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 Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy

2017 ◽  
Vol 39 (1-4) ◽  
pp. 124-140 ◽  
Author(s):  
Ryan M. McAdams ◽  
Bobbi Fleiss ◽  
Christopher Traudt ◽  
Leslie Schwendimann ◽  
Jessica M. Snyder ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
White Matter ◽  
Cesarean Section ◽  
Nonhuman Primate ◽  
Cortical Neurons ◽  
Macaca Nemestrina ◽  
Hypoxic Ischemic Encephalopathy ◽  
Brainstem Injury ◽  
Ischemic Encephalopathy

Background: Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited. Methodology: Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed. Results: All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP. Conclusions/Significance: In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.

scholarly journals Magnetic Resonance Imaging Findings of Term and Preterm Hypoxic-Ischemic Encephalopathy: A Review of Relevant Animal Models and Correlation to Human Imaging

2018 ◽  
Vol 12 (1) ◽  
pp. 55-65 ◽  
Author(s):  
Kyle A. Jisa ◽  
Dillon D. Clarey ◽  
Eric S. Peeples
Keyword(s):  
Magnetic Resonance Imaging ◽  
Brain Injury ◽  
Magnetic Resonance ◽  
Animal Models ◽  
Disease Process ◽  
Hypoxic Ischemic Encephalopathy ◽  
Imaging Findings ◽  
Resonance Imaging ◽  
Human Neonates ◽  
Ischemic Encephalopathy

Background:Neonatal hypoxic-ischemic encephalopathy is brain injury caused by decreased perfusion and oxygen delivery that most commonly occurs in the context of delivery complications such as umbilical cord compression or placental abruption. Imaging is a key component for guiding treatment and prediction of prognosis, and the most sensitive clinical imaging modality for the brain injury patterns seen in hypoxic-ischemic encephalopathy is magnetic resonance imaging.Objective:The goal of this review is to compare magnetic resonance imaging findings demonstrated in the available animal models of hypoxic-ischemic encephalopathy to those found in preterm (≤ 36 weeks) and term (>36 weeks) human neonates with hypoxic-ischemic encephalopathy, with special attention to the strengths and weaknesses of each model.Methods:A structured literature search was performed independently by two authors and the results of the searches were compiled. Animal model, human brain age equivalency, mechanism of injury, and area of brain injury were recorded for comparison to imaging findings in preterm and term human neonates with hypoxic-ischemic encephalopathy.Conclusion:Numerous animal models have been developed to better elicit the expected findings that occur after HIE by allowing investigators to control many of the clinical variables that result in injury. Although modeling the same disease process, magnetic resonance imaging findings in the animal models vary with the species and methods used to induce hypoxia and ischemia. The further development of animal models of HIE should include a focus on comparing imaging findings, and not just pathologic findings, to human studies.

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 Rotura uterina intraparto: reporte de caso

2020 ◽  
Vol 80 (04) ◽  
pp. 343-347
Author(s):  
Franklin Espitia ◽  
Keyword(s):  
Brain Injury ◽  
Cesarean Section ◽  
Hemorrhagic Shock ◽  
Uterine Rupture ◽  
Hypoxic Ischemic Encephalopathy ◽  
Fetal Hypoxia ◽  
Peripartum Hysterectomy ◽  
Keywords Pregnancy ◽  
Ischemic Encephalopathy ◽  
Infrequent Event

Uterine rupture is an infrequent event, but of immeasurable seriousness and most of the time tragic. It is usually accompanied by catastrophic complications, both for the mother and the fetus, such as hemorrhagic shock, the need for peripartum hysterectomy, hypoxic ischemic encephalopathy, permanent brain injury and even the death of both. Keywords: Pregnancy, Uterine rupture, Complications, Fetal hypoxia, Cesarean section.

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.

Induced Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy: Pathophysiology, Current Treatment, and Nursing Considerations

2011 ◽  
Vol 30 (1) ◽  
pp. 29-36 ◽  
Author(s):  
DeLinda Jo Cooper
Keyword(s):  
Brain Injury ◽  
Healing Process ◽  
Current Treatment ◽  
Therapeutic Interventions ◽  
Hypoxic Ischemic Encephalopathy ◽  
Second Phase ◽  
Induced Hypothermia ◽  
Compensatory Mechanism ◽  
Neuroprotective Strategy ◽  
Ischemic Encephalopathy

AbstractHypoxic-ischemic encephalopathy (HIE) can lead to devastating neurodevelopmental consequences such as cerebral palsy, seizure disorders, and significant developmental delays. HIE in the newborn is often the result of a hypoxic event, such as uterine rupture, placental abruption, or cord prolapse. Biphasic brain injury occurs in HIE. The first phase involves activation of the sympathetic nervous system as a compensatory mechanism. The second phase, known as reperfusion brain injury, occurs hours later. Induced hypothermia, a neuroprotective strategy for treating HIE, targets the second phase to prevent reperfusion injury. NICU nurses are in a unique position to detect patient instability and to maintain the therapeutic interventions that contribute to the healing process. This article highlights the significant role nurses play in the management of infants diagnosed with HIE who are treated with induced hypothermia.

scholarly journals Current Controversies in Newer Therapies to Treat Birth Asphyxia

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Pia Wintermark
Keyword(s):  
Brain Injury ◽  
Neurological Outcome ◽  
Mild Hypothermia ◽  
Birth Asphyxia ◽  
Hypoxic Ischemic Encephalopathy ◽  
Monitoring Technology ◽  
The Past ◽  
Neuroprotective Strategy ◽  
Ischemic Encephalopathy

Despite major advances in monitoring technology and knowledge of fetal and neonatal pathophysiology, neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the main causes of severe adverse neurological outcome in children. Until recently, there were no therapies other than supportive measures. Over the past several years, mild hypothermia has been proven to be safe to treat HIE. Unfortunately, this neuroprotective strategy seems efficient in preventing brain injury in some asphyxiated newborns, but not in all of them. Thus, there is increasing interest to rapidly understand how to refine hypothermia therapy and add neuroprotective or neurorestorative strategies. Several promising newer treatments to treat birth asphyxia and prevent its devastating neurological consequences are currently being tested. In this paper, the physiopathology behind HIE, the currently available treatment, the potential alternatives, and the next steps before implementation of these other treatments are reviewed.

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