Inhaled Xenon in Comatose Survivors of Out-of-Hospital Cardiac Arrest
What is the effect of inhaled xenon on ischemic white matter damage after acute global hypoxic-ischemic brain injury, assessed with magnetic resonance imaging (MRI)?
This was a randomized, single-blind, phase 2 clinical drug trial conducted between August 2009 and March 2015 at two multipurpose intensive care units in Finland. One hundred ten comatose patients (ages 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. 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). The primary endpoint 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 endpoints included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months.
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 (standard deviation [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% confidence interval [CI], 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016; 95% CI, 0.005-0.027; p = 0.006). At 6 months, 75 patients (68.2%) were alive. Secondary endpoints 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 = 0.68). 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 = 0.053).
The authors concluded that 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.
This study reports that inhaled xenon in combination with therapeutic hypothermia treatment preserved white matter tracts better than hypothermia treatment alone in survivors of cardiac arrest. However, although a benefit of xenon on white matter damage was observed, there were no significant differences in either neurological or cognitive outcomes between the two treatment groups, or in mortality. It should be noted that the study was underpowered to detect a statistically significant difference in clinical outcome. These pilot findings need to be confirmed in adequately powered randomized clinical trials with hard clinical endpoints.
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