scholarly journals Serial Plasma Metabolites Following Hypoxic-Ischemic Encephalopathy in a Nonhuman Primate Model

2015 ◽  
Vol 37 (2) ◽  
pp. 161-171 ◽  
Author(s):  
Pattaraporn T. Chun ◽  
Ronald J. McPherson ◽  
Luke C. Marney ◽  
Sahar Z. Zangeneh ◽  
Brendon A. Parsons ◽  
...  
Keyword(s):  
Brain Injury ◽  
Citric Acid ◽  
Fumaric Acid ◽  
Macaca Nemestrina ◽  
Hypoxic Ischemic Encephalopathy ◽  
Plasma Metabolites ◽  
Propanoic Acid ◽  
Neurodevelopmental Outcomes ◽  
Treatment Groups ◽  
Ischemic Encephalopathy

Biomarkers that indicate the severity of hypoxic-ischemic brain injury and response to treatment and that predict neurodevelopmental outcomes are urgently needed to improve the care of affected neonates. We hypothesize that sequentially obtained plasma metabolomes will provide indicators of brain injury and repair, allowing for the prediction of neurodevelopmental outcomes. A total of 33 Macaca nemestrina underwent 0, 15 or 18 min of in utero umbilical cord occlusion (UCO) to induce hypoxic-ischemic encephalopathy and were then delivered by hysterotomy, resuscitated and stabilized. Serial blood samples were obtained at baseline (cord blood) and at 0.1, 24, 48, and 72 h of age. Treatment groups included nonasphyxiated controls (n = 7), untreated UCO (n = 11), UCO + hypothermia (HT; n = 6), and UCO + HT + erythropoietin (n = 9). Metabolites were extracted and analyzed using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry and quantified by PARAFAC (parallel factor analysis). Using nontargeted discovery-based methods, we identified 63 metabolites as potential biomarkers. The changes in metabolite concentrations were characterized and compared between treatment groups. Further comparison determined that 8 metabolites (arachidonic acid, butanoic acid, citric acid, fumaric acid, lactate, malate, propanoic acid, and succinic acid) correlated with early and/or long-term neurodevelopmental outcomes. The combined outcomes of death or cerebral palsy correlated with citric acid, fumaric acid, lactate, and propanoic acid. This change in circulating metabolome after UCO may reflect cellular metabolism and biochemical changes in response to the severity of brain injury and have potential to predict neurodevelopmental outcomes.

scholarly journals Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates

2017 ◽  
Vol 39 (1-4) ◽  
pp. 107-123 ◽  
Author(s):  
Ryan M. McAdams ◽  
Ronald J. McPherson ◽  
Raj P. Kapur ◽  
Sandra E. Juul
Keyword(s):  
Brain Injury ◽  
Cesarean Section ◽  
Brain Stem ◽  
In Utero ◽  
Negative Regulator ◽  
Macaca Nemestrina ◽  
Hypoxic Ischemic Encephalopathy ◽  
Microscopy Imaging ◽  
Human Neonates ◽  
Ischemic Encephalopathy

