Cerebral palsy is one of the most devastating consequence of exposure to low oxygen levels or infection before birth. It can happen both after term and premature birth. Despite 35 years in electronic fetal monitoring, earlier C-sections and advances in obstetric care the incidence of cerebral palsy of perinatal origin has not decreased and has even increased in some Western countries. The costs to society are huge, estimated in 2002 for USA patients as $8.2 billion USD with 800,000 persons affected in USA alone, due to the combination of loss of potential productive members of society and the direct burden of care on the individual, family, and social institutions for the whole of life.
At term abnormal brain function occurs in two or three babies out of every thousand births. Twisted cords, weak placentas or contractions that are too strong can all cause such damage. Until recently, there was no treatment for these brain injuries.
Brain cooling, the first ever practical treatment for brain injury in babies was developed at the University of Auckland over nearly two decades. The possibility that getting a little cold might be good for babies was first proposed in antiquity, and strongly argued in Britain more than 300 years ago. What changed was that the team of researchers supported by the Health Research Council systematically showed in animal models that brain damage developed over time after the initial injury, and that key stages of this developing brain injury could be identified using brain monitoring. Professor Alistair Gunn and his colleagues found that cooling was actually a side effect of many supposedly brain protective drugs, and showed for the first time that cooling by itself was highly protective in certain stages after injury but not others. Cooling also had to be continued for several days, long enough to let the brain irritation settle down.
Using this knowledge, they first cautiously tested cooling in newborn babies who had signs of brain injury after birth. They introduced practical innovations that have been widely taken up, including the use of a simple neurological examination as well as brain monitoring shortly after birth to select babies for treatment. This led to the first large, randomised trial of head cooling, in collaboration with an American company, and other trials around the world. Together these trials have shown that cooling reduces severe disability in about one in eight affected babies, providing the first practical and effective treatment for this devastating problem. This research has established a critical base that will let the team find ways to further improve babies’ care.
Q. We would like to include some information about you and how you came to choose this career. Please can you tell us a bit about yourself and how you came to be in this area of research?
A. While I was training as a Paediatrician, I became fascinated by the way that after resuscitating babies who had been exposed to low oxygen, some would seem to improve for a few hours, and then get worse again, often with bad seizures. Nobody at the time knew for sure what this meant but some wondered if the damage was still progressing. I undertook a PhD with Sir Peter Gluckman in order to try to understand what was happening. My first experimental studies were giving rats supposedly protective drugs. I found that often the drugs made the animals cold – and when I kept them warm, the protection was much less. It seemed to me at the time that it would be more sensible to study this side effect directly, and leave out the middle man, so to speak.
Q. How has AMRF funding allowed your research to evolve or progress to the next stage?
A. Grants from the AMRF allowed me to purchase cooling machines for both preclinical studies and the clinical pilot studies. Further, project support helped me to complete preclinical studies that were vital to establish how deeply too cool, how late we could wait after cooling and how long we needed to continue cooling for to achieve protection. This information provided the critical scientific basis for a series of randomized clinical trials around the world, and gave clinicians and funding bodies the confidence that this was an important treatment that needed to be pragmatically tested.
Q. Please can you tell us a bit about how your research outcomes are being used in New Zealand, and the benefit to New Zealanders from your research:
A. Our research was the first to show that delayed cooling up to 6 hours after a severe insult could reduce brain injury, the first preclinical studies to define when and how much cooling was needed to protect the brain, the first clinical study to show that early neurological examination within the first few hours after birth could reliably identify babies at high risk of long-term death or disability, and the first large, international randomized trial to show that therapeutic hypothermia could improve the outcome of babies with hypoxic brain injury at birth. The trial led to licensing of the CoolCap by the FDA for Olympic Medical, USA.
Q. Have there been significant overseas breakthroughs or collaborations resulting from your research? Please can you describe your team’s contribution to the global research effort in your area:
A. Our research led directly to collaboration on the first ever international randomized clinical trial, the CoolCap trial. Its results were published in the Lancet in 2005. As a result of this research, therapeutic hypothermia is now the standard of care for babies with abnormal brain function after hypoxia (low oxygen) at birth around the world. This successful clinical proof that it is possible to prevent brain injury after exposure to severe oxygen deprivation has reinvigorated the search for additional treatments for brain injury.
Q. What is the next step in your research plan?
A. We are now looking for ways to make hypothermia work better. At the moment hypothermia increases the chances of completely normal outcome after hypoxic injury at birth by about 40% (a relative risk of 1.4), that is to say that many more babies surviving with no disability at all. This is a tremendously exciting improvement. Nevertheless, it also means that many babies still die or survive with disability despite cooling. To do this we are improving our knowledge of what combinations of therapies work together to improve outcomes better than hypothermia alone. Finally, I am working with Professor Laura Bennet also of the University of Auckland, an expert on preterm brain injury, to find ways to make it applicable to a wider range of babies, including premature infants.
Q. What is your greatest hope or dream for research in this field?
A. That one day we will be able to prevent or treat all cerebral palsy due to perinatal brain injuries.
Quote: Hypothermia is an overnight success, after 20 years of preclinical research to establish the evolution of injury and testing of many possible approaches.
Quote: Many people around the world and in New Zealand made critical contributions to developing brain cooling. Among these, it was my privilege to have worked with my late mother, Professor Tania Gunn, a tertiary care neonatologist at National Women’s Hospital, on these studies. Her rueful comment was that she started her career trying to stop babies getting cold and finished it actively cooling selected babies instead!