Potential biomarkers for hypoxic–ischemic encephalopathy

Summary

Cerebral hypothermia reduces brain injury and improves behavioral recovery after hypoxia–ischemia (HI) at birth. However, using current enrolment criteria many infants are not helped, and conversely, a significant proportion of control infants survive without disability. In order to further improve treatment we need better biomarkers of injury. A ‘true’ biomarker for the phase of evolving, ‘treatable’ injury would allow us to identify not only whether infants are at risk of damage, but also whether they are still able to benefit from intervention. Even a less specific measure that allowed either more precise early identification of infants at risk of adverse neurodevelopmental outcome would reduce the variance of outcome of trials, improving trial power while reducing the number of infants unnecessarily treated. Finally, valid short-term surrogates for long term outcome after treatment would allow more rapid completion of preliminary evaluation and thus allow new strategies to be tested more rapidly. Experimental studies have demonstrated that there is a relatively limited ‘window of opportunity’ for effective treatment (up to about 6–8 h after HI, the ‘latent phase’), before secondary cell death begins. We critically evaluate the utility of proposed biochemical, electronic monitoring, and imaging biomarkers against this framework. This review highlights the two central limitations of most presently available biomarkers: that they are most precise for infants with severe injury who are already easily identified, and that their correlation is strongest at times well after the latent phase, when injury is no longer ‘treatable’. This is an important area for further research.

Introduction

The seminal discovery about perinatal hypoxia–ischemia (HI) in the last century was that although some brain injury can occur during a sufficiently prolonged/severe episode of HI, in many cases damage actually continued to evolve for hours after resuscitation, during the recovery period.1, 2 This evolution offered the tantalizing prospect that there might be a ‘window of opportunity’ to provide treatment to reduce or prevent injury. This potential has been confirmed by the finding that hypothermia can significantly reduce neurodevelopmental disability in infants with acute moderate–severe HI encephalopathy (HIE) at birth (e.g. as highlighted by the systematic meta-analysis by P.S. Shah in this issue of Seminars and by Edwards et al.³). However, these data also clearly show that protection is only partial, so that many infants still die or have disabilities at 18 months of age. Conversely, approximately a third or more of infants receiving conventional normothermic care in the major trials survived without severe disability.4, 5, 6

Clearly, this is not an ideal base from which to further improve outcomes. As for any active intervention, all parents and clinicians would greatly prefer to deliver therapeutic hypothermia only to infants who would benefit from it. Even more importantly, the implication for future studies of improved treatment strategies is that the combination of limited precision plus the reduced rate of adverse outcome with current hypothermic treatment markedly reduces trial power, and so we will need trials that are at least an order of magnitude larger than previous randomized trials of hypothermia against normothermia.⁷ Thus, it will be important to more precisely target infants who will go on to develop clinically significant injury without treatment and determine whether they are ‘treatable’, i.e. whether they are likely to benefit from hypothermia or other interventions. A further hindrance to progress is that currently several years are needed after treatment before neurodevelopmental outcome can be evaluated.

These considerations show why better biological markers (biomarkers) to better quantify the severity of the initial HI insult, and to rapidly determine prognosis before treatment (risk of bad outcome) and then after treatment (valid early surrogates for long term neurodevelopmental outcome) would be of huge benefit for further trials. Even better would be a biomarker for the biological processes involved in the evolving brain injury, since this would both allow us to identify infants who were ‘treatable’, and to provide immediate feedback on whether the intervention was modifying the course of injury.

This chapter dissects the evidence for some of biomarkers already in use and the potential of novel biomarkers to contribute to refinement of therapeutic hypothermia for treatment of infants after HI at birth. We will particularly focus on their potential to answer the central questions: (1) Will the insult cause injury and (2) Are we still in time to treat? The potential for biomarkers such as magnetic resonance imaging (MRI) and electroencephalogram (EEG) to provide robust surrogate outcomes is addressed in detail by others in this issue of Seminars (D. Azzopardi and A.D. Edwards, and M. Thoresen, respectively).