This will be a multi-centre, prospective, randomised study of term infants after perinatal asphyxia comparing those allocated to "intensive care plus total body cooling for 72 hours" with those allocated to "intensive care without cooling". Clinical staff will be unblinded because they must know the rectal temperature of the infants in order to adjust the cooling and heating appropriately. The primary outcome measure (severe neurodevelopmental disability) will be assessed blind to allocation.
The infant will be assessed sequentially by criteria A, B and C listed below:
A. Infants ≥ 36 completed weeks gestation admitted to the 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:
• abnormal reflexes including oculomotor or pupillary abnormalities
• absent or weak suck
• clinical seizures
Infants that meet criteria A & B will be assessed by aEEG (read by trained personnel):
C. At least 30 minutes duration of aEEG 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
• 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
Every effort will be made to ensure entry to the study before 3 hours of age. Delays should be avoided because there may be rapid attenuation of neuroprotection with delay in the start of cooling [69
Informed written consent will be obtained from a parent after a full verbal and written explanation of the study. The attending physician will meet with parents during the intervention period to ensure that they understand the study procedures and continue to consent to participate in the study.
Approval for the study has been obtained from the London Multicentre Research Ethics Committee and the Local Research Ethics Committee of each participating hospital.
Patient allocation will be by central telephone randomisation, provided by the National Perinatal Epidemiology Unit (NPEU). As soon as parental consent has been obtained for an eligible infant, the recruiting TOBY clinician will telephone the randomisation service and obtain treatment assignment, which will be either to "intensive care with cooling" or "intensive care". Minimisation will be used to ensure balance between the groups with respect to severity of encephalopathy.
All infants recruited to the study will be cared for in a tertiary referral centre that has the equipment necessary for providing hypothermia treatment to the "intensive care with cooling" group ("Treatment Centres"). Infants may be recruited from hospitals that transfer babies to these centres. Babies that are thought to be eligible will be assessed by trained retrieval teams from the referral centres, who will perform the aEEG, seek consent if eligible, telephone the randomisation service and begin the cooling treatment, if allocated (see TOBY Handbook for more details).
1. Intensive care group
All infants who are randomised to this group will receive the present standard of clinical care. Infants will thus receive symptomatic therapy aimed at homeostasis. In particular, the management of the temperature of the infants will aim to maintain normothermia. All infants will be dried at birth, and kept warm during resuscitation. The infants will be cared for under an overhead radiant heater or in closed incubators, servo controlled to the infants' abdominal skin temperature, to maintain the rectal temperature at 37.0°C ± 0.2°C. Infants born in referring hospitals that are randomised to this group will be transferred to the Treatment Centre. The incubator heater will be adjusted during transport to maintain a rectal temperature as close to 37.0°C as possible.
2. Intensive care with cooling group
All infants randomised to intensive care with cooling will be treated in closed incubators to facilitate cooling. Hypothermia will be maintained using the Tecotherm cooling system, which induces hypothermia by circulating fluid within a special mattress. A temperature thermostat can be regulated to alter the temperature of the fluid. Typically the thermostat should be set at 25–30°C to achieve a target rectal temperature of 33–34°C.
Infants born outside Treatment Centres who are allocated to intensive care with cooling will be nursed prior to transfer with the overhead radiant warmer turned off. During transport the infant will be nursed in a transport incubator. The incubator heater will be turned on and adjusted if necessary to maintain the rectal temperature between 33 and 34°C. Cooled gel packs will be placed around the infant if necessary to maintain the target temperature.
Some referring hospitals may have quick access to a Treatment Centre. If it is likely that the infant can be transferred within three hours of birth, assessment and randomisation may be postponed until admission to the Treatment Centre. These infants will receive the normal standard of care, including maintaining a rectal temperature of 37 ± 0.2°C, during the transfer
When cooling is concluded 72 hours after randomisation, or earlier if clinical circumstances dictate, the rectal temperature will be allowed to rise by no more than 0.5°C per hour, to 37 ± 0.2°C. The thermostat set point of the Tecotherm system will be adjusted as needed, to rewarm the infants. The infants' temperature will be carefully monitored for at least 4 hours to prevent rebound hyperthermia, as this might be detrimental [71
Discontinuing cooling treatment
Cooling may be discontinued if any of the following occurs:
• Parents request that cooling be withdrawn prior to 72 hours after randomisation. This decision should be made in discussion with the TOBY Clinician whenever possible.
• Attending clinician withdraws cooling. Reasons will be recorded, and might include clinical, EEG and imaging evidence of severe, irreversible brain injury, or continued inability to maintain rectal temperature in the desired range.
• Baby receives extra-corporeal membrane oxygenation (ECMO).
If the parents or the attending paediatrician elect to discontinue cooling, then rewarming and follow-up procedures will be commenced. Apparent improvement on continuous aEEG recording, after trial entry, is not an indication for discontinuing cooling.
3. Both groups
Treatment centres will provide a uniform standard of clinical care, to minimise potential bias that could arise from differential use of co-interventions. Following resuscitation, ventilatory requirement will be judged by assessing the infant's spontaneous breathing efforts and blood gas analysis. Infants who appear distressed will receive standard sedation. Seizures (whether noted on aEEG or clinically) will be treated using a standardised approach. Blood electrolyte analysis, urine volume and analysis and infant weight will be monitored to guide fluid management. See the TOBY Handbook for more details.
