Neonatal Hypoxic-ischemic Encephalopathy Research Articles

Peptidomic Analysis of Neonate Umbilical Cord Blood for the Identification of Endogenous Peptides Involved in Hypoxic-Ischemic Encephalopathy.

Neonatal hypoxic–ischemic encephalopathy (HIE) is a common neurological disorder triggered by perinatal cerebral ischemia and hypoxia. Accumulating evidence has shown that peptides have neuroprotective effects in nerve injury. However, the function of endogenous peptides in the pathogenesis of HIE has not been studied. In the present study, a comparative peptidomic profile was performed in the serum of the human umbilical cord blood with HIE (three patients) and the control group (three health control) by liquid chromatography–mass spectrometry (LC-MS). Our study demonstrated that a total of 49 peptides derived from 25 precursor proteins were differentially expressed in the serum of HIE compared with normal controls, including 33 upregulated peptides and 16 downregulated peptides. Each of the differentially expressed peptides has specific characteristics, including pI, Mw, and cleavage pattern. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that the precursor proteins of differentially expressed peptides participate in the different biological process. Moreover, among the 49 differentially expressed peptides, 21 peptides were identified from the fibrinogen chain family, which plays a role in neurological diseases, suggesting that these peptides may play an important role in maintaining brain health. In conclusion, our results showed a comparative peptidomic profile from human umbilical cord blood of HIE patients and normal controls. These dysregulated peptides may have potentially important functions in umbilical cord blood with HIE and may be involved in the pathogenesis of the HIE.

NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes.

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.

1H-MR Spectroscopy of the Early Developmental Brain, Neonatal Encephalopathies, and Neurometabolic Disorders.

MRI interpretations of the pediatric brain are often challenging for general radiologists and clinicians because MR signals and morphology are continuously changing in the developing brain. Furthermore, the developing brain reacts differently to injuries, resulting in imaging characteristics that differ from those of the mature brain. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive method for assessing neurological abnormalities at the microscopic level and measures in vivo brain metabolites using a clinical MR machine. In MR examinations of the pediatric brain, 1H-MRS demonstrates its powerful diagnostic capability when MRI is insufficient for diagnostic features. MRI and 1H-MRS may be complementary tools for diagnosing and monitoring diseases. However, there is currently no consensus on how to include 1H-MRS in clinical MR examinations. An overview of the clinical implementation of 1H-MRS for the assessment of early pediatric developmental brains as well as the diagnosis, prognostification, and disease monitoring of various non-neoplastic brain disorders, including neonatal encephalopathies and neurometabolic/neurodegenerative diseases, was provided herein. Qualitative and quantitative 1H-MRS is a powerful non-invasive tool for accessing various brain metabolites to confirm age appropriate peaks and detect abnormal peaks or deficient or reduced peaks, which may facilitate the identification of metabolic and neurodegenerative disorders as well as damage associated with hypoxic-ischemic encephalopathy (HIE). Moreover, 1H-MRS has potential as a biomarker for monitoring therapeutic efficacy in metabolic diseases and neonatal HIE. It also provides insights into the pathophysiologies of various disorders, which may facilitate the use of novel therapeutic approaches. Therefore, 1H-MRS needs to be included more frequently in routine clinical MR examinations of pediatric patients with neurological disorders.

LncRNA TCONS_00041002 improves neurological outcomes in neonatal rats with hypoxic-ischemic encephalopathy by inhibiting apoptosis and promoting neuron survival

It has been reported that Neonatal hypoxic-ischemic encephalopathy (HIE) could induce apoptosis in neonates and result in cognitive and sensory impairments, which are associated with poor developmental outcomes. Despite the improvement in neonatology, there is still no clinically effective treatment for HIE presently. Long non-coding RNAs (lncRNAs) play important roles in cellular homeostasis. Nevertheless, their effects in developing rat brains with HI is little known. Here, we established HIE model in neonate rats and explored the expression and function of lncRNAs in HI, and found the expression of 19 lncRNAs was remarkably changed in the brains of HI rats, compared to the sham group. Among them, three lncRNAs (TCONS_00041002, TCONS_00070547, TCONS_00045572) were enriched in the apoptotic process via gene ontology (GO) and pathway analysis, which were selected for the further qRT-PCR verification. Through lentivirus-mediated overexpression of these three lncRNAs, we found that overexpression of TCONS_00041002 attenuated the cell apoptosis, and increased the vitality of neurons after oxygen-glucose deprivation (OGD), therefore reduced the brain infarction and further promoted the neuron survival as well as improved the neurological disorders in the rats subjected to HIE. What's more, ceRNA network prediction and co-expression verification showed that the expression of TCONS_00041002 was positively associated with Foxe1, Pawr and Nfkbiz. Altogether, this study has exhibited that lncRNA TCONS_00041002 participates in the cell apoptosis and neuronal survival of HIE and represents a potential new target for the treatment of HIE.

