Cooling Babies Limits Brain Injury
Submitting InstitutionImperial College London
Unit of AssessmentPsychology, Psychiatry and Neuroscience
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Neurosciences, Paediatrics and Reproductive Medicine, Public Health and Health Services
Summary of the impact
Imperial College researchers have pioneered the implementation of
therapeutic hypothermia to improve survival of neonates following
Following their programme of clinical research to prove feasibility,
Professors Azzopardi and Edwards led the Total Body Hypothermia for
Neonatal Encephalopathy Trial (TOBY), a multicentre, randomised trial
investigating the effects of total-body cooling for 72 hours in babies
with asphyxial encephalopathy from a lack of oxygen at birth. This work
demonstrated that infants in the cooled group had an increased rate of
survival without neurologic abnormality. This work has influenced public
policy and healthcare provision, through the implementation and audit of
therapeutic hypothermia nationally and internationally. In the UK, cooling
therapy is now carried out in 1000- 1500 cases annually (Data reported to
the UK National Register of Cooling). Cooling following perinatal asphyxia
is now standard of care in most resource rich and intermediate countries.
Key Imperial College Researchers:
Professor Denis Azzopardi, Professor of Neonatal Medicine (1993-present)
Professor A David Edwards, Weston Professor of Neonatal Medicine
(1992-2012) now Visiting
Following his appointment at Imperial College in 1993, Professor
Azzopardi focused on developing clinical trials of neuroprotective
intervention in newborns. In 1999, Professor Azzopardi developed a simple
classification for the cot side analysis of amplitude integrated EEG to
assess objectively the severity of neonatal encephalopathy. The
classification facilitated the first clinical trials of hypothermia in
encephalopathic newborns and has since been adopted widely, including by
major international trials. The report of this work has been cited more
than 170 times to date .
In 2005, Professor Azzopardi and Professor Edwards published results of
the first pilot study of intervention with total body hypothermia in
newborns. The study provided evidence that neural rescue is possible after
birth asphyxia, with hypothermia providing a simple, cost effective
treatment . To date this work has been cited over 732 times since
publication in 2005, and has been the subject of position statements by
the NIH, Royal College of Paediatrics and Child Health, and the American
To pursue this work Professors Azzopardi and Edwards obtained funding
from the Medical Research Council (MRC) to carry out the largest
international trial of this therapy, the TOBY study, which recruited in
excess of target, and confirmed the preliminary findings of their previous
studies [3-4]. The TOBY trial (325 infants enrolled) demonstrated that
following induction of moderate hypothermia for 72 hours in infants who
had perinatal asphyxia Infants in the cooled group had an increased rate
of survival without neurologic abnormality. Among survivors, Cooling
resulted in significantly reduced risks of cerebral palsy and improved
scores on the Mental Developmental Index .
The trials [2-4] and synthesis of the trial data  confirm in larger
populations that 72 hours of cooling to a core temperature of 33-34oC,
started within six hours of birth, reduces death and disability at 18
months of age and improves a range of neurodevelopmental outcomes in
survivors. The studies carried out by Professors Azzopardi and Edwards
showed that therapeutic hypothermia increases the rate of survival with a
normal outcome by about 50%. This Imperial programme and clinical trials
has demonstrated that therapeutic hypothermia improved the rate of intact
survival following perinatal asphyxia. An economic evaluation showed that
the treatment is cost effective .
References to the research
(1) al Naqeeb, N., Edwards, A.D., Cowan, F.M., Azzopardi, D. (1999).
Assessment of neonatal encephalopathy by amplitude-integrated
electroencephalography. Pediatrics, 103 (6), 1263-71.
Times cited: 170 (as at 23rd September 2013 on ISI Web of
Science). Journal Impact Factor: 5.43
(2) Gluckman, P.D., Wyatt, J.S., Azzopardi, D., Ballard, R., Edwards,
A.D., Ferriero, D.M., Polin, R.A., Robertson, C.M., Thoresen, M.,
Whitelaw, A., Gunn, A.J. (2005). Selective head cooling with mild systemic
hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet,
365 (9460), 663-670. DOI.
Times cited: 732 (as at 23rd September 2013 on ISI Web of Science).
