Hypoxic Ischaemic Encephalopathy
Conditions
Keywords
perinatal asphyxia, encephalopathy, neuroprotection
Brief summary
This is a randomised controlled trial in newborn infants with perinatal asphyxial encephalopathy assessing whether a combination of hypothermia and inhaled xenon preserve cerebral metabolism and structure.
Detailed description
The study hypothesis is that: Following perinatal asphyxia treatment with a combination of hypothermia and inhaled xenon preserves cerebral metabolism and structure. Following informed parental consent, infants that continue to require endotracheal tube ventilation following resuscitation will be randomised to treatment with hypothermia only or hypothermia and xenon. All infants in both groups will be treated with hypothermia for 72 hours started within 6 hours of delivery and infants allocated to hypothermia and xenon will also receive 30% xenon (balanced with oxygen and air) for 24 hours through a purpose designed delivery system. Structured neurological examination will be done daily during the 1st week after birth and at discharge. MRS and MRI will be performed once between 4-10 days of age. MRS/MRI data analysis will be by investigators blinded to the allocated intervention.
Interventions
OTHERXenon gas
30% Xenon gas inhaled for 24 hours
Sponsors
University College London Hospitals
Guy's and St Thomas' NHS Foundation Trust
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Hours to 12 Hours
Healthy volunteers
No
Inclusion criteria
Infants will be eligible for enrolment into the trial if each of the following criteria is fulfilled: * Infants 36 to 43 weeks gestation with at least one of the following: * Apgar score of \<5 at 10 minutes after birth; * Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth; * Acidosis defined as pH \<7.00 and/or base deficit \>15 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood). * Moderate to severe encephalopathy consisting of altered state of consciousness (reduced or absent response to stimulation) and hypotonia, and abnormal primitive reflexes (weak or absent suck or Moro response). Clinical severity of HIE will be assessed by Thompson encephalopathy score, and modified Sarnat score. * At least 30 minutes duration of amplitude integrated EEG (aEEG) recording that shows moderately abnormal or suppressed background aEEG activity or seizures
Exclusion criteria
* If treatment with hypothermia is delayed beyond 6 hours, or infants are expected to be \>12 hours of age at the time of randomisation; Infants with ventilatory oxygen requirement \> 70%; Attending clinician considers infant not suitable to participate because of other serious congenital abnormalities, or the infant's condition appears terminal.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lactate (Lac) / N Acetyl Aspartate (NAA) Ratio on Magnetic Resonance Spectroscopy | 10 days | Cerebral Lac/NAA ratio measured by magnetic resonance spectroscopy in patents |
| Cerebral Fractional Anisotropy Measured by Diffusion Weighted Magnetic Resonance Imaging | 10 days | Fractional anisotropy (FA) is a measure of tissue integrity in white matter tracts measured by diffusion tensor MRI, and it has been used in work in animals to assess potential neuroprotectants and can be used to predict subsequent neurological outcomes after birth asphyxia, including in infants treated with moderate hypothermia. It is a scalar value between 0-1 that describe anisotropy of a diffusion process. A value of zero means that diffusion is unrestricted (or equally restricted) in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions or similar. Fractional anisotropy data were extracted froma mask of the posterior limb of the internal capsule via tract-based spatial statistics. \*Coefficient of variation=√(exp(var)-1), where var is the variance on the log scale |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Amiel Tison Evaluation at Hospital Discharge | At discharge from hospital | Amiel Tison neurological assessment at discharge from hospital. Amiel Tison evaluation was developed to detect transient and permanent abnormalities in an infant's neuromotor development. Its main focus is to examine active and passive muscle tone. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Combination of Hypothermia and Xenon Combination of whole body cooling to 33.5 rectal and 30% Xenon gas inhaled for 24 hours | 46 |
