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Silencing the seizure: Phenytoin vs. Levetiracetam in paediatric status epilepticus

Author: Charlotte Kennedy / Editor: Govind Oliver / Codes: CC20, CC21, HAP29, PMP6 / Published: 06/06/2019

I remember the excitement in the room at the European Society of Emergency Medicine (EuSEM) conference in September 2018 as the room waited to hear the results of the EcLiPSE trial. EcLIiPSE ran for just under 3 years and was the first large randomised-control trial to compare the effectiveness of second-line anticonvulsants in paediatric status epilepticus. It was also the first multi-centre randomised trial to be delivered by the PERUKI collaborative (Paediatric Emergency Research in the United Kingdom and Ireland) and helped set a precedent for the use of research without prior consent (i.e. deferred consent) in emergency research. Here we present a summary of the trial including how the study was designed, the key results and how the findings may affect our practice (1).

Why was the study needed? What knowledge gap does this paper address?

Globally, there is variation in which medications are used in the second-line treatment of paediatric status epilepticus following unsuccessful treatment with benzodiazepines. Clinicians familiar with Advanced Paediatric Life Support in the United Kingdom (UK) will know the guideline recommends a phenytoin infusion after two doses of benzodiazepine if seizure activity is ongoing (2). More recently, levetiracetam has come into favour for seizure control due to its ease of administration and good safety profile. Whether one is superior to the other in children has not really been known up until now though. Studies comparing phenytoin and levetiracetam have either not been applicable to the paediatric population or have had important methodological limitations (1,4). This study aimed to address that knowledge gap.

What question were the researchers trying to answer?

The EcLiPSE trial (Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in Children) aimed to determine whether levetiracetam was more effective than phenytoin when given intravenously as a second-line agent for paediatric status epilepticus.

How did they answer their research question?

The study was a prospective, open-label randomised control trial in children aged 6 months to 18 years, presenting to the Emergency Department in convulsive status epilepticus. It was conducted in 30 Emergency Departments (ED) across the UK, including both secondary and tertiary centers and both paediatric specific centres and those treating both adults and children. It ran between July 2015 and April 2018.

Children were randomised at the point of first-line treatment failure to receive either intravenous phenytoin (20 mg/kg or max dose 2g, infusion rate 1 mg/kg/min) or intravenous levetiracetam (40 mg/kg or max dose 2.5g, infused over 5 minutes). The primary outcome was the time from randomisation to termination of the seizure, defined as the cessation of all visible signs of convulsive activity. Secondary outcomes included the need for further anti-convulsants, admission to a high-dependency area, rapid sequence induction (RSI) for ongoing seizure activity and the rate of serious adverse reactions.

What are the main findings from the research?

In total, 286 patients were included in the analysis with a roughly equal split between the treatment groups (134 allocated to receive phenytoin, 152 allocated to receive levetiracetam). Key baseline demographics were similar between groups.

Overall, levetiracetam was not superior to phenytoin.

The rate of seizure termination was similar between groups (70% and 64% respectively), as was the time to cessation of seizure activity. It’s worth noting that the team analysed time to seizure cessation both from the time of initial randomisation and from the start of the infusions and both times were comparable between groups.

Secondary outcomes also showed no significant differences between the drugs. Additional anticonvulsant use, rates of RSI rates for ongoing seizures and rates of high-dependency admission were all comparable between groups. Overall, the number of adverse events were roughly equal between groups, with 20 adverse events with levetiracetam versus 23 with phenytoin. There were 5 serious adverse events, only 2 of which were thought to be treatment related. These were life-threatening hypotension and increased focal seizures with decreased consciousness, both of which occurred in the same patient who received phenytoin.

Are there any limitations we should be aware of?

The main limitation of the study was that it had an open-label design. This means that both the participants and the treating clinicians were aware of which group the child had been allocated to. Realistically it would have been difficult to conduct the study in any other way given the difference in infusion rates of the two drugs, however, it is an important factor to consider as it may have introduced bias into the results. This is especially important given the primary outcome (time to seizure cessation) was determined by the treating physician and was potentially subjective, relying on their assessment of when seizure activity had stopped.

The only other aspect to be mindful of is how the study was powered. As this was a superiority study, the sample size for the trial was calculated based on the hypothesis that levetiracetam would be better than phenytoin at terminating status epilepticus. This means that whilst it is possible to comment on whether levetiracetam is superior to phenytoin, it is not possible to comment on equivalency of the two. It also means that, like most studies, it is difficult to draw conclusions about the secondary outcomes, meaning that caution must be applied when drawing inferences about the side-effect profiles of the two medications.

What is the take home message from this paper, will it change how we practice?

The take-home message from this paper is that levetiracetam is not superior to phenytoin. However, rates of seizure termination and time to cessation were similar and both appear to have a low side effect rate. Given that levetiracetam is quicker to administer and many consider it easier to prepare, this may lead the way to considering it as an alternative second-line agent in status epilepticus algorithms.

It is worth noting that a similar trial was conducted in Australia and New Zealand around the same time. The ConSEPT trial (Convulsive Status Epilepticus Paediatric Trial) also compared levetiracetam with phenytoin and although it differed slightly in how it was conducted, it also showed that levetiracetam was not superior to phenytoin (4).

Outcome measure Levetiracetam Phenytoin Statistical comparison 95% confidence interval Statistical significance
Time to CSE termination Median time
35 minutes
Median time
45 minutes
Hazard ratio
= 1.20
0.91 – 1.60 p = 0.20
Additional anticonvulsants administered 57 participants
(38%)
50 participants
(37%)
Relative risk
= 1.01
0.74 – 1.36 p = 0.97
RSI for ongoing seizure activity 44 participants
(29%)
47 participants
(35%)
Relative risk
= 0.83
0.59 – 1.16 p = 0.27
Admission to high -dependency 97 participants
(64%)
72 participants
(54%)
Relative risk
= 1.19
0.97 – 1.45 p = 0.08

References

  1. Lyttle MD, Rainford NEA, Gamble C, Messahel S, Humphreys A, Hickey H, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. The Lancet [Internet]. 2019 Apr [cited 2019 May 21]; Available from: https://linkinghub.elsevier.com/retrieve/pii/S014067361930724X
  2. Samuels M, Wieteska S, editors. Advanced paediatric life support: a practical approach. Sixth edition. Chichester, West Sussex, UK; Hoboken, NJ, USA: John Wiley & Sons, Ltd; 2016.
  3. McTague A, Martland T, Appleton R. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Epilepsy Group, editor. Cochrane Database of Systematic Reviews [Internet]. 2018 Jan 10 [cited 2019 May 22]; Available from: http://doi.wiley.com/10.1002/14651858.CD001905.pub3
  4. Dalziel SR, Borland ML, Furyk J, Bonisch M, Neutze J, Donath S, et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. The Lancet [Internet]. 2019 Apr [cited 2019 May 22]; Available here.

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