Cases Of Hypoxic-ischemic Encephalopathy Research Articles

Early Postnatal Administration of Erythropoietin and Its Association with Neurodevelopmental Outcomes and Incidence of Intraventricular Hemorrhage and Hypoxic-Ischemic Encephalopathy: A Four-Week Observational Study.

This study aimed to investigate the impact of early erythropoietin (EPO) administration on the neurodevelopment of newborns, specifically focusing on its effects on hypoxic-ischemic encephalopathy (HIE) and intraventricular hemorrhage (IVH). The primary objective was to determine whether early EPO administration could impact the short-term neurodevelopmental outcomes and provide safety in neonates at risk for neurodevelopmental disorders. Conducted at the "Louis Turcanu" Children's Emergency Clinical Hospital in Timisoara, Romania, this observational study included 121 neonates receiving EPO and 130 No EPO controls. EPO was administered within the first 48 h of life, with doses of 1000 U/kg that escalated to 2000 U/kg if necessary. Besides observing the occurrence of IVH and HIE, this study measured clinical and biochemical markers, including LDH, blood glucose, urea, creatinine, CPK, CRP, PCT, and erythropoietin levels alongside hematology and coagulation profiles. There were no significant differences in baseline characteristics between the groups. The EPO group showed significant reductions in LDH levels from days 1-3 to 7-10 (695.0 U/L to 442.0 U/L) and the APTT value (54.0 s) compared with the No EPO group (38.0 s). Notably, early EPO administration was associated with a significant decrease in HIE severity (beta coefficient: -0.38, p = 0.001). Additionally, lower gestational ages and hemoglobin levels correlated with increased severity of HIE. By week four, there was a significant reduction in moderate and severe HIE cases in the EPO group compared with controls (p = 0.001). Early administration of EPO in neonates significantly reduced the severity of IVH and HIE, suggesting its potential as a neuroprotective agent in neonatal care.

Eucapnic pH coupled with arterial cord pH improves hypoxic-ischemic encephalopathy prediction.

To consider the classical use of "pH < 7.0 and/or a base deficiency ≥12 mmol/L" as markers of the risk of neonatal hypoxic-ischemic encephalopathy (HIE), recalling various criticisms of the use of these markers in favor of that of neonatal eucapnic pH, which appears to be a better marker of this risk. Fifty-five cases of acidemia with pH < 7.00 were collected from a cohort from the Nice University Hospital with eight cases of HIE. We compared the receiver operating characteristics curves established from the positive likelihood ratio (+LR) for each case of: umbilical cord artery pH (pHa), neonatal eucapnic pH (pH euc-n) in isolation (not matched to pHa), and matched pHa to its own pH euc-n. The areas under the curve (AUC) are identical for pHa and pH euc-n, but AUC for the matched pair pHa-pH euc-n appears superior but non-significant because of the small number in our cohort. However, using the bootstrap method, the partial AUC for a sensitivity greater than 75% indicates the significant superiority (P < 0.01) of the matched pair pHa-pH euc-n approach. The originality of this study lies in the use of two methodologic approaches: (1) standardized partial analysis of the AUCs of the pHa curve and that of pHa matched to its own pH euc-n, and (2) bootstrap statistical technique, that allowed us to conclude (P < 0.01) that the combined use of pH measured at the cord coupled with its eucapnic correction is better for diagnosing metabolic acidosis and best predicting the risk of HIE.

A predictive model for perinatal hypoxic ischemic encephalopathy using linked maternal and neonatal hospital data

PurposeTo build an evidence-based model to estimate case-specific risk of perinatal hypoxic ischemic encephalopathy. MethodsA retrospective, cross-sectional study of all births in Hawaii, Michigan, and New Jersey between 2010 and 2015, using linked maternal labor/delivery and neonatal birth records. Stepwise logistic regression and competitive Akaike information criterion were used to identify the most parsimonious model. Predictive ability of the model was measured with bootstrapped optimism-adjusted area under the ROC curve. ResultsAmong 836,216 births there were 376 (0.45 per 1000) cases of hypoxic ischemic encephalopathy. The final model included 28 variables, 24 associated with increased risk, and 4 that were protective. The optimism-adjusted area under the ROC curve was 0.84. Estimated risk in the study population ranged from 1 in ∼323,000 to 1 in 2.5. The final model confirmed known risk factors (e.g., sentinel events and shoulder dystocia) and identified novel risk factors, such as maternal race and insurance status. ConclusionOur study shows that risk of perinatal hypoxic ischemic encephalopathy injury can be estimated with high confidence. Our model fills a notable gap in the study of hypoxic ischemic encephalopathy prevention: the estimation of risk, particularly in the United States population which is unique with respect to racial and socioeconomic disparities.

