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Xenon and Cooling Therapy in Babies at High Risk of Brain Injury Following Poor Condition at Birth (CoolXenon2)

Primary Purpose

Hypoxic Ischaemic Encephalopathy

Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
xenon gas
Whole body cooling
Sponsored by
University Hospitals Bristol and Weston NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoxic Ischaemic Encephalopathy focused on measuring Xenon, Hypothermia, Hypoxic Ischemic Encephalopathy, Newborn, Term, Neuroprotection, Cooling, HIE

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 ≤ 6cm H2O
  8. Arterial pCO2 within acceptable range (<7kPa)
  9. 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

  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.

Sites / Locations

  • St Michael's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

72h cooling + 18h xenon inhalation

Standard 72 h whole body cooling therapy

Arm Description

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

Whole body cooling therapy to rectal temperature of 33.5 degree Centigrade (standard therapy)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Brain MRI
Magnetic Resonance Imaging findings at 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

Full Information

First Posted
February 29, 2012
Last Updated
December 12, 2022
Sponsor
University Hospitals Bristol and Weston NHS Foundation Trust
Collaborators
University of Bristol
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1. Study Identification

Unique Protocol Identification Number
NCT01545271
Brief Title
Xenon and Cooling Therapy in Babies at High Risk of Brain Injury Following Poor Condition at Birth
Acronym
CoolXenon2
Official Title
Xenon and Cooling Therapy in Babies at High Risk of Brain Injury Following Poor Condition at Birth: A Randomised Pilot Study
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
May 2012 (undefined)
Primary Completion Date
October 2013 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospitals Bristol and Weston NHS Foundation Trust
Collaborators
University of Bristol

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoxic Ischaemic Encephalopathy
Keywords
Xenon, Hypothermia, Hypoxic Ischemic Encephalopathy, Newborn, Term, Neuroprotection, Cooling, HIE

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
72h cooling + 18h xenon inhalation
Arm Type
Experimental
Arm Description
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
Arm Title
Standard 72 h whole body cooling therapy
Arm Type
Active Comparator
Arm Description
Whole body cooling therapy to rectal temperature of 33.5 degree Centigrade (standard therapy)
Intervention Type
Drug
Intervention Name(s)
xenon gas
Other Intervention Name(s)
LENOXe
Intervention Description
Inhalation via endotracheal tube of 50% xenon for 18 hours, including during transport for outborn babies, starting within 5 hours after birth.
Intervention Type
Device
Intervention Name(s)
Whole body cooling
Intervention Description
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.
Primary Outcome Measure Information:
Title
Death and moderate or severe disability - Bayley III
Description
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.
Time Frame
at 18 months of age
Secondary Outcome Measure Information:
Title
Brain MRI
Description
Magnetic Resonance Imaging findings at less than 2 weeks of age
Time Frame
less than 2 weeks of age
Title
Amplitude Integrated Electroencephalogram (aEEG) grading
Description
Number of hours after birth when aEEG voltage has reached a normal or discontinuous normal pattern
Time Frame
Before hospital discharge; usually within one week of birth
Other Pre-specified Outcome Measures:
Title
Number of normal infants
Description
Bayley III composite score ≥ 85 and no neurosensory disability as described above
Time Frame
18-24 months

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
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: 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marianne Thoresen, Professor
Organizational Affiliation
University of Bristol
Official's Role
Principal Investigator
Facility Information:
Facility Name
St Michael's Hospital
City
Bristol
State/Province
Avon
ZIP/Postal Code
BS2 8EG
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
19608817
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.
Results Reference
background
PubMed Identifier
18309163
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.
Results Reference
background
PubMed Identifier
19142190
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.
Results Reference
background
PubMed Identifier
20658563
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.
Results Reference
background
PubMed Identifier
22160201
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.
Results Reference
background
PubMed Identifier
25794112
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.
Results Reference
derived
PubMed Identifier
24524452
Citation
Shankaran S. Outcomes of hypoxic-ischemic encephalopathy in neonates treated with hypothermia. Clin Perinatol. 2014 Mar;41(1):149-59. doi: 10.1016/j.clp.2013.10.008.
Results Reference
derived

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

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