midazolam 10 mg if >40 kg, 5 mg if 13–40 kg when no IV). Under-dosed benzodiazepines are common and may contribute to pseudo-refractory SE.

Case Presentation

  • A 62-year-old is in generalized convulsive status epilepticus.
    • She received lorazepam 4 mg IV ×2 and levetiracetam 60 mg/kg, but is still seizing at 30 minutes on cEEG.
    • This is refractory status epilepticus (RSE). She is intubated and ventilated.
  • Which continuous IV anesthetic drip, and at what dose?
    • No single agent is proven best, choose by hemodynamics, PRIS risk, and titration to cEEG.

Clinical Detail

Pharmacology: The Four RSE Anesthetic Infusions

Units switch: boluses are mg/kg; propofol infusion is mcg/kg/min; midazolam, ketamine, and pentobarbital infusions are mg/kg/h. Do not carry a unit across. Dose on your institution's specified weight (IBW/adjusted for propofol and ketamine in obesity).

DrugLoading bolusMaintenance infusion (titrate to cEEG)Re-bolusKey adverse effects / monitoringRole / notes
Midazolam (GABA)0.2 mg/kg IV0.05–2 mg/kg/h (start ~0.2); max 2 mg/kg/h0.1 mg/kg before each increaseHypotension (less than propofol/pento); tachyphylaxis (rising rate is expected, not failure); active metabolite accumulates in renal failure (delayed awakening; wean earlier/slower)Common first CIVAD; hemodynamically gentler. Target seizure cessation
Propofol (GABA)1–2 mg/kg IV, pushed slowly by an authorized provider; vasopressor ready first50 mcg/kg/min, titrate by 10; operational ceiling ~100 (up to 200 for burst suppression is physician-directed with explicit PRIS caution)Optional / physician-directed; rate can rise without a routine bolusPRIS: metabolic acidosis/lactate, rhabdomyolysis (CK), hypertriglyceridemia, hyperkalemia, AKI, cardiac failure, arrhythmias, Brugada-type ST (not QTc). Risk = dose × duration (>48 h) × catecholamines/steroids. Lipid emulsion 1.1 kcal/mL (count calories, check triglycerides); dedicated line. Hypotension (usually needs a pressor)First-line CIVAD, esp. hemodynamically stable and/or renal failure; if sustained high-dose >48 h, plan to switch
Ketamine (NMDA)1 mg/kg IV0.5 mg/kg/h, titrate by 0.5; max ~7.5 mg/kg/h (some protocols to 10)1 mg/kg with each changeUsually hemodynamically neutral-to-favorable, but a direct myocardial depressant that can drop pressure once catecholamine reserve is exhausted. Emergence reactions (mitigate with a benzodiazepine). Avoid in uncontrolled hypertension or intracranial hypertension (the older ICP concern is now considered overstated in ventilated/sedated patients)Added when GABA agents stall or BP will not tolerate more; growing interest in earlier use as GABA-A receptors internalize and NMDA up-regulate over time
Pentobarbital (barbiturate)10 mg/kg IV given SLOWLY (e.g. ≤25–50 mg/min), vasopressors + volume ready first0.5–5 mg/kg/h (NCS 2012; some protocols cap 4), titrate by 0.5 to burst suppression5 mg/kg for breakthrough seizuresProfound dose-dependent hypotension (needs vasopressors); ileus, immunosuppression; very long context-sensitive half-life. Hepatic enzyme inducer (phenytoin/valproate interactions variable or bidirectional, monitor levels). Alkaline (pH ~9.5) → dedicated line, verify Y-site incompatibility. Serum level 20–40 mcg/mL if obtainedLast resort (super-refractory); Neurology + critical-care JOINT decision. Target burst suppression

Sequence, Targets & Safety

ParameterDetail
SE definition
  • ≥5 minutes of continuous clinical seizure activity, OR recurrent seizures without recovery of consciousness between them
  • NCSE = electrographic seizures on cEEG without clinical signs
Stepwise sequence
  • (1) Benzodiazepine first-line, adequately dosed (lorazepam 0.1 mg/kg IV, max 4 mg/dose, repeat once; or midazolam 10 mg IM if >40 kg / 5 mg if 13–40 kg)
  • (2) Urgent-control ASM as soon as the first BZD is given: levetiracetam 60 mg/kg (max 4.5 g), fosphenytoin, or valproate. ESETT (NEJM 2019) found these three roughly equivalent (~45–47% reached the 60-min composite of no clinical seizures plus improved responsiveness; no significant difference)
  • (3) RSE (still seizing after a benzodiazepine + one ASM): for generalized convulsive RSE, intubate + cEEG + start a CIVAD (midazolam or propofol) and optimize maintenance ASMs; a further nonsedating ASM before an anesthetic is context-dependent (focal / NCSE without coma)
  • (4) Escalate: ketamine, then pentobarbital
cEEG target
  • Titrate to cessation of clinical AND electrographic seizures (midazolam, ketamine)
  • For deep agents (high-dose propofol, pentobarbital) the goal may be burst suppression; a commonly used operational target is ~2–3 bursts per 15 seconds (a convention, not a consensus definition, follow your protocol)
  • If EEG shows no seizures, stop up-titration
The bolus rule
  • Precede starting midazolam or ketamine, and each of their rate increases, with a bolus (midazolam 0.1 mg/kg; ketamine 1 mg/kg)
  • Propofol's initial bolus is optional and its rate can be up-titrated without a routine bolus; pentobarbital 5 mg/kg boluses are for breakthrough seizures
  • Confirm who is authorized to push each bolus at your institution
Hemodynamics
  • Propofol and pentobarbital cause dose-dependent hypotension (have vasopressors ready BEFORE the bolus); midazolam less so; ketamine usually neutral-to-supportive but can fail in catecholamine-depleted patients
  • Choose the agent to the blood pressure
Preparation / lines
  • Dosing weight per your institution; in obesity IBW or adjusted weight is often preferred for propofol and ketamine
  • Propofol = dedicated line + lipid-emulsion tubing, hang-time limits, counts as calories
  • Pentobarbital = alkaline, dedicated line, verify Y-site incompatibility before co-running anything
Weaning
  • After 24–48 h of clinical + electrographic seizure freedom, wean one agent at a time in reverse order of initiation (ketamine by 0.5 mg/kg/h, midazolam by 0.1 mg/kg/h, propofol by 10 mcg/kg/min, pentobarbital by 0.5 mg/kg/h, each ~q1h)
  • Keep scheduled ASMs unchanged; maintain cEEG 24–48 h after weaning
  • Before weaning pentobarbital, RESTART a midazolam infusion (high recurrence risk)

