What is the management of refractory status epilepticus in a pediatric patient?

Refractory Status Epilepticus in Pediatric Patients

Refractory status epilepticus (RSE) in pediatric patients is defined as seizures that continue despite treatment with benzodiazepines and one second-line antiepileptic drug, requiring escalation to continuous anesthetic infusions with ICU-level care. 1, 2

Definition and Clinical Recognition

Refractory status epilepticus occurs when seizure activity persists after:

• First-line benzodiazepine therapy (lorazepam 0.1 mg/kg IV for convulsive SE or 0.05 mg/kg for non-convulsive SE) 3, 1
• One adequate trial of a second-line agent such as levetiracetam (40 mg/kg IV), valproate (20-30 mg/kg IV), fosphenytoin (20 mg/kg PE IV), or phenobarbital (10-20 mg/kg IV) 3, 1

The operational definition of status epilepticus itself has evolved to 5 minutes of continuous seizure activity for treatment purposes, though the traditional definition remains 20 minutes or more of unremitting seizure activity. 1

Management Algorithm for Pediatric RSE

Immediate Actions Upon Recognition

Transfer to pediatric intensive care unit (PICU) immediately when RSE is diagnosed, as mechanical ventilation and hemodynamic support will likely be required. 3, 1

• Assess and secure airway, breathing, and circulation (CAB) with airway protection interventions 3, 4
• Provide high-flow oxygen to prevent hypoxia, which worsens seizures 3, 4
• Establish secure IV access for continuous medication infusions 4
• Initiate continuous EEG monitoring to detect ongoing electrical seizure activity, as clinical manifestations may be subtle or absent 3, 1

Third-Line Anesthetic Agents for Pediatric RSE

When seizures persist despite benzodiazepines and one second-line agent, initiate continuous anesthetic infusion with one of the following:

Midazolam infusion (preferred first-choice anesthetic):

• Loading dose: 0.15-0.20 mg/kg IV 3, 1
• Continuous infusion: 1 mg/kg/min, titrate up by 1 mg/kg/min every 15 minutes to maximum 5 mg/kg/min 3, 1
• Efficacy: 80% overall success rate 1
• Hypotension risk: 30% (lowest among anesthetic agents) 1

Propofol (alternative option, use with caution in pediatrics):

• Loading dose: 2 mg/kg bolus 3, 1
• Continuous infusion: 3-7 mg/kg/hour 3, 1
• Efficacy: 73% seizure control 1
• Hypotension risk: 42% 1
• Critical pediatric warning: Propofol has been associated with increased mortality in pediatric ICU patients compared to standard sedative agents (11% vs 4% mortality), though the difference was not statistically significant. 5
• Requires mechanical ventilation but shorter duration than barbiturates (4 days vs 14 days) 1

Pentobarbital (most effective but highest risk):

• Loading dose: 13 mg/kg 3, 1
• Continuous infusion: 2-3 mg/kg/hour 3, 1
• Efficacy: 92% (highest among all agents) 1
• Hypotension risk: 77% requiring vasopressors 1
• Prolonged mechanical ventilation (mean 14 days) 1

Critical Monitoring Requirements

Continuous vital sign monitoring is mandatory:

• Respiratory status with pulse oximetry—be prepared to provide mechanical ventilation regardless of agent chosen 3, 1
• Blood pressure monitoring—have vasopressors (norepinephrine or phenylephrine) immediately available 1
• Cardiac monitoring for dysrhythmias, especially with barbiturates 1
• Continuous EEG monitoring to guide titration and detect subclinical seizures 3, 1

Laboratory monitoring every 6-8 hours:

• Electrolytes to prevent rebound cerebral edema and abnormalities 3
• Renal function to adjust medications and prevent failure 3
• Volume status to prevent hypovolemia/hypotension 3

Maintenance Antiepileptic Therapy

Load with long-acting antiepileptic drugs during anesthetic infusion to ensure adequate baseline levels before tapering anesthetics:

For convulsive status epilepticus after resolution:

• Levetiracetam 30 mg/kg IV every 12 hours (maximum 1,500 mg) 3, 1
• Phenobarbital 1-3 mg/kg IV every 12 hours 3, 1

For non-convulsive status epilepticus after resolution:

• Levetiracetam 15 mg/kg IV every 12 hours (maximum 1,500 mg) 3, 1
• Lorazepam 0.05 mg/kg (maximum 1 mg) IV every 8 hours for 3 doses 3

Corticosteroid Administration

Administer corticosteroids concurrently when treating refractory status epilepticus, particularly if CRES (CAR T cell-related encephalopathy syndrome) or inflammatory etiology is suspected. 3

Simultaneous Evaluation for Underlying Causes

Search for and treat reversible causes immediately:

• Hypoglycemia—check fingerstick glucose and correct 1, 4
• Hyponatremia and other electrolyte abnormalities 1
• Hypoxia 1
• Drug toxicity or withdrawal syndromes 1
• CNS infection (meningitis, encephalitis) 1
• Ischemic stroke or intracerebral hemorrhage 1
• Increased intracranial pressure (CSF opening pressure ≥20 mmHg requires osmotherapy) 3

Obtain laboratory studies including electrolytes, complete blood count, toxicology screen, and anticonvulsant drug levels. 4

Consider neuroimaging (CT or MRI) once patient is stabilized, but do not delay anticonvulsant administration for imaging. 1

Critical Pitfalls to Avoid

Never use neuromuscular blockers alone (such as rocuronium), as they only mask motor manifestations while allowing continued electrical seizure activity and ongoing brain injury. 1

Do not skip directly to third-line anesthetic agents until benzodiazepines and at least one second-line agent have been adequately trialed. 1

Avoid first-line anti-seizure medications with unfavorable cardiotoxicity profiles (such as lacosamide and phenytoin) when possible in the setting of concurrent cytokine release or cardiac dysfunction. 3

In obese pediatric patients, adjust midazolam doses based on ideal body weight, as younger children (under 6 years) may require higher mg/kg doses than older children. 1

Tapering Strategy

Once seizures have been controlled for 12-24 hours on continuous anesthetic therapy:

• Gradually taper midazolam or propofol while maintaining continuous EEG monitoring 6
• Barbiturates (pentobarbital) may not require gradual tapering 6
• Ensure adequate levels of long-acting antiepileptics are maintained during withdrawal to prevent recurrence 6

Prognosis and Long-Term Considerations

Even with aggressive treatment, mortality in refractory status epilepticus approaches 50%, with only a minority returning to premorbid functional baseline. 6 Treatment lasting weeks or months can sometimes result in good outcomes, particularly in cases of encephalitis or autoimmune disorders. 7

The aggressiveness of treatment should be tailored to the clinical situation—focal RSE without impairment of consciousness might initially be approached more conservatively, while generalized convulsive forms require early induction of pharmacological coma. 7