The goal of this comparative effectiveness trial is to study electrographic status epilepticus (ESE) treatment in comatose patients after cardiac arrest. The main questions the trial aims to answer are:

• Does ESE treatment improve outcome?
• What is the impact of ESE treatment on healthcare costs?

Participants in the the intervention group will receive standard care completed with anti-seizure treatment. The control group will receive standard care without anti-seizure treatment.

Rationale: Around 7500 comatose patients after cardiac arrest and resuscitation are admitted to intensive care units (ICUs) in the Netherlands and Belgium, yearly. Approximately half eventually dies from severe brain injury. EEG is used as a predictor of outcome, helping decide whether life sustaining therapies should be pursued or withdrawn. EEG shows epileptiform patterns meeting criteria for electrographic status epilepticus (ESE) in up to 10% of patients, with 80-100% case fatality. With the TELSTAR-1 trial, we showed that anti-seizure treatment of unselected patients with epileptiform patterns is not associated with a better outcome. However, it remains unclear whether treatment of (possible) ESE will improve outcome, or if ESE simply represents irreversible severe brain damage, in which case such treatment will be futile. This translates into ongoing practice variation. To provide comatose cardiac arrest survivors with the best medical treatment options, while at the same time preventing unnecessary costly ICU treatment, unequivocal evidence of efficacy or futility of ESE treatment is needed.

Objectives: It is the primary objective to study whether ESE treatment improves outcome of comatose patients after cardiac arrest. It is the secondary objective to study the impact on healthcare costs of ESE treatment.

Main trial endpoints: The primary outcome measure will be functional recovery expressed as the score on the extended Glasgow Outcome Scale (eGOS) at six months after cardiac arrest. The primary effect parameter will be the common odds ratio for any shift towards a better outcome in the intervention group, analyzed by multivariable ordinal logistic regression.

Secondary trial endpoints: Secondary outcome measures include data on quality of life, cognitive functioning, and the use of resources. Cost-effectiveness will be assessed, separately for Belgium and for the Netherlands, adhering to 'KCE' and 'Zorginstituut' guidelines for pharmaco-economic evaluations, respectively.

Trial design: This will be a comparative effectiveness study, comparing two standard treatment regimens. We will conduct a prospective multicentre trial with randomized treatment allocation, open label treatment, and blinded endpoint assessment on twenty intensive care units in the Netherlands and Belgium.

Trial population: The study population consists of adult comatose patients after out of hospital cardiac arrest and successful cardiopulmonary resuscitation, admitted on the intensive care unit of any of the participating centres, with ESE on continuous EEG. Continuous EEG is part of standard care in all participating hospitals. For the definition of ESE, we adhere to international consensus criteria.

Interventions: Treatment in the intervention group will consist of standard care completed with anti-seizure treatment according to protocols for clinically overt status epilepticus with the goal of definitive seizure suppression. This consists of a stepwise approach, step 1 being a single dose of a parenteral benzodiazepine (lorazepam, midazolam, or diazepam) and a first parenteral anti-seizure medication (levetiracetam, valproate, or lacosamide), step 2, a second parenteral anti-seizure medication plus a first continuous parenteral sedative agent (midazolam or propofol), and step 3, a second continuous parenteral sedative agent (midazolam, propofol, or ketamine). Each next step will be taken as soon as possible (within 30 minutes) if the previous step was insufficiently effective to suppress ESE. The control group will receive standard care without anti-seizure treatment.

Inclusion Criteria:

1. Coma (Glasgow Coma Scale score ≤ 8) after out of hospital cardiac arrest and resuscitation
2. Age ≥ 18 years
3. Continuous EEG with at least eight electrodes started < 24h after return of spontaneous circulation (ROSC)
4. ESE or possible ESE according to the Salzburg and ACNS criteria
5. Possibility to start treatment within three hours after detection of ESE

Exclusion Criteria:

1. Known history of another medical condition with limited life expectancy (< six months)
2. Any progressive brain illness, such as a brain tumor or neurodegenerative disease
3. Pre-admission Glasgow Outcome Scale score of 3 or lower
4. Reason other than the neurological condition to withdraw treatment
5. EEG background activity prior to the emergence of ESE indicative of extensive irreversible anoxic brain injury
6. Follow-up impossible due to logistic reasons, for example not living in the Netherlands or Belgium