Asphyxia Neonatorum, Encephalopathy, Hypoxia, Seizures
Conditions
Keywords
Hypoxia, Ischaemia, Encephalopathy, Neonatal, Hypothermia, Perinatal, Cooling, Whole/Total Body
Brief summary
Hypothesis: Prolonged whole body cooling in term infants with perinatal asphyxial encephalopathy reduces death and severe neurodevelopmental disability. This study aims to determine whether whole body cooling to 33-34°C is a safe treatment that improves survival, without severe neurological or neurodevelopmental impairments at 18 months, of term infants suffering perinatal asphyxial encephalopathy.
Detailed description
This is a multicentre prospective randomised controlled trial to determine whether a reduction of body temperature by 3-4°C following perinatal asphyxia improves survival without neurodevelopmental disability. Full term infants will be randomised within 6 hours of birth to either a control group with the rectal temperature kept at 37 ± 0.2°C or to whole body cooling with the rectal temperature kept at 33.5 ± 0.5°C for 72 hours followed by slow rewarming. The outcome will be assessed at 18 months of age by survival and neurological and neurodevelopmental testing. Eligibility criteria: Term infants less than 6 hours after birth with moderate or severe perinatal asphyxia (a combination of clinical and EEG criteria). Exclusion criteria: Infants expected to be 6 hours of age at the time of randomisation or infants with major congenital abnormalities. Intervention: Intensive care with whole body cooling versus intensive care without whole body cooling (babies are cooled to 33.5°C for 72 hours) Main Outcomes: Death and severe neurodevelopmental impairment at 18 months of age Secondary Outcomes: Cerebral thrombosis or haemorrhage, persistent hypotension, pulmonary hypertension, abnormal coagulation, arrhythmia and sepsis in the neonatal period. Neurological impairments at 18 months Number of patients required: 236. On 30th November 2006, when recruitment closed, 325 babies had been recruited.
Interventions
PROCEDUREWhole body mild induced hypothermia
Target rectal temperature 33-34°C for 72 hours, commencing by 6 hours of age; followed by re-warming at 0.5°C to normothermia
Sponsors
Medical Research Council
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Hours to 6 Hours
Healthy volunteers
No
Inclusion criteria
The infant will be assessed sequentially by criteria A, B and C listed below: A. Infants =\>36 completed weeks gestation admitted to the Neonatal Intensive Care Unit (NICU) 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 within 60 minutes of birth (defined as any occurrence of umbilical cord, arterial or capillary pH \<7.00) * Base Deficit =\>16 mmol/L in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth Infants that meet criteria A will be assessed for whether they meet the neurological abnormality entry criteria (B) by trained personnel: B. Moderate to severe encephalopathy, consisting of altered state of consciousness (lethargy, stupor or coma) AND at least one of the following: * hypotonia * abnormal reflexes including oculomotor or pupillary abnormalities * absent or weak suck * clinical seizures Infants that meet criteria A & B will be assessed by amplitude-integrated electroencephalogram (aEEG) (read by trained personnel): C. At least 30 minutes duration of amplitude integrated EEG recording that shows abnormal background aEEG activity or seizures. There must be one of the following: * normal background with some seizure activity * moderately abnormal activity * suppressed activity * continuous seizure activity
Exclusion criteria
* Infants expected to be \> 6 hours of age at the time of randomisation * Major congenital abnormalities, such as diaphragmatic hernia requiring ventilation, or congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors | 18 months | Severe neurodevelopmental disability was defined as a score of less than 70 on the Mental Developmental Index of the Bayley Scales of Infant Development II (BSID-II) (on which the standardization mean \[± standard deviation (SD)\] is 100±15 and higher scores indicate better performance), a score of 3 to 5 on the Gross Motor Function Classification System (GMFCS) (on which scores can range from 1 to 5, with higher scores indicating greater impairment), or bilateral cortical visual impairment with no useful vision. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Persistent Hypotension | Duration of hospital stay, on average 22 days | Hypotension was defined as a mean blood pressure of 40 mm Hg or less and was persistent if causes of hypotension had been sought and appropriate treatment provided, without success. |