A narrative review on treatment strategies for neonatal hypoxic ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of death and disability worldwide. Therapeutic hypothermia (TH) represents a significant achievement in the translation of scientific research to clinical application, but it is currently the only neuroprotective treatment for HIE. This review aims to revisit the use of TH for HIE and its longitudinal impact on patient outcomes to readers new to the field of HIE. We discuss how emerging therapies address the broader pathophysiology of injury progression in the neonatal brain days to years after HIE. We included full articles and book chapters published in English on PubMed with references to "hypoxic ischemic encephalopathy", "birth asphyxia", "therapeutic hypothermia", or "neonatal encephalopathy". We limited our review to outcomes on term infants and to new therapeutics that are in the second phase of clinical trials. Despite the use of TH for HIE, mortality remains high. Analysis of longitudinal studies reveals a high incidence of ongoing disability even with the implementation of TH. New therapeutics addressing the secondary phase and the less understood tertiary phase of brain injury are in clinical trials as adjunctive treatments to TH to support additional neurological repair and regeneration. TH successfully improves outcomes after HIE, and it continues to be optimized. Larger studies are needed to understand its use in mild cases of HIE and if certain factors, such as sex, affect long term outcomes. TH primarily acts in the initial phases of injury, while new pharmaceutical therapies target additional injury pathways into the tertiary phases of injury. This may allow for more effective approaches to treatment and improvement of long-term functional outcomes after HIE.

Learning From the Law: A Review of 21 Years of Litigation for Anesthetic Negligence Resulting in Peripartum Hypoxic Ischemic Encephalopathy

(Anaesthesia. 2022;77:919–928) The authors of this study reviewed 367 negligence claims in the United Kingdom in order to highlight anesthesia-service related errors. Specifically, they reviewed cases of hypoxic ischemic encephalopathy (HIE), which is caused by interrupted oxygen supply to the fetal/neonatal brain. The causes and effects range, but HIE may lead to a neonate requiring lifelong care. Verified maternity negligent claims are expensive and represent a comparatively large quantity of claims submitted to and granted by the NHSLA. In addition, because peripartum HIE is so severe, millions of pounds can be awarded decades after the inciting incident took place. Anesthetists are often included in obstetric and HIE negligence claims as they play an integral role in the wellbeing of both mother and child.

Clinical Characteristics and Risk Factors of Neonatal Hypoxic-Ischaemic Encephalopathy and Its Associated Neurodevelopmental Outcomes During the First Two Years of Life: A Retrospective Study in Saudi Arabia.

This study aimed to determine the clinical characteristics and factors associated with neonatal hypoxic-ischaemic encephalopathy (HIE) and its neurodevelopmental outcomes. We conductedretrospective case-control researchto investigate the clinical and labour-related risk factors for HIE. In addition, a single-centre cohort study was conducted on infants with HIE to describe their neurodevelopment from birth to 24 months. For this investigation, cases with a diagnosis of HIE who were born at King Abdullah Children's Specialist Hospital (KASCH), Riyadh, Saudi Arabia, between 2015 and 2019 were identified and matched with controls from the same facility (1:4). Each case's clinical information was extracted using electronic medical records. In addition,24-monthfollow-up HIE cases were included in a cohort study to describe their neurodevelopmental outcomes. The sample includes 60 infants diagnosed with HIE and 234 infants serving as controls, with a mean gestational age of 38.8 weeks (SD 1.6)and a predominance of males (56.4%). Around one-thirdof the HIE cases (36.6%) had moderate HIE (stage 2), whereas 35.1% of infants had severe HIE (stage 3), according to Sarnat staging. Compared to the control group, children with HIE were twice as likely to be born to mothers with maternal comorbidities and more likely to have prepartum and intrapartum complications. A 24-month follow-up of neurodevelopmental outcomes for HIE babies revealed that approximately 24% exhibited delays in gross motor skill development, 22% in fine motor skill development, 33% in language skill development, and 22% in social skill development. In the HIE group, maternal comorbidities and prepartumor intrapartum complications were more common. The severity grade of HIE can be used to predict neurodevelopmental consequences. Enhancing patient care and rehabilitation requires a minimum of 24 months of neurodevelopmental follow-up.

