Urgent Therapy

Use of Anti-epileptic Drugs (AED) in SE

For patients with continuous seizure activity despite the use of emergency Benzodiazepine therapy, Anti-epileptic Drugs (AED) must be added. These drugs include Phenytoin, Levetiracetam, Valproic Acid, Lacosamide, and Phenobarbital all given intravenously. These drugs do not have a significant benefits over the others. 

These anti-epileptic drugs are used following the initial dose of Benzodiazepine to further manage continuous seizures. This is considered the second therapy phase and is done when the seizure persists at the 20-minute mark. 

---

1. Phenytoin or Fosphenytoin

• Mechanism of Action: Blockade of voltage-dependent membrane sodium channels that increases action potential therefore obstructing positive feedback that sustains repetitive seizures
• Route of Administration: Intravenous
• Dose:
  • Phenytoin: 20 mg/kg IV, maximum infusion rate: 50 mg/min
  • Fosphenytoin: 20 mg/kg PE IV, maximum infusion rate: 150 mg/min, may add 5-10 mg/kg for persistent seizures
  • Maintenance Dose: 5-7 PE/kg/day in 2-3 divided doses
  • PE = Phenytoin Equivalent
• Pharmacokinetics: Absorbed entirely at 1.5 to 3 hours, but absorption may last logner than 2 weeks due to reduction of effects of GI motility and poor water solubility
• Adverse Effects: Hypotension, bradycardia, Steven-Johnsons syndrome, Pancytopenia, Delirium
• Comments or Pearls: Avoid combination with Valproate, Numerous contraindications (pregnancy, hepatic and renal dysfunction) and adverse effects thus is not the first agent for second-line therapy of SE

2. Levetiracetam (Keppra)

• Mechanism of Action: Involves neuronal binding to synaptic vesicle protein, inhibiting calcium release therefore opposing the activity of negative modulators of GABA
• Route of Administration: Intravenous
• Dose:  20-60 mg/kg IV, maximum infusion rate of 4.5g over 10 minutes
  • Maintenance Dose: 1 – 1.5g q12hr
• Pharmacokinetics: Infuses rapidly, with same equivalent efficacy as that of Fosphenytoin and Valproate for SE 
• Adverse Effects: Syndrome of Inappropriate AdH (SIADH), Mood Disturbance
• Comments or Pearls: Generally the preferred AED as second-line therapy for SE because of zero contraindications, Avoid combination with Fosphenytoin, Renally cleared therefore maintenance dose need not be adjusted based on renal function

3. Valproic Acid

• Mechanism of Action: acts on GABA levels in the CNS and blocks voltage-gated ion channels to prevent further seizure propagation
• Route of Administration: Intravenous
• Dose: 40 mg/kg IV, maximum infusion rate up to 3000mg over 5-10 minutes, may add 20 mg/kg over 5 minutes
  • Maintenance Dose: 30-60 mg/kg daily, divided TID
• Pharmacokinetics: 13 – 19 hours halflife
• Adverse Effects: Hyperammonemia, Encepalopathy, Steven-Johnson syndrome, SIADH, Pancreatitis, Hepatotoxicity, Thrombocytopenia
• Comments or Pearls: Used for mood stabilization therefore is a good choice for patients with agitated delirium or known psychiatric disorders; Interferes with pharmacokinetics of Phenytoin and Phenytoin equivalents and Phenobarbital; Contraindicated to pregnant patients

4. Lacosamide (Vimpat)

• Mechanism of Action: Inhibits voltage-gated sodium channels
• Route of Administration: Intravenous
• Dose: 400mg IV over 5 minutes
  • Maintenance Dose: 200 mg IV q12hr
• Pharmacokinetics: Minimally bound to plasma protein with no known relevant drug to drug interactions, half-life of 14 hours
• Adverse Effects: Atrioventricular block, Hypotension
• Comments or Pearls: New agent with safe and minimal drug interactions

5. Phenobarbital

• Mechanism of Action: acts on GABA receptors to increase synaptic inhibition
• Route of Administration: Intravenous
• Dose: 15-20 mg/kg IV, maximum infusion rate of 50-70 mg/min
• Pharmacokinetics: Long half-life increases risk of prolonged sedation
• Adverse Effects: Somnolence, Respiratory Suppression
• Comments or Pearls: Preferred anti-epileptic for alcohol withdrawal seizures, useful to assist in weaning patients off a barbiturate coma

