TOBY (TOtal Body hYpothermia): a Study of Treatment for Perinatal Asphyxia
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.
|Asphyxia Neonatorum Hypoxia Encephalopathy Seizures||Procedure: Whole body mild induced hypothermia|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy|
- Combined Incidence of Mortality and Severe Neurodevelopmental Disability in Survivors [ Time Frame: 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.
- Intracranial Haemorrhage [ Time Frame: Duration of hospital stay, on average 22 days ]Intracranial hemorrhage was identified on magnetic resonance imaging (MRI).
- Persistent Hypotension [ Time Frame: 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 [ Time Frame: Duration of hospital stay, on average 22 days ]
- Pulmonary Hypertension [ Time Frame: Duration of hospital stay, on average 22 days ]
- Prolonged Blood Coagulation Time [ Time Frame: Duration of hospital stay, on average 22 days ]
- Culture Proven Sepsis [ Time Frame: Duration of hospital stay, on average 22 days ]
- Necrotising Enterocolitis [ Time Frame: Duration of hospital stay, on average 22 days ]
- Cardiac Arrhythmia [ Time Frame: Duration of hospital stay, on average 22 days ]Arrhythmia identified on electrocardiogram (ECG), e.g. sinus bradycardia <80 beats per minute, ventricular arrhythmia.
- Thrombocytopenia [ Time Frame: Duration of hospital stay, on average 22 days ]
- Major Venous Thrombosis [ Time Frame: Duration of hospital stay, on average 22 days ]
- Renal Failure Treated With Dialysis [ Time Frame: Duration of hospital stay, on average 22 days ]
- Pneumonia [ Time Frame: Before discharge from hospital ]
- Pulmonary Airleak [ Time Frame: Duration of hospital stay, on average 22 days ]
- Duration of Hospitalisation [ Time Frame: Duration of hospital stay, on average 22 days ]Total duration of hospital care
- Mortality [ Time Frame: 18 months ]
- Severe Neurodevelopmental Disability [ Time Frame: 18 months ]
- Multiple Handicap [ Time Frame: 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) [ Time Frame: 18 months ]Bayley Psychomotor Developmental Index score (PDI) <70
- Sensorineural Hearing Loss [ Time Frame: 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) [ Time Frame: 18 months ]
- Microcephaly [ Time Frame: 18 months ]Head circumference at follow-up >2 standard deviations below the mean
|Study Start Date:||December 2002|
|Study Completion Date:||August 2008|
|Primary Completion Date:||November 2006 (Final data collection date for primary outcome measure)|
Active Comparator: cooled
Whole body mild induced hypothermia for 72 hours, starting by 6 hours of age, in addition to standard intensive care. After 72 hours of cooling, rewarming by a maximum of 0.5 degree C / hour to normothermia.
Procedure: Whole 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
No Intervention: non-cooled
Standard intensive care
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.
Term infants less than 6 hours after birth with moderate or severe perinatal asphyxia (a combination of clinical and EEG criteria).
Infants expected to be 6 hours of age at the time of randomisation or infants with major congenital abnormalities.
Intensive care with whole body cooling versus intensive care without whole body cooling (babies are cooled to 33.5°C for 72 hours)
Death and severe neurodevelopmental impairment at 18 months of age
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00147030
|London, United Kingdom, W12 0NN|
|Principal Investigator:||Denis Azzopardi, MD; FRCPCH||Imperial College London|