Xenon Reduces Brain Damage After Cardiac Arrest

March 17, 2016

Inhalation of xenon gas resulted in less white matter damage in patients among comatose survivors of out-of-hospital cardiac arrest in a randomized trial.

The study, published in the March 15 issue of JAMA, was conducted by a group led by Timo Laitio, MD, Turku University Hospital, Finland.

"Our results are very promising,” Dr Laitio told Medscape Medical News. "They show the first demonstration of neuroprotection with xenon in humans. But this was quite a small study focusing primary on MRI parameters and the results will need to be confirmed in a larger study to know if they will translate into clinical benefits. If this does turn out to be the case, xenon could become a new treatment for cardiac arrest and maybe also for other types of brain injury."

Xenon gas is being developed by NeuroproteXeon. The company is now awaiting approval from the US Food and Drug Administration to launch a pivotal phase 3 clinical study beginning later this year.

Dr Laitio explained that xenon has been suspected to have neuroprotective properties for some time. It has several possible actions that may be useful in this regard, including blocking NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate), and kainate receptors.

Animal studies have shown neuroprotective effects, especially when combined with hypothermia when both additive and synergistic interactions, have been reported, the researchers note.

For the current study, 110 comatose patients who had experienced out-of-hospital cardiac arrest were randomly assigned to receive inhaled xenon combined with hypothermia (91.4°F) for 24 hours or hypothermia treatment alone.

The primary end point was cerebral white matter damage as evaluated by fractional anisotropy (FA) from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest.

Dr Laitio explained that FA measures the movement of water molecules in the white matter tract. If the white matter is damaged, water can move more freely, resulting in a lower FA value.

The study showed that xenon treatment was associated a significantly higher FA score, signalling less white matter damage.

Specifically, the mean global FA values were 0.433 in the xenon group and 0.419 in the control group. The age-, sex-, and site-adjusted mean global FA value was 3.8% higher in the xenon group (P = .006).

Results also showed lower radial diffusivity scores in patients treated with xenon. This measures myelin injury and suggests less myelin damage in the xenon group.

"So we concluded that xenon protects the white matter by preventing myelin damage," Dr Laitio said. "Myelin is needed for normal function of the central nervous system, and its damage leads to neurocognitive problems such as attention, memory, language, executive processing," he added.

Prediction of Short-term Mortality

He noted that the FA score also predicted short-term mortality in the study. "Patients who died had significantly lower FA scores. We believe this FA measure has predictive value for mortality and could be clinically important. "The FA difference of 3.8% between xenon and controls should be considered in the context of statistically significant difference between survivors and those who died of 6.4%," he reported.

Because the xenon group showed higher FA scores than the controls, could this translate into lower mortality? Dr Laitio says the current trial is too small to show anything definitive on this, but the mortality results are intriguing, suggesting a strong trend toward a reduction in 6-month mortality in the xenon group.

In the intention-to-treat population, the Kaplan-Meier survival estimate after 6-month follow-up was 27.3% (15 of 55) in the xenon group and 34.5% (19 of 55) in the control group (adjusted hazard ratio, 0.49 [95% confidence interval, 0.23 - 1.01]; P = .053).

However, neurologic outcomes did not differ between the groups, as assessed with the Cerebral Performance Category score and the modified Rankin Scale score. But Dr Laitio said neither of these scales is that good at detecting fine differences, and he suggested that future trials should use more sensitive measures of neurocognitive status.

The rates of serious adverse events were not significantly different between the groups at 6 months.

Dr Laitio reported that researchers from Imperial College London have recently published a study of xenon in neonatal asphyxia but this did not show a benefit. But he pointed out that xenon was not given until around 10 hours after asphyxia in that study, which may be too late; animal studies have suggested no effect after about 4 to 6 hours.

In the current study, the mean time to treatment was 4 hours, 15 minutes, and 75% of the patients were treated within 5 hours of cardiac arrest.

Dr Laitio said that ideally xenon would be given even earlier — preferably in the ambulance — but at present this is not possible because it is not easy to administer and the equipment needed was not suitable to be used in an ambulance.

He commented: "Xenon permeates through the regular breathing apparatus used, and we have to use special delivery devices which at present are large and cumbersome. New devices are being developed which may facilitate use in a prehospital environment in future."

Commenting on the study for Medscape Medical News, Nicolas Deye, MD, Lariboisiere University Hospital, Paris, France, who has been involved in studies of hypothermia in cardiac arrest, said, "This is an important issue because prognosis of cardiac arrest is still so dramatic. Furthermore there is to date no magic treatment to drastically improve neurological recovery. Thus innovative treatments are mandatory."

Dr Deye said he thought the current study was promising, but because no effect was seen on the main clinical endpoints, this suggests that xenon may not have a major impact in the studied population "or it needs to be better defined in larger studies, or needs to be applied in more highly selected patients."

He added that "implementation of xenon gas seems potentially difficult in some conditions (availability, high FiO2 needs, prehospital field, cost). These are other challenges to solve before applying xenon in practice."

The study was funded by the Academy of Finland and by the Hospital District of Southwest Finland. Dr Laitio reported receiving institutional funding from NeuroproteXeon, which intends to commercialize the use of xenon for ongoing acute neurologic injury. Coauthor Mervyn Maze, MB, is a founder, board director, and equity shareholder of NeuroproteXeon.

JAMA. Published March 15, 2016. Abstract

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