Hypoxic Ischemic Encephalopathy in Neonates with Birth Asphyxia - A Hospital Based Study

Introduction: Each year approximately 4 million babies are born asphyxiated, which results in 1 million deaths and an equal number of serious neurological sequelae. One of the commonest organs involved in birth asphyxia is brain which may lead to a syndrome of clinical manifestation called Hypoxic Ischemic Encephalopathy (HIE).
 Aims: To find out possible maternal and neonatal risk factors for Hypoxic Ischemic Encephalopathy, to analyze clinical presentations and outcome of HIE in asphyxiated newborns.
 Methods: Hospital based observational study was carried out among fifty newborns with Apgar score less than 7 at 1 minute of life admitted in Nepalgunj Medical College Teaching Hospital, Kohalpur, Banke.
 Results: The incidence of birth asphyxia and birth asphyxia with HIE were 37.2 per 1000 live births and 14 per 1000 live births with male: female ratio of 1.27:1. Most of the neonates 22(44%) were in HIE stage II. Meconium stained amniotic fluid 18 (36%) was the most common intrapartum risk factor followed by maternal use of intrapartum medications 14 (28%), Premature Rupture of Membrane (PROM) 8 (16%), prolonged labor 5 (10%) and obstructed labor 6 (12%). Four (8%) asphyxiated neonates with HIE had cord prolapse and 7 (14%) had cord around the neck. The most common resuscitation done was bag and mask ventilation (56%) (P<0.05). Majority of the studied neonates were of normal birth weight (76%) and head circumference (84%) (P<0.05) with clinical presentations of respiratory distress (88%), seizures (44%), apnea (22%), bradycardia (8%), tachycardia (6%) and bulged anterior fontanel (6%). The overall mortality of neonates with HIE was 20% of which most were of HIE stage III.
 Conclusion: Certain measures could be taken to prevent birth asphyxia: early detection and intervention of high risk pregnancy, prompt and effective resuscitation of asphyxiates newborns.

Hypoxic ischemic encephalopathy in offspring of immigrant women in Sweden: A population-based cohort study.

One in four women giving birth in Sweden is foreign-born. Immigrant status has been suggested as a risk factor for adverse perinatal outcomes. It is not known if infants to foreign-born women have an increased risk of severe birth asphyxia, or which factors might mediate such association. A population-based cohort study of 726730live births at 36weeks of gestation or more in Sweden in 2009-2015. The exposure was maternal country of birth, grouped according to the World Bank country classification: low-, lower-middle, upper-middle, and high-income economies. The main outcome was neonatal hypoxic ischemic encephalopathy (HIE). The outcome was estimated by severity and classified as non-hypothermia-treated HIE, representing mainly mild cases, and hypothermia-treated HIE, representing moderate to severe cases. A secondary outcome was low Apgar score at 5minutes, defined as <7 or <4. Odds ratios with 95% CI were calculated, using Swedish-born women as the reference. Structural equation modeling was used to investigate potential mediation of known antepartum risk factors. A total of 854 infants were diagnosed with HIE and 398 received therapeutic hypothermia. Offspring of mothers born in low-income countries had the highest incidences of HIE and low Apgar score, with an incidence of therapeutic hypothermia of 1.1 per 1000. Compared with offspring of Swedish-born mothers, these neonates had an almost two-fold increased risk of HIE, with or without hypothermia treatment (odds ratio 1.7; 95% CI 1.2-2.7 and odds ratio 1.7; 95% CI 1.2-2.6, respectively), and a 2- to 3-fold increased risk of low Apgar score. The structural equation model analysis indicated an exclusive direct effect of country of birth on HIE. Factors reflecting socio-economic status mediated a small proportion of the risk of Apgar score <7 at 5minutes. Offspring of women born in low-income countries had associations with severe birth asphyxia, with increased risk of both HIE and low Apgar score at 5minutes. The associations seemed only to be marginally mediated by other antepartum factors. The associations are complex and further studies are needed to find explanatory and potentially preventable factors.

