What are the preferred medications for managing seizures, including status epilepticus, and their indications and contraindications?

Status Epilepticus and Seizure Management: Medication Selection

Why Lorazepam Over Other Benzodiazepines?

Lorazepam is the preferred first-line benzodiazepine because it achieves 65% success in terminating status epilepticus—statistically superior to phenytoin alone (44%, p=0.002)—and maintains therapeutic brain levels for several hours compared to diazepam's 20-30 minute duration of action. 1, 2

Pharmacokinetic Superiority

• Lorazepam has a much smaller volume of distribution of unbound drug compared to diazepam, resulting in an effective duration of action of several hours versus only 20-30 minutes for diazepam 3
• This longer duration allows orderly administration of long-term anticonvulsants without seizure recurrence 3, 4
• Lorazepam requires significantly fewer repeat doses and has fewer seizure recurrences compared to diazepam in both premonitory and established status epilepticus 4

Standard Dosing Protocol

• Administer lorazepam 4 mg IV at 2 mg/min, repeatable once for a total of 8 mg if seizures persist 2
• For pediatric patients: 0.1 mg/kg IV (maximum 4 mg) for convulsive status epilepticus 5

When to Choose Other Benzodiazepines

Midazolam (IM or Intranasal)

• Use when IV access is unavailable or delayed 2, 5
• IM midazolam is equally efficacious to IV lorazepam in prehospital settings 6
• Intranasal or buccal midazolam is appropriate for pediatric patients without IV access 7

Diazepam (Rectal)

• Reserve for outpatient/home rescue therapy when other routes are unavailable 6, 8
• Rectal diazepam is currently the only FDA-approved outpatient benzodiazepine for acute seizure clusters 6
• Inferior to lorazepam for in-hospital status epilepticus management due to short duration of action 3, 4

Midazolam Infusion (Third-Line)

• Use for refractory status epilepticus after benzodiazepines and second-line agents fail 2, 5
• Loading dose: 0.15-0.20 mg/kg IV, then continuous infusion at 1 mg/kg/min, titrated up to maximum 5 mg/kg/min 2, 5
• Achieves 80% efficacy with 30% hypotension risk—better safety profile than pentobarbital (77% hypotension) 2, 5

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Why Phenytoin/Fosphenytoin Over Levetiracetam?

Phenytoin/fosphenytoin is NOT superior to levetiracetam—in fact, valproate (88% efficacy, 0% hypotension) and levetiracetam (68-73% efficacy, minimal cardiovascular effects) are often preferred over phenytoin (84% efficacy, 12% hypotension risk) in modern practice. 2, 5

The Traditional Role of Phenytoin

• Phenytoin remains widely used because 95% of neurologists recommend it for benzodiazepine-refractory seizures, making it the most extensively studied and universally available second-line agent 2, 5
• Fosphenytoin allows faster administration (150 PE/min vs 50 mg/min for phenytoin) with less cardiovascular toxicity 2
• Dose: 20 mg PE/kg IV at maximum rate of 150 PE/min 5

When Phenytoin/Fosphenytoin is Preferred

• When valproate and levetiracetam are contraindicated or unavailable 2, 5
• In settings where institutional protocols mandate phenytoin as standard second-line therapy 2
• When long-term phenytoin maintenance is already planned 5

Contraindications to Phenytoin/Fosphenytoin

• Hypotension or cardiovascular instability (12% hypotension risk) 2, 5
• Cardiac conduction abnormalities—requires continuous ECG and blood pressure monitoring 5
• Elderly patients at higher risk for cardiovascular complications 2

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Second-Line Agent Comparison: Indications and Contraindications

Valproate: Highest Efficacy, Best Safety Profile

Valproate achieves 88% efficacy with 0% hypotension risk, making it superior to phenytoin when cardiovascular stability is a concern. 2, 5

Indications

• First choice in patients with hypotension or cardiovascular instability 2, 5
• Preferred in elderly patients 2
• Benzodiazepine-refractory status epilepticus 1, 5

Contraindications

• Women of childbearing potential (significantly increased risk of fetal malformations and neurodevelopmental delay) 5
• Hepatic dysfunction (hepatotoxicity risk) 5
• Mitochondrial disorders 5

Dosing

• 20-30 mg/kg IV over 5-20 minutes 2, 5

Levetiracetam: Safest Cardiovascular Profile

Levetiracetam achieves 68-73% efficacy with minimal cardiovascular effects, making it the preferred second-line agent in elderly patients or those with hypotension. 2, 5