Journal Impact Factor: 38.27
(3) Azzopardi, D.V., Strohm, B., Edwards, A.D., Dyet, L., Halliday, H.L.,
Juszczak, E., et al. TOBY Study Group. (2009). Moderate hypothermia to
treat perinatal asphyxial encephalopathy. New England Journal of
Medicine, 361(14), 1349-1358. DOI.
Times cited: 322 (as at 23rd September 2013 on ISI Web of Science).
Journal Impact Factor: 53.29
(4) Rutherford, M., Ramenghi, L.A., Edwards, A.D., Brocklehurst, P.,
Halliday, H., Levene, M., Strohm, B., Thoresen, M., Whitelaw, A., &
Azzopardi, D. (2010). Assessment of brain tissue injury after moderate
hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested
substudy of a randomised controlled trial. Lancet Neurology, 9
(1), 39-45. DOI.
Times cited: 85 (as at 23rd September 2013 on ISI Web of Science). Journal
Impact Factor: 23.46
(5) Edwards, A.D., Brocklehurst, P., Gunn, A.J., Halliday, H., Juszczak,
E., Levene, M., Strohm, B., Thoresen, M., Whitelaw, A., & Azzopardi,
D. (2010). Neurological outcomes at 18 months of age after moderate
hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and
meta- analysis of trial data. British Medical Journal, 340,
c363. DOI. Times cited:
140 (as at 23rd September 2013 on ISI Web of Science). Journal Impact
(6) Regier, D.A., Petrou, S., Henderson, J., Eddama, O., Patel, N.,
Strohm, B., Brocklehurst, P., Edwards, A.D., & Azzopardi, D. (2010).
Cost-effectiveness of therapeutic hypothermia to treat neonatal
encephalopathy. Value in Health, 13 (6), 695-702. DOI.
Times cited: 3 (as at 23rd September 2013 on ISI Web of Science). Journal
Impact Factor: 2.19
• MRC (2002-2008; £676,497), Principal Investigator (PI) D. Azzopardi,
Whole body hypothermia for perinatal asphyxial encephalopathy.
• MRC (2010-2014; £1,045,270), PI D. Azzopardi, Outcomes at school age
following therapeutic hypothermia for perinatal asphyxial encephalopathy.
Details of the impact
Impacts include: health and welfare, commerce, public policy and
services, practitioners and
Main beneficiaries include: patients, NHS, NICE, industry, international
Severe perinatal asphyxia is a serious complication occurring in about
1-3 infants in every 1000 births (approximately 1500-2000 infants in the
UK) with a 60% risk of death or disability in survivors. Following the
studies carried out by Professors Azzopardi and Edwards, therapeutic
hypothermia is now recognised as a significant advance in clinical
medicine by the National Institute of Health and Clinical Excellence
(NICE) and the British Association of Perinatal Medicine (BAPM) in 2010
for general introduction into the NHS [1-2].
Professor Azzopardi set up a National Registry, known as the TOBY
register, of treatment with hypothermia which provides guidance for
clinicians and has led to co-ordinated implementation of this therapy
nationally . The Register, coordinated by the National Perinatal
Epidemiology Unit, Oxford, also undertakes surveillance and audit and
provides feedback to participants and publishes regular newsletters and
reports. Professor Azzopardi developed guidelines and protocols on
therapeutic hypothermia that are used widely in neonatal networks
throughout the UK. Both NICE and the BAPM recommend that the details of
neonates who receive the cooling treatment be entered into the TOBY
register [1-2]. The latest analysis of Register data published by
Professor Azzopardi in PLOS in 2012 showed that this therapy is now
standard care in the UK . For example, the TOBY register clinician's
handbook provides practical guidelines to the selection of infants and
their clinical management and is widely used . Data from the clinical
trials of hypothermia and the National Register indicate that as a result
of therapeutic hypothermia 100 fewer infants annually develop cerebral
palsy due to birth asphyxia. Since inception of the Register it is
estimated that there has been a cost saving to the health economy of about
£150M. Nationwide surveys modelled on the UK Register have been carried
out in Switzerland and Japan .