Amplitude Integrated Electroencephalography and Continuous Electroencephalography Monitoring Is Crucial in High-Risk Infants and Their Findings Correlate With Neurodevelopmental Outcomes.

Background: To evaluate seizure diagnosis in sick infants in the neonatal intensive care unit (NICU) based on electroencephalography (EEG) monitoring combined with amplitude integrated electroencephalography (aEEG).Methods: We retrospectively reviewed EEG and aEEG findings and determined their correlations with neurodevelopmental outcomes at the age of >1 year in 65 patients with diagnosed seizures, encephalopathy, or both.Results: Seizure identification rate was 43.1%. The rate in nonstructural groups (hypocalcemic, hypoglycemic, and genetic seizures) was 71.4%, which was higher (p < 0.05) than the rate of 35.3% of structural brain lesion group [hypoxic–ischemic encephalopathy (HIE) and congenital brain structural malformation]. The aEEG background correlating with neurodevelopmental outcomes had 70.0% positive prediction value (PPV), 65.5%% negative prediction value (NPV), 67.7% specificity, and 67.9% sensitivity (p < 0.005). The aEEG background strongly (PPV, 93.8%; p < 0.005) correlated with the outcomes in HIE. For genetic seizures, the detected rate was high. The ictal recordings for the nonstructural seizures revealed downflected on the aEEG background initially, which differed from the structural lesion.Conclusions: EEG monitoring combined with aEEG can detect seizures, facilitating early treatment. EEG changes during seizures could exhibit delta-theta waves with or without clinical seizures in patients with brain lesions. In non-structural etiologies (hypocalcemic and KCNQ2 seizures), aEEG initially exhibited lower background during seizures that could aid in differentiating these EEG changes from those of other etiologies. The aEEG background was correlated with neurodevelopmental outcome and exhibited high PPV but not NPV in neonatal HIE.

Hypoxic ischaemic encephalopathy in low resource settings—time to stop cooling?

Perinatal asphyxia is a notable cause of mortality in newborn babies and of neurodevelopmental disability in infancy and childhood, especially in low-income and middle-income countries (LMICs). Therapeutic hypothermia has profoundly changed the management of hypoxic ischaemic encephalopathy. This therapy is the standard of care for neonatal hypoxic ischaemic encephalopathy in high-income countries (HICs). Despite having a higher burden of this injury than HICs, LMICs have been slow to adopt therapeutic hypothermia for several reasons: the non-availability of expensive cooling equipment, need for well equipped neonatal intensive care units with trained staff, the high incidence of home deliveries, frequent comorbid sepsis, and delayed transport and referral.

Development and Evaluation of Computable Phenotypes in Pediatric Epilepsy:3 Cases.

Computable phenotypes allow identification of well-defined patient cohorts from electronic health record data. Little is known about the accuracy of diagnostic codes for important clinical concepts in pediatric epilepsy, such as (1) risk factors like neonatal hypoxic-ischemic encephalopathy; (2) clinical concepts like treatment resistance; (3) and syndromes like juvenile myoclonic epilepsy. We developed and evaluated the performance of computable phenotypes for these examples using electronic health record data at one center. We identified gold standard cohorts for neonatal hypoxic-ischemic encephalopathy, pediatric treatment-resistant epilepsy, and juvenile myoclonic epilepsy via existing registries and review of clinical notes. From the electronic health record, we extracted diagnostic and procedure codes for all children with a diagnosis of epilepsy and seizures. We used these codes to develop computable phenotypes and evaluated by sensitivity, positive predictive value, and the F-measure. For neonatal hypoxic-ischemic encephalopathy, the best-performing computable phenotype (HIE ICD-9/10 and [brain magnetic resonance imaging (MRI) or electroencephalography (EEG) within 120 days of life] and absence of commonly miscoded conditions) had high sensitivity (95.7%, 95% confidence interval [CI] 85-99), positive predictive value (100%, 95% CI 95-100), and F measure (0.98). For treatment-resistant epilepsy, the best-performing computable phenotype (3 or more antiseizure medicines in the last 2 years or treatment-resistant ICD-10) had a sensitivity of 86.9% (95% CI 79-93), positive predictive value of 69.6% (95% CI 60-79), and F-measure of 0.77. For juvenile myoclonic epilepsy, the best performing computable phenotype (JME ICD-10) had poor sensitivity (52%, 95% CI 43-60) but high positive predictive value (90.4%, 95% CI 81-96); the F measure was 0.66. The variable accuracy of our computable phenotypes (hypoxic-ischemic encephalopathy high, treatment resistance medium, and juvenile myoclonic epilepsy low) demonstrates the heterogeneity of success using administrative data to identify cohorts important for pediatric epilepsy research.

