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Lesson 10 of 13
In Progress

Pharmacologic Agents For Refractory Status Epilepticus

Jimmy September 4, 2021

When seizure fails to terminate after the first and second-line therapy of SE has been administered and the seizure has reached the 40-minute mark, the patient is now considered to be at Refractory Status Epilepticus (RSE) stage. The diagnosis of RSE includes the use of EEG to show continuous seizure activity. At this stage, patients are often intubated, paralyzed, and sedated. The mortality rate for RSE is three times higher compared to non-RSE.

To manage RSE, escalation to pharmacoresistance and progressive neurological injury must be avoided therefore anesthetic agents are used at this stage. The most commonly used anesthetic drugs for the management of RSE are Midazolam, Propofol, and Pentobarbital all administered as IV bolus.


Midazolam and Propofol tend to be the first-line anesthetic agents for the treatment and management of RSE because of their rapid onset. The half-life of Midazolam is initially short but this increases as the duration of treatment also increase.

However, prolonged administration of Midazolam is linked to tachyphylaxis, an acute decrease in drug response, therefore and adjustment to the initial dose is necessary to maintain seizure suppression.

Meanwhile, Propofol has excellent potency. The only exception would be for patients with severe hypotension. In such cases, Midazolam would provide more hemodynamic stability. Rapid discontinuation should be avoided as the pharmacologic effect of Propofol only lasts 5 – 10 minutes once discontinued and would eventually cause an immediate continuation of seizures. Also, Propofol infusion should also be made with caution as an infusion of more than 48 hours can cause Propofol Infusion Syndrome (PRIS) which is a potentially life-threatening phenomenon that can immediately lead to cardiovascular collapse and ultimately death.


Midazolam

  • Mechanism of Action: Increases the activity of GABA  through binding to benzodiazepine receptor sites
  • Route of Administration: Intravenous
  • Dose: 0.2 mg/kg IV over 2-5 minutes, repeat 0.2 to 0.4 mg/kg bolus every  5 minutes until seizure stops, maximum loading dose of 2 mg/kg
    • Maintenance Dose: 0.05 to 2.9 mg/kg/h
  • Pharmacokinetics: Rapid onset, short half-life requiring continuous infusion
  • Adverse Effects: CNS Depression, Hypotension, Extended half-life with prolonged use
  • Comments or Pearls: Prolonged administration is associated with decrease in drug response, therefore adjustment to dose should be made as treatment continues to maintain pharmacologic effect; Development of tachyphylaxis with prolonged infusions

Propofol

  • Mechanism of Action: Decreases dissociation of GABA from GABA receptors therefore potentiating inhibitory effects of the neurotransmitter
  • Route of Administration: Intravenous
  • Dose: 1 to 2 mg/kg IV over 3 – 5 minutes, repeat boluses every 3 – 5 minutes until seizure stops, maximum loading dose of 10 mg/kg
    • Maintenance Dose: 30 to 200 μg/kg/min
  • Pharmacokinetics: Onset of action  is within 3 to 5 minutes and activity persists only for 5 – 10 minutes after discontinuation
  • Adverse Effects: Hypotension, Occasional bradycardia, Hypertriglyceridemia, Propofol Infusion Syndrome (PRIS) which is a potentially lethal complication characterized by dysrhythmia, heart failure, hyperkalemia, hypertriglyceridemia, metabolic acidosis, and rhabdomyolysis with subsequent renal failure and death
  • Comments or Pearls: Best induction drug given its potent anti-epileptic activity; If abruptly stopped, patients may have rebound seizure

Pentobarbital

  • Mechanism of Action: Binds to GABA for acute potentiation of inhibitory GABA tone
  • Route of Administration: Intravenous
  • Dose: 5 – 15 mg/kg, may repeat 5 mg/kg doses until seizure lyses
    • Maintenance Dose: 0.5 – 5 mg/kg/h
  • Pharmacokinetics: Half-life is 15 to 60 hours
  • Adverse Effects: Myocardial Depression, Hypotension, Ileus, Persistent Coma due to long half-life,  Allergic reactions such as angioedema and Steven-Johnson syndrome
  • Comments or Pearls: Prolonged mechanical ventilation due to very long half-life; Must be used in caution in patients with hepatic or renal impairments; High-dose barbiturates are potentially immunosuppressive and may increase risk for nosocomial infections

The treatment of RSE should include consistent EEG monitoring as AEDs are administered. A 1-2 second burst of cerebral activity with 10-second suppression needs to be achieved and this pattern is continued for 24-48 hours before sedation is lightened. This is known as the burst suppression phenomenon and is the goal of the RSE therapy. And even at the reduction of sedation, maintenance using AEDs must be done at the therapeutic level to prevent relapse.

When burst suppression is not achieved despite high doses or if adverse effects occur, consider transitioning to another therapeutic option.


Ketamine

Intravenous ketamine is one of the alternative options for pharmacologic coma for RSE patients. And while it does not have anti-epileptic mechanisms not will produce burst suppressions, IV ketamine antagonizes the pro-convulsant receptor NMDA found at the post-synapse and this acts on persistent seizures.

  • Mechanism of Action: Antagonized pro-convulsant receptor NMDA found at the post-synapse
  • Route of Administration: Intravenous
  • Dose: 1 – 2 mg/kg, may repeat to maximum dose of 10 mg/kg
    • Maintenance Dose: 5 to 125 μg/kg/min
  • Pharmacokinetics: Onset: within 30 seconds, Short half-life: 2-3 hours
  • Adverse Effects: Dissociative psychosis, Hypertension, Airway complications
  • Comments or Pearls: Under-appeciated; Synergistic effect with benzodiazepine, therefore combines nicely with Propofol; Possibility of Dissociative Psychosis can be reduced by combining with Midazolam

High dose ketamine Infusion is an emerging preferred agent to control Status Epilepticus due to several advantages over barbiturate coma such as:

  • More hemodynamically stable
  • Shorter half-life
  • Can be rapidly up-titrated to determine efficacy