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

Ischemic Brain Injury Clinical Trial

— Xe-hypotheca  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00879892
• Other study ID #: Eudra CT2009-009505-25
• Status: Completed
• Phase: Phase 2
• First received: April 10, 2009
• Last updated: January 16, 2015
• Start date: May 2009
• Est. completion date: September 2014

Study information

• Verified date: January 2015
• Source: Turku University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Finland: Finnish Medicines Agency
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 110
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Ventricular fibrillation or non-perfusive ventricular tachycardia as initial cardiac rhythm

2. The 1st attempt at resuscitation by emergency medical personnel must appear within 15 minutes after the collapse

3. 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

4. Patient should be still unconscious in the emergency room

5. Age: 18 - 80 years

6. Obtained consent within 4 hours after arrival to the hospital

Exclusion criteria

1. Hypothermia (< 30°C core temperature)

2. Unconsciousness before cardiac arrest (cerebral trauma, spontaneous cerebral hemorrhages, intoxications etc.)

3. Response to verbal commands after the return of spontaneous circulation and before randomization

4. Pregnancy

5. Coagulopathy

6. Terminal phase of a chronic disease

7. Systolic arterial pressure < 80 mmHg or mean arterial pressure < 60 mmHg for over 30 min period after ROSC

8. Evidence of hypoxemia (arterial oxygen saturation < 85%) for > 15 minutes after ROSC and before randomization.

9. Factors making participation in follow-up unlikely

10. Enrolment in another study

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Ischemia
• Heart Arrest
• Hypothermia
• Ischemic Brain Injury

Intervention

Drug:
• xenon
Gas, 24 hour inhalation, en tidal target concentration 40%

Other:
• Hypothermia
24 hour, target core temperature 33

Locations

Country	Name	City	State
Finland	Department of Cardiology, Meilahti, Helsinki University Hospital	Helsinki
Finland	Department of Neurology, Meilahti, Helsinki University Hospital	Helsinki
Finland	Department of Radiology, HUSRontgen, Meilahti, Helsinki University Hospital	Helsinki
Finland	Intensive Care Unit, Meilahti, Helsinki University Hospital	Helsinki
Finland	Adult Intensive Care Unit, Turku University Hospital	Turku
Finland	Department of Internal Medicine, Division of Cardiology, Turku University Hospital	Turku
Finland	Department of Neurology; Turku University Hospital	Turku
Finland	Department of Radiology, Turku University Hospital	Turku
Finland	PET Centre	Turku
United States	Department of Anesthesia and Perioperative Care	San Fransisco	California

Sponsors (3)

Lead Sponsor	Collaborator
Turku University Hospital	Academy of Finland (Risto O Roine), University of Turku

Countries where clinical trial is conducted

United States,  Finland, 

References & Publications (1)

Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002 Feb 21;346(8):549-56. Erratum in: N Engl J Med 2002 May 30;346(22):1756. — View Citation

Outcome

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