Evaluation and Neurodevelopmental Outcomes of Infants with Hypoxic Ischemic Encephalopathy Treated with Therapeutic Hypothermia: A Single Center Experience

Hypoxic ischemic encephalopathy (HIE) is an important cause of mortality and morbidity in newborns. Our study aimed to determine the neurodevelopmental outcomes, risk factors, and the relationship between risk factors and prognosis of cases followed up with HIE diagnosis and who were treated with hypothermia treatment. Medical records of 23 patients who were followed up with HIE diagnosis in the pediatric neurology outpatient clinic between January 1, 2018, and December 31, 2021, and treated with therapeutic hypothermia in the newborn period were retrospectively reviewed. Denver Developmental Screening Test II was used in the developmental evaluation. Neurodevelopment was normal in 12 (52.2%) of 23 cases and retarded for age in 11 (47.8%) cases. Variables such as Sarnat encephalopathy score in the neonatal period, need for prolonged ventilation, presence of severe acidosis at birth, Apgar scores at the 1st and 5th minutes, and abnormal cranial magnetic resonance (Mrg) findings were determined to be major factors in determining neurodevelopmental prognosis in asphyxic cases. The male gender was found to be riskier in terms of prognosis. Of the patients with HIE, retardation was determined for fine motor skills in 52.2%, speaking in 39.1%, gross motor skills in 26.1%, and personal development in 21.7%. Epilepsy, cerebral palsy, and speech disorders were the most common chronic period problems in patients with HIE. Despite therapeutic hypothermia treatment, neurodevelopmental problems are still observed in newborns with HIE. We found that male gender, low Apgar score, severe acidosis, and abnormal cranial Mrg findings in the neonatal period are risk factors in determining the neurodevelopmental prognosis of newborns with HIE. Monitoring and supporting the development of HIE cases with risk factors from the first months of life and intervening in developmental problems promptly are crucial in order to improve long-term outcomes.

Development of the corpus callosum and cognition after neonatal encephalopathy.

Neonatal imaging studies report corpus callosum abnormalities after neonatal hypoxic-ischaemic encephalopathy (HIE), but corpus callosum development and relation to cognition in childhood are unknown. Using magnetic resonance imaging (MRI), we examined the relationship between corpus callosum size, microstructure and cognitive and motor outcomes at early school-age children cooled for HIE (cases) without cerebral palsy compared to healthy, matched controls. A secondary aim was to examine the impact of HIE-related neonatal brain injury on corpus callosum size, microstructure and growth. Participants aged 6-8 years underwent MRI, the Movement Assessment Battery for Children Second Edition and Wechsler Intelligence Scale for Children Fourth Edition. Cross-sectional area, volume, fractional anisotropy and radial diffusivity of the corpus callosum and five subdivisions were measured. Multivariable regression was used to assess associations between total motor score, full-scale IQ (FSIQ) and imaging metrics. Adjusting for age, sex and intracranial volume, cases (N=40) compared to controls (N=39) demonstrated reduced whole corpus callosum area (β=-26.9, 95% confidence interval [CI]=-53.17, -0.58), volume (β=-138.5, 95% CI=-267.54, -9.56), fractional anisotropy and increased radial diffusivity (P < 0.05) within segments II-V. In cases, segment V area (β=0.18, 95% CI=0.004, 0.35), volume (β=0.04, 95% CI=0.001, 0.079), whole corpus callosum fractional anisotropy (β=13.8 95% CI=0.6, 27.1) and radial diffusivity (β=-11.3, 95% CI=-22.22, -0.42) were associated with FSIQ. Growth of the corpus callosum was restricted in cases with a FSIQ ≤85, and volume was reduced in cases with mild neonatal multifocal injury compared to white matter injury alone. Following neonatal HIE, morphological and microstructural changes in the corpus callosum are associated with reduced cognitive function at early school age.

