Evaluation of Therapeutic Hypothermia in Convulsive Status EPILEPTICUS in Adults in Intensive Care (HYBERNATUS)

Evaluation of the Interests of a Therapeutic Hypothermia Procedure in Convulsive Status EPILEPTICUS in Adults in Intensive Care - HYBERNATUS Study

Status EPILEPTICUS (SE) is a major medical emergency. The incidence per 100,000 population has been estimated at 9.9 episodes in Europe and 41 episodes in the US. The overall morbidity and mortality associated with convulsive SE (CSE) is 60% at three months. The alteration of functional prognosis of these patients is more conventionally attributed to the cause than to CSE itself. Longer seizure duration, progression to refractory status EPILEPTICUS and presence of cerebral insult are strong factors independently associated with a poor functional outcome. These three factors offer may be amenable to improvement and hope for preventive strategies. Current guidelines recommend the use of anticonvulsant treatment whose goal is prompt cessation of clinical and electrical seizures. None of these treatments has demonstrated NEUROPROTECTICE property. Therapeutic moderate hypothermia (between 32 and 34 ° C) showed interest in neuroprotection of post anoxic coma patients after a cardiovascular arrest on ventricular fibrillation by reducing morbidity and mortality in about 20% without major side effects. This technique has been used successfully in various pathologies such as stroke or traumatic brain injury. Pathophysiological mechanisms involved in epileptogenesis and neurotoxicity induced by persistence of seizures can be blocked by therapeutic hypothermia. Recent work on experimental models of SE demonstrated neuroprotective and anticonvulsant interest of therapeutic hypothermia. Therapeutic hypothermia has also been successfully used in some cases of particularly refractory CSE. Its early use in patients with SE would have a double interest: neuroprotective and anticonvulsant. There is currently no published studies or ongoing to determine the interest of its early use in patients with CSE.

Study Overview

• Status: Completed
• Conditions: Convulsive Status EPILEPTICUS
• Intervention / Treatment: Procedure: Moderate hypothermia

Detailed Description

Status EPILEPTICUS (SE) is a major medical emergency. The incidence per 100,000 population has been estimated at 9.9 episodes in Europe and 41 episodes in the US. The overall morbidity and mortality associated with convulsive SE (CSE) is 60% at three months. The alteration of functional prognosis of these patients is more conventionally attributed to the cause than to CSE itself. Longer seizure duration, progression to refractory status EPILEPTICUS and presence of cerebral insult are strong factors independently associated with a poor functional outcome. These three factors offer may be amenable to improvement and hope for preventive strategies. Current guidelines recommend the use of anticonvulsant treatment whose goal is prompt cessation of clinical and electrical seizures. None of these treatments has demonstrated NEUROPROTECTICE property. Therapeutic moderate hypothermia (between 32 and 34 ° C) showed interest in neuroprotection of post anoxic coma patients after a cardiovascular arrest on ventricular fibrillation by reducing morbidity and mortality in about 20% without major side effects. This technique has been used successfully in various pathologies such as stroke or traumatic brain injury. Pathophysiological mechanisms involved in epileptogenesis and neurotoxicity induced by persistence of seizures can be blocked by therapeutic hypothermia. Recent work on experimental models of SE demonstrated neuroprotective and anticonvulsant interest of therapeutic hypothermia. Therapeutic hypothermia has also been successfully used in some cases of particularly refractory CSE. Its early use in patients with SE would have a double interest: neuroprotective and anticonvulsant. There is currently no published studies or ongoing to determine the interest of its early use in patients with CSE.

Thus, the current study AIMAS at evaluating the effectiveness of the implementation of a procedure of moderate hypothermia therapy, between 32 ° and 34 ° C for 24 hours, to reduce morbidity and mortality at 3 months (+ / - 1 week) in mechanically ventilated ICU patients with convulsive status EPILEPTICUS.

• Study Type: Interventional
• Enrollment (Actual): 270
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Le Chesnay, France, 78150
    • Hôpital André MIGNOT- Service de réanimation médico-chirurgical

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• patient age ≥ 18 years
• patient hospitalized in intensive care unit
• patient already under mechanical ventilation
• patient who presented a convulsive status EPILEPTICUS episode (defined as continuous SEIZURING for longer than 5 min or three seizures not separated by recovery of normal consciousness or of the level of consciousness present before the seizures)
• whose motor manifestations had begun less than 8 hours before randomization
• after having informed written consent signed by a parent or a close if present.