Worldwide, hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. To better understand the mechanisms contributing to brain injury and improve outcomes in neonates with HIE, better preclinical animal models that mimic the clinical situation following birth asphyxia in term newborns are needed. In an effort to achieve this goal, we modified our nonhuman primate model of HIE induced by in utero umbilical cord occlusion (UCO) to include postnatal hypoxic episodes, in order to simulate apneic events in human neonates with HIE. We describe a cohort of 4 near-term fetal Macaca nemestrina that underwent 18 min of in utero UCO, followed by cesarean section delivery, resuscitation, and subsequent postnatal mechanical ventilation, with exposure to intermittent daily hypoxia (3 min, 8% O2 3-8 times daily for 3 days). After delivery, all animals demonstrated severe metabolic acidosis (pH 7 ± 0.12; mean ± SD) and low APGAR scores (<5 at 10 min of age). Three of 4 animals had both electrographic and clinical seizures. Serial blood samples were collected and plasma metabolites were determined by 2-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC × GC-TOFMS). The 4 UCO animals and a single nonasphyxiated animal (delivered by cesarean section but without exposure to UCO or prolonged sedation) underwent brain magnetic resonance imaging (MRI) on day 8 of life. Thalamic injury was present on MRI in 3 UCO animals, but not in the control animal. Following necropsy on day 8, brain histopathology revealed neuronal injury/loss and gliosis in portions of the ventrolateral thalamus in all 4 UCO, with 2 animals also demonstrating putamen/globus pallidus involvement. In addition, all 4 UCO animals demonstrated brain stem gliosis, with neuronal loss present in the midbrain, pons, and lateral medulla in 3 of 4 animals. Transmission electron microscopy imaging of the brain tissues was performed, which demonstrated ultrastructural white matter abnormalities, characterized by perinuclear vacuolation and axonal dilation, in 3 of 4 animals. Immunolabeling of Nogo-A, a negative regulator of neuronal growth, was not increased in the injured brains compared to 2 control animals. Using GC × GC-TOFMS, we identified metabolites previously recognized as potential biomarkers of perinatal asphyxia. The basal ganglia-thalamus-brain stem injury produced by UCO is consistent with the deep nuclear/brainstem injury pattern seen in human neonates after severe, abrupt hypoxic-ischemic insults. The UCO model permits timely detection of biomarkers associated with specific patterns of neonatal brain injury, and it may ultimately be useful for validating therapeutic strategies to treat neonatal HIE.

scholarly journals Inhaled H2 or CO2 Do Not Augment the Neuroprotective Effect of Therapeutic Hypothermia in a Severe Neonatal Hypoxic-Ischemic Encephalopathy Piglet Model

2020 ◽  
Vol 21 (18) ◽  
pp. 6801
Author(s):  
Viktória Kovács ◽  
Gábor Remzső ◽  
Valéria Tóth-Szűki ◽  
Viktória Varga ◽  
János Németh ◽  
...  
Keyword(s):  
Caudate Nucleus ◽  
Therapeutic Hypothermia ◽  
Neuroprotective Effect ◽  
Fold Increase ◽  
Hypoxic Ischemic Encephalopathy ◽  
Mrna Levels ◽  
Treatment Groups ◽  
Apoptosis Inducing Factor ◽  
Co2 Treatment ◽  
Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is still a major cause of neonatal death and disability as therapeutic hypothermia (TH) alone cannot afford sufficient neuroprotection. The present study investigated whether ventilation with molecular hydrogen (2.1% H2) or graded restoration of normocapnia with CO2 for 4 h after asphyxia would augment the neuroprotective effect of TH in a subacute (48 h) HIE piglet model. Piglets were randomized to untreated naïve, control-normothermia, asphyxia-normothermia (20-min 4%O2–20%CO2 ventilation; Tcore = 38.5 °C), asphyxia-hypothermia (A-HT, Tcore = 33.5 °C, 2–36 h post-asphyxia), A-HT + H2, or A-HT + CO2 treatment groups. Asphyxia elicited severe hypoxia (pO2 = 19 ± 5 mmHg) and mixed acidosis (pH = 6.79 ± 0.10). HIE development was confirmed by altered cerebral electrical activity and neuropathology. TH was significantly neuroprotective in the caudate nucleus but demonstrated virtually no such effect in the hippocampus. The mRNA levels of apoptosis-inducing factor and caspase-3 showed a ~10-fold increase in the A-HT group compared to naïve animals in the hippocampus but not in the caudate nucleus coinciding with the region-specific neuroprotective effect of TH. H2 or CO2 did not augment TH-induced neuroprotection in any brain areas; rather, CO2 even abolished the neuroprotective effect of TH in the caudate nucleus. In conclusion, the present findings do not support the use of these medical gases to supplement TH in HIE management.

scholarly journals Serum Biomarkers of MRI Brain Injury in Neonatal Hypoxic Ischemic Encephalopathy Treated With Whole-Body Hypothermia

2013 ◽  
Vol 14 (3) ◽  
pp. 310-317 ◽  
Author(s):  
An N. Massaro ◽  
Andreas Jeromin ◽  
Nadja Kadom ◽  
Gilbert Vezina ◽  
Ronald L. Hayes ◽  
...  
Keyword(s):  
Brain Injury ◽  
Serum Biomarkers ◽  
Hypoxic Ischemic Encephalopathy ◽  
Whole Body ◽  
Mri Brain ◽  
Ischemic Encephalopathy

scholarly journals Wavelet Autoregulation Monitoring Identifies Blood Pressures Associated With Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiuyun Liu ◽  
Aylin Tekes ◽  
Jamie Perin ◽  
May W. Chen ◽  
Bruno P. Soares ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Brain Injury ◽  
Therapeutic Hypothermia ◽  
Near Infrared ◽  
Brain Regions ◽  
Hypoxic Ischemic Encephalopathy ◽  
Volume Index ◽  
Arterial Blood ◽  
Blood Pressures ◽  
Ischemic Encephalopathy