---

Clinical Trials for the Use of Anti-Epileptic Drugs in SE

Author	Design/Sample	Intervention and Comparison	Outcome
Chakravathi et al, 2015	Prospective, Randomized, Open-LabelN=44	IV Leviteracetam 20 mg/kg infused at 100 mg/mgVsIV Phenytoin 20 mg/kg infused over 30 minutes; max rate 50 mg/min	No difference in seizure termination or seizure recurrence More adverse effects in Phenytoin
Guijjar et al, 2017	Prospective, Randomized, Open-LabelN= 52	IV Leviteracetam 20 mg/kg infused over 30 minutesVsIV Phenytoin 20 mg/kg infused over 30 minutes	No difference in seizure termination or outcome at discharge Less severe adverse effects in IV Leviteracetam group
Nakamura et al, 2017	ObservativeN=63	IV Leviteracetam 1000mg infused over 30 minutesVsFosphenytoin 22.5 mg/kg	No difference in seizure cessation, adverse effects
Dalziel et al, 2019	Prospective, Randomized, Open-LabelN= 52	IV or IO Leviteracetam 40 mg/kg over 5 minutesVsIV or IO Phenytoin 20 mg/kg over 20 minutes	No difference in seizure termination or seizure recurrence
Lyttle et al, 2019	Prospective, Randomized, Open-LabelN= 286	IV Leviteracetam 40 mg/kg over 5 minutesVsIV Phenytoin 20 mg/kg over 20 minutes	No difference in time to seizure cessation
Shaner et al, 1998	Prospective, Randomized, Non-blindedN=36	IV Diazepam 2 mg/min up to 20 mg + IV Phenytoin, up to 18 mg/kgVsPhenobarbital 10 mg/kg	Phenobarbital is as effective as IV Diazepam + IV Phenytoin
Misra et al, 2006	Prospective, Randomized Pilot Study, used as first-lie and second-line AEDN=68	IV Pheytoin 18 mg/kgVsIV Valproic Acid30 mg/kg	IV Valproic  Acid is more effective than IV Phenytoin
Agarwal et al, 2007	Prospective, Randomized, Non-blinded, Refractory to IV DiazepamN=100	IV Pheytoin 20 mg/kgVsIV Valproic Acid20 mg/kg	IV Valproic Acid is equivalent to IV Phenytoin
Gilad et al, 2008	Prospective, Randomized, Without prior Benzodiazepine AdministrationN=74	IV Pheytoin 18 mg/kgVsIV Valproic Acid30 mg/kg	IV Valproic Acid is equivalent to IV Phenytoin
Alvarez et al, 2011	Retrospective, Non-randomized, Refractory to BenzodiazepinesN=187	IV Pheytoin 20 mg/kgVsIV Leviteracetam20 mg/kg	IV Leviteracetam is less effective than IV Valproic Acid No significant difference between IV Valproic Acid and IV Phenytoin
Misra et al, 2012	Prospective, Randomized, Open-Label Pilot StudyN=79	IV Leviteracetam20 mg/kgVsIV Lorazepammg/kg	IV Leviteracetam is equivalent to IV Lorazepam
Mundlamuri, 2015	RCTN=150	IV Valproic Acid30 mg/kgVsIV Leviteracetam25 mg/kgVsIV Phenytoin20 mg/kg	No statistically significant difference for control of SE
Kapur et al, 2019	Randomized, Double-blind, Adaptive Comparative Effectiveness TrialN=400	IV Leviteracetam 60 mg/kg, max dose 4500mgVsIV Fosphenytoin 20 mgPE/kg, max dose 1500 mgPEVsIV Valproate 40 mg/kg, max dose 3000mg	No significant difference in seizure cessation among the AED group Hypotension and Endotracheal intubation were more frequent with IV Leviteracetam

Conclusions

1. IV Phenytoin and IV Leviteracetam show no significant difference in terms of seizure cessation but IV Phenytoin showed more adverse effects
2. Some studies show IV Valproic Acid to be better than IV Phenytoin but some conclude both drugs to have no significant difference as an AED drug for SE
3. IV Leviteracetam shows more adverse effects but is equally effective with IV Valproic Acid and IV Fosphenytoin
4. Despite the less frequent usage due to its long half-life, Phenobarbital is as effective as IV Diazepam + IV Phenytoin