Optimal resuscitation and rapid exposure to cooling and xenon protects the newborn brain and heart after oxygen deprivation.

In the Western world, 2 out of 1000 children suffer oxygen deprivation (asphyxia) at birth. Without treatment, 66% of these births result in permanent brain damage or death. Research work led by Marianne Thoresen found that controlled cooling for 3 days of the newborns to 33.5°C after birth reduces the number with permanent injury to 50%. Cooling is now standard treatment for moderate and severly asphyxiated newborns in the western world This project continues this research to improve the cooling treatment and explore additional treatments. In what timeframe does cooling have a protective effect? Which temperature is optimal-is cooler better? How late after birth may treatment begin and still have an effect? Which other circumstances at birth may affect outcomes? Does letting the newborns inhale Xenon gas during the cooling treatment improve outcomes? Which effects does letting the newborns breathe pure Oxygen instead of air during resuscitation immediately after birth have? Is the effect of treatment dependent on how severe oxygen deprivation the child suffered during birth? Questions like these are being investigated through this project. The project funds three researchers at the University of Oslo and collaborative projects in England and Germany. One key focus is research into what makes up the optimal timeframe for cooling, and at what temperature. An important new discovery is that the damage in fact increases if treatment starts late, after twelve hours. In experimental models, we have further shown that cooling after very severe brain damage has no effect, even if treatment is started immediately after the initial injury. It has been standard practice to have oxygen-deprived newborns breathe pure Oxygen during the immediate, post-birth resuscitation. We have shown that this worsens brain damage in seven day old rats (the maturity of these rat pups equals that of humans born after a 34-35 week pregnancy, i.e. somewhat prematurely). However, we found that breathing pure Oxygen does not harm ten day old rats (at ten days after birth, their maturity equals that of humans born at term). Finally, our experimental results show that breathing pure Oxygen is beneficial for rat pups with the most severe brain damage. In recent experiments with newborn, oxygen-deprived rat pups, we demonstrated that cooling to below 32°C worsened the damage. Since the normal temperature for such rats is approximately 33.5-34.5°C, cooling to 32°C can be considered a mild cooling. In the context of a human child, this may mean that cooling children to 33.5°C goes too deep. We are researching this matter further. If the newborn suffered severe oxygen deprivation during birth, maintaining the child at as little as 1°C too high a temperature thereafter is also damaging. Similar results have also been found in adult cardiac arrest patients, which are often cooled protectively. Since cooling alone only results in a 'good' outcome (a surviving, healthy child) for approximately 25% of the children, we are studying Xenon gas (an anesthetic) as an additional treatment. Xenon treatment has been shown to protect nerve cells against damage after oxygen deprivation. In experiments with rats and newborn pigs (which are more similar to human children than rats are), we have shown that cooling combined with the inhalation of Xenon resulted in twice as good protection against brain damage as cooling or Xenon alone. We also showed that if Xenon treatment starts later than five hours after an acute brain injury, the effect is significantly reduced. As a result, a clinical, randomized study is being done at the University of Bristol in collaboration with our researchers in Oslo. The effects of treatments in controlled experiments are always better than in 'real life'. Which other circumstances at birth may influence the efficiency of treatment? If the mother has a low grade infection during the pregnancy, which role may this play? One of our experiments with animals showed that a mild infection, which in itself did not cause damage to the animal, completely blocked the protective effects which cooling otherwise results in. This may explain why cooling treatment has not been effective in developing countries. When a body is deprived of Oxygen, the heart may also be damaged. In experiments with 120 piglets, we studied whether cooling and Xenon treatment protected the heart. The study is a collaboration with Professor of Pathology Else-Marit Løberg at Oslo University Hospital. Xenon treatment was shown to have beneficial results on blood pressure. Neither cooling nor Xenon treatment, separately nor in combination, was shown to reduce tissue damage in the heart, but did not have any adverse effects either. This demonstrates that treatments which are beneficial for the brain do not necessarily have the same effects on the heart, which stems from the different ways in which cells are damaged and repaired in different types of tissue.

Since 1992 I designed and carried out through a series of animal experiments to investigate mechanisms and limitations of post insult hypothermia as neuroprotective treatment in the newborn. Through international collaboration we developed a clinical tria l protocol that proved to reduce death and disability in asphyxiated babies in 3 large international randomised trials of which I was a PI and author on 2. Death and disability was reduced from 70 to 50% in this group of newborns and more effective treatm ent is needed. Since 2003 I have investigated with Dr Dingley a combination therapy; breathing the inert gas xenon while cold which has doubled neuroprotection both in the small 7 day old rat and our term newborn pig mode. The safety data from 120 pig sur vival experiments allowed us ethical permission to give xenon to a small (n=14) number of babies who underwent cooling therapy to examine the feasibility of delivering 50% xenon gas via the endotracheal tube. This applicati on outlines a series of experiments deciding the time window for effective HT-Xe treatment in the rat model. We will examine the interaction with resuscitation in air or 100% oxygen as we recently found that hyperoxia counteracted hypothermic protection . We will examine the effect of only 1 degree increase in body temperature during resuscitation- which is very common under the overhead heater. In the pig model we will further examine cardiac protection by xenon, a recent added benefit of this treat ment. With the large pig model to study cardiovascular and cerebrovascular mechanisms during hypothermia and xenon. Based on these data the optimal clinical protocol can be designed. I hope we will be equally successful with our translation to clinica l practice with this treatment as we were with the hypothermia research. From the start in 1992 through steps of small and large animal models and RCT human studies this treatment was established as standard care