How to manage non-convulsive status epilepticus (NCSE) in a child with stage 5 chronic kidney disease (CKD) and impaired renal function, currently on midazolam (Benzodiazepine) drip, phenytoin (Antiepileptic) and levetiracetam (Antiepileptic), and recently administered high dose methylprednisolone (Corticosteroid)?

Management of Refractory Non-Convulsive Status Epilepticus in a Child with Stage 5 CKD

Your patient requires immediate escalation to third-line anesthetic therapy with continuous midazolam infusion while simultaneously addressing the likely cefepime-induced neurotoxicity through continued hemodialysis and corticosteroid therapy. 1

Immediate Next Steps for Seizure Control

Since your patient has failed benzodiazepines (midazolam drip), phenytoin, and levetiracetam, this represents refractory non-convulsive status epilepticus requiring anesthetic-level treatment. 2

Optimize Current Midazolam Infusion

• Increase midazolam infusion rate systematically: Start at 1 mcg/kg/min and titrate upward by 1 mcg/kg/min every 15 minutes until seizure suppression is achieved, up to a maximum of 5 mcg/kg/min (0.06-0.12 mg/kg/hr initial rate). 1, 2
• If not already done, administer a loading dose of 0.15-0.20 mg/kg IV over 2-3 minutes before increasing the infusion rate. 1, 3
• Midazolam demonstrates 80% efficacy in refractory status epilepticus with only 30% hypotension risk, making it preferable to pentobarbital (92% efficacy but 77% hypotension risk) in a hemodynamically fragile CKD patient. 2

Add Phenobarbital as Fourth-Line Agent

• Administer phenobarbital 10-20 mg/kg IV over 10 minutes (maximum 1,000 mg) if seizures persist despite optimized midazolam. 1
• Maintenance dosing: 1-3 mg/kg IV every 12 hours after loading. 1
• Be prepared for respiratory depression requiring mechanical ventilation, particularly given the combination with midazolam. 2

Alternative: Consider Valproate Addition

• Valproate 20-30 mg/kg IV over 5-20 minutes can be added if phenobarbital is contraindicated, with 88% efficacy and 0% hypotension risk. 2, 4
• However, valproate requires dose adjustment in severe renal impairment and may have been avoided initially for this reason. 2

Critical Monitoring Requirements

Continuous EEG Monitoring

• Mandatory continuous video-EEG to guide titration of anesthetic agents to achieve seizure suppression, as clinical examination is unreliable in non-convulsive status epilepticus. 1, 2, 5
• Titrate medications to achieve burst suppression pattern or complete seizure suppression on EEG. 2

Cardiorespiratory Monitoring

• Continuous blood pressure monitoring for hypotension (occurs in 30% with midazolam). 2
• Prepare for mechanical ventilation if not already intubated, as midazolam infusion at higher rates typically requires respiratory support. 2, 3
• Monitor for respiratory depression, especially with phenobarbital addition. 2

Renal Function and Drug Dosing

• Levetiracetam clearance is reduced by 60% in severe renal impairment (CrCl <30 mL/min) and 70% in anuric patients. 6
• Approximately 50% of levetiracetam is removed during a standard 4-hour hemodialysis session, requiring supplemental dosing post-dialysis. 6
• Adjust levetiracetam to 250-500 mg every 12 hours (instead of standard 500-1500 mg) with supplemental 250-500 mg after each dialysis session. 6
• Midazolam dosing does not require adjustment for renal failure, but monitor for prolonged effects. 3

Addressing Cefepime Neurotoxicity

Continue Aggressive Dialysis

• Cefepime-induced neurotoxicity is the likely precipitant given the temporal relationship (severe infection dose in stage 5 CKD patient). 1
• Continue hemodialysis sessions to remove cefepime, as it is dialyzable. 6
• Consider daily dialysis until neurological improvement occurs. 6

Corticosteroid Therapy Rationale

• High-dose methylprednisolone is appropriate for suspected drug-induced encephalopathy and may help reduce cerebral inflammation. 1
• Continue current corticosteroid regimen as already initiated. 1

Treatment Algorithm for Persistent Seizures

If seizures continue despite optimized midazolam and phenobarbital:

1. Transfer to PICU if not already there (likely already accomplished). 1

2. Consider propofol as alternative anesthetic:

   • 2 mg/kg bolus followed by 3-7 mg/kg/hour infusion. 2, 4
   • Requires mechanical ventilation but has shorter ventilation time than barbiturates (4 days vs 14 days). 2
   • 73% efficacy with 42% hypotension risk (less than pentobarbital's 77%). 2

3. Pentobarbital for super-refractory status epilepticus:

   • Reserve for failure of midazolam and propofol. 2
   • 13 mg/kg bolus followed by 2-3 mg/kg/hour infusion. 2, 4
   • Highest efficacy (92%) but significant hypotension risk (77%) and prolonged ventilation. 2

Maintenance Antiepileptic Strategy

Load Long-Acting Antiepileptics During Infusion

• Add valproate 20-30 mg/kg IV if not already on board, to ensure adequate levels of long-acting anticonvulsants before tapering midazolam. 2
• Continue levetiracetam at renally-adjusted doses with post-dialysis supplementation. 6
• Maintain phenobarbital 1-3 mg/kg IV every 12 hours. 1

Avoid Phenytoin Continuation

• Phenytoin has already been tried and failed. 1
• Phenytoin requires cardiac monitoring due to 12% hypotension risk and potential arrhythmias. 2, 7
• Consider transitioning to valproate or continuing levetiracetam as primary maintenance agent. 2

Common Pitfalls to Avoid

Do Not Underdose Midazolam

• Many clinicians use inadequate midazolam infusion rates in refractory status epilepticus. 2
• Titrate aggressively up to 5 mcg/kg/min (0.3 mg/kg/hr) if needed, guided by continuous EEG. 1, 2

Do Not Delay Mechanical Ventilation

• Respiratory depression is expected with anesthetic doses of midazolam, especially combined with phenobarbital. 2, 3
• Early intubation allows aggressive seizure control without respiratory compromise. 2

Do Not Forget Post-Dialysis Supplementation

• Levetiracetam requires supplemental dosing after each hemodialysis session (50% removed during 4-hour session). 6
• Failure to supplement will result in subtherapeutic levels and seizure recurrence. 6

Do Not Use Neuromuscular Blockers Alone

• Neuromuscular blockers only mask motor manifestations while allowing continued electrical seizure activity and ongoing brain injury. 2
• If paralysis is needed for ventilator management, continuous EEG is absolutely mandatory. 2

Prognosis and Duration of Therapy

• Refractory status epilepticus has 25% mortality, rising to 40% in super-refractory cases. 5
• However, cefepime-induced neurotoxicity is typically reversible with drug removal and supportive care. 1
• Continue anesthetic infusions for at least 24 hours after last electrographic seizure, then taper slowly (over 12-24 hours) while monitoring continuous EEG. 5
• Maintain continuous EEG for at least 24 hours after patient awakens to detect subclinical seizure recurrence. 1, 5