Optimized Clustering Algorithm for Comparative Analysis of Different Prenatal Corticosteroid Neurological Deficits in Premature Infants through Magnetic Reasoning Imaging (MRI).

Objective This study aimed to explore the application of different prenatal corticosteroids in the assessment of neurological deficits and prognosis in premature infants through Magnetic Reasoning Imaging (MRI) under optimized cluster algorithm. Methods 100 pregnant women with threatened preterm labor were retrospectively analyzed, in which 38 pregnant women with lasting threatened preterm labor (group A) were treated with multiple courses of antenatal corticosteroids (dexamethasone treatment) and 62 cases of pregnant women with threatened preterm labor (group B) were treated with single course of dexamethasone treatment. Craniocerebral MRI images based on optimal clustering algorithm were used to examine neonates. Neonatal hypoxic-ischemic encephalopathy (HIE) rate, serum neuron-specific enolase (NSE) concentration, neonatal behavioral neurological score (NBNA), respiratory distress syndrome (RDS) rate, perinatal mortality, neonatal birth weight, and maternal complications rate of two groups were compared. Results Compared with other traditional image segmentation algorithms, this algorithm had the best segmentation effect, the shortest running time (1.43 s), the least number of iterations (5 times), and the highest segmentation accuracy (97.98%). There was no significant difference in the HIE rate, serum NSE concentration, NBNA score, RDS score, and perinatal mortality in group A and group B (P > 0.05). Compared with group B, neonates' body weight in group A was decreased, while the maternal complication rate in group A was increased (P < 0.05). Conclusion MRI images based on optimized clustering algorithm can be used in the diagnosis of neonatal hypoxic-ischemic encephalopathy. There is no significant difference in the application of different antenatal corticosteroids affecting premature nerve function defect and prognosis, but multiple courses of antenatal corticosteroids can affect neonatal body mass and increased maternal complications to a certain extent; therefore, before threatened premature delivery treatment, the pros and cons of multiple courses of antenatal corticosteroids should fully be considered and in the treatment, measures should be actively taken to alleviate the side effect.

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.

Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Catalase, an antioxidant enzyme, is a promising therapeutic due to its ability to scavenge toxic reactive oxygen species and improve tissue oxygen status. However, upon in vivo administration, catalase is subject to a short half-life, rapid proteolytic degradation, immunogenicity, and an inability to penetrate the brain. Polymeric nanoparticles can improve pharmacokinetic properties of therapeutic cargo, although encapsulation of large proteins has been challenging. In this paper, we investigated hydrophobic ion pairing as a technique for increasing the hydrophobicity of catalase and driving its subsequent loading into a poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticle. We found improved formation of catalase-hydrophobic ion complexes with dextran sulfate (DS) compared to sodium dodecyl sulfate (SDS) or taurocholic acid (TA). Molecular dynamics simulations in a model system demonstrated retention of native protein structure after complexation with DS, but not SDS or TA. Using DS-catalase complexes, we developed catalase-loaded PLGA-PEG nanoparticles and evaluated their efficacy in the Vannucci model of unilateral hypoxic-ischemic brain injury in postnatal day 10 rats. Catalase-loaded nanoparticles retained enzymatic activity for at least 24 h in serum-like conditions, distributed through injured brain tissue, and delivered a significant neuroprotective effect compared to saline and blank nanoparticle controls. These results encourage further investigation of catalase and PLGA-PEG nanoparticle-mediated drug delivery for the treatment of neonatal brain injury.

Early Use of Transcranial Doppler Ultrasonography to Stratify Neonatal Encephalopathy

BackgroundThe dynamic nature of neonatal hypoxic-ischemic encephalopathy (HIE) after birth necessitates reliable biomarkers to identify infants with evolving brain injury. This prospective cohort aims to use serial Doppler ultrasonography (US) to measure cerebral blood flow velocity and resistance index (RI) to help detect the time and evolution of the clinical encephalopathy. MethodsA total of 60 neonates were enrolled all ≥36 weeks’ gestation with perinatal acidemia, defined as a blood gas pH ≤ 7.0 or base deficit ≥16 mmol/L and encephalopathy including a matched control group without encephalopathy. Each neonate received one to three serial Doppler recordings starting at six to 24 hours of life. Mean RI ≤ 0.55 was considered abnormal. ResultsMean RIs obtained shortly after birth were significantly lower with increasing severity of encephalopathy. On the first Doppler recordings, abnormal mean RIs were seen in 11 of 18 (61%) neonates with mild, 13 of 17 (76%) with moderate, and two of two (100%) with severe HIE. Of the neonates with mild HIE and abnormal mean RIs, congruity abnormal amplitude electroencephalography (45%), brain magnetic resonance imaging (45%), and abnormal head ultrasound (44%) are here reported. ConclusionsDoppler measurements can provide bedside adjunct biomarkers indicating the time and severity of neonatal HIE.

