JOURNAL CLUB

Omar Albaroudi, EM fellow

Tim Harris, EM senior consultant
EM leadership fellowship program
I have no conflict of interest or disclosure
in relation to this presentation
 * https://doi.org/10.1111/j.1528-1157.1999.tb02000.x
* https://doi.org/10.1111/epi.13121

status epilepticus
• persistent single seizure
or recurrent with incomplete recovery of consciousness in between

• 30 min >>> 20 min >>> 10 min >>> 5 min (Lowenstein 1999*)

• t1 5 min & t2 30 min (ILAE 2015*)
 * https://doi.org/10.1378/chest.126.2.582
* https://doi.org/10.1046/j.1365-2044.2001.02115.x
time is brain
• directly cause neuronal death through excitotoxicity (Marik 2004)
• indirectly cause brain injury through cerebral hypoperfusion,
hypoglycemia, and hypoxia (Chapman 2001)

• poor neurologic outcomes and death

• more likely to become refractory
SE types
• convulsive
• generalized
• tonic-clonic
• myoclonic
• clonic
• tonic
• atonic
• focal = partial (epilepsia partialis continua)
• non-convulsive
• generalized (absence status epilepticus)
• focal = partial (complex-partial status epilepticus)
the treatment
Check glucose (RBS) Childbearing female?
Check sodium (VBG) Alcoholic?
Tox?
Start benzodiazepine TCA
isoniazid
O2 (NC/NRB)
Vascular access (IV/IO)

More benzodiazepine
2nd-line AED & prepare for RSI
lines of treatment

levetiracetam propofol
benzos valproate midazolam
fosphenytoin ketamine
reduced the time to administer 2nd-line AED
from 58 minutes to 22 minutes
benzodiazepins
• IV?
• lorazepam 0.1 mg/kg [4-8 mg] q3-5min
• diazepam 0.2 mg/kg [10 mg] q3-5min [max 30 mg]
• midazolam 0.1 mg/kg [5-10 mg] q3-5min

• no IV?
• midazolam 0.2 mg/kg [10 mg] IM/IN/buccal
• diazepam 0.2 mg/kg [10-20 mg] PR
LORAZEPAM
• ↑ GABA receptors affinity >> ↑ potency

• ↓ lipophilicity <<
• ↓ adipose tissue redistribution >> ↑ DOA
• ↓ BBB >> ↑ OOA

• ↓ hepatic clearance
• ↓ risk of drug interactions
• ↓ risk in hepatic impairment

• water-insoluble
2ND-LINE
• Phenytoin: water insoluble, contain propylene glycol
• hypotension & arrhythmia, infusion rate <50 mg/min
• IV precipitation >> local irritation
• reported to intensify seizures caused by lidocaine, cocaine, theophylline..
• Fosphenytoin: water soluble, higher infusion rate

• Valproate:
• hepatoxicity, hyper-ammonia, thrombocytopenia, pancreatitis
• interaction with phenytoin
• Levetiracetam: minimal drug interactions, no hepatic metabolism
EcLiPSE & ConSEPT trials
• multicentre, open-label, RCTs
• paediatric population
• levetiracetam (40mg/kg) vs. phenytoin (20mg/kg)
• superiority study (levetiracetam better than phenytoin?)

• no difference in outcomes

• data for these trials were collected at a similar time to ESETT trial
• 13 EDs in Australia and New Zealand
• P: 234 pt, convulsive SE who already received 2 doses of
benzodiazepine
• O: cessation of seizure activity 5 min after the infusion of the trial
drug
• Results: phenytoin 60% vs levetiracetam 50% (p=0.16)
• 30 Eds in UK
• P: 286 pt, convulsive status epilepticus (generalised tonic-clonic,
generalised clonic, or focal clonic seizure)
• O: time from randomisation to cessation of all visible signs of
convulsive activity
• Results: pheytoin 45 min vs levetiracetam 35 min (p=0.2)
study desgin & setting
• multicentre, double-blind, comparative effectiveness,
response-adaptive, RCT

• run by NETT network & PECARN

• 58 EDs across USA [14 adults/children, 25 adults, 19 children]
• Between Nov 3, 2015 & Dec 29, 2018
NETT hubs PECARN sites
PICO
POPULATION
• ≥2 years old
• generalised convulsive seizure >5 min duration
• treated with adequate doses of benzodiazepines
• ≥32 kg: diazepam 10 mg IV, lorazepam 4 mg IV, or midazo­lam 10 mg IV/IM
• <32 kg: diazepam 0.3 mg/kg IV, lorazepam 0.1 mg/kg IV, midazolam 0.3 mg/kg IM or 0·2 mg/kg IV
• continued to have persistent or recurrent convulsions in ED >5 min &
<30 min after the last dose of benzodiazepine
INTERVENSION/COMPARISON
• fosphenytoin 20 PE/kg [max 1500 PE]
• valproate 40 mg/kg [max 3000 mg]
• levetiracetam 60 mg/kg [max 4500 mg]

• infusion duration: 10 min

• infusion rate: based on weight (determined from an enclosed dose
administration chart)
OUTCOME
• absence of clinically apparent seizures with improving responsiveness @60
min after the start of study drug infusion, without additional antiseizure
medication

• follow up until hospital discharge or 30 days

• safety outcomes:
• life-threatening hypotension or cardiac arrhythmia
• need for endotracheal intubation within 60 min
• acute seizure recurrence 60 min to 12 h
• acute respiratory depression at any time during the study period
• mortality
EFIC
• Exception From Informed Consent for emergency research under US
FDA regu­lation
• patients or their legally authorised representatives were notified
about enrolment in the trial ASAP & were asked for their consent for
continued data collection
Exclusion Criteria
• pregnant, prisoner, postanoxic
• trauma, hypoglycaemia or hyperglycaemia
• had already been treated for this episode of status epilepticus with
non­benzodiazepine AED

• pre­emptively opted out

• known allergies or contraindications to any of the study drugs
Randomization
• response-­adaptive
• stratified by age group: <18 years, 18–65 years, >65 years

• allocation was equal (1:1:1) for the first 300 patients, then the target
allocation ratio was updated every 100 patients

• allocation was concealed with the use of age-stratified “use-next”

medication box
• All investigators, patients, clinical and study teams, and pharmacists
were masked to study drug allocation
Analysis
• sample size of 795 provided 90% power to identify the most effective
treatment when one treatment group has a true response rate of 65%
and the true response rate is 50% in the other two groups
• sample size of 336 children would have 80% power to detect a 20%
difference in response rates between drugs

• interim analyses were planned after 400, 500, 600, and 700 patients
were enrolled
• early stopping allowed if the best treatment could be identified with
high probability or for futility
results
author conclusion
Children, adults, and older adults with established status epilepticus
respond similarly to levetiracetam, fosphenytoin, and valproate, with
treatment success in approximately half of patients.
Any of the three drugs can be considered as a potential first-choice,
second-line drug for benzodiazepine-refractory status epilepticus
strengths
• multicenter
• response-adaptive randomization
• allocation concealment
• double-blinded
limitations
• improvement in responsiveness is a subjective outcome
• study was stopped early due to an interim analysis showing no
difference between medications
• 25% of patients had eligibility criteria violations, but were kept in ITT
analysis
• 50% unblinding to permit choosing a second antiseizure medication
for ongoing seizures
discussion