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

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.

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Comparison of Uncontrolled and Device-Induced Therapeutic Hypothermia in Newborn Infants with Hypoxic Ischemic Encephalopathy

Acta biomedica scientifica ◽

10.29413/abs.2021-6.1.13 ◽

2021 ◽

Vol 6 (1) ◽

pp. 88-93

Author(s):

A. A. Zarubin ◽

E. S. Filippov ◽

A. S. Vanyarkina ◽

O. G. Ivanova ◽

A. A. Shishkina

Keyword(s):

High Risk ◽

Body Temperature ◽

Therapeutic Hypothermia ◽

Neuroprotective Effect ◽

Newborn Infants ◽

The Body ◽

Hypoxic Ischemic Encephalopathy ◽

Temperature Management ◽

Hypothermia Group ◽

Ischemic Encephalopathy

Background. Newborn infants who have undergone severe birth asphyxia have a high risk of neurological disorders and death. The most effective method for the treatment of hypoxic ischemic encephalopathy caused by intrapartum asphyxia is therapeutic hypothermia, or targeted temperature management. Currently, there are no large studies comparing its different methods, therefore the aim of our study was to compare the effectiveness of device-induced and uncontrolled therapeutic hypothermia in newborn infants who underwent intrapartum asphyxia.Materials and methods. Study design: we conducted a retrospective, longitudinal, cohort study in 39 newborn infants born in severe asphyxia and receiving uncontrolled therapeutic hypothermia (group 1), and in 48 newborn infants born in severe asphyxia and receiving device-induced therapeutic hypothermia (group 2). Statistical data processing was carried out using standard techniques.Results. The body temperature in newborn infants of both groups was reduced to 33.5 °C within the first hour, but when using uncontrolled therapeutic hypothermia, the body temperature fluctuated from 32 to 35 °C. Device-induced therapeutic hypothermia has a more effective neuroprotective effect as compared to uncontrolled hypothermia (p< 0.05) and more rapidly stabilizes metabolism in newborns due to a decrease in lactate levels (p < 0.05). In newborns device-induced therapeutic hypothermia stabilizes hemodynamics more quickly compared to uncontrolled therapeutic hypothermia (p < 0.05). Device-induced therapeutic hypothermia reduces the period of hospitalization in the neonatal intensive care unit (p < 0.05), the risk of cerebral edema (p < 0.05) and of the repeated episodes of seizures (p < 0.05). Conclusion. Using uncontrolled therapeutic hypothermia causes a high risk of unintentional fluctuations in rectal temperature towards both hypothermia and rewarming, which can aggravate the severe condition of newborn infants. Device-induced therapeutic hypothermia has a more effective neuroprotective effect.

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Therapeutic Hypothermia Inhibits the Classical Complement Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy

Frontiers in Neuroscience ◽

10.3389/fnins.2021.616734 ◽

2021 ◽

Vol 15 ◽

Author(s):

Tushar A. Shah ◽

Haree K. Pallera ◽

Cortney L. Kaszowski ◽

William Thomas Bass ◽

Frank A. Lattanzio

Keyword(s):

Therapeutic Hypothermia ◽

Developing Brain ◽

Hypoxic Ischemic Encephalopathy ◽

Treatment Groups ◽

Classical Complement Pathway ◽

Rat Pups ◽

Downstream Effectors ◽

Immunofluorescence Labeling ◽

The Impact ◽

Ischemic Encephalopathy

ObjectiveComplement activation is instrumental in the pathogenesis of Hypoxic-ischemic encephalopathy (HIE), a significant cause of neonatal mortality and disability worldwide. Therapeutic hypothermia (HT), the only available treatment for HIE, only modestly improves outcomes. Complement modulation as a therapeutic adjunct to HT has been considered, but is challenging due to the wide-ranging role of the complement system in neuroinflammation, homeostasis and neurogenesis in the developing brain. We sought to identify potential therapeutic targets by measuring the impact of treatment with HT on complement effector expression in neurons and glia in neonatal HIE, with particular emphasis on the interactions between microglia and C1q.MethodsThe Vannucci model was used to induce HIE in term-equivalent rat pups. At P10-12, pups were randomly assigned to three different treatment groups: Sham (control), normothermia (NT), and hypothermia (HT) treatment. Local and systemic complement expression and neuronal apoptosis were measured by ELISA, TUNEL and immunofluorescence labeling, and differences compared between groups.ResultsTreatment with HT is associated with decreased systemic and microglial expression of C1q, decreased systemic C5a levels, and decreased microglial and neuronal deposition of C3 and C9. The effect of HT on cytokines was variable with decreased expression of pro and anti-inflammatory effectors. HT treatment was associated with decreased C1q binding on cells undergoing apoptosis.ConclusionOur data demonstrate the extreme complexity of the immune response in neonatal HIE. We propose modulation of downstream effectors C3a and C5a as a therapeutic adjunct to HT to enhance neuroprotection in the developing brain.

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Visual outcomes in children with neonatal hypoxic ischemic encephalopathy treated with therapeutic hypothermia

Journal of Perinatology ◽

10.1038/s41372-021-01101-x ◽

2021 ◽

Author(s):

Jerry Hsu ◽

Noreen Shaikh ◽

Hantamalala Ralay Ranaivo ◽

Andrea C. Pardo ◽

Rebecca B. Mets-Halgrimson

Keyword(s):

Therapeutic Hypothermia ◽

Hypoxic Ischemic Encephalopathy ◽

Visual Outcomes ◽

Ischemic Encephalopathy

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Mammillary body atrophy and other MRI correlates of school-age outcome following neonatal hypoxic-ischemic encephalopathy

Scientific Reports ◽

10.1038/s41598-021-83982-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kim V. Annink ◽

Linda S. de Vries ◽

Floris Groenendaal ◽

Rian M. J. C. Eijsermans ◽

Manouk Mocking ◽

...

Keyword(s):

Therapeutic Hypothermia ◽

Memory Function ◽

Neurodevelopmental Outcome ◽

Standard Of Care ◽

Hypoxic Ischemic Encephalopathy ◽

School Age ◽

Brain Volumes ◽

Mammillary Bodies ◽

Memory Problems ◽

Ischemic Encephalopathy

AbstractThe mammillary bodies (MB) and hippocampi are important for memory function and are often affected following neonatal hypoxic ischemic encephalopathy (HIE). The aim of this study was to assess neurodevelopmental outcome in 10-year-old children with HIE with and without therapeutic hypothermia. Additional aims were to assess the associations between MB atrophy, brain volumes (including the hippocampi), white matter microstructure and neurodevelopmental outcome at school-age. Ten-year-old children with HIE were included, who were treated with therapeutic hypothermia (n = 22) or would have qualified but were born before this became standard of care (n = 28). Children completed a neuropsychological and motor assessment and MRI. Mammillary bodies were scored as normal or atrophic at 10 years. Brain volumes were segmented on childhood MRI and DTI scans were analysed using tract-based spatial statistics. Children with HIE suffered from neurocognitive and memory problems at school-age, irrespective of hypothermia. Hippocampal volumes and MB atrophy were associated with total and performance IQ, processing speed and episodic memory in both groups. Normal MB and larger hippocampi were positively associated with global fractional anisotropy. In conclusion, injury to the MB and hippocampi was associated with neurocognition and memory at school-age in HIE and might be an early biomarker for neurocognitive and memory problems.

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