This work has also impacted international guidelines and clinical
protocols . For example; the American Heart Association (AHA) &
American Academy of Paediatrics (2010) recommends "Therapeutic hypothermia
(whole body or selective head cooling) recommended for infants ≥ 36 weeks
with moderate to severe hypoxic ischemic encephalopathy as per the
protocol used in major cooling trials with provision for monitoring for
side effects and long term follow up". In 2010 this guidance was updated
and changed to reflect the findings of the Imperial lead TOBY study
published in 2009 .
Professor Azzopardi's classification of the amplitude integrated EEG for
assessing the severity of neonatal encephalopathy and its use for infant
selection into neuroprotective trials using a British designed monitor
first developed in the 1960s, led to the further development of modern
digital portable cot-side brain function monitors that now are used
routinely in neonatal intensive care units (eg The CFM Olympic Brain
To carry out the MRC-funded international TOBY trial of cooling therapy
for neonatal encephalopathy Professor Azzopardi successfully used a
simple, modified cooling mattress originally designed for topical cooling
in adults and this subsequently was developed into a CE marked servo
controlled neonatal cooling system that is used widely (Tecotherm Neo, Inspiration Healthcare
Ltd Leicester UK). The positive results of the clinical trials led
by Professor Azzopardi drove the development of other specific cooling
equipment (eg Criticool, MTRE Ltd, Israel). This work has led to the
international sale and distribution of neonatal cooling equipment .
Patients and patient advocacy groups have played an important role in
Imperial's clinical research. A representative from SCOPE participated in
the Trial Management Group for the TOBY cooling trial and helped develop
the patient information literature. BLISS,
the UK charity supporting newborn care, hosted an internet forum for
parents of infants participating in the TOBY trial. A parent of a child
who participated in the TOBY trial is a member of the Children's Study
Trial Steering Committee, led by Professor Azzopardi, and now lay members
participate in the Management Group for neonatal neuroimaging research at
A Neonatal Taskforce (Department of Health) has developed a toolkit to
facilitate the delivery of equitable, transparent and auditable neonatal
care. The aim of the toolkit is to ensure that premature and sick newborn
babies receive the care necessary to produce the best long-term outcomes.
The toolkit provides a set of principles for quality neonatal services.
These standards of care provision reflect the findings of the Imperial
lead TOBY study .
Sources to corroborate the impact
 NICE clinical guidelines reflecting TOBY findings:
National Institute for Health and Clinical Excellence. Therapeutic
hypothermia with intracorporeal temperature monitoring for hypoxic
perinatal brain injury. 2010. http://guidance.nice.org.uk/IPG347
 Position statement and national treatment guidelines:
 The TOBY Cooling Register:
- Azzopardi, D., Strohm, B., Linsell, L., Hobson, A., Juszczak, E.,
Kurinczuk, J.J., Brocklehurst, P., Edwards, A.D.; UK TOBY Cooling
Register (2012). Implementation and conduct of therapeutic hypothermia
for perinatal asphyxial encephalopathy in the UK--analysis of national
data. PLoS One, 7(6):e38504. DOI.
- Professor Azzopardi developed guidelines and protocols on therapeutic
hypothermia that are used widely in neonatal networks throughout the UK
8th November 2013).
- TOBY register clinician's handbook https://www.npeu.ox.ac.uk/tobyregister/docs
8th November 2013)
 Iwata, O., Nabetani, M., Takenouchi, T., Iwaibara, T., Iwata, S.,
Tamura, M. (2012). Working Group on Therapeutic Hypothermia for Neonatal
Encephalopathy, Ministry of Health, Labor and Welfare, Japan; Japan
Society for Perinatal and Neonatal Medicine. Hypothermia for neonatal
encephalopathy: Nationwide Survey of Clinical Practice in Japan as of
August 2010. Acta Paediatr, 101(5), e197-202. DOI.
 International standards/guidance:
 Neonatal cooling equipment is sold and distributed internationally.
- Within Europe neonatal cooling equipment is distributed by: Eurocare
(France), AdQUIPMENT MEDICAL BV (Netherland), Heinen & Lowenstein
GmbH & Co.KG (Germany), Medical Market INT. AB (Sweden). In addition
the equipment is distributed in Russia (MODUS Closed Joint Stock
Company) China (Beijing Oumike Science and Technology Co Ltd) and Chile
8th November 2013)
For High Quality Neonatal Services (Department of Health)