Xenon and Cooling Therapy in Babies at High Risk of Brain Injury Following Poor Condition at Birth

Study Overview
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Brief Summary
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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.

Official Title
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Xenon and Cooling Therapy in Babies at High Risk of Brain Injury Following Poor Condition at Birth: A Randomised Pilot Study

Conditions
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Hypoxic Ischaemic Encephalopathy

Intervention / Treatment
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* Drug: xenon gas
* Device: Whole body cooling


Participation Criteria
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Eligibility Criteria
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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: Apgar score of ≤5 at ten minutes after birth Continued need for resuscitation, including tracheal or mask ventilation, at ten minutes after birth Acidosis, defined as either umbilical cord pH or any arterial, venous or capillary pH within 60 minutes of birth less < 7.00 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: Altered state of consciousness (reduced or absent responses or pathological irritability and hyper responsive and at least ONE or more of the following: Hypotonia Abnormal reflexes including oculomotor or pupillary abnormalities Absent or weak suck 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: Normal background with some (> 5 min) electrical seizure activity Moderately abnormal activity (upper margin of trace >10μV and lower margin <5μV) Suppressed activity (upper margin of trace <10μV and lower margin of trace <5μV) 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): Intubated, ventilated, sedated, being cooled ≤ 5 hours old Any seizures under control Weight > 2nd centile for gestational age Stable cardiovascular parameters; Mean arterial pressure >40mmHg. Oxygen requirement via mechanical ventilator ≤ 40%. Positive End Expiratory Pressure (PEEP) requirement ≤ 6cm H2O Arterial pCO2 within acceptable range (<7kPa) 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 CoolXenon2 study Infants expected to be greater than 3 hours of age at the time of starting cooling treatment. Futility. Where prognosis is considered to be hopeless e.g. no cardiac output for 20 minutes.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 72h cooling + 18h xenon inhalation<br>Babies in poor condition at birth and referred to our neonatal unit for standard therapy of cooling to 33.5 degree C body temperature will be randomised to receive xenon gas at 50% concentration for 18 hours | Drug: xenon gas<br>* Inhalation via endotracheal tube of 50% xenon for 18 hours, including during transport for outborn babies, starting within 5 hours after birth.<br>* Other names: LENOXe;Device: Whole body cooling<br>* Cooling of baby to reduce rectal temperature to 33.5 degree Centigrade(standard treatment), including during transport for outborn babies, starting within 3 hours after birth.<br>|
| Active Comparator: Standard 72 h whole body cooling therapy<br>Whole body cooling therapy to rectal temperature of 33.5 degree Centigrade (standard therapy) | Device: Whole body cooling<br>* Cooling of baby to reduce rectal temperature to 33.5 degree Centigrade(standard treatment), including during transport for outborn babies, starting within 3 hours after birth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death and moderate or severe disability - Bayley III | Bayley Scales of Infant and Toddler Development III (Bayley III) has three domains: cognition, language and motor skills. Each domain is based on a series of examinations of different severity. The lower cut off level is 55 for cognition, 47 for language and 46 for motor. The upper value can be 145. Assessment of hearing and vision: severe hearing loss defined as inability to hear without amplification; severe visual loss defined as being unable to move independently. | at 18 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain MRI | Magnetic Resonance Imaging findings at less than 2 weeks of age | less than 2 weeks of age | 
| Amplitude Integrated Electroencephalogram (aEEG) grading | Number of hours after birth when aEEG voltage has reached a normal or discontinuous normal pattern | Before hospital discharge; usually within one week of birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Xenon, Hypothermia, Hypoxic Ischemic Encephalopathy, Newborn, Term, Neuroprotection, Cooling, HIE