Refining neuroprotection strategies in the Era of therapeutic hypothermia

Brain injury around the time of birth continues to be a great tragedy for parents and affected children. Although ‘‘only’’ 2 to 3 per 1,000 term live-born infants develop acute, moderate to severe evolving encephalopathy in developed countries, rates are 10-fold higher in the less developed nations, and nearly all babies were normal before birth. The majority either die, mainly from neural injury, or develop neurodevelopmental disabilities. Even among survivors who are not disabled, at least half will show learning difficulties at school. Despite major advances in obstetric and neonatal care, the incidence of acute encephalopathy has remained discouragingly unchanged for decades in the developed world. In an exciting example of successful clinical translation, a series of large randomized clinical trials have now shown that mild to moderate induced hypothermia for infants with neonatal encephalopathy reduces death and neurodevelopmental disabilities, including cerebral palsy, and conversely improves survival without disability. Metaanalysis of trials with 18 months of follow-up suggests a number needed to treat of approximately 9, with a relative risk for death or disability of 0.81 (95% confidence interval, 0.71–0.93; p 1⁄4 0.002). As a result, therapeutic hypothermia is being widely adopted in clinical practice. This dramatic advance is the culmination of >40 years of basic and clinical research, and provides a strong platform from which to further improve outcomes. The key to future progress is the concept that there is a latent phase of many hours after resuscitation during which the brain cells are still viable and can be rescued, before a terminal and apparently irreversible secondary deterioration marked by seizures, cytotoxic swelling, and failure of mitochondrial oxidative metabolism. There is increasing evidence that treatment with a variety of agents during this critical early recovery phase can reinforce hypothermic neuroprotection. In this issue of Annals of Neurology, Chakkarapani and colleagues report a strikingly ambitious preclinical study in which newborn piglets exposed to hypoxia-ischemia received either ventilation with the noble gas Xenon, mild hypothermia, or both, starting immediately after the insult. Xenon is expensive, and requires special recirculating ventilators, but is a clinically established anaesthetic with a favorable safety profile. This study makes several important points. First, it demonstrates in a large animal species that xenon by itself does offer partial neuroprotection. Second, it confirms previous evidence that hypothermia is most protective if continued for relatively prolonged intervals; in this study, 24 hours of hypothermia (plus gradual rewarming over 10 hours) was unequivocally better than 12 hours. Still better protection might have been achieved if cooling had been continued for longer, but this approach allowed a reasonable period of recovery at normal temperatures. Finally, the protective effects of xenon and hypothermia were independent, denoting a simple additive improvement. This is clearly seen with the combination of xenon plus short (12 hours) cooling, which was better than either alone, consistent with data from neonatal rodents. The specific mechanisms are unclear, but likely include augmented suppression of abnormal excitatory activity or of excessive intracellular calcium fluxes that activate a common mitochondrial pathway of programmed cell death. One limitation is that all of these studies used hypothermia regimes that were markedly shorter than the 48 hours or more of cooling that has been shown to be effective in clinical trials. Indeed, in this study from Chakkarapani et al, cotreatment of prolonged hypothermia (>24 hours of moderate hypothermia) plus xenon was associated with an apparently modest improvement in overall histological scores compared with prolonged hypothermia alone, and no further improvement in the neurological score. This discrepancy between the neurological scores and histology is unexplained. It may partly reflect the incremental difference in histological damage. However, we should also note that there are increasing data from clinical studies that therapeutic hypothermia can be associated with significantly greater delay in recovery of neurological and electroencephalographic abnormalities. What then can we deduce from the histological findings?