| Pulmonary Haemorrhage | Duration of hospital stay, on average 22 days | — |
| Pulmonary Hypertension | Duration of hospital stay, on average 22 days | — |
| Prolonged Blood Coagulation Time | Duration of hospital stay, on average 22 days | — |
| Culture Proven Sepsis | Duration of hospital stay, on average 22 days | — |
| Necrotising Enterocolitis | Duration of hospital stay, on average 22 days | — |
| Cardiac Arrhythmia | Duration of hospital stay, on average 22 days | Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia \<80 beats per minute, ventricular arrhythmia. |
| Thrombocytopenia | Duration of hospital stay, on average 22 days | — |
| Major Venous Thrombosis | Duration of hospital stay, on average 22 days | — |
| Renal Failure Treated With Dialysis | Duration of hospital stay, on average 22 days | — |
| Intracranial Haemorrhage | Duration of hospital stay, on average 22 days | Intracranial hemorrhage was identified on magnetic resonance imaging (MRI). |
| Pulmonary Airleak | Duration of hospital stay, on average 22 days | — |
| Duration of Hospitalisation | Duration of hospital stay, on average 22 days | Total duration of hospital care |
| Mortality | 18 months | — |
| Severe Neurodevelopmental Disability | 18 months | — |
| Multiple Handicap | 18 months | defined as the presence of any two of the following in an infant; neuromotor disability (Level 3-5 on Gross Motor Function classification), mental delay (Bayley Mental Developmental Index (MDI) score \< 70), epilepsy, cortical visual impairment, sensorineural hearing loss |
| Bayley Psychomotor Developmental Index Score (PDI) | 18 months | Bayley Psychomotor Developmental Index score (PDI) \<70 |
| Sensorineural Hearing Loss | 18 months | Normal or near normal hearing, no sensorineural hearing loss |
| Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment) | 18 months | — |
| Microcephaly | 18 months | Head circumference at follow-up \>2 standard deviations below the mean |
| Pneumonia | Before discharge from hospital | — |
Countries
United Kingdom
Participant flow
Recruitment details
Infants who met trial entry criteria were recruited at 40 Neonatal Intensive Care Units mainly in the United Kingdom and also in Europe. Recruitment took place over 4 years, from December 2006 to November 2006.
Pre-assignment details
494 infants were assessed for eligibility; 94 did not meet inclusion criteria, 30 declined to participate 45 were not enrolled for other reasons. 325 underwent randomization.
Participants by arm
| Arm | Count |
|---|---|
| Cooled Whole body mild induced hypothermia 72 hours, commencing by 6 hours of age followed by re-warming to normothermia. | 163 |
| Non-cooled Standard intensive care | 162 |
| Total | 325 |
Baseline characteristics
| Characteristic | Cooled | Non-cooled | Total |
|---|---|---|---|
| Age, Customized Age 0-4 hours | 48 participants | 57 participants | 105 participants |
| Age, Customized Age 4-6 hours | 115 participants | 105 participants | 220 participants |
| Sex: Female, Male Female | 62 Participants | 74 Participants | 136 Participants |
| Sex: Female, Male Male | 101 Participants | 88 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 126 / 163 | 134 / 162 |
| serious Total, serious adverse events | 8 / 163 | 3 / 162 |
Outcome results
Primary
Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors
Severe neurodevelopmental disability was defined as a score of less than 70 on the Mental Developmental Index of the Bayley Scales of Infant Development II (BSID-II) (on which the standardization mean \[± standard deviation (SD)\] is 100±15 and higher scores indicate better performance), a score of 3 to 5 on the Gross Motor Function Classification System (GMFCS) (on which scores can range from 1 to 5, with higher scores indicating greater impairment), or bilateral cortical visual impairment with no useful vision.
Time frame: 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors | 74 participants |
| Non-cooled | Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors | 86 participants |
Secondary
Bayley Psychomotor Developmental Index Score (PDI)
Bayley Psychomotor Developmental Index score (PDI) \<70
Time frame: 18 months
Population: Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Bayley Psychomotor Developmental Index Score (PDI) | 27 participants |
| Non-cooled | Bayley Psychomotor Developmental Index Score (PDI) | 37 participants |
Secondary
Cardiac Arrhythmia
Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia \<80 beats per minute, ventricular arrhythmia.
