title: Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies.
  
  
  OBJECTIVE
  To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI).
  
  
  METHODS
  A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized.
  
  
  METHODS
  Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group).
  
  
  METHODS
  The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months.
  
  
  RESULTS
  Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053).
  
  
  CONCLUSIONS
  Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00879892.
authors.affiliation: Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland2Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
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authors.initials: R
authors.lastname: Laitio
authors.affiliation: Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki, Helsinki, Finland4Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki.
authors.forename: Marja
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authors.lastname: Hynninen
authors.affiliation: Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland2Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
authors.forename: Olli
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authors.lastname: Arola
authors.affiliation: Department of Radiology, University of Turku, Turku, Finland6Turku University Hospital, Turku, Finland.
authors.forename: Sami
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authors.lastname: Virtanen
authors.affiliation: Department of Radiology, University of Turku, Turku, Finland6Turku University Hospital, Turku, Finland.
authors.forename: Riitta
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authors.lastname: Parkkola
authors.affiliation: Department of Medical Physics, Turku University Hospital, Turku, Finland8University of Turku, Turku, Finland.
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authors.lastname: Saunavaara
authors.affiliation: Turku University Hospital, Turku, Finland9Division of Clinical Neurosciences, University of Turku, Turku, Finland.
authors.forename: Risto O
authors.initials: RO
authors.lastname: Roine
authors.affiliation: Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland2Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
authors.forename: Juha
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authors.affiliation: Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki, Helsinki, Finland4Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki.
authors.forename: Emmi
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authors.lastname: Ylikoski
authors.affiliation: Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki, Helsinki, Finland4Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki.
authors.forename: Johanna
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authors.lastname: Wennervirta
authors.affiliation: Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki, Helsinki, Finland4Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki.
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authors.affiliation: Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki, Helsinki, Finland4Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki.
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authors.affiliation: Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki, Helsinki, Finland4Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki.
authors.forename: Eija
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authors.affiliation: Department of Neurology, University of Helsinki, Helsinki, Finland11Department of Neurology, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Marjaana
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authors.lastname: Tiainen
authors.affiliation: Turku University Hospital, Turku, Finland12Heart Center, University of Turku, Turku, Finland.
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authors.affiliation: Turku University Hospital, Turku, Finland12Heart Center, University of Turku, Turku, Finland.
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authors.affiliation: Turku University Hospital, Turku, Finland12Heart Center, University of Turku, Turku, Finland.
authors.forename: Juhani
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authors.affiliation: Department of Radiology, University of Helsinki, Helsinki, Finland14Department of Radiology, Helsinki University Hospital, Helsinki, Finland.
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authors.lastname: Valanne
authors.affiliation: Department of Radiology, University of Helsinki, Helsinki, Finland14Department of Radiology, Helsinki University Hospital, Helsinki, Finland.
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authors.lastname: Martola
authors.affiliation: Department of Radiology, University of Helsinki, Helsinki, Finland14Department of Radiology, Helsinki University Hospital, Helsinki, Finland.
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authors.lastname: Silvennoinen
authors.affiliation: Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland2Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
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authors.lastname: Scheinin
authors.affiliation: Emergency Medicine, Department of Emergency Medicine and Services, University of Helsinki, Helsinki, Finland16Emergency Medicine, Department of Emergency Medicine and Services, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Veli-Pekka
authors.initials: VP
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authors.affiliation: Department of Cardiology, University of Helsinki, Helsinki, Finland18Department of Cardiology, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Jussi
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authors.lastname: Niiranen
authors.affiliation: Department of Cardiology, University of Helsinki, Helsinki, Finland18Department of Cardiology, Helsinki University Hospital, Helsinki, Finland.
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authors.affiliation: Department of Cardiology, University of Helsinki, Helsinki, Finland18Department of Cardiology, Helsinki University Hospital, Helsinki, Finland.
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authors.lastname: Varpula
authors.affiliation: Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland2Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
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authors.affiliation: Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki, Helsinki, Finland4Division of Intensive Care Medicine, Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
authors.affiliation: Department of Biostatistics, University of Turku, Turku, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Vahlberg
authors.affiliation: Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland2Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
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mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D016880:Anisotropy; D016887:Cardiopulmonary Resuscitation / Q000379:methods; D003128:Coma / Q000401:mortality / Q000628:therapy*; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005387:Finland; D006801:Humans; D007036:Hypothermia, Induced; D008297:Male; D008875:Middle Aged; D058687:Out-of-Hospital Cardiac Arrest / Q000401:mortality / Q000628:therapy*; D016037:Single-Blind Method; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D017741:Survivors; D013997:Time Factors; D016896:Treatment Outcome; D066127:White Matter / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D014978:Xenon / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D014978:Xenon