Targeted Hypothermia Versus Targeted Normothermia After Convulsive Refractory Status Epilepticus

The HYBERNATUS-II study is a phase-III, open-label, randomized controlled trial in patients with convulsive refractory SE receiving mechanical ventilation. Patients are allocated at random to either early targeted hypothermia for 24 hours or targeted normothermia at the acute phase of ICU management. This trial is a superiority multicentric trial and patients will be randomized in a 1:1 ratio using an electronic Cas Report Form. Before any examination or intervention related to the study may be carried out, the investigator must obtain the freely given, informed and written consent of the participant, or of his/her substitute decision maker (family member, close relative or legal representative) where applicable. However, eligible subjects are unconscious and inherently not able to consent. Two situations of inclusion are therefore envisaged: \- In case a substitute decision maker is present or contactable: a freely given, informed and written consent of the substitute decision maker will be performed. \- In case a substitute decision maker is not present or contactable in the inclusion time frame, the patient may be included through a process of differed consent. Substitute decision maker will be informed as soon as possible and a freely given, informed and written pursuit consent will be performed. In all cases, the patient will have to confirm his participation to the study through a freely given, informed and written pursuit consent as soon as their condition allows it. If the patient is under curatorship, the pursuit consent may be given based on his or her own decision. If the patient is under guardianship, the written guardian's consent will also be required. Individuals liable to participate in studies stipulated in line 1° of article L. 1121-1 of the Code de la Santé Publique (French Public Health Code) benefit from a preliminary medical examination adapted to the study. Patients will be included after informed consent as soon as possible once they satisfied all eligibility criteria. The inclusion window is until 3.5 hours (210 minutes) after convulsive SE onset. Consecutive eligible patients will be included and randomly allocated in a 1:1 ratio to one of the two procedure groups. Randomization and concealment will be ensured by using a secure, computer-generated, interactive, response system accessible via the Internet available at each study centre 24H/24. Randomization list will be prepared by an independent statistician who will not be in charge of the analysis. Randomization lists will be generated by a dedicated computer program, with randomly varying sized blocks, and stratified as follows: according to sites, previous history of epilepsy \[yes or not\], and results of brain imaging \[Abnormal Brain Imaging or not\]. Each investigator will be able to access the randomization site using a personal password. Randomization will be carried out after checking of the inclusion criteria and the absence of exclusion criteria and after obtaining a written and informed consent or according to the emergency procedure by the principal investigator or a physician representing the investigator before the person is enrolled in the study of each centre involved in the study. Each patient will be assigned a unique identification number. An inclusion confirmation will be sent by email to the investigator specifying the allocated procedure arm. Patients will be randomly allocated to one of the two study procedure groups. The two groups will differ only in the administration of early targeted hypothermia for 24 hours or targeted normothermia at the acute phase of ICU management. All other treatment will be standardized in the two groups. Targeted Hypothermia group : Implementation of allocation arm is started within 30 min after randomization.The objective is to lower the core body temperature to 33°C \[32-34°C\] rapidly after randomization then to maintain this temperature for 24 hours. The management in the targeted hypothermia group will include the following. Targeted normothermia group. Implementation of allocation arm is started within 30 min after randomization. The objective of the control group is to ensure normothermia 37° \[36.5-37.5°C\] for 72 hours after randomization. Antipyretic treatments will be given in case of a core temperature higher than 37.8°C. In case of failure, cooling with a surface non-invasive loop-feedback TTM device associating pads directly adhering to the patient's skin (Artic Sun TM provided by the study, similar in all participating centers) will be initiated with a target temperature of 37° \[36.5-37.5°C\]. No active warming will be provided for patients in the normothermia group who had a spontaneous body temperature below 36.5°C. Patients included in the study will be followed until the 90th day after inclusion. The duration of the participation will therefore be 3 months for each patient.

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.