Evidence

Overview of Evidence

Author, yearDesign / NFocusKey point
Vossler, 2025Narrative review (Continuum)First seizures, ARS, SEFor nonanoxic convulsive RSE, equipoise between adding a second nonsedating ASM vs starting an anesthetic CIVAD
Au, 2024Systematic review, 66 studies, N=1637 (JAMA Neurology)Comparing initial CIVAD in RSEDifferences in short-term failure, hypotension, substitution; NO clear optimal agent; non-epilepsy RSE higher substitution (50% vs 26%) and mortality (43% vs 11%). A seizure- vs burst-suppression signal (OR 7.72) is noncausal and imprecise
Kapur (ESETT), 2019Blinded RCT, N=384 (NEJM)LEV vs fosphenytoin vs valproate for benzo-refractory established SE~45–47% reached the 60-min composite (no clinical seizures + improved responsiveness, no added med); no significant difference, the basis for the interchangeable step-2 options
Almohaish, 2024Review (Semin Neurol)SE pharmacological managementConfirms the staged approach; midazolam, propofol, pentobarbital, ketamine are the RSE infusions; most efficacious not defined
Brophy (NCS), 2012Consensus practice guideline (Neurocrit Care)Evaluation + management of SEFoundational weight-based CIVAD dosing; bolus before infusion

Conclusions

  • Refractory SE (still seizing after an adequately-dosed benzodiazepine + one urgent-control ASM): for generalized convulsive RSE, intubate, start cEEG, and begin a continuous IV anesthetic infusion while optimizing maintenance ASMs (trying a further nonsedating ASM first is more for focal RSE or NCSE without coma).
  • Four agents, no proven winner (JAMA Neurology 2024, 66 studies): midazolam and propofol are typical first CIVADs, ketamine is added when GABA agents stall or the blood pressure will not tolerate more, pentobarbital is the last resort (joint Neuro + critical-care decision).
  • Dose to the blood pressure: propofol and pentobarbital drop it (have pressors ready before the bolus); midazolam less; ketamine is usually neutral but can fail once catecholamine reserve is gone. Avoid ketamine in uncontrolled hypertension or intracranial hypertension.
  • Bolus before starting midazolam or ketamine and before each of their increases (propofol can up-titrate without one; pentobarbital 5 mg/kg is for breakthrough); use your institution's dosing weight (IBW/adjusted for propofol/ketamine in obesity); RSE dosing is far higher than ICU sedation. Watch propofol for PRIS (acidosis/lactate, CK, triglycerides, Brugada-type ECG), especially sustained high dose beyond 48 h.
  • Wean one agent at a time in reverse order after 24–48 h of seizure freedom, keep scheduled ASMs on board, and restart midazolam before weaning pentobarbital.

References

  • Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23. PMID: 22528274
  • Au YK, Kananeh MF, Rahangdale R, et al. Treatment of Refractory Status Epilepticus With Continuous Intravenous Anesthetic Drugs: A Systematic Review. JAMA Neurol. 2024;81(5):534-548. PMID: 38466294
  • Kapur J, Elm J, Chamberlain JM, et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus (ESETT). N Engl J Med. 2019;381(22):2103-2113. PMID: 31774955
  • Almohaish S, Tesoro EP, Brophy GM. Status Epilepticus: An Update on Pharmacological Management. Semin Neurol. 2024;44(3):324-332. PMID: 38580318
  • Vossler DG. First Seizures, Acute Repetitive Seizures, and Status Epilepticus. Continuum (Minneap Minn). 2025;31(1):95-124. PMID: 39899098
  • Wiss AL, Samarin M, Marler J, Jones GM. Continuous Infusion Antiepileptic Medications for Refractory Status Epilepticus: A Review for Nurses. Crit Care Nurs Q. 2017;40(1):67-85. PMID: 27893511
Tags:Status Epilepticus Anesthetic Infusions Neurocritical Care Neurology