Exclusion Criteria:

• patients with full recovery, postanoxic status EPILEPTICUS after cardia arrest
• convulsive status EPILEPTICUS for which an intervention (neurosurgical or other) is urgently needed not allowing the application of the procedure for therapeutic hypothermia
• dying patient, limitations in care, or whose life expectancy is estimated at baseline of less than 1 year
• patients whose follow-up to 3 months (+ / - 1 week) seems a PRIORI not possible
• pregnant women (pregnancy positive urine test or known before inclusion),
• participation in another biomedical therapeutic intervention whose primary endpoint was not reached at inclusion in HYBERNATUS study
• not affiliation to a social insurance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: control
EXPERIMENTAL: hypothermia	Procedure: Moderate hypothermia; procedure of moderate hypothermia therapy, between 32 ° and 34 ° C for 24 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional impairment at 3 months	Functional impairment is defined by a Glasgow Outcome Scale strictly less than 5. The time of evaluation should be 3 months (+/- 1 week)	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mortality		90 days
mortality		hospital discharge
mortality		ICU discharge
Incidence of functional sequelae	Judged on the frequency of seizures, the recurrence of epileptic status after hospitalization, the number of anti-epileptic drug, mini mental score (MMS).	3 months
length of icu stay		3 months
length of hospital stay		3 months
Percentages of convulsive and non-convulsive seizure recurrences	Progression to status epilepticus	6 to 12 hours
Seizure duration in minutes		3 days
Percentage of refractory status epilepticus cases	Judged on the frequency of seizures within 24 hours after status epilepticus onset (refractory status epilepticus on day 1) and on the frequency of seizures within 48 hours after anesthetic treatment withdrawal (super refractory status epilepticus)	3 days

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Stéphane LEGRIEL, MD,, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Fontaine C, Lemiale V, Resche-Rigon M, Schenck M, Chelly J, Geeraerts T, Hamdi A, Guitton C, Meziani F, Lefrant JY, Megarbane B, Mentec H, Chaffaut C, Cariou A, Legriel S; HYBERNATUS Study Group. Association of systemic secondary brain insults and outcome in patients with convulsive status epilepticus: A post hoc study of a randomized controlled trial. Neurology. 2020 Nov 3;95(18):e2529-e2541. doi: 10.1212/WNL.0000000000010726. Epub 2020 Sep 10.
• Legriel S, Lemiale V, Schenck M, Chelly J, Laurent V, Daviaud F, Srairi M, Hamdi A, Geri G, Rossignol T, Hilly-Ginoux J, Boisrame-Helms J, Louart B, Malissin I, Mongardon N, Planquette B, Thirion M, Merceron S, Canet E, Pico F, Tran-Dinh YR, Bedos JP, Azoulay E, Resche-Rigon M, Cariou A; HYBERNATUS Study Group. Hypothermia for Neuroprotection in Convulsive Status Epilepticus. N Engl J Med. 2016 Dec 22;375(25):2457-2467. doi: 10.1056/NEJMoa1608193.
• Legriel S, Pico F, Tran-Dinh YR, Lemiale V, Bedos JP, Resche-Rigon M, Cariou A. Neuroprotective effect of therapeutic hypothermia versus standard care alone after convulsive status epilepticus: protocol of the multicentre randomised controlled trial HYBERNATUS. Ann Intensive Care. 2016 Dec;6(1):54. doi: 10.1186/s13613-016-0159-z. Epub 2016 Jun 21.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (ACTUAL): August 1, 2016
• Study Completion (ACTUAL): August 1, 2016

Study Registration Dates

• First Submitted: May 23, 2011
• First Submitted That Met QC Criteria: May 23, 2011
• First Posted (ESTIMATE): May 24, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): September 29, 2016
• Last Update Submitted That Met QC Criteria: September 28, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: hypothermia therapy; Convulsive status EPILEPTICUS; (defined as continuous SEIZURING for longer than 5 min or three seizures; not separated by recovery of normal consciousness; or of the level of consciousness present before the; seizures)
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Body Temperature Changes; Seizures; Hypothermia; Status Epilepticus
• Other Study ID Numbers: P081249