Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy

• Register: ISRCTN
• Last refreshed on: 17 October 2016
• Main ID: ISRCTN89547571
• Date of registration: 21/09/2000
• Prospective Registration: Yes
• Primary sponsor: Imperial College London (UK)
• Public title: Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy
• Scientific title: Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial
• Date of first enrolment: 01/09/2002
• Target sample size: 325
• Recruitment status: Completed
• URL: http://isrctn.com/ISRCTN89547571
• Study type: Interventional
• Study design: Randomised controlled trial; subsequent cohort study at school age follow up (Treatment)
• Phase: Not Applicable

Countries of recruitment

Finland, Hungary, Ireland, Israel, Sweden, United Kingdom

Contacts

• Name: Denis Azzopardi

Key inclusion & exclusion criteria

Inclusion criteria: Infants will be assessed sequentially by criteria 1, 2 and 3 listed below:

1. Infants greater than or equal to 36 weeks gestation admitted to the Neonatal Intensive Care Unit (NICU) with ONE of the following:
1.1. Apgar score of less than five at ten minutes after birth
1.2. Continued need for resuscitation, including endotracheal or mask ventilation, at ten minutes after birth
1.3. Acidosis defined as either umbilical cord pH or any arterial pH within 60 minutes of birth less than pH 7.00
1.4. Base deficit greater than or equal to 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 criteria 1 then assess for neurological abnormality (by trained study personnel):

2. Moderate to severe encephalopathy consisting of altered state of consciousness (lethargy, stupor or coma) and at least one or more of hypotonia, abnormal reflexes including oculomotor or pupillary abnormalities, an absent or weak suck or clinical seizures, as recorded by study personnel.

If the infant meets criteria 1 & 2 then assess by amplitude-integrated electroencephalography (aEEG) (read by trained study personnel):

3. 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:
3.1. Normal background with some seizure activity
3.2. Moderately abnormal activity
3.3. Suppressed activity
3.4. Continuous seizure activity

TCS study:
1. Previously specified that they do not want to be contacted again
2. Previously recruited in the TOBY study within 6 hours of birth
3. Confirmed moderate or severe neonatal encephalopathy
Exclusion criteria: 1. Infants expected to be greater than 5.5 hours of age at the time of randomization
2. Major congenital abnormalities, such as diaphragmatic hernia requiring ventilation, or congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis

TCS study:
Non-participation will only occur if consent is not obtained or contact with the family cannot be achieved. Children who did not take part in the TOBY study are not eligible.

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Perinatal asphyxial encephalopathy, child development, cerebral palsy
Pregnancy and Childbirth
Other birth injuries to central nervous system

Intervention(s)

Full term infants will be randomised within six hours of birth to either a control group with the rectal temperature kept at 37 +/- 0.2 degrees celsius or to whole body cooling with the rectal temperature kept at 33.5 +/- 0.5 degrees celsius for 72 hours followed by slow rewarming.
Relevant physiological parameters will be monitored and outcome assessed at 18 months of age by survival and neurological and neurodevelopmental testing.

TCS study:
No intervention, comparison of outcomes at school age in the treatment and control groups.

Primary Outcome(s)

The primary outcome for this trial is a combined endpoint: death in the first 18 months of life OR Severe neurodevelopmental disability.

TCS study:
Frequency of survival with an IQ greater than 84; timepoint: 6 years to 7 years and 4 months.

Secondary Outcome(s)

Secondary outcome measures added as of 16/10/2007:
Short term (before discharge from hospital):
1. Intracranial haemorrhage
2. Persistent hypotension
3. Pulmonary haemorrhage
4. Pulmonary hypertension
5. Prolonged blood coagulation time
6. Culture proven sepsis
7. Necrotising enterocolitis
8. Cardiac arrhythmia
9. Thrombocytopenia
10. Major venous thrombosis
11. Renal failure treated with dialysis
12. Pneumonia
13. Pulmonary airleak
14. Duration of hospitalisation

Long term (at 18 months):
1. Mortality
2. Severe neurodevelopmental disability
3. Multiple handicap, defined as the presence of any two of the following in an infant:
3.1. Neuromotor disability (Level 3-5 on General Motor Function (GMF) Assessment Scale classification), mental delay (the Bayley Scales of Infant Development - Mental Development Indices (MDI) score less than 70), epilepsy, cortical visual impairment, sensorineural hearing loss
4. The Bayley Scales of Infant Development - Psychomotor Development Indices (PDI) score
5. Sensorineural hearing loss: greater than or equal to 40 dB
6. Epilepsy (defined as recurrent seizures beyond the neonatal period, requiring anticonvulsant therapy at the time of assessment)
7. Microcephaly (head circumference more than 2 standard deviations below the mean)

TCS study:
1. Overall IQ from Wechsler Preschool and Primary Scale of Intelligence tests (WPPSI III)
2. Overall Working Memory Test Battery for Children (WMTB-C) Scale
3. Overall Strengths and Difficulties Quotient score (SDQ) for behavioural problems
4. Overall ADHD Score (Du Paul RS IV)
5. Prevalence of Cerebral Palsy
6. Gross Motor Function Classification System level GMFCS)
7. Unimpaired outcome and overall grade of disability
8. Teachers academic achievement score
9. Health Utility Index (HUI-III)
10. Overall number of deaths in each group to age 7 years and 4 months

Secondary ID(s)

MRC ref: G0100126; G0801320

NCT00147030, NCT01092637

Source(s) of Monetary Support

Medical Research Council (MRC) (UK) (ref: G0100126), The TCS study has also been funded by the Medical Research Council (MRC) (UK) (ref: G0801320)