Maternal &amp; fetal risk factors for hypoxic-ischemic encephalopathy (HIE) in newborns

Introduction- Perinatal hypoxia leading to hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal and under 5 mortality across the world and in India. There are wide regional and social variations in the risk factors associated with HIE and this study was conducted to assess the maternal &amp; fetal risk factors in newborns with moderate to severe HIE. Methodology- This was a case-control study at the SNCU of MKCG Medical College and Hospital in southern Odisha where 100 cases of HIE and 100 matched controls were recruited over a period of 2 years. Data on maternal, antenatal, intrapartum, and post-delivery risk factors were collected from medical records and history taking using a pre-defined proforma. Comparative bivariate analysis was done to assess the strength of association of these risk factors between the two groups. Results- The incidence of HIE is more in 20-30 years age group, however, risk of HIE is significant in &lt;20 years age group. Maternal anemia is a significant risk factor but Bad Obstetric History (BOH) has only clinical correlation. There is no statistical significance for antepartum hemorrhage (APH), pregnancy-induced hypertension (PIH) or gestational diabetes mellitus (GDM) in cases of HIE.

Profile of minor neurological findings after perinatal asphyxia.

AimTo characterise the spectrum of findings in sequential neurological examinations, general movements (GM) assessment and magnetic resonance imaging (MRI) of infants with perinatal asphyxia.MethodsThe prospective cohort study of term infants with perinatal asphyxia treated at Helsinki University Hospital's neonatal units in 2016–2020 used Hammersmith Neonatal Neurological Examination (HNNE) and brain MRI at 2 weeks and Hammersmith Infant Neurological Examination (HINE) and GM assessment at 3 months of age.ResultsAnalysis included 50 infants: 33 displaying perinatal asphyxia without hypoxic‐ischaemic encephalopathy (HIE), seven with HIE1 and 10 with HIE2. Of the infants with atypical HNNE findings, 24/25 perinatal asphyxia without HIE cases, 5/6 HIE1 cases and all 10 HIE2 cases showed atypical findings in the HINE. The HINE identified atypical spontaneous movements significantly more often in infants with white matter T2 hyperintensity.ConclusionIn this cohort, most infants with perinatal asphyxia, with or without HIE, presented atypical neurological findings in sequential examinations. The profile of neurological findings for children with perinatal asphyxia without HIE resembled that of children with HIE. White matter T2 hyperintensity was associated with atypical spontaneous movements in the HINE and was a frequent MRI finding also in perinatal asphyxia without HIE.

Potential use of lactate for the treatment of neonatal hypoxic-ischemic encephalopathy.

Potential use of lactate for the treatment of neonatal hypoxic-ischemic encephalopathy.

Comparative Study Between Serum Level of Total L-carnitine in Neonatal Hypoxic Ischemic Encephalopathy (HIE) and Transient Tachypnea of the Newborn (TTN)

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common causes of cerebral palsy. Objectives: We aimed to compare the serum levels of total L-carnitine in newborns with HIE and Transient tachypnea of the newborn and to determine the correlation between associated demographic data, associated changes in laboratory findings, and outcome in cases with HIE. Methods: This comparative, prospective, and observational study was conducted at the Neonatal Intensive Care Unit (NICU) of Assiut University Children Hospital. All the cases of perinatal asphyxia and TTN admitted to the NICU during 2016 - 2018 were included. Results: It was found that the serum level of total L-carnitine decreased in both HIE (I) and TTN (II) cases, but the difference was not significant (5.51 ± 1.30 µmol/L in group I vs. 6.22 ± 2.56 µmol/l in group II). Male factor with changes in the serum sodium level (132.63 ± 9.30) and abnormal serum creatinine level (1.4 [0.7 - 15.0]) were significantly related to the outcome of HIE cases. Conclusions: The serum level of total L-carnitine declined in both HIE and TTN cases. Male factor with changes in serum sodium level and abnormal serum creatinine level were significantly related to the mortality of cases with HIE.