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Cardiac Arrhythmia | 8 participants |
| Non-cooled | Cardiac Arrhythmia | 3 participants |
Secondary
Culture Proven Sepsis
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Culture Proven Sepsis | 20 participants |
| Non-cooled | Culture Proven Sepsis | 20 participants |
Secondary
Duration of Hospitalisation
Total duration of hospital care
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cooled | Duration of Hospitalisation | 12 days |
| Non-cooled | Duration of Hospitalisation | 13 days |
Secondary
Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment)
Time frame: 18 months
Population: Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment) | 12 participants |
| Non-cooled | Epilepsy (Defined as Recurrent Seizures Beyond the Neonatal Period, Requiring Anticonvulsant Therapy at the Time of Assessment) | 16 participants |
Secondary
Intracranial Haemorrhage
Intracranial hemorrhage was identified on magnetic resonance imaging (MRI).
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Intracranial Haemorrhage | 25 participants |
| Non-cooled | Intracranial Haemorrhage | 21 participants |
Secondary
Major Venous Thrombosis
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Major Venous Thrombosis | 2 participants |
| Non-cooled | Major Venous Thrombosis | 1 participants |
Secondary
Microcephaly
Head circumference at follow-up \>2 standard deviations below the mean
Time frame: 18 months
Population: Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Microcephaly | 24 participants |
| Non-cooled | Microcephaly | 28 participants |
Secondary
Mortality
Time frame: 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Mortality | 42 participants |
| Non-cooled | Mortality | 44 participants |
Secondary
Multiple Handicap
defined as the presence of any two of the following in an infant; neuromotor disability (Level 3-5 on Gross Motor Function classification), mental delay (Bayley Mental Developmental Index (MDI) score \< 70), epilepsy, cortical visual impairment, sensorineural hearing loss
Time frame: 18 months
Population: Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Multiple Handicap | 21 participants |
| Non-cooled | Multiple Handicap | 33 participants |
Secondary
Necrotising Enterocolitis
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Necrotising Enterocolitis | 1 participants |
| Non-cooled | Necrotising Enterocolitis | 0 participants |
Secondary
Persistent Hypotension
Hypotension was defined as a mean blood pressure of 40 mm Hg or less and was persistent if causes of hypotension had been sought and appropriate treatment provided, without success.
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Persistent Hypotension | 126 participants |
| Non-cooled | Persistent Hypotension | 134 participants |
Secondary
Pneumonia
Time frame: Before discharge from hospital
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Pneumonia | 5 participants |
| Non-cooled | Pneumonia | 5 participants |
Secondary
Prolonged Blood Coagulation Time
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Prolonged Blood Coagulation Time | 67 participants |
| Non-cooled | Prolonged Blood Coagulation Time | 72 participants |
Secondary
Pulmonary Airleak
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Pulmonary Airleak | 9 participants |
| Non-cooled | Pulmonary Airleak | 3 participants |
Secondary
Pulmonary Haemorrhage
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Pulmonary Haemorrhage | 5 participants |
| Non-cooled | Pulmonary Haemorrhage | 3 participants |
Secondary
Pulmonary Hypertension
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Pulmonary Hypertension | 16 participants |
| Non-cooled | Pulmonary Hypertension | 9 participants |
Secondary
Renal Failure Treated With Dialysis
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Renal Failure Treated With Dialysis | 0 participants |
| Non-cooled | Renal Failure Treated With Dialysis | 0 participants |
Secondary
Sensorineural Hearing Loss
Normal or near normal hearing, no sensorineural hearing loss
Time frame: 18 months
Population: Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Sensorineural Hearing Loss | 110 participants |
| Non-cooled | Sensorineural Hearing Loss | 97 participants |
Secondary
Severe Neurodevelopmental Disability
Time frame: 18 months
Population: Number of participants analyzed is reduced due to deaths prior to assessment and not all survivors could complete all elements of the examination. Number analyzed represents the participants on whom the relevant data for this outcome could be documented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Severe Neurodevelopmental Disability | 32 participants |
| Non-cooled | Severe Neurodevelopmental Disability | 42 participants |
Secondary
Thrombocytopenia
Time frame: Duration of hospital stay, on average 22 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cooled | Thrombocytopenia | 94 participants |
| Non-cooled | Thrombocytopenia | 80 participants |