What is the recommended acute management of status epilepticus, including first‑line benzodiazepine dosing, second‑line antiepileptic choices, and refractory‑status protocols?

Status Epilepticus Management

First-Line Treatment: Benzodiazepines (0-5 minutes)

Administer IV lorazepam 4 mg at 2 mg/min immediately for any actively seizing patient—this terminates status epilepticus in 65% of cases and is superior to diazepam (59.1% vs 42.6% seizure cessation). 1

• Status epilepticus is defined as any seizure lasting ≥5 minutes or recurrent seizures without return to baseline 1, 2
• Have airway equipment immediately available before administering any benzodiazepine due to respiratory depression risk 1
• Lorazepam is preferred over diazepam because of its longer duration of action (several hours vs 20-30 minutes) 1, 3

Alternative routes when IV access is unavailable:

• IM midazolam 10 mg provides equivalent efficacy to IV lorazepam 1
• Intranasal midazolam with onset within 1-2 minutes 1
• Rectal diazepam 0.5 mg/kg if other routes are not feasible 1
• Never use IM diazepam due to erratic absorption 1, 4

Critical concurrent action: Check fingerstick glucose immediately and correct hypoglycemia while administering benzodiazepines 1

---

Second-Line Treatment: Anticonvulsants (5-20 minutes)

If seizures persist after adequate benzodiazepine dosing, escalate immediately to a second-line agent—do not delay. 1 The 2019 ESETT trial demonstrated no significant efficacy difference among valproate, levetiracetam, and fosphenytoin (46-47% seizure cessation), so selection should prioritize safety profile and contraindications. 1

Recommended Second-Line Agents (in order of safety profile):

1. Valproate (preferred for most patients):

• Dose: 20-30 mg/kg IV (maximum 3000 mg) over 5-20 minutes 1, 2
• Efficacy: 88% seizure control with 0% hypotension risk 1, 2, 4
• Absolute contraindication: Women of childbearing potential due to teratogenicity 1
• Superior safety profile compared to phenytoin (88% efficacy/0% hypotension vs 84% efficacy/12% hypotension) 1, 2, 4

2. Levetiracetam (excellent alternative):

• Dose: 30 mg/kg IV (maximum 2500-3000 mg) over 5 minutes 1, 2
• Efficacy: 68-73% seizure control 1, 2
• Minimal cardiovascular effects (≈0.7% hypotension) and 20% intubation rate 1
• No cardiac monitoring required 1
• Requires renal dose adjustment in kidney dysfunction 1

3. Fosphenytoin (traditional option):

• Dose: 20 mg PE/kg IV at maximum rate of 150 PE/min (not to exceed 50 mg/min) 1, 4
• Efficacy: 84% seizure control but 12% hypotension risk 1, 2, 4
• Requires continuous ECG and blood pressure monitoring 1, 2, 4
• Intubation rate 26.4% 1
• Never mix with dextrose-containing solutions due to precipitation 4
• Reduce infusion rate if heart rate decreases by 10 beats/min 4

4. Phenobarbital (reserve option):

• Dose: 20 mg/kg IV over 10 minutes (maximum 1000 mg in pediatrics) 1, 4
• Efficacy: 58.2% seizure control 1, 2
• Higher risk of respiratory depression and hypotension due to vasodilatory and cardiodepressant effects 1, 2, 4

Critical pitfall: Never skip directly to third-line anesthetic agents without trying benzodiazepines and at least one second-line agent 1, 4

---

Simultaneous Evaluation for Reversible Causes

While administering anticonvulsants, immediately search for and treat underlying etiologies: 1, 2

• Hypoglycemia (most rapidly reversible)
• Hyponatremia (most common electrolyte disturbance causing seizures) 1
• Hypoxia
• Drug toxicity or withdrawal (alcohol, benzodiazepines, barbiturates)
• CNS infection
• Ischemic stroke or intracerebral hemorrhage (especially age >40 years) 1
• Do not delay anticonvulsant therapy to obtain neuroimaging 1

