Detecting brain injury in neonatal hypoxic ischemic encephalopathy: Closing the gap between experimental and clinical research

Moderate to severe neonatal hypoxic ischemic encephalopathy remains an important cause of infant death and childhood disability. Early and accurate diagnosis of encephalopathy is difficult but critical for timely intervention. Thus, we have utilized a clinically relevant large animal model of asphyxia in-utero, followed by immediate lamb delivery, resuscitation and clinical care over the next 72 h for assessment of potential biomarkers of brain injury. In-utero asphyxia was induced in twelve near-term lambs and outcomes compared with seven controls. Asphyxia resulted in bradycardia (97 +/- 12 beats/min), hypotension (12.1 +/- 1 mm Hg) and metabolic acidosis (pH 6.9 +/- 0.02; base-excess -13.8 +/- 0.8 mmol/l). 72 h following asphyxia, cerebrospinal concentrations of malondialdehyde and S100B were elevated 2-fold and 5-fold, respectively, in asphyxic lambs compared to control lambs. Magnetic resonance spectroscopy (MRS) at 72 h showed a significant decrease in n-acetyl aspartate: choline ratio in asphyxia lambs compared to that observed at 12 h (0.56 +/- 0.23 vs. 0.82 +/- 0.15, respectively); lactate:choline ratio was not changed over this time. Marked neuropathology was observed in asphyxia lambs with neuronal degeneration in the hippocampus, thalamus, striatum and cortex. Astrogliosis was observed in the hippocampus and thalamus. Early blood markers of metabolic state showed limited predictive value of histological damage at 72 h. MRS outcomes at 72 h showed a modest but significant correlation with histological evidence of neuronal brain injury (lactate:N-acetyl aspartate ratio in the thalamus r(2) = 0.2, p < 0.01). MRS at 72 h was best able to detect established brain injury, but a combination of biomarkers over multiple phases of injury may be able to assess the evolution of neonatal brain injury. (C) 2014 Elsevier Inc. All rights reserved.