Clinical trial NCT02071394: Xenon and Cooling Therapy in Babies at High Risk of Brain Injury Following Poor Condition at Birth
Official title: Xenon and Cooling Therapy in Babies at High Risk of Brain Injury Following Poor Condition at Birth: A Randomised Pilot Outcomes Study (COOLXENON3 Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypoxic Ischaemic Encephalopathy
Keywords: Xenon
Hypothermia
Hypoxic Ischemic Encephalopathy
Newborn
Neonate
Term
Neuroprotection
Cooling
HIE
Lead sponsor: University Hospitals Bristol and Weston NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University of Bristol
First posted: 2014-02-25
Enrollment: 50
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study examines the effect of inhaled xenon gas in the treatment of newborn infants with hypoxic-ischemic encephalopathy (HIE) in combination with cooling, which is the standard treatment for this condition. The hypothesis is that the xenon + cooling combination will produce better neuroprotection than the standard treatment of cooling alone.


Eligibility criteria: Infants will be eligible for for the trial if the St Michael's hospital standard inclusion criteria for cooling and additional inclusion criteria for xenon administration are met.

St Michael's hospital standard inclusion criteria for standard hypothermia treatment of 72 hrs:

A: Neonates born at greater than 36 weeks gestation (estimated or clinical assessment) with at least ONE of the following:

1. Apgar score of ≤5 at ten minutes after birth
2. Continued need for resuscitation, including tracheal or mask ventilation, at ten minutes after birth
3. Acidosis, defined as either umbilical cord pH or any arterial, venous or capillary pH within 60 minutes of birth less \< 7.00
4. Base deficit ≥16 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood).

If the infant meets criterion A then assess for neurological abnormality using criterion B and C (by trained personnel):

B: Moderate or Severe encephalopathy as evidenced by any of the following:

1. Altered state of consciousness (reduced or absent responses or pathological irritability and hyper responsive and at least ONE or more of the following:
2. Hypotonia
3. Abnormal reflexes including oculomotor or pupillary abnormalities
4. Absent or weak suck
5. Clinical seizures, as recorded by trained personnel

And

C: At least 30 minutes duration of amplitude-integrated electroencephalography (aEEG) recording that shows abnormal background aEEG activity. The decision to cool is based on the worst 30 min section of the aEEG, not the best \[35\] or seizures (clinical or electrical) thus meeting ONE of the following:

1. Normal background with some (\> 5 min) electrical seizure activity
2. Moderately abnormal activity (upper margin of trace \>10μV and lower margin \<5μV)
3. Suppressed activity (upper margin of trace \<10μV and lower margin of trace \<5μV)
4. Definite seizure activity

Additional inclusion criteria for xenon:

Before being considered for additional inhaled xenon therapy via the breathing gas mixture, the infant would need to meet further additional entry criteria (all must be met):

1. Intubated, ventilated, sedated, being cooled
2. ≤ 5 hours old
3. Any seizures under control
4. Weight \> 2nd centile for gestational age
5. Stable cardiovascular parameters; Mean arterial pressure \>40mmHg.
6. Oxygen requirement via mechanical ventilator ≤ 40%.
7. Positive End Expiratory Pressure (PEEP) requirement ≤ 8cm H2O
8. Arterial (preferable)/capillary/venous pCO2 within acceptable range (\<7kPa)
9. Postnatal age ≤ 5 hours
10. Absence of major congenital abnormalities, imperforate anus and in particular any bowel obstruction, congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis. Congenital syndromes affecting the brain should be excluded when diagnosed.

Exclusion criteria for cooling in the CoolXenon3 study:

1. Infants expected to be greater than 3 hours of age at the time of starting cooling treatment.
2. Futility. Where prognosis is considered to be hopeless e.g. no cardiac output for 20 minutes.

Primary outcomes:
measure: Death and moderate or severe disability - Bayley III neurodevelopmental outcome score
timeFrame: 18 months of age
Secondary outcomes:
measure: Brain MRI
timeFrame: Before hospital discharge, within 2 weeks of birth
measure: Amplitude Integrated Electroencephalogram (aEEG) grading
timeFrame: Before hospital discharge, usually within 1 week of birth
Other outcomes:
measure: Number of normal infants
timeFrame: 18-24 months
Locations:
city: Bristol
country: United Kingdom
facility: St Michael's Hospital
city: London
country: United Kingdom
facility: Imperial College / Hammersmith Hospital
Study officials:
affiliation: University of Bristol
name: Marianne Thoresen, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chakkarapani E, Thoresen M, Hobbs CE, Aquilina K, Liu X, Dingley J. A closed-circuit neonatal xenon delivery system: a technical and practical neuroprotection feasibility study in newborn pigs. Anesth Analg. 2009 Aug;109(2):451-60. doi: 10.1213/ane.0b013e3181aa9550.
citation: Hobbs C, Thoresen M, Tucker A, Aquilina K, Chakkarapani E, Dingley J. Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke. 2008 Apr;39(4):1307-13. doi: 10.1161/STROKEAHA.107.499822. Epub 2008 Feb 28.
citation: Thoresen M, Hobbs CE, Wood T, Chakkarapani E, Dingley J. Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia. J Cereb Blood Flow Metab. 2009 Apr;29(4):707-14. doi: 10.1038/jcbfm.2008.163. Epub 2009 Jan 14.
citation: Chakkarapani E, Dingley J, Liu X, Hoque N, Aquilina K, Porter H, Thoresen M. Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs. Ann Neurol. 2010 Sep;68(3):330-41. doi: 10.1002/ana.22016.
citation: Chakkarapani E, Thoresen M, Liu X, Walloe L, Dingley J. Xenon offers stable haemodynamics independent of induced hypothermia after hypoxia-ischaemia in newborn pigs. Intensive Care Med. 2012 Feb;38(2):316-23. doi: 10.1007/s00134-011-2442-7. Epub 2011 Dec 13.
citation: Dingley J, Tooley J, Liu X, Scull-Brown E, Elstad M, Chakkarapani E, Sabir H, Thoresen M. Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics. 2014 May;133(5):809-18. doi: 10.1542/peds.2013-0787.
citation: Dingley J, Liu X, Gill H, Smit E, Sabir H, Tooley J, Chakkarapani E, Windsor D, Thoresen M. The feasibility of using a portable xenon delivery device to permit earlier xenon ventilation with therapeutic cooling of neonates during ambulance retrieval. Anesth Analg. 2015 Jun;120(6):1331-6. doi: 10.1213/ANE.0000000000000693.