Pharmacologic Agents For Refractory Status Epilepticus

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.

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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.

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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

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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

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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.

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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

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Clinical Trials for the Use of Drugs in RSE

Midazolam

• A meta-analysis of 111 children indicated that IV Midazolam was as effective as other coma-inducing medications and involved a lower mortality (zero with midazolam) (Gilbert DL et al, 2009)
• Several studies reported on the use of midazolam in refractory status epilepticus, using different dosing and treatment goals (Brevoord JC et al, 2005; Kumar A et al, 1992; Koul et al, 1997; Hayashi K et al, 2007)
• Another study compared IV Midazolam and IV Diazepam in 40 children and indicated a similar efficacy (86% and 89%, respectively), but midazolam was associated with a higher recurrence (57% versus 16%) and higher mortality (38% versus 10.5%) (Singhi S et al, 2002)
• Breakthrough seizures were reported in 47-57% of patients (Singhi S et al, 2002; Morrison G et al, 2006) and relapse was reported in 6-19% (Singhi S et al, 2002; Morrison G et al, 2006; Koul et al, 1997 )

• Adverse Effects: Some studies reported no adverse reactions while some coined transient desaturation (Koul et al, 1997), or respiratory depression (Hayashi K et al, 2007). Whereas some studies described hypotension requiring intravenous fluid administration (Morrison G et al, 2006) or, rarely, vasopressor support (Singhi S et al, 2002), other studies described cardiovascular stability even in children receiving high doses of midazolam (Holtkamp M et al, 2003).
• Conclusion:

Together, these studies suggest that an initial bolus of 0.1-0.5 mg/kg, followed by an infusion is increased as needed, controls RSE in most children. Higher boluses and more rapid escalation may be associated with more prompt seizure control. Side effects are minimal, but may rarely include hypotension. Breakthrough and recurrent seizures are common.

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Propofol

• Studies in adults indicated that Propofol infusion terminates seizures in 67% of patients (Rossetti AO et al, 2004).
• Propofol induces burst suppression within 35 minutes of initiation, but maintenance of burst suppression requires frequent titration (Parviainen I et al, 2006)
• Hypotension requiring vasopressor administration occurs in 50-70% of patients (Rossetti AO et al, 2004; Parviainen I et al, 2006).
• Adverse Effects: Complications, including rhabdomyolysis and hypertriglyceridemia, prompted discontinuation in 18% of patients, although these laboratory values normalized after Propofol was discontinued, and no deaths were attributable to Propofol (Van Gestel JP et al, 2005).
• Conclusion:

These studies suggest that Propofol may be effective in terminating RSE quickly, but Propofol was not demonstrated to be more effective than other medications.

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Pentobarbital

• A meta-analysis of 28 articles that included 193 adults with refractory status epilepticus compared Pentobarbital, Midazolam, and Propofol. Pentobarbital was associated with a significantly lower incidence of short-term treatment failure, breakthrough seizures, and the need to change to a different medication, but was also associated with a significantly higher frequency of hypotension (Claassen J et al, 2002)
• Studies of pentobarbital for RSE in children reported an efficacy of 74-100% (Gilbert Dl et al, 1999; Kim SJ et al, 2001; Holmes GL et al, 1999) and a high incidence of hypotension (Holmes GL et al, 1999)
• Conclusion:

These studies suggest that pentobarbital is effective in promptly controlling seizures and producing a burst suppression pattern. But continuous blood-pressure monitoring is important, because hypotension may occur with dose escalation.

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Ketamine

• Five children, aged 4-7 years and with known severe epilepsy with refractory nonconvulsive SE were treated with oral ketamine, and all demonstrated a response within 48 hours. Only one child had a recurrence of nonconvulsive SE several months later, which was again treated effectively with ketamine. No side effects were noted. (Mewasingh LD et al, 2003)
• Possible Adverse Effects: some studies identify cerebellar toxicity with prolonged ketamine administration (Ubogo Ee et al, 2003), increased intracranial pressure with ketamine administration for lumbar-puncture sedation (Ben Yehuda et al, 2006).
• Other studies suggest improved cerebral blood flow by increasing blood pressure because of its sympathomimetic properties, in contrast with most medications used for RSE, which reduce blood pressure (Himmelseher S et al, 2005)
• Conclusion:

Ketamine may be a useful adjuvant in the treatment of RSE, especially in late stages when medications that rely on Benzodiazepine drug interventions are ineffective. However, further study is needed to determine the optimal dosing, timing of administration, and effects on intracranial pressure and cerebral blood flow

Author	Design/Sample	Intervention	Outcome
Alkachroum, 2020	Retrospective StudyN=68	IV Ketamine in Super-Refractory SE	2.2 mg/kg/h for 2 days: Average dose of IV Ketamine ↓ seizure burden by ≥50% within 24 hours of starting IV Ketamine in 81% of patients Complete seizure cessation in 63% of patients Limitation: IV Midazolam 1 mg/kg/h was started 0.4 days before IV Ketamine contributing to confounding effects of IV Ketamine
Höfler, 2016	Retrospective StudyN=42	IV Ketamine in Super-Refractory SE	2.39 mg/kg/h for 4 days: Average dose of IV Ketamine Ketamine is the last drug administered to the 64% of patients (27/42) before SE cessation Limitation: Only 17% of patients received a loading dose
Sabharwal, 2015	Retrospective StudyN=67	IV Ketamine in Super-Refractory SE	IV Ketamine ranged from 1.5 – 10.5 mg/kg/h SE was controlled in 91% of patients (61/67) IV Ketamine was used in the early phase, within 24 to 48 hours Infusion duration: 3.6 days, 5.97 days, and 6.5 days for Propofol-Ketamine, Ketamine, and Propofol respectively
Gaspard, 2013	Retrospective StudyN=60	IV Ketamine in Super-Refractory SE	Average load with 1.5 mg/kg, followed by 2.75 mg/kg/h Likely responsible for SE control in 12% of cases (7/60), and possibly responsible for SE control in 20% of cases (12/20) Likely response to IV Ketamine if administered within 12 hours
Synowiec, 2013	Retrospective StudyN=11	IV Ketamine in Super-Refractory SE	Average load with 2 mg/kg, followed by 1.3 mg/kg/h 45% of cases all co-infusions were weaned within 24 hours 27% of cases of co-infusions were discontinued within 72 hours RSE was terminated  in all 11 patients No adverse effects Limitation: IV Ketamine administered at sub-anesthetic doses