Blood Plasma Metabolic Profile of Newborns with Hypoxic-Ischaemic Encephalopathy by GC-MS.

Background Early diagnosis of hypoxic-ischaemic encephalopathy (HIE) is crucial in preventing neurodevelopmental disabilities and reducing morbidity and mortality. The study was to investigate the plasma metabolic signatures in the peripheral blood of HIE newborns and explore the potential diagnostic biomarkers. Method In the present study, 24 newborns with HIE and 24 healthy controls were recruited. The plasma metabolites were measured by gas chromatography-mass spectrometry (GC-MS), and the raw data was standardized by the EigenMS method. Significantly differential metabolites were identified by multivariate statistics. Pathway enrichment was performed by bioinformatics analysis. Meanwhile, the diagnostic value of candidate biomarkers was evaluated. Result The multivariate statistical models showed a robust capacity to distinguish the HIE cases from the controls. 52 metabolites were completely annotated. 331 significantly changed pathways were enriched based on seven databases, including 33 overlapped pathways. Most of them were related to amino acid metabolism, energy metabolism, neurotransmitter biosynthesis, pyrimidine metabolism, the regulation of HIF by oxygen, and GPCR downstream signaling. 14 candidate metabolites showed great diagnostic potential on HIE. Among them, alpha-ketoglutaric acid has the potential to assess the severity of HIE in particular. Conclusion The blood plasma metabolic profile could comprehensively reflect the metabolic disorders of the whole body under hypoxia-ischaemic injury. Several candidate metabolites may serve as promising biomarkers for the early diagnosis of HIE. Further validation based on large clinical samples and the establishment of guidelines for the clinical application of mass spectrometry data standardization methods are imperative in the future.

Neonatal hypoxic-ischemic encephalopathy diagnosis and treatment: a National Survey in China

BackgroundNeonatal hypoxic-ischemic encephalopathy (HIE) affects as many as 100,000 infants each year in China. Therapeutic hypothermia reduces HIE related mortality and long-term neurodevelopmental disabilities. National guidelines for HIE management were published a decade ago. This study aimed to investigate the current status of HIE diagnosis and treatment in China.MethodThis prospective cross-sectional national survey used a questionnaire evaluating practices related to HIE management. Descriptive statistics and Chi-square or Fisher’s exact test were used, and a p-value of < 0.05 was considered significant.ResultsThe 273 hospitals that completed the survey were located in 31 of the 34 provincial districts in China. Eighty-eight percent of the hospitals were Level III hospitals, and 74% treated 10 or more HIE cases annually. Awareness rates of the national guidelines for HIE diagnosis, HIE treatment, and therapeutic hypothermia protocol were 85, 63, and 78%, respectively. Neurological manifestations and blood gas were used as HIE diagnostic criteria by 96% (263/273) and 68% (186/273) of the hospitals, respectively. Therapeutic hypothermia was used in 54% (147/273) of hospitals. The percentage of general hospitals that implemented therapeutic hypothermia (43%, 71/165) was significantly lower than that in maternity and infant hospitals (67%, 49/73) (χ2 = 11.752, p = 0.001) and children’s hospitals (77%, 27/35) (χ2 = 13.446, p < 0.001). Reasons for not providing therapeutic hypothermia included reduction of HIE cases in recent years (39%), high cost of cooling devices and treatment (31%), lack of training (26%), and safety concerns (4%). Among the hospitals that provided therapeutic hypothermia, 27% (39/147) were in full compliance with the recommended protocol. Eighty-one percent (222/273) of the hospitals treated HIE infants with putative neuroprotective agents alone or in combination with cooling. Ninety-one percent of the hospitals had long-term neurodevelopmental follow-up programs for infants with HIE.ConclusionsThere is significant heterogeneity in HIE diagnosis and treatment in China. Therapeutic hypothermia has not become a standard of care for neonatal HIE nationwide. Unproven agents are widely used for HIE treatment. Nationwide standardization of HIE management and dissemination of therapeutic hypothermia represent the opportunities to reduce mortality and improve long-term neurodevelopmental outcomes of children affected by HIE.

