ConSEPT
PubMed
Clinical Question
In pediatric patients presenting to the emergency department in convulsive status epilepticus who already received two doses of benzodiazepine, is levetiracetam superior to phenytoin for cessation of seizure activity.
Bottom Line
Powered to detect superiority of levetiracetam over phenytoin, it did not find a statistical difference between agents for second line cessation of seizure in paediatric patients.
Major Points
If a seizure lasts longer than 5 minutes, the chances of spontaneous resolution dramatically decreases without intervention. Abortive therapy ranges from benzodiazepines to barbiturates. Second-line therapy, either as an abortive or to prevent further seizure activity, may include any number of anti-convulsants, including but not limited to phenytoin, fosphenytoin, levetriacetam, or lacosamide. Guideline recommendations have been largely based on generally small and observational trials. Phenytoin, developed in the mid-last century has been the mainstay of second line therapy for decades and thus is a reasonable benchmark for comparison.
The Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT), a multicenter, open-label, randomized controlled trial was designed to find superiority of levetiracetam over phenytoin as a second line agent for cessation of status epilepticus. Enrolling 233 children presenting to 13 emergency departments in Australia and New Zealand between 2015-2017. Enrolling pediatric patients who had failed to abort clinical seizure activity after receiving 2 doses of first line benzodiazepine, they compared phenytoin 20 mg/kg (max 1g, n=114) over 20 minutes to levetriacetam 40 mg/kg (max 3g, n=119) over 5 minutes. Primary outcome of clinical cessation of seizure activity 5 minutes after infusion of study drug was reached in 60% vs. 50% (Risk difference -9.2, 95% CI -21.9 to 3.5, p=0.16). Overall there was no statistical difference between the agents for any outcome or adverse event.
These findings differ with the EcLiPSE trial, published in the same edition of the journal, that found intravenous levetriacetam to be non-inferior to phenytoin for emergency management of status epilepticus. There was some potential for bias with the longer infusion time for phenytoin allowing for natural cessation of seizure, EEG were not utilized for patient screening or assessment of outcome, dose cap for phenytoin may have left some patients underexposed, and 40% of the population was exposed to the other study drug. Comparing the two drugs, if there is no major outcome difference then the risk with administration (phenytoin IV diluent) and the numerous drug-drug interactions need to be included in the selection of therapy for a given patient.
Guidelines
Guidelines for Treating Convulsive Status Epilepticus by the American Epilepsy Society, 2016[1], adapted
Second line options, none preferred over another:
- IV fosphenytoin 20 mg PE/kg, MAX 1500mg PE/dose
- IV valproic acid 40 mg/kg, MAX 3000mg/dose
- IV levetriacetam 60mg/kg, MAX 4500mg/dose
Design
- Multicenter, open-label, randomized controlled trial
- N=233
- Phenytoin (n=114)
- Levetriacetam (n=119)
- Setting: 13 emergency departments, Australia and New Zealand
- Enrollment: 19 March 2015 to 29 November 2017
- Mean follow-up:
- Analysis: intention-to-treat
- Primary Outcome: cessation of seizure activity 5 minutes after completion of infusion
Population
Inclusion Criteria
- age 3 months to 16 years
- presented in convulsive status epilepticus
- unresponsive with continuing abnormality in movement > 5 minutes, or
- ≥ 2 recurrent convulsions without recovery of consciousness between
- ≥ 3 convulsions within the preceding hour and current convulsion
- received two doses benzodiazepines
Exclusion Criteria
- previously enrolled
- receiving regular levetiracetam or phenytoin
- received second-line anticonvulsants in past 24 hours (phenytoin, levetiracetam, phenobarbitone, or paraldehyde)
- known refractory to phenytoin
- known allergy/sensitivity to study drugs
- convulsion due to head injury
- eclampsia in late pregnancy
Baseline Characteristics
Phenytoin Group displayed
- Demographics: Mean age 4 years, 72% ≤ 5 years, 54% female
- History of presenting seizure: 72% febrile, 12% focal onset, 74 minutes median length
- First line treatment of seizure: 93% midazolam, 20% IV, 52% IM, 19% buccal, 9% intranasal
- Clinical management in Emerg before study enrolment: 66% Manual airway repositioning, 11% oral/nasal airway, 32% positive pressure ventilation, 3% tracheal intubation, 18% fluid bolus
Interventions
- Phenytoin 20 mg/kg IV or IO over 20 minutes, maximum 1g
- Levetiracetam 40mg/kg IV/IO over 5 minutes, maximum 3g
If convulsion continued after the assessment period, the alternative study drug was given.
Outcomes
Comparisons are Phenytoin vs. Levetiracetam.
Primary Outcomes
- Clinical cessation of seizure activity 5 min after infusion of study drug
- 60% vs. 50% (Risk difference -9.2, 95% CI -21.9 to 3.5, p=0.16)
Secondary Outcomes
- Clinical cessation of seizure activity at 2 h without further seizure management
- 54% vs. 51% (risk difference -3.1, 95% CI -15.9 to 9.7, p=0.63
- Received alternative study drug in first 2 h
- 37% vs. 40% (risk difference 3.5, 95% CI -9 to 16, p=0.58)
There was no statistical difference for any other secondary outcome including time to seizure cessation, intubation, ICU admission, cessation of seizure at 2 hours without further medical treatment, or length of stay.
Subgroup Analysis
Not statistically significant when analyzed by age (above/below 5 years), onset (focal/generalized), fever, or midazloam as initial management.
Adverse Events
- Airway events within 2 hours of study drug
- Manual airway repositioning 37% vs. 38% (risk difference 1.3, 95% CI -11.2 to 13.8, p=0.84)
- oral/nasal airway 4% vs. 8% (risk difference 4.1, 95% CI -1.7 to 10, p=0.17)
- Positive pressure ventilation 17% vs. 25% (risk difference 8.8, 95% CI -1.7 to 19.2) p=0.1
- Tracheal intubation 14% vs. 19% (risk difference 5.5, 95% -4.1 to 15%, p=0.26)
Criticisms
- Unblinded (but reviewers were blinded and videos were blinded)
- EEG was not utilized
- Inclusion errors for patients with pseudo-seizures or seizure mimics
- assessment of cessation so some mis-labelling could have occurred
- Bias towards phenytoin possible with longer time to meet outcome could allow for natural cessation
Funding
- Health Research Council of New Zealand
- A+ Trust
- Emergency Medicine Foundation
- Townsville Hospital Private Practice Fund
- Eric Ormond Baker Charitable Fund
- Princess Margaret Hospital Foundation