Cerebral Blood Flow of the Neonatal Brain after Hypoxic-Ischemic Injury.

Hypoxic-ischemic encephalopathy (HIE) in infants can have long-term adverse neurodevelopmental effects and markedly reduce quality of life. Both the initial hypoperfusion and the subsequent rapid reperfusion can cause deleterious effects in brain tissue. Cerebral blood flow (CBF) assessment in newborns with HIE can help detect abnormalities in brain perfusion to guide therapy and prognosticate patient outcomes. The review will provide an overview of the pathophysiological implications of CBF derangements in neonatal HIE, current and emerging techniques for CBF quantification, and the potential to utilize CBF as a physiologic target in managing neonates with acute HIE. The alterations of CBF in infants during hypoxia-ischemia have been studied by using different neuroimaging techniques, including nitrous oxide and xenon clearance, transcranial Doppler ultrasonography, contrast-enhanced ultrasound, arterial spin labeling MRI, 18F-FDG positron emission tomography, near-infrared spectroscopy (NIRS), functional NIRS, and diffuse correlation spectroscopy. Consensus is lacking regarding the clinical significance of CBF estimations detected by these different modalities. Heterogeneity in the imaging modality used, regional versus global estimations of CBF, time for the scan, and variables impacting brain perfusion and cohort clinical characteristics should be considered when translating the findings described in the literature to routine practice and implementation of therapeutic interventions. · Hypoxic-ischemic injury in infants can result in adverse long-term neurologic sequelae.. · Cerebral blood flow is a useful biomarker in neonatal hypoxic-ischemic injury.. · Imaging modality, variables affecting cerebral blood flow, and patient characteristics affect cerebral blood flow assessment..

Children with neonatal Hypoxic Ischaemic Encephalopathy (HIE) treated with therapeutic hypothermia are not as school ready as their peers.

We aimed to determine whether children with neonatal Hypoxic Ischaemic Encephalopathy (HIE) treated with therapeutic hypothermia (TH) differ from their peers on measures of fine motor skills, executive function, language and general cognitive abilities, factors that are important for school readiness. We compared school readiness in 31children with HIE treated with TH (without Cerebral Palsy; mean age 5years 4months) with 20 typically developing children without HIE (mean age 5years 6months). Children with HIE scored significantly lower than typically developing children on fine motor skills, executive functions, memory and language. While general cognitive abilities and attainment were in the normal range, our findings suggest those scores mask specific underlying difficulties identified by more focussed assessments. Children with HIE treated with TH may not be as 'school ready' as their typically developing classmates and may benefit from long-term follow-up until starting school.

Prognostic value of neonatal EEG following therapeutic hypothermia in survivors of hypoxic-ischemic encephalopathy

ObjectiveEarly prediction of neurological deficits following neonatal hypoxic-ischemic encephalopathy (HIE) may help to target support. Neonatal animal models suggest that recovery following hypoxia-ischemia depends upon cortical bursting. To test whether this holds in human neonates, we correlated the magnitude of cortical bursting during recovery (≥postnatal day 3) with neurodevelopmental outcomes. MethodsWe identified 41 surviving infants who received therapeutic hypothermia for HIE (classification at hospital discharge: 19 mild, 18 moderate, 4 severe) and had 9-channel electroencephalography (EEG) recordings as part of their routine care. We correlated burst power with Bayley-III cognitive, motor and language scores at median 24 months. To examine whether EEG offered additional prognostic information, we controlled for structural MRI findings. ResultsHigher power of central and occipital cortical bursts predicted worse cognitive and language outcomes, and higher power of central cortical bursts predicted worse motor outcome, all independently of structural MRI findings. ConclusionsClinical EEG after postnatal day 3 may provide additional prognostic information by indexing persistent active mechanisms that either support recovery or exacerbate brain damage, especially in infants with less severe encephalopathy. SignificanceThese findings could allow for the effect of clinical interventions in the neonatal period to be studied instantaneously in the future.

