Table 2.

Medications used for refractory status epilepticus (RSE)

Medication	Loading dose (rate of administration) CI maintenance dose and rate Breakthrough SE management [11, 50, 51, 125, 126]	Pharmacokinetics and other considerations [51, 125]	Mechanism of action [51, 125]	Serious adverse effects [50, 51, 125]	Rational polytherapy—synergistic action tested in animal or human studiesa
Midazolam	Loading: 0.2 mg/kg (2 mg/min infusion) CI: 0.05–2 mg/kg/h Breakthrough SE: 0.1–0.2 mg/kg bolus, titrate rate with EEG in steps of 0.05–0.1 mg/kg/h in time intervals as clinically indicated	Tachyphylaxis with prolonged infusion, may necessitate progressively higher doses; Active metabolite is renally eliminated; CYP 3A4 substrate	Positive allosteric modulator of GABAA receptor; therefore, increases frequency of Cl channel opening	Hypotension, respiratory depression (requires intubation)	Animal study: Midazolam-ketamine: P [112]
Pentobarbital	Loading: 5 mg/kg (≤ 50 mg/min) CI: 0.5–5 mg/kg/h Breakthrough SE: 5 mg/kg bolus, titrate rate with EEG in steps of 0.5–1 mg/kg/h in time intervals as clinically indicated	CYP 2A6 enzyme inducer; Can exacerbate porphyria; Drug accumulation with prolonged use	Activation of GABA receptors increase mean CI channel opening duration, inhibition of NMDA receptors, alteration in conductance of Cl−, K+, Ca2+ ion channels	Hypotension, respiratory depression (requires intubation), paralytic ileus, cardiac depression
Thiopental	Loading: 2–7 mg/kg (≤ 50 mg/min) CI: 0.5–5 mg/kg/h Breakthrough SE: 1–2 mg/kg bolus titrate in steps of 0.5–1 mg/kg/h as clinically indicated with EEG	Non-linear metabolism; long half-life, ranging from 11 to 36 h; Autoinduction of its metabolism (takes days to occur); Several drug interactions	Same as pentobarbital	Hypotension, respiratory depression (requires intubation), cardiac depression
Ketamine	Loading: 1–3 mg/kg every 3–5 min until seizures stop [49, 55] CI: 10–100 µg/kg/min Breakthrough SE: 1–2 mg/kg bolus with titration in steps of 5–10 µg/kg/min with EEG as clinically indicated up to a maximum of 100 µg/kg/min [55]	High lipid solubility–fast onset, extensive distribution; Elimination half-life is 2–3 h; Metabolized by cytochrome P450 system (CYP3A4) into norketamine (active metabolite); Acts as an enzyme inducer and inhibitor (CYP2C9)	Noncompetitive NMDA glutamate receptor antagonist that reduces neuronal excitability	Induces positive sympathetic response sometimes leading to drug-induced hypertension, possible increased intracranial pressure, hypersalivation. Agitation, confusion, psychosis may be observed after ketamine is stopped	Animal studies: Diazepam-ketamine-valproate: P [100] Ketamine-brivaracetam: P [127] Human study: Propofol-ketamine: P [128] Ongoing human study: Ketamine-midazolam [55]
Propofol	Loading: 1–2 mg/kg, repeat if necessary CI: 20–200 µg/kg/min, caution with doses > 65 µg/kg/min Breakthrough SE: increase CI by 5–10 µg/kg/min stepwise with EEG as clinically indicated	While propofol is sometimes used for short durations in pediatric CSE, there exists a relative contraindication in children and mitochondrial disorders or hypertriglyceridemia, as it may cause propofol infusion syndrome (PRIS), which is associated with a high mortality rate	Chloride channel conductance, enhances GABAA receptor	PRIS, hypotension, cardiac depression, respiratory depression, reduces intracranial pressure	Human study: Propofol-ketamine: P [128]
IV methylprednisolone	30 mg/kg/dose once daily (max 1000 mg) for 3–5 days	Concomitant use with ketogenic diet may result in difficulty obtaining or loss of ketosis; use with proton-pump inhibitor or H2 antagonist to prevent gastritis	Decreases effects of pro-inflammatory cytokines and immune cells, improves blood–brain barrier integrity [129]	Immunosuppression/infections, irritability/psychiatric disturbance, insomnia, hyperglycemia/electrolyte disturbance, hypertension, bradycardia; osteoporosis, weight gain, and adrenal suppression may occur with long-term use [130]
IV immunoglobulin (IVIg)	1000 mg/kg/dose once daily for 2 days or 400 mg/kg/dose once daily for 3–5 days	Anaphylaxis may occur in patients with antibodies to Immunoglobulin A (IgA)	Decreases cytokines via alteration of immunoglobulin receptors; decreases effects of complement-mediated cascades [131, 132]	Black box warnings include acute renal failure and thrombotic events; other side effects include headache/aseptic meningitis, infusion/hypersensitivity reactions, and rarely transfusion-related acute lung injury [132, 133]
Plasmapheresis	5 exchanges typically occurring every other day	Use with direction by transfusion medicine physician	Removes immune proteins, such as antibodies	Electrolyte disturbance, coagulopathy, transfusion-related acute lung injury, catheter-associated complications, infection [134, 135]
Anakinra	Dose in refractory status epilepticus not well established		IL-1 receptor antagonist	Immunosuppression/infections, neutropenia, hepatitis, malignancy [136]
Tocilizumab	Dose in refractory status epilepticus not well established		IL-6 receptor antagonist	Immunosuppression/infections, neutropenia, hepatitis, malignancy, hyperlipidemia [137]

Ca2+ calcium, CI continuous infusion, Cl chloride, CSE convulsive status epilepticus, CYP cytochromes P450, EEG electro-encephalography, GABA gamma-aminobutyric acid, Ig immunoglobulin, IL interleukin, IV intravenous, IVIg intravenous immunoglobulin, K+ potassium, NMDA N-methyl-d-aspartate, SE status epilepticus

^aN no additional benefit with polytherapy, P polytherapy had better outcomes