Indications

• Elderly patients with cardiovascular comorbidities 2
• Patients with hypotension or requiring vasopressor support 2, 5
• When rapid administration without cardiac monitoring is needed 5
• Benzodiazepine-refractory status epilepticus 2, 5

Contraindications

• Severe renal dysfunction (requires dose adjustment) 5
• No absolute contraindications otherwise 2, 5

Dosing

• 30 mg/kg IV over 5 minutes (approximately 2000-3000 mg for average adults) 2, 5

Phenobarbital: High Respiratory Depression Risk

• Use when valproate, levetiracetam, and phenytoin are all contraindicated or have failed 2, 5
• Achieves 58.2% efficacy but carries higher risk of respiratory depression 2, 5
• Dose: 20 mg/kg IV over 10 minutes 2, 5

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Why Not Propofol or Ketamine as Second-Line Agents?

Propofol: Third-Line Only

Propofol is reserved for third-line treatment of refractory status epilepticus and should only be used in intubated patients without hypotension. 2, 5

Why Not Earlier?

• Requires mechanical ventilation 2, 5
• Causes hypotension in 42% of patients 5
• Lower efficacy (73%) compared to second-line agents like valproate (88%) 2, 5
• Reserved for seizures continuing despite benzodiazepines AND one second-line agent 5

Indications for Propofol

• Refractory status epilepticus in intubated patients with adequate blood pressure support 2, 5
• When shorter ventilation time is desired (4 days vs 14 days with pentobarbital) 5

Contraindications

• Hypotension or hemodynamic instability 5
• Non-intubated patients 2, 5

Dosing and Monitoring

• 2 mg/kg bolus, then 3-7 mg/kg/hour infusion 2, 5
• Requires continuous blood pressure monitoring, mechanical ventilation, and EEG monitoring to guide titration 5

Ketamine: Fourth-Line for Super-Refractory Status Epilepticus

Ketamine is a fourth-line agent reserved for super-refractory status epilepticus, with 64% efficacy when used early (within 3 days), but efficacy drops to 32% when delayed. 2, 5

Why Not Earlier?

• Works through NMDA receptor antagonism rather than GABA mechanisms—mechanistically distinct from first/second-line agents 5
• Should only be used after benzodiazepines, second-line agents, AND third-line anesthetic agents have failed 2, 5
• Requires continuous EEG monitoring and mechanical ventilation 5

Indications for Ketamine

• Super-refractory status epilepticus failing midazolam, propofol, or pentobarbital 2, 5
• Early use (within 3 days of refractory status epilepticus) for maximal efficacy 5

Contraindications

• Elevated intracranial pressure 5
• Severe cardiovascular instability 5

Dosing

• 0.45-2.1 mg/kg/hour infusion, with maximal daily doses of 1392-4200 mg based on clinical response 5

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Febrile Seizure Management

Simple febrile seizures do not require acute benzodiazepine treatment or prophylactic anticonvulsants, unless the seizure is prolonged (>5 minutes) or recurrent. 2

When to Treat Febrile Seizures

• Only if seizure duration exceeds 5 minutes 2
• If seizure is recurrent within the same febrile illness 2

Treatment Protocol

• Lorazepam 0.1 mg/kg IV (maximum 4 mg) if seizure is ongoing >5 minutes 2, 5
• For pediatric patients: 0.1 mg/kg IV (maximum 2 mg), repeatable after at least 1 minute up to maximum of 2 doses 5

What NOT to Do

• Do not administer prophylactic anticonvulsants for simple febrile seizures 2
• Do not treat brief (<5 minutes), self-limited febrile seizures with benzodiazepines 2

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Critical Pitfalls to Avoid

Never Skip Treatment Steps

• Do not skip to third-line agents (propofol, pentobarbital) until benzodiazepines and a second-line agent have been tried 5
• Do not use neuromuscular blockers alone (e.g., rocuronium)—they only mask motor manifestations while allowing continued electrical seizure activity and brain injury 5

Simultaneous Evaluation Required

• Always search for and treat reversible causes while administering anticonvulsants: hypoglycemia, hyponatremia, hypoxia, drug toxicity, CNS infection, stroke, intracerebral hemorrhage, and withdrawal syndromes 5
• Check fingerstick glucose immediately and correct hypoglycemia 5

Monitoring Requirements

• Have airway equipment immediately available before administering any benzodiazepine 5
• Continuous vital sign monitoring is essential, particularly respiratory status and blood pressure 5
• Phenytoin/fosphenytoin requires continuous ECG and blood pressure monitoring 5
• All third-line agents require continuous EEG monitoring to guide titration 5