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Lesson 11 of13
In Progress

Clinical Trials for the Use of Drugs in RSE

Jimmy September 4, 2021

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.


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.


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.


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

AuthorDesign/SampleInterventionOutcome
Alkachroum, 2020Retrospective StudyN=68IV Ketamine in Super-Refractory SE2.2 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, 2016Retrospective StudyN=42IV 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, 2015Retrospective StudyN=67IV 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, 2013Retrospective StudyN=60IV Ketamine in Super-Refractory SEAverage 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, 2013Retrospective StudyN=11IV 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