title: Detecting brain injury in neonatal hypoxic ischemic encephalopathy: closing the gap between experimental and clinical research.
abstract: 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 72h 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±12beats/min), hypotension (12.1±1mm Hg) and metabolic acidosis (pH6.9±0.02; base-excess -13.8±0.8mmol/l). 72h 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 72h showed a significant decrease in n-acetyl aspartate: choline ratio in asphyxia lambs compared to that observed at 12h (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 72h. MRS outcomes at 72h 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 72h 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.
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia.
authors: James D S
authors: JD
authors: Aridas
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia.
authors: Tamara
authors: T
authors: Yawno
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia.
authors: Amy E
authors: AE
authors: Sutherland
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
authors: Ilias
authors: I
authors: Nitsos
authors: Monash Children's, Monash Health, Clayton, Victoria, Australia.
authors: Michael
authors: M
authors: Ditchfield
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia; Monash Children's, Monash Health, Clayton, Victoria, Australia.
authors: Flora Y
authors: FY
authors: Wong
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia; Monash Children's, Monash Health, Clayton, Victoria, Australia.
authors: Michael C
authors: MC
authors: Fahey
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia; Monash Children's, Monash Health, Clayton, Victoria, Australia.
authors: Atul
authors: A
authors: Malhotra
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
authors: Euan M
authors: EM
authors: Wallace
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
authors: Graham
authors: G
authors: Jenkin
authors: The Ritchie Centre, MIMR-PHI Institute, Clayton, Victoria, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia. Electronic address: suzie.miller@monash.edu.
authors: Suzanne L
authors: SL
authors: Miller
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000502:physiology; D001930:Brain Injuries / Q000175:diagnosis* / Q000209:etiology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004622:Embryo, Mammalian; D005260:Female; D006339:Heart Rate / Q000502:physiology; D006439:Hemodynamics; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D019344:Lactic Acid / Q000097:blood; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008315:Malondialdehyde / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology* / Q000473:pathology; D011247:Pregnancy; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D012756:Sheep
chemical_list: D064568:S100 Calcium Binding Protein beta Subunit; D019344:Lactic Acid; D008315:Malondialdehyde
keywords: Animal models; Asphyxia; Biomarker; Cell death; Hypoxia–ischemia; Hypoxic ischemic encephalopathy; Magnetic resonance imaging; Neuroprotection; Newborn infant; Oxidative stress; Sheep