| Hypothermia and Standard Intensive Care 72 hours of whole body cooling to 33.5 rectal and standard intensive care | 46 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 8 | 3 |
| Overall Study | missing scan | 5 | 9 |
Baseline characteristics
| Characteristic | Hypothermia and Standard Intensive Care | Total | Combination of Hypothermia and Xenon |
|---|---|---|---|
| Age, Continuous | 39.8 weeks, gestation STANDARD_DEVIATION 1.3 | 39.8 weeks, gestation STANDARD_DEVIATION 1.5 | 39.8 weeks, gestation STANDARD_DEVIATION 1.7 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United Kingdom | 46 participants | 92 participants | 46 participants |
| Sex: Female, Male Female | 25 Participants | 45 Participants | 20 Participants |
| Sex: Female, Male Male | 21 Participants | 47 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 46 | 9 / 46 |
| other Total, other adverse events | 2 / 46 | 0 / 46 |
| serious Total, serious adverse events | 0 / 46 | 0 / 46 |
Outcome results
Primary
Cerebral Fractional Anisotropy Measured by Diffusion Weighted Magnetic Resonance Imaging
Fractional anisotropy (FA) is a measure of tissue integrity in white matter tracts measured by diffusion tensor MRI, and it has been used in work in animals to assess potential neuroprotectants and can be used to predict subsequent neurological outcomes after birth asphyxia, including in infants treated with moderate hypothermia. It is a scalar value between 0-1 that describe anisotropy of a diffusion process. A value of zero means that diffusion is unrestricted (or equally restricted) in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions or similar. Fractional anisotropy data were extracted froma mask of the posterior limb of the internal capsule via tract-based spatial statistics. \*Coefficient of variation=√(exp(var)-1), where var is the variance on the log scale
Time frame: 10 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination of Hypothermia and Xenon | Cerebral Fractional Anisotropy Measured by Diffusion Weighted Magnetic Resonance Imaging | 0.40 units on a scale | Standard Deviation 0.05 |
| Hypothermia and Standard Intensive Care | Cerebral Fractional Anisotropy Measured by Diffusion Weighted Magnetic Resonance Imaging | 0.40 units on a scale | Standard Deviation 0.05 |
Primary
Lactate (Lac) / N Acetyl Aspartate (NAA) Ratio on Magnetic Resonance Spectroscopy
Cerebral Lac/NAA ratio measured by magnetic resonance spectroscopy in patents
Time frame: 10 days
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Combination of Hypothermia and Xenon | Lactate (Lac) / N Acetyl Aspartate (NAA) Ratio on Magnetic Resonance Spectroscopy | 0.25 ratio | Geometric Coefficient of Variation 1.3 |
| Hypothermia and Standard Intensive Care | Lactate (Lac) / N Acetyl Aspartate (NAA) Ratio on Magnetic Resonance Spectroscopy | 0.28 ratio | Geometric Coefficient of Variation 1.45 |
Secondary
Amiel Tison Evaluation at Hospital Discharge
Amiel Tison neurological assessment at discharge from hospital. Amiel Tison evaluation was developed to detect transient and permanent abnormalities in an infant's neuromotor development. Its main focus is to examine active and passive muscle tone.
Time frame: At discharge from hospital
Population: Infants survivors at time of hospital discharge
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Combination of Hypothermia and Xenon | Amiel Tison Evaluation at Hospital Discharge | Normal or mildly abnormal | 30 Participants |
| Combination of Hypothermia and Xenon | Amiel Tison Evaluation at Hospital Discharge | Moderately abnormal | 3 Participants |
| Combination of Hypothermia and Xenon | Amiel Tison Evaluation at Hospital Discharge | Very abnormal | 2 Participants |
| Hypothermia and Standard Intensive Care | Amiel Tison Evaluation at Hospital Discharge | Normal or mildly abnormal | 29 Participants |
| Hypothermia and Standard Intensive Care | Amiel Tison Evaluation at Hospital Discharge | Moderately abnormal | 7 Participants |
| Hypothermia and Standard Intensive Care | Amiel Tison Evaluation at Hospital Discharge | Very abnormal | 1 Participants |