Serum calcium derangements in neonates with moderate to severe hypoxic ischemic encephalopathy and the impact of therapeutic hypothermia: a cohort study

Seizures are common in newborn infants with hypoxic-ischemic encephalopathy and are highly associated with adverse neurodevelopmental outcomes. The impact of seizure activity on the developing brain and the most effective way to manage these seizures remain surprisingly poorly understood, particularly in the era of therapeutic hypothermia. Critically, the extent to which seizures exacerbate brain injury or merely reflect the underlying evolution of injury is unclear. Current anticonvulsants, such as phenobarbital and phenytoin have poor efficacy and preclinical studies suggest that most anticonvulsants are associated with adverse effects on the developing brain. Levetiracetam seems to have less potential neurotoxic effects than other anticonvulsants but may not be more effective. Given that therapeutic hypothermia itself has significant anticonvulsant effects, randomized controlled trials of anticonvulsants combined with therapeutic hypothermia, are required to properly determine the safety and efficacy of these drugs. Small clinical studies suggest that prophylactic phenobarbital administration may improve neurodevelopmental outcomes compared to delayed administration; however, larger high-quality studies are required to confirm this. In conclusion, there is a distinct lack of high-quality evidence for whether and to what extent neonatal seizures exacerbate brain damage after hypoxia-ischemia and how best to manage them in the era of therapeutic hypothermia.

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Serum calcium concentrations and incidence of hypocalcemia in infants with moderate or severe hypoxic-ischemic encephalopathy: Effect of therapeutic hypothermia

Early Human Development ◽

10.1016/j.earlhumdev.2015.06.008 ◽

2015 ◽

Vol 91 (9) ◽

pp. 535-540 ◽

Cited By ~ 7

Author(s):

Chatchay Prempunpong ◽

Ionut Efanov ◽

Guilherme Sant’Anna

Keyword(s):

Therapeutic Hypothermia ◽

Serum Calcium ◽

Hypoxic Ischemic Encephalopathy ◽

Ischemic Encephalopathy

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Lactate Predicts Neurological Outcomes after Perinatal Asphyxia in Post-Hypothermia Era: A Prospective Cohort Study

Life ◽

10.3390/life11111193 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1193

Author(s):

Yi-Fang Tu ◽

Po-Ming Wu ◽

Wen-Hao Yu ◽

Chung-I Li ◽

Cheng-Lin Wu ◽

...

Keyword(s):

Cohort Study ◽

Therapeutic Hypothermia ◽

Blood Lactate ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Perinatal Asphyxia ◽

Adverse Outcomes ◽

Hypoxic Ischemic Encephalopathy ◽

Neurological Outcomes ◽

Ischemic Encephalopathy

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is the most common cause of mortality and neurological disability in infancy after perinatal asphyxia. Reliable biomarkers to predict neurological outcomes of neonates after perinatal asphyxia are still not accessible in clinical practice. Methods: A prospective cohort study enrolled neonates with perinatal asphyxia. Biochemical blood tests and cerebral Doppler ultrasound were measured within 6 h of age and at the 4th day old. Neurological outcomes were assessed at 1 year old. Results: Sixty-four neonates with perinatal asphyxia were enrolled. Fifty-eight (90%) had hypoxic-ischemic encephalopathy (HIE) including 20 (34%) Stage I, 21 (36%) Stage II, and 17 (29%) Stage III. In the asphyxiated infants without therapeutic hypothermia, HIE stage, PH, and base excess levels within 6 h of age were the predictors of adverse outcomes. In the asphyxiated infants receiving therapeutic hypothermia, HIE stage failed to predict outcomes. Instead, blood lactate levels and pulsatility index (PI) of medial cerebral arteries (MCA) either in 6 h of age or at the 4th day old independently predicted adverse outcomes. Conclusions: Blood lactate, which is a common accessible test at the hospital and MCA PI on cerebral ultrasound could predict adverse outcomes in asphyxiated infants receiving therapeutic hypothermia.

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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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A pilot cohort study of cerebral autoregulation and 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy who received therapeutic hypothermia

BMC Neurology ◽

10.1186/s12883-015-0464-4 ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 25

Author(s):

Vera Joanna Burton ◽

Gwendolyn Gerner ◽

Elizabeth Cristofalo ◽

Shang-en Chung ◽

Jacky M. Jennings ◽

...

Keyword(s):

Cohort Study ◽

Therapeutic Hypothermia ◽

Cerebral Autoregulation ◽

Hypoxic Ischemic Encephalopathy ◽

Neurodevelopmental Outcomes ◽

Ischemic Encephalopathy

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

International Journal of Molecular Sciences ◽

10.3390/ijms21186801 ◽

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.

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