CoolXenon3
Research type
Research Study
Full title
XENON AND COOLING THERAPY IN BABIES AT HIGH RISK OF BRAIN INJURY FOLLOWING POOR CONDITION AT BIRTH: A RANDOMISED OUTCOME STUDY (COOLXENON3 STUDY)
IRAS ID
139010
Contact name
Marianne Thoresen
Contact email
Sponsor organisation
University Hospital Bristol NHS Foundation Trust
Eudract number
2013-004478-80
Research summary
Summary of Results
Worldwide, severe complications during childbirth are the most common reason for newborn babies to survive disabled, or to die. The infants suffer lack of oxygen or blood flow to the brain which causes the subsequent brain injury. Fifty percent of the injured infants develop Cerebral Palsy (CP), a permanent movement disorder, which often includes learning problems. The remaining 50% of those with injury have a learning disability and need support. Previously there was no treatment that could lessen the impact of this brain injury.
Fifteen years ago, research by the CI and other experts in this field showed that cooling the baby from 37°C to 33.5°C for three days (called ‘Therapeutic hypothermia’ (TH)) reduced death and disability; after the period of TH, infants are carefully rewarmed. In the south west of England, there is an average of 34,000 deliveries annually, of which about 60 newborns will receive TH. Of these, six die and 11 survive with disability. In other regions of the world, these numbers can be up to 25 times higher.
The aim of this study (in conjunction with a previous study, CoolXenon2, which had separate Ethical approval) was to examine whether adding a new, complementary treatment to TH could reduce both movement (CP) and cognitive disability further. The treatment involved breathing the inert gas xenon while being cooled. Earlier laboratory research gave promising results using this combination.
Because the CX2 and CX3 studies have identical treatment protocols, it was agreed that the results from CX2 and CX3 would be combined. Between March 2012 and March 2018, 82 patients were recruited and randomised, either to be treated with TH only, starting within three hours after birth, or receiving TH within three hours, plus breathing 50% xenon gas for 18 hours, starting xenon within five hours after birth. The xenon treatment for 18 hours was the only difference between the two groups; the intensive care treatment and clinical follow-up was the same. We used a recognised testing method (Bayley III) to assess cognition, language and motor abilities and these results determine good or poor outcome. Normal children will score within the range of 85-115 with a median value of 100 on these tests. We also examined other brain and body functions looking for potential adverse effects of cooling and/or xenon gas.
The groups were small, 41 infants in each, and we postulated beforehand that we were unlikely to show significant differences, only trends.
Overall, there was no difference in the primary outcome, ‘death and disability’, between the two groups. Of the 41 in the Cool+Xenon group, 28 (68%) had ‘good’ outcome and 13 (32%) had ‘poor’. Of these 13, six died due to the severity of the birth injury and these deaths were not related to xenon. Three had severe CP and four had cognitive delay only. Of the 41 in the cooling-only group, 32 (78%) had ‘good’ outcome and nine (22%) had ‘poor’. Two died early, three had severe CP and four had cognitive delay. One child with severe CP died at five years of age. The specialised xenon ventilator did not have any adverse effects on lung function as compared to being on a standard ventilator. The time to breathing unaided, days in hospital before going home, and time to full oral feeds were not different between the groups. Blood values, low blood pressure and seizures were also similar between the two groups, as was the pattern of regional MRI injury on brain scan at one week of age.
A strength of this study was starting the xenon treatment early, before five hours of age. We were able to start xenon delivery in the remote birth hospitals and build a small version of the xenon delivery equipment for use during ambulance transport. A potential limitation of the study was the duration of only 18h breathing xenon, as compared to 72h TH. However, as we were testing a new treatment it was important to be cautious. Cooling+xenon was safe but did not offer any improvement, nor cause any harm, compared with cooling only. The outcome of children treated with cooling+xenon was similar for cognition, language and motor abilities to those who received cooling only. We do not know whether giving xenon for longer than 18h (up to 72h) would have been beneficial. In our laboratory studies we found that delivering xenon for 72 hours was feasible.
Another strength of the study was that, compared with previous studies where cooling was started within six hours (the current standard of care), our patients in both groups were cooled earlier (<3 hours) and had better outcome than comparable studies.REC name
South West - Central Bristol Research Ethics Committee
REC reference
13/SW/0300
Date of REC Opinion
8 Jan 2014
REC opinion
Further Information Favourable Opinion