Trends and predictors of in-hospital mortality among babies with hypoxic ischaemic encephalopathy at a tertiary hospital in Nigeria: A retrospective cohort study

Globally, approximately 9 million neonates develop perinatal asphyxia annually of which about 1.2 million die. Majority of the morbidity and mortality occur in Low and middle-income countries. However, little is known about the current trend in incidence, and the factors affecting mortality from hypoxic ischaemic encephalopathy (HIE), in Nigeria. We assessed the trends in incidence and fatality rates and evaluated the predictors of mortality among babies admitted with HIE over five years at the Lagos University Teaching Hospital. A temporal trend analysis and retrospective cohort study of HIE affected babies admitted to the neonatal unit of a Nigerian Teaching Hospital was conducted. The socio-demographic and clinical characteristics of the babies and their mothers were extracted from the neonatal unit records. Kaplan-Meir plots and Multivariable Cox proportional hazard ratio was used to evaluate the survival experienced using Stata version 16 (StataCorp USA) statistical software. The median age of the newborns at admission was 26.5 (10-53.5) hours and the male to female ratio was 2.1:1. About one-fifth (20.8%) and nearly half (47.8%) were admitted within 6 hours and 24 hours of life respectively, while majority (84%) of the infants were out-born. The prevalence and fatality rate of HIE in our study was 7.1% and 25.3% respectively. The annual incidence of HIE among the hospital admissions declined by 1.4% per annum while the annual fatality rate increased by 10.3% per annum from 2015 to 2019. About 15.7% died within 24 hours of admission. The hazard of death was related to the severity of HIE (p = 0.001), antenatal booking status of the mother (p = 0.01) and place of delivery (p = 0.03). The case fatality rate of HIE is high and increasing at our centre and mainly driven by the pattern of admission of HIE cases among outborn babies. Thus, community level interventions including skilled birth attendants at delivery, newborn resuscitation trainings for healthcare personnel and capacity building for specialized care should be intensified to reduce the burden of HIE.

Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies.

Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of mortality and morbidity in the perinatal period. This condition results from a period of ischemia and hypoxia to the brain of neonates, leading to several disorders that profoundly affect the daily life of patients and their families. Currently, therapeutic hypothermia (TH) is the standard of care in developing countries; however, TH is not always effective, especially in severe cases of HIE. Addressing this concern, several preclinical studies assessed the potential of stem cell therapy (SCT) for HIE. With this systematic review, we gathered information included in 58 preclinical studies from the last decade, focusing on the ones using stem cells isolated from the umbilical cord blood, umbilical cord tissue, placenta, and bone marrow. Outstandingly, about 80% of these studies reported a significant improvement of cognitive and/or sensorimotor function, as well as decreased brain damage. These results show the potential of SCT for HIE and the possibility of this therapy, in combination with TH, becoming the next therapeutic approach for HIE. Nonetheless, few preclinical studies assessed the combination of TH and SCT for HIE, and the existent studies show some contradictory results, revealing the need to further explore this line of research.

Role of grayscale transcranial ultrasound in the diagnosis of neonatal hypoxic–ischemic encephalopathy: a clinical audit study

Background Neonatal hypoxic–ischemic encephalopathy (HIE) is still accounts for a significant percentage of mortality and morbidity in the neonates. Transcranial ultrasound (US) is the investigation of choice for the initial assessment of these cases. Aim To evaluate the practice of transcranial US in the diagnosis of suspected cases of neonatal HIE in the ICU of Assiut University Hospital (AUH). Patients and methods This clinical audit study was conducted during the period from April 2017 till June 2018 (first audit cycle about 13 months and second audit cycle about 2 months) in the ICU in AUH on neonates who underwent transcranial US for the diagnosis of neonatal HIE. Six criteria were set and were measured with 40 indicators with a 100% standard set for each indicator. Results The study included 110 neonates (90 in the first audit cycle and 20 in the second audit cycle). The adherence to the audit criteria was about 17.5% in the first audit cycle and 25% in the second audit cycle, which indicates that there was just a slight improvement in the second audit cycle. Conclusion Transcranial US is the modality of choice in the initial evaluation of suspected cases of neonatal HIE. Adherence to the audit criteria of this study in the neonatal ICU of AUH fell below expected standards in both the audit cycles with a slight improvement in the second audit cycle. Further reauditing is recommended.