Dysfunctional cerebrovascular autoregulation may contribute to neurologic injury in neonatal hypoxic-ischemic encephalopathy (HIE). Identifying the optimal mean arterial blood pressure (MAPopt) that best supports autoregulation could help identify hemodynamic goals that support neurologic recovery. In neonates who received therapeutic hypothermia for HIE, we hypothesized that the wavelet hemoglobin volume index (wHVx) would identify MAPopt and that blood pressures closer to MAPopt would be associated with less brain injury on MRI. We also tested a correlation-derived hemoglobin volume index (HVx) and single- and multi-window data processing methodology. Autoregulation was monitored in consecutive 3-h periods using near infrared spectroscopy in an observational study. The neonates had a mean MAP of 54 mmHg (standard deviation: 9) during hypothermia. Greater blood pressure above the MAPopt from single-window wHVx was associated with less injury in the paracentral gyri (p = 0.044; n = 63), basal ganglia (p = 0.015), thalamus (p = 0.013), and brainstem (p = 0.041) after adjustments for sex, vasopressor use, seizures, arterial carbon dioxide level, and a perinatal insult score. Blood pressure exceeding MAPopt from the multi-window, correlation HVx was associated with less injury in the brainstem (p = 0.021) but not in other brain regions. We conclude that applying wavelet methodology to short autoregulation monitoring periods may improve the identification of MAPopt values that are associated with brain injury. Having blood pressure above MAPopt with an upper MAP of ~50–60 mmHg may reduce the risk of brain injury during therapeutic hypothermia. Though a cause-and-effect relationship cannot be inferred, the data support the need for randomized studies of autoregulation and brain injury in neonates with HIE.

scholarly journals Correlation Between White Matter Injury Identified by Neonatal Diffusion Tensor Imaging and Neurodevelopmental Outcomes Following Term Neonatal Asphyxia and Therapeutic Hypothermia: An Exploratory Pilot Study

2019 ◽  
Vol 34 (10) ◽  
pp. 556-566 ◽  
Author(s):  
Gwendolyn J. Gerner ◽  
Eric I. Newman ◽  
V. Joanna Burton ◽  
Brenton Roman ◽  
Elizabeth A. Cristofalo ◽  
...  
Keyword(s):  
Diffusion Tensor Imaging ◽  
White Matter ◽  
Pilot Study ◽  
Therapeutic Hypothermia ◽  
Diffusion Tensor ◽  
White Matter Injury ◽  
Hypoxic Ischemic Encephalopathy ◽  
Group Differences ◽  
Neurodevelopmental Outcomes ◽  
Ischemic Encephalopathy

Aim: Hypoxic-ischemic encephalopathy is associated with damage to deep gray matter; however, white matter involvement has become recognized. This study explored differences between patients and clinical controls on diffusion tensor imaging, and relationships between diffusion tensor imaging and neurodevelopmental outcomes. Method: Diffusion tensor imaging was obtained for 31 neonates after hypoxic-ischemic encephalopathy treated with therapeutic hypothermia and 10 clinical controls. A subgroup of patients with hypoxic-ischemic encephalopathy (n = 14) had neurodevelopmental outcomes correlated with diffusion tensor imaging scalars. Results: Group differences in diffusion tensor imaging scalars were observed in the putamen, anterior and posterior centrum semiovale, and the splenium of the corpus callosum. Differences in these regions of interest were correlated with neurodevelopmental outcomes between ages 20 and 32 months. Conclusion: Therapeutic hypothermia may not be a complete intervention for hypoxic-ischemic encephalopathy, as neonatal white matter changes may continue to be evident, but further research is warranted. Patterns of white matter change on neonatal diffusion tensor imaging correlated with neurodevelopmental outcomes in this exploratory pilot study.

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