BiHiVE 2 Study. The Investigation and Validation of Predictive Biomarkers in Hypoxic-ischaemic Encephalopathy.

Background and current knowledge in the area:

Perinatal asphyxia is one of the commonest causes of neonatal death and long term disability, occurring in 20 per 1000 live births. Of these, approximately 2-3 per 1000 will go on to develop hypoxic-ischaemic encephalopathy (HIE) (1). In Ireland and the UK HIE is the third commonest cause of neonatal mortality, accounting for 9% of all deaths, and 21% of term deaths, while globally it is estimated to cause over 1 million neonatal deaths each year. For the survivors there is significant secondary morbidity associated, including cerebral palsy (15%), severe cognitive delay (11%), seizure disorders (8%), sensori-neural deafness (7%), and visual loss (3%)(2).

HIE is an evolving process, which can be simplified into two insults. The initial insult is significant cerebral hypoxia and/or ischaemia which is followed by energy depletion, from anaerobic metabolism leading to the accumulation of lactate, and loss of cellular integrity. This sets in motion a cascade of events with the resultant formation of free radicals, proteases and caspases leading to cell damage and apoptosis, the secondary insult(3). The secondary energy failure has been shown to occur between 6-48 hours after the initial insult.

Until recently no therapeutic intervention which could reduce the associated morbidity or mortality existed. However the recent publications of several international trials, and their subsequent meta-analysis has shown that early induced hypothermia is beneficial in HIE, improving survival and reducing neurological disability (4-5). Induced hypothermia has now become a standard of care in moderate/severe HIE. However to be effective it must be commenced within 6 hours of delivery, before the secondary energy failure occurs. In this narrow window of time the population who would benefit from treatment must be identified, resuscitated, stabilised and cooled.

Unfortunately the ability to recognise and diagnose those who would benefit from therapy is not always possible within this time period. We have shown that the current standard methods to identify those at risk of HIE such as acid-base balance, lactate and Apgar score and initial neurological assessment are unreliable (6). Neonatal electroencephalography (EEG) is useful for the grading of encephalopathy and is an excellent predictor of long term outcome. In particular its evolution over the first 24 hours following delivery strongly correlates with outcome (7). However it requires a highly specialised skill set that is rarely available to the neonatologist in the acute setting. Amplitude integrated EEG is more widely used by clinicians, but its interpretation is user dependent, and the majority of neonatologists report they are not confident in their own interpretive ability (8). The need for early and reliable prediction of outcome in HIE has never been greater. A quick, cheap, reproducible, non-user dependent method for quantifying severity of HIE and likely prognosis is an urgent need. Many biochemical and haematological markers have been proposed in perinatal asphyxia, but none have led to clinical advances, or commercially viable bedside tests (9).