Regulatory Mechanism of MicroRNA-30b on Neonatal Hypoxic-Ischemic Encephalopathy (HIE)

ObjectiveThis study is to investigate the role of microRNA (miR)-30b in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonates. MethodsTotally 26 cases of neonatal HIE were included in this study. The protein expression levels of CD26P and PAI-1 were detected with ELISA. Serum levels of miR-30b and PAI-1 mRNA was measured by quantitative real-time PCR. Human brain microvascular endothelial cells (HBMECs) were cultured under hypoxic condition, and the intracellular expression levels of miR-30b and PAI-1 were evaluated. Dual-luciferase reporter assay was performed to confirm the interaction between miR-30b and PAI-1. ResultsCompared with the control group, both the mRNA and protein expression levels of PAI-1 in the serum were up-regulated in the neonates with HIE, together with up-regulated serum CD26P levels. However, the serum expression level of miR-30b was down-regulated in neonatal HIE. In hypoxia-induced HBMECs, the mRNA and protein expression levels of PAI-1 were significantly up-regulated, while the miR-30b expression level was significantly down-regulated. Dual-luciferase reporter assay showed that PAI-1 was the direct target of miR-30b. ConclusionNeonatal HIE is accompanied with abnormal platelet activation, significantly up-regulated serum PAI-1 expression levels, and down-regulated miR-30b expression. MiR-30b might regulate the disease pathogenesis and immune responses via modulating PAI-1.

Combination treatments with therapeutic hypothermia for hypoxic‐ischemic neuroprotection

Therapeutic hypothermia is now proven to reduce death or disability in term and near-term born infants with moderate to severe hypoxic-ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite treatment with hypothermia. Recent preclinical and clinical studies suggest that current protocols for therapeutic hypothermia are near-optimal. The obvious strategy, in addition to improving early initiation of therapeutic hypothermia after birth, is to combine hypothermia with other neuroprotective agents. We review evidence that the mechanisms of action of many promising agents overlap with the anti-excitotoxic, anti-apoptotic, and anti-inflammatory mechanisms of hypothermia, leading to a lack of benefit from combination treatment. Moreover, even apparently beneficial combinations have failed to translate in clinical trials. These considerations highlight the need for preclinical studies to test clinically realistic protocols of timing and duration of treatment, before committing to large randomized controlled trials.

Deregulated miR-384 serves as a biomarker in neonatal hypoxic-ischemic encephalopathy and alleviates microglia-mediated neuroinflammation.

Microglia-mediated neuroinflammation is important in the pathogenesis of neonatal hypoxic-ischemic encephalopathy (HIE). This study aimed to investigate the expression of microRNA-384 (miR-384) in HIE newborns and evaluate the clinical and functional role of miR-384 in HIE diagnosis and neuroinflammation. The expression of miR-384 was estimated using quantitative real-time PCR. The levels of proinflammatory cytokines were examined using ELISA. Receiver operating characteristic (ROC) analysis was applied to evaluate the diagnostic performance of miR-384. The oxygen-glucose deprivation (OGD) experiment was adopted to activate primary neonatal microglia. A putative target of miR-384 was analyzed by bioinformatics prediction and a luciferase reporter assay. The expression of miR-384 was decreased in the serum of HIE newborns and OGD-induced activated microglia. Serum miR-384 had relatively high diagnostic accuracy for the screening of HIE cases from healthy newborns and the differentiation between newborns with different HIE severities. The OGD-induced increase in microglial neuroinflammation was significantly attenuated by the overexpression of miR-384, and AKT3, as a downstream target of miR-384, was inhibited by miR-384 in activated microglia. The data of this study demonstrated that decreased serum miR-384 expression may be a novel noninvasive biomarker for the diagnosis and progression of neonatal HIE. miR-384 can inhibit the neuroinflammation in activated microglia, which may be mediated by targeting AKT3.