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The death knell for Xenon?



Azzopardi D, et al. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial. The Lancet Neurology. 2016;15(2):145-53.  Babies who undergo therapeutic hypothermia for perinatal encephalopathy are still at high risk of significant long term impairments. Other therapies to add to hypothermia are being sought and tested, one of them being Xenon. Inhaled xenon gas has neuroprotective effects in many models; but it is expensive and difficult to use, in order to make it affordable for use over several hours you need to recirculate the exhaled xenon, so you need a special ventilator, which has been developed for this trial. In this "pilot' RCT, eligible babies were typical of infants who are cooled, and had to have started on hypothermia within 6 hours after birth. As is usual, most of the 92 enrolled babies (2/3) were born in peripheral hospitals and transported in, many babies were cooled quite quickly, 93% before 4 hours of age. Xenon or standard care was started after randomization which was after arrival in the study centre, so the assigned treatment didn't start until an average of 10 hours of age.  Xenon (or no xenon) was then continued for exactly 24 hours of age.

The primary outcomes of the study were MR findings; using spectroscopy they calculated the ration of lactate to N-acetyl aspartate in the thalamus, and using diffusion tensor imaging they calculated the fractional inosotropy of the posterior limb of the internal capsule. Scans were performed after the end of cooling at about 6 days of age. Because of deaths and a small number of scans not done in survivors, they ended up with around 75 babies with data for each of the two primary outcomes, data from the MRI were analyzed by a masked individual (images of the lone ranger... radiologist) . Basically the study showed no effect of Xenon.

Which is a bummer. (that is colloquial English for "a real shame")

Why didn't it work? I think first off we have to be careful in saying it didn't work, there was no effect on the primary outcomes, but the primary outcomes are surrogates. Surrogates should always be mistrusted, even when they are called "biomarkers". Is the surrogate an accurate enough predictor of good or adverse clinically important outcomes? I think that is questionable here, mostly because I don't know the data well enough to answer the question, but is it possible that a clinically significant benefit of xenon will be shown if (hopefully when) these babies are followed up? My guess is that such an outcome is quite unlikely, but possible. In fact I think this study is a good opportunity to prove the value of the MR surrogates. If the authors are right (and usually Dennis Azzopardi, Dave Edwards and the many associated luminaries who wrote this article are indeed right) then using similar surrogates in future trials will help to screen for effective adjunctive therapies in cooled babies, and more quickly than waiting 2 years or so for follow up.

Maybe starting xenon at 10 hours of age is just too late? As the authors point out, they performed a trial in a real world environment, it would be possible, if you had the ventilator always ready and available, to start Xenon the moment a baby enters the referral NICU, but that would still lead to significant delays of evaluation and transport. Maybe 24 hours is too short? It was based on the best previously available literature, and again technically feasible, before doing another study with longer Xenon administration I think we would need some very good rationale.

In the end, this real-life application of xenon in cooled babies didn't show any sign of being effective. We should look elsewhere I guess, something that could be given very quickly when a baby is cooled, such as melatonin, or erythropoietin look like they are the most worthy of further investigation. A review of the literature from 3 to 4 years ago concluded that, and I haven't seen much to change the situation since then. Robertson NJ, et al. Which Neuroprotective Agents are Ready for Bench to Bedside Translation in the Newborn Infant? The Journal of pediatrics. 2012;160(4):544-52.e4.

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Usually the dramaturgy of research is

1. Small trial shows effect, typically on surrogate markers

2. Large trial with clinically meaningful outcomes shows less/no effect

So I think: the results from this xenon trial doesn't give much hope, unfortunately :( 

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