The HYBERNATUS-II trial is a continuation of the collaboration of the previously published HYBERNATUS trial1 supplemented by new collaborations from the ICTALGROUP research network (https://ictalgroup.org).
The HYBERNATUS trial (NCT01359332) was a multicenter, open-label, outcome assessor-blinded, parallel-group, randomized, controlled trial in patients with convulsive status epilepticus (SE) requiring admission to the intensive care unit (ICU) and mechanical ventilation. The main goal of the HYBERNATUS trial was to determine whether therapeutic hypothermia 33°C \[32-34°C\] for 24 hours has neuroprotective effects compared to standard care alone. The trial showed no significant benefit with respect to good functional outcome from the addition of therapeutic hypothermia to standard antiseizure therapy: a maximum Glasgow Outcome Scale (GOS) score of 5 occurred in 67 of 138 patients (49%) in the hypothermia group and in 56 of 130 patients (43%) in the control group (odds ratio, 1.22; 95% confidence interval (CI), 0.75 to 1.99; P=0.43).
The HYBERNATUS-II study is a phase-III, open-label, randomized controlled trial in which a targeted hypothermia \[targeted temperature management (TTM) at 33°C \[32-34°C\] in patients with convulsive refractory SE will be compared with targeted normothermia 37°C \[36.5-37.5°C\] (See more details of objectives in Sections 4.1 and 4.2). Patients eligible for inclusion will be unconscious adult patients aged from 18 to 65 years with convulsive refractory SE receiving mechanical ventilation (See more details for inclusion in Sections 5.1 and 5.2).
Consent will be obtained from a substitute decision maker as eligible subjects are unconscious and inherently not able to consent. Thus, the patient will have to confirm his participation to the study as soon as their condition allows for informed consent. Patients who are eligible but incapable of receiving information and for whom substitute decision maker is not present or contactable may be included through a process of differed consent. Substitute decision maker will be informed as soon as possible, and patient will be informed about participation as soon as their clinical status allows. In this case, substitute decision maker's and/or patient's written consent will be obtained as soon as possible. (See more details for ethical considerations in Sections 11.0). Once consent obtained, patients will be included and randomized in one of the two following allocation arms: targeted hypothermia at 33°C \[32-34°C\] or targeted normothermia 37°C \[36.5-37.5°C\]. Randomization will be centralized and stratified according to sites, previous history of epilepsy \[yes or not\], and results of brain imaging \[Abnormal Brain Imaging or not\]. The two groups will differ only in the administration of TTM at 33°C \[32-34°C\] or normothermia during the first 24 hours. For the targeted hypothermia group: the temperature will be rapidly decreased and maintained at 33°C \[32-34°C\] for 24 hours using servo-regulated temperature management devices. Thus, patients will be progressively rewarmed and maintained at normothermia for a total of 72 hours of temperature targeted management. For the normothermia group: patients will be maintained at normothermia 37°C \[36.5-37.5°C\] for 72 hours.
The choice of TTM at 33°C has been guided by the experimental data indicating dual neuroprotective and antiseizure effects of hypothermia, and the compromise of tolerance of moderate hypothermia in humans.2,3 The duration of 24 hours for targeted hypothermia can be argued by the experience of safety and preliminary data coming from the HYBERNATUS trial1, and the recommended timeframe of seizure suppression (cessation of electrographic seizures or suppression burst).4,5 In both treatment groups, anesthetic agent will be Propofol, a powerful antiseizure agent with a short half-life, at a maximal rate of 5 mg/kg/hour for the maximal duration of 48 hours, minimizing the time of sedation and the risk of Propofol related infusion syndrome. All other treatments will be standardized in the two groups. Anesthetic withdrawal will be progressively performed according to the half-life of Propofol to avoid the risk of Super Refractory Status Epilepticus.
Patients will be continuously monitored for core temperature (bladder or esophageal probes) and continuous electroencephalography (cEEG) during the first 72 hours of management in both groups. In both allocation arms, the therapeutic goal will be seizure suppression. Patients will be followed-up daily from randomization to day 3, then periodically at day-7, day-14, day-28, ICU/hospital discharge and day-90. In addition to the usual demographic data, the data collected will relate to comorbidities, the current clinical history, cause of convulsive refractory SE, treatments and anesthetics received, core temperature every hour during the first 72 hours, performed diagnostic procedures, the observed adverse events and the various parameters allowing the calculation of different severity and organ failure scores (Simplified Acute Physiology Score 2 (SAPS 2), Logistic Organ Dysfunction score (LODs)) at baseline and up to ICU discharge.
Patients receiving targeted hypothermia will be closely monitored for adverse effects such as infections, and Propofol related infusion syndrome will be carefully checked in both allocation arms.
Discharged patients will receive a centralized phone call interview by an independent assessor blinded of allocation arms at 90 days after randomization to assess GOS-E status (multiple primary outcome). Continuous EEG recordings will be posteriori reviewed by an adjudication committee, composed of three independent neurophysiologist blinded of allocation arms, for identification of patients with progression to electrographic SE (multiple-primary outcome). Follow-up will be censored at day-90.
