Effect of Xenon and Therapeutic Hypothermia, on the Brain and on Neurological Outcome Following Brain Ischemia in Cardiac Arrest Patients (Xe-hypotheca)

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

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.

Study Overview

• Status: Completed
• Conditions: Ischemic Brain Injury
• Intervention / Treatment: Drug: xenon; Other: Hypothermia

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 340
    • Department of Neurology, Meilahti, Helsinki University Hospital
  • Helsinki, Finland, 340
    • Department of Radiology, HUSRontgen, Meilahti, Helsinki University Hospital
  • Helsinki, Finland, 340
    • Intensive Care Unit, Meilahti, Helsinki University Hospital
  • Helsinki, Finland, 800
    • Department of Cardiology, Meilahti, Helsinki University Hospital
  • Turku, Finland, 20521
    • Adult Intensive Care Unit, Turku University Hospital
  • Turku, Finland, 20521
    • Department of Internal Medicine, Division of Cardiology, Turku University Hospital
  • Turku, Finland, 20521
    • Department of Neurology; Turku University Hospital
  • Turku, Finland, 20521
    • Department of Radiology, Turku University Hospital
  • Turku, Finland, 20521
    • PET centre
• United States
  • California
    • San Fransisco, California, United States
      • Department of Anesthesia and Perioperative Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 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
ACTIVE_COMPARATOR: Hypothermia and xenon	Drug: xenon; Gas, 24 hour inhalation, en tidal target concentration 40%; Other: Hypothermia; 24 hour, target core temperature 33
ACTIVE_COMPARATOR: Hypothermia	Other: Hypothermia; 24 hour, target core temperature 33

What is the study measuring?

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
Mortality		6 months
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
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

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Collaborators: University of Turku; Academy of Finland
• Investigators: Principal Investigator: Timo T Laitio, MD, PhD, Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine

Publications and helpful links

General Publications

• 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. doi: 10.1056/NEJMoa012689. Erratum In: N Engl J Med 2002 May 30;346(22):1756.
• Koskensalo K, Virtanen S, Saunavaara J, Parkkola R, Laitio R, Arola O, Hynninen M, Silvasti P, Nukarinen E, Martola J, Silvennoinen HM, Tiainen M, Roine RO, Scheinin H, Saraste A, Maze M, Vahlberg T, Laitio TT; XeHYPOTHECA Research Group. Comparison of the prognostic value of early-phase proton magnetic resonance spectroscopy and diffusion tensor imaging with serum neuron-specific enolase at 72 h in comatose survivors of out-of-hospital cardiac arrest-a substudy of the XeHypotheca trial. Neuroradiology. 2023 Feb;65(2):349-360. doi: 10.1007/s00234-022-03063-z. Epub 2022 Oct 17.
• Laitio R, Hynninen M, Arola O, Virtanen S, Parkkola R, Saunavaara J, Roine RO, Gronlund J, Ylikoski E, Wennervirta J, Backlund M, Silvasti P, Nukarinen E, Tiainen M, Saraste A, Pietila M, Airaksinen J, Valanne L, Martola J, Silvennoinen H, Scheinin H, Harjola VP, Niiranen J, Korpi K, Varpula M, Inkinen O, Olkkola KT, Maze M, Vahlberg T, Laitio T. Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2016 Mar 15;315(11):1120-8. doi: 10.1001/jama.2016.1933.
• Arola OJ, Laitio RM, Roine RO, Gronlund J, Saraste A, Pietila M, Airaksinen J, Perttila J, Scheinin H, Olkkola KT, Maze M, Laitio TT. Feasibility and cardiac safety of inhaled xenon in combination with therapeutic hypothermia following out-of-hospital cardiac arrest. Crit Care Med. 2013 Sep;41(9):2116-24. doi: 10.1097/CCM.0b013e31828a4337.

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (ACTUAL): September 1, 2014
• Study Completion (ACTUAL): September 1, 2014

Study Registration Dates

• First Submitted: April 10, 2009
• First Submitted That Met QC Criteria: April 10, 2009
• First Posted (ESTIMATE): April 13, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): January 19, 2015
• Last Update Submitted That Met QC Criteria: January 16, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: xenon; hypothermia; out-of-hospital cardiac arrest
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Body Temperature Changes; Brain Ischemia; Ischemia; Brain Injuries; Heart Arrest; Hypothermia; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, General; Anesthetics; Anesthetics, Inhalation; Xenon
• Other Study ID Numbers: Eudra CT2009-009505-25