---

Refractory Status Epilepticus (20+ minutes)

Refractory SE is defined as ongoing seizures despite adequate benzodiazepines AND failure of one second-line anticonvulsant. 1 At this stage, initiate continuous EEG monitoring and escalate to anesthetic agents. 1

Third-Line Anesthetic Agents:

1. Midazolam infusion (first choice for refractory SE):

• Loading dose: 0.15-0.20 mg/kg IV 1, 2
• Continuous infusion: Start at 1 mg/kg/min, titrate up by 1 mg/kg/min every 15 minutes to maximum 5 mg/kg/min 1
• Efficacy: 80% seizure control with 30% hypotension risk 1, 2
• Before tapering midazolam, load with a long-acting anticonvulsant (phenytoin/fosphenytoin, valproate, levetiracetam, or phenobarbital) to ensure adequate baseline coverage 1

2. Propofol (alternative for intubated patients):

• Loading dose: 2 mg/kg IV bolus 1, 2
• Continuous infusion: 3-7 mg/kg/hour 1, 2
• Efficacy: 73% seizure control with 42% hypotension risk 1, 2
• Requires mechanical ventilation but shorter duration than barbiturates (4 days vs 14 days) 1, 2
• Continuous blood pressure monitoring mandatory 1

3. Pentobarbital (highest efficacy, highest complication rate):

• Loading dose: 13 mg/kg IV 1
• Continuous infusion: 2-3 mg/kg/hour 1
• Efficacy: 92% seizure control but 77% hypotension risk requiring vasopressors 1, 2
• Mean mechanical ventilation duration: 14 days 1
• Have vasopressors (norepinephrine or phenylephrine) immediately available 1

4. Ketamine (fourth-line for super-refractory SE):

• Dose: 0.45-2.1 mg/kg/hour 1
• Efficacy: 64% when administered early (within 3 days), drops to 32% when delayed to mean 26.5 days 1
• Mechanistically distinct NMDA receptor action provides alternative to GABA-ergic agents 1

---

Critical Monitoring Requirements

For all anesthetic agents:

• Continuous EEG monitoring to guide titration and detect ongoing electrical seizure activity 1, 5, 6
• Continuous vital sign monitoring, particularly blood pressure and respiratory status 1
• Prepare for mechanical ventilation and respiratory support 1
• Maintain continuous EEG for minimum 24-48 hours after complete anesthetic discontinuation, as breakthrough seizures occur in >50% of patients and are often only detectable by EEG 1

Common pitfall: Do not attribute altered mental status solely to post-ictal state—obtain urgent EEG if patient does not awaken within expected timeframe, as nonconvulsive status epilepticus occurs in >50% of cases 1

---

Prognosis

• Overall mortality for status epilepticus: 5-22% 1
• Refractory status epilepticus mortality: approximately 65% 1, 7
• Time is brain—prolonged seizures lead to changes in synaptic receptors creating a more proconvulsant state and increased risk of brain lesion 6

---

Pediatric Dosing Considerations

Lorazepam:

• Convulsive SE: 0.1 mg/kg IV (maximum 2 mg), may repeat after ≥1 minute up to 2 doses 1
• Non-convulsive SE: 0.05 mg/kg IV (maximum 1 mg), may repeat every 5 minutes up to 4 doses 1

Levetiracetam:

• Loading: 40 mg/kg IV (maximum 2500 mg) over 5-15 minutes 1
• Maintenance: 30 mg/kg IV every 12 hours (maximum 1500 mg) for convulsive SE; 15 mg/kg every 12 hours for non-convulsive SE 1

Fosphenytoin:

• Pediatric rate should not exceed 1-3 mg/kg/min or 50 mg/min, whichever is slower 1, 4

Phenobarbital:

• 20 mg/kg IV over 10 minutes (maximum 1000 mg), may repeat after 15 minutes not exceeding total 40 mg/kg 1, 4