• Combined incidence of mortality and severe neurodevelopmental disability in survivors at 18 months of age.
Neurodevelopment will be assessed, blind to study group, by a developmental paediatrician. Severe neurodevelopmental disability will be defined as the presence of at least one of:
• Bayley mental development scale (MDI) score < 70
• Gross motor function (GMF) neuromotor impairment Level 3–5
• Bilateral cortical visual impairment
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
10. Major venous thrombosis
11. Renal failure treated with dialysis
13. Pulmonary air leak
14. Duration of hospitalisation
Long term (at 18 months)
2. Severe neurodevelopmental disability
3. Multiple handicaps (defined as the presence of any two of the following in an infant; neuromotor disability (Level 3–5 on GMF classification), mental delay (Bayley MDI score < 70), epilepsy, cortical visual impairment, sensorineural hearing loss)
4. Bayley PDI score
5. Sensorineural hearing loss: ≥ 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).
Short-term outcomes (up to discharge from hospital) will be assessed from hospital notes. Major morbidity at 18 months will be assessed by a research paediatrician, blind to study allocation, using a standardised neurological examination and the revised Bayley Scales of Infant Development (BSID-II).
The relative risks of outcomes between the intensive care with cooling group and the intensive care group will be calculated, along with 95% confidence intervals.
Subgroup analyses will be carried out stratifying by:
(a) severity of encephalopathy at study entry (graded moderate or severe based on pre-specified aEEG criteria);
(b) interval from birth to randomisation (0–2 hours, 2–4 hours, 4–6 hours)
An independent Data Monitoring and Ethics Committee (DMEC) will be established, whose remit will be to review the study's progress. The DMEC will be independent of the trial organisers. Interim analyses will be supplied, in strict confidence, to the DMEC, as frequently as its Chair requests. Meetings of the committee will be arranged periodically, as considered appropriate by the Chair. In the light of interim data on the trial's outcomes, adverse event data, accumulating evidence from the NICHD study (see below) and any other relevant evidence (including updated overviews of the relevant randomised controlled trials), the DMEC will inform the Trial Steering Committee (TSC) if in their view (i) there is proof beyond reasonable doubt that the data indicate that any part of the protocol under investigation is either clearly indicated or contra-indicated, either for all infants or for a particular subgroup of trial participants or (ii) it is evident that no clear outcome will be obtained. Appropriate criteria for proof beyond reasonable doubt cannot be specified precisely. A difference of at least 3 standard deviations in the interim analysis of a major endpoint may be needed to justify halting, or modifying, such a study prematurely. If this criterion were to be adopted, it would have the practical advantage that the exact number of interim analyses would be of little importance, and so no fixed schedule is proposed. Unless modification or cessation of the study is recommended by the DMEC, the TSC, investigators, collaborators and administrative staff (except those who supply the confidential information) will remain ignorant of the results of the interim analysis. Collaborators and all others associated with the study, may write to the DMEC via the TOBY Co-ordinating Centre, to draw attention to any concern they may have about the possibility of harm arising from the treatment under study, or any other relevant matters.
The DMEC will liaise closely with a related trial of whole body cooling being conducted by the NICHD in the United States. This trial uses the same intervention but different eligibility criteria. Its results are likely to be relevant to decisions about continuation of recruitment to TOBY.
The membership of the DMEC is:
Professor Richard Cooke (Chair)
Dr Ann Johnson (Developmental Paediatrician)
Dr Sam Richmond (Neonataologist)
Dr Hugh Davies (Paediatrician and former MREC Chairman)
Dr Pat Yudkin (Statistician)
Serious adverse event reporting
All unexpected serious adverse events will be reported to the TOBY co-ordinating centre at the National Perinatal Epidemiology Unit in Oxford within 24 hours. The study administrator will inform the Chair of the Data Monitoring and Ethics Committee and the Multicentre Research Ethics Committee of any serious adverse events.
The overall rate of the primary outcome in the non cooled group is assumed to be approximately 70%. A sample size of 188 infants will be necessary to detect a 30% relative risk reduction between the cooled and non cooled groups, at a significance level of 5% and with 80% power. The incidence of the primary outcome in the cooled group would be 49%. Allowing for a rate of loss to follow up of 10%, 207 infants will need to be recruited to reach this target.
However, this calculation needs to be modified to ensure that meaningful subgroup analyses can be performed for both infants with moderate and severe encephalopathy. The event rates of the primary outcome will be approximately 100% for infants with a severely abnormal aEEG, and about 60% for infants in the moderately abnormal group. Each subgroup needs to be large enough to detect a relative risk between the cooled and non cooled groups of about 0.6. For the moderately abnormal subgroup, the sample size required for 80% power will be 150.
It is expected that about 70% of infants will be in the moderately abnormal subgroup, so to ensure that 150 will be recruited to this subgroup, the total sample size will be 214. This would mean that 64 recruits would be in the severely abnormal subgroup, a sufficient number to detect the same difference in this subgroup with greater than 80% power. Allowing for 10% loss to follow up, the original total sample size to be recruited is 236.