Effect of Xenon and Therapeutic Hypothermia, on the Brain and on Neurological Outcome Following Brain Ischemia in Cardiac Arrest Patients

Study Overview
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Brief Summary
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The main purpose of this study is to explore whether xenon is neuroprotective in humans. In addition, the purpose is to explore the underlying mechanisms for the possible synergistic neuroprotective interaction of xenon and hypothermia in patients suffering cerebral ischemia post cardiac arrest, by undertaking brain imaging to evaluate their effects on cerebral hypoxia, neuronal loss and mitochondrial dysfunction. In addition, the investigators aim to correlate these findings with neurological outcome to determine surrogate markers of favourable clinical outcome at six months.

Detailed Description
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If cardiac resuscitation is successful, the state-of-the-art management is to actively cool these patients into a state of moderate hypothermia (32-34º C) for 24 hours in an intensive care unit. Guidelines regarding the use of hypothermia following witnessed cardiac arrest have been formally adopted by the European Resuscitation Council as well as the American Heart Association. Therapeutic hypothermia provides a significant but moderate improvement in these patients. Thus, strategies designed to increase the efficacy of therapeutic hypothermia are needed. Preclinical animal studies have now demonstrated a remarkable neuroprotective interaction with hypothermia in a synergistic manner. The data suggest that xenon's neuroprotective effect can be triggered with subanesthetic concentrations in humans when combined with modest hypothermia. The aim of this study is to explore whether xenon is neuroprotective in humans. We also explore whether xenon in combination with standard hypothermia treatment has better neuroprotective effect than can be achieved with the hypothermia treatment alone in the patients who have experienced global ischemic brain injury after out-of-hospital cardiac arrest (OHCA). Hundred-and- ten patients who have experienced ventricular fibrillation or non-perfusive ventricular tachycardia as initial cardiac rhythm will be enrolled and they will be randomized into two treatment groups: 1) standard hypothermia treatment for 24 hours, 2) xenon inhalation combined with standard hypothermia treatment for 24 hours. Sophisticated brain imaging techniques will be performed before intervention (i.e. standard CT scan), within 24 hours after intervention (i.e. positron emission tomography), and on day 3 and on day 10 after cardiac arrest (i.e. various proton magnetic resonance imaging techniques) to identify ischemic burden, injured tissue and deranged energy metabolism in the brain. Our objective is to show a significant reduction in the degree of severity of the ischemic brain injury in the hypothermia+Xenon group as compared with the hypothermia group.

Official Title
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Phase 2 Study of Effect of Xenon, in Combination With Therapeutic Hypothermia, on the Brain and on Neurological Outcome Following Brain Ischemia in Cardiac Arrest Patients

Conditions
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Ischemic Brain Injury

Intervention / Treatment
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* Drug: xenon
* Other: Hypothermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ventricular fibrillation or non-perfusive ventricular tachycardia as initial cardiac rhythm The 1st attempt at resuscitation by emergency medical personnel must appear within 15 minutes after the collapse The cause for collapse should be considered primary as cardiogenic and the return of spontaneous circulation (ROSC) should have been gained in 45 minutes after the collapse Patient should be still unconscious in the emergency room Age: 18 - 80 years Obtained consent within 4 hours after arrival to the hospital Exclusion criteria Hypothermia (< 30°C core temperature) Unconsciousness before cardiac arrest (cerebral trauma, spontaneous cerebral hemorrhages, intoxications etc.) Response to verbal commands after the return of spontaneous circulation and before randomization Pregnancy Coagulopathy Terminal phase of a chronic disease Systolic arterial pressure < 80 mmHg or mean arterial pressure < 60 mmHg for over 30 min period after ROSC Evidence of hypoxemia (arterial oxygen saturation < 85%) for > 15 minutes after ROSC and before randomization. Factors making participation in follow-up unlikely Enrolment in another study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hypothermia and xenon<br> | Drug: xenon<br>* Gas, 24 hour inhalation, en tidal target concentration 40%<br>Other: Hypothermia<br>* 24 hour, target core temperature 33<br>|
| Active Comparator: Hypothermia<br> | Other: Hypothermia<br>* 24 hour, target core temperature 33<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary outcome is to show a significant reduction in the degree of severity of the ischemic brain injury in the hypothermia+Xenon group as compared with the hypothermia group, reflected by various MRI techniques | Power analysis was done with fractional anisotropy of diffusion tensor MRI | within 24 hours after treatment and 10 +/-2 days after cardiac arrest | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurological outcome |  | 6 months after cardiac arrest | 
| A transthoracic echocardiography will be performed for all feasible patients to investigate cardiac safety of the treatments |  | Before, during and after treatments | 
| Mortality |  | 6 months | 
| Complication rate | epileptic status, severe bleeding, pneumonia, sepsis, pancreatitis, acute kidney injury according to RIFLE, pulmonary oedema, arrhythmias | 7 days | 
| Morbidity | cardiac and cerebral morbidity | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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xenon, hypothermia, out-of-hospital cardiac arrest