Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

• Published in: JAMA : the journal of the American Medical Association Vol. 315; no. 11; pp. 1120 - 1128
• Main Authors: Laitio, Ruut, Hynninen, Marja, Arola, Olli, Virtanen, Sami, Parkkola, Riitta, Saunavaara, Jani, Roine, Risto O, Grönlund, Juha, Ylikoski, Emmi, Wennervirta, Johanna, Bäcklund, Minna, Silvasti, Päivi, Nukarinen, Eija, Tiainen, Marjaana, Saraste, Antti, Pietilä, Mikko, Airaksinen, Juhani, Valanne, Leena, Martola, Juha, Silvennoinen, Heli, Scheinin, Harry, Harjola, Veli-Pekka, Niiranen, Jussi, Korpi, Kirsi, Varpula, Marjut, Inkinen, Outi, Olkkola, Klaus T, Maze, Mervyn, Vahlberg, Tero, Laitio, Timo
• Format: Journal Article
• Language: English
• Published: United States American Medical Association 15-03-2016
• Subjects: Administration, Inhalation; Adult; Aged; Anisotropy; Cardiopulmonary Resuscitation - methods; Clinical trials; Coma - mortality; Coma - therapy; Diffusion Magnetic Resonance Imaging; Female; Finland; Heart attacks; Humans; Hypothermia, Induced; Ischemia; Male; Middle Aged; Out-of-Hospital Cardiac Arrest - mortality; Out-of-Hospital Cardiac Arrest - therapy; Scientific imaging; Single-Blind Method; Statistics, Nonparametric; Survival Analysis; Survivors; Time Factors; Treatment Outcome; White Matter - drug effects; White Matter - injuries; White Matter - pathology; Xenon - administration & dosage; Xenon - pharmacology; Finland
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.2016.1933

IMPORTANCE: 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). DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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). MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892