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.

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.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , . Bookmark the permalink.

4 Responses to The death knell for Xenon?

  1. Elisa Smit says:

    Dear Prof. Barrington,

    Thanks for a great posting on Xenon for term infants with hypoxic-ischaemic encephalopathy. You are absolutely right to say we should not disregard Xenon yet.

    Most laboratory work shows cooling not to be effective after a longer delay (ie >6 hours), so why would anyone expect Xenon to be any different? Xenon offers additive brain protection with hypothermia and it works by ameliorating excitotoxicity, which occurs immediately after hypoxia-ischaemia. Consistent with this data, Liu et al. have shown that the therapeutic window of Xenon lasts until 5 hours after the hypoxic-ischaemic insult when combined with cooling (Pediatric Research (2015);77:779–783). This is the only study where the animals survived till adulthood and the functional improvement after delayed Xenon-hypothermia was as good as what we found previously (Stroke 2008; 39: 1307-1313).

    Consequently our current CoolXenon clinical study in Bristol (UK) randomises infants to Xenon+cooling or cooling alone, with Xenon (50% for 18 hours) started before 5 postnatal hours and cooling before 3 postnatal hours: https://clinicaltrials.gov/ct2/show/NCT02071394. Primary outcome is Bayley III neurodevelopmental score.

    We are managing to administer Xenon early by starting it in the referral hospital and continuing throughout the transport period (The Feasibility of Using a Portable Xenon Delivery Device to Permit Earlier Xenon Ventilation with Therapeutic Cooling of Neonates During Ambulance Retrieval, Anesthesia and Analgesia 2015 – volume 120;6:1331-1336).

    In adults this exciting study post cardiac arrest of rapidly instituted Xenon + cooling in adults on brain function was completed in 2014 and therefore the results should be published very soon:
    https://clinicaltrials.gov/ct2/show/study/NCT00879892.

    There is also the open question about which Xenon concentration and duration to use. The animal work has shown higher concentrations of Xenon to be more protective, so why then choose 30% Xenon, like in the TOBY-Xe study, which did not show a neuroprotective effect in the animal studies?

    Lots of unanswered questions still, but hopefully some answers in the next few years!

    The Bristol Neonatal Neuroscience Group; Dr J Dingley, Dr E Chakkarapani, Dr E Smit, Prof M Thoresen

    • That is amazing, I wasn’t aware of your transport Xenon ventilator. I didn’t say anything about the dose/concentration issue in my post, but you obviously are one of the experts in the field, so its good to know there are on-going trials that will answer different questions.
      I am interested in how often you get babies cooled at less than 3 hours. In our region we cool on transport like most programs, and we often counsel referring physicians to start passive cooling in their hospital when they call us, but the ones who get cooled very early are, I think, the worst affected babies who had the worst start in life. So my guess would be that you might select a very high risk group, just on that basis. I know you have a great database that could answer that question, is it true? Are babies cooled before 3 hours a higher risk group, or do they just have more alert doctors who realize that they have encephalopathy sooner?

  2. Pingback: Interesting comments | Neonatal Research

  3. David Edwards says:

    Hi Keith,
    Thanks for your kind comments. Unfortunately I am frequently wrong and so is Denis occasionally and we certainly were on this occasion although I’m still scratching my head to understand what othe the many possibilities was the critical mistake. But a couple of thiughts. First, you may be right about the need for speed, but work in this field has quite rightly focused on the period of secondary energy failure as defined by Os Reynolds and Co with MRS. But I hope we are moving on to consider the long period of cell death that continues after this and consider treatments that work over the week or month after asphyxia. I think we should look out for Sonny Juul’s long running Epo programme as this might work in this space. Second, the reason why MR was called a biomarker in this paper was that the FDA requirements to call something a surrogate are much stricter: we did the work to show that MR was qualified to be a biomarker, but it wouldn’t make the grade as a surrogate.. Nevertheless don’t think the MR was one of the mistakes and it certainly shortened the project by several years.
    Best wishes and keep blogging
    David

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