Different antecedents and neonatal condition in neonatal arterial ischemic stroke and hypoxic-ischemic neonatal encephalopathy.

ObjectiveTo define similarities and differences between neonatal arterial ischemic stroke (NAIS) and hypoxic‐ischemic neonatal encephalopathy (HINE).MethodsA retrospective case‐control study was conducted of neonates born at 35 weeks or more and weighing 1800 g or more at a tertiary care university hospital, between 2005 and 2016, with NAIS (group A), perinatal asphyxia (PA) with Stage II–III HINE (group B), and PA with or without Stage I HINE (group C). Ante‐ and intrapartum data, neonatal characteristics, and placental histopathology were compared.ResultsEleven neonates were identified in group A, 10 in group B, and 227 in group C. Sentinel events occurred exclusively in groups B (80%) and C (41.4%). Umbilical cord blood gas values and Apgar score were worse in groups B and C compared to group A. No group A neonates required resuscitation at birth, whereas all group B and one‐third of group C neonates did. Seizures developed only in neonates in groups A and B. One neonatal death occurred in group A. There were no significant differences in placental histopathology.ConclusionNAIS and PA/HINE cases have different intrapartum and neonatal features. PA does not seem necessary for the occurrence of NAIS. More research is needed regarding associated placental abnormalities.

Near-Infrared Spectroscopy Monitoring of Cerebral Oxygenation and Influencing Factors in Neonates from High-Altitude Areas

Background: Accurate detection of cerebral oxygen saturation (rSO₂) may be useful for neonatal brain injury prevention, and the normal range of rSO₂ of neonates at high altitude remained unclear. Objective: To compare cerebral rSO₂ and cerebral fractional tissue oxygen extraction (cFTOE) at high-altitude and low-altitude areas in healthy neonates and neonates with underlying diseases. Methods: 515 neonates from low-altitude areas and 151 from Tibet were enrolled. These neonates were assigned into the normal group, hypoxic-ischemic encephalopathy (HIE) group, and other diseases group. Near-infrared spectroscopy was used to measure rSO₂ in neonates within 24 h after admission. The differences of rSO₂, pulse oxygen saturation (SpO₂), and cFTOE levels were compared between neonates from low- and high-altitude areas. Results: (1) The mean rSO₂ and cFTOE levels in normal neonates from Tibet were 55.0 ± 6.4% and 32.6 ± 8.5%, significantly lower than those from low-altitude areas (p < 0.05). (2) At high altitude, neonates with HIE, pneumonia (p < 0.05), anemia, and congenital heart disease (p < 0.05) have higher cFTOE than healthy neonates. (3) Compared with HIE neonates from plain areas, neonates with HIE at higher altitude had lower cFTOE (p < 0.05), while neonates with heart disease in plateau areas had higher cFTOE than those in plain areas (p < 0.05). Conclusions: The rSO₂ and cFTOE levels in normal neonates from high-altitude areas are lower than neonates from the low-altitude areas. Lower cFTOE is possibly because of an increase in blood flow to the brain, and this may be adversely affected by disease states which may increase the risk of brain injury.

Does Severity of Brain Injury on Magnetic Resonance Imaging Predict Short-Term Outcome in Neonates Who Received Therapeutic Hypothermia?

The National Institute of Child Health and Human Development (NICHD) magnetic resonance imaging (MRI) pattern of brain injury is a known biomarker of childhood outcome following therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE). However, usefulness of this classification has not been evaluated to predict short-term outcomes. The study aimed to test the hypothesis that infants with NICHD MRI pattern of severe hypoxic-ischemic brain injury will be sicker with more severe asphyxia-induced multiorgan dysfunction resulting in prolonged length of stay (LOS) following therapeutic hypothermia. We also evaluated the role of other risk factors which may prolong LOS. We retrospectively reviewed the medical records of 71 consecutively cooled neonates to examine the ability of MRI patterns of brain injury to predict the LOS. A neuroradiologist masked to outcomes classified the patterns of brain injury on MRI as per NICHD. Pattern 2A (basal ganglia thalamic, internal capsule, or watershed infarction), 2B (2A with cerebral lesions), and 3 (hemispheric devastation) of brain injury was deemed "severe injury." Out of 71 infants, 59 surviving infants had both MRI and LOS data. LOS was higher for infants who had Apgar's score of ≤5 at 10 minutes, severe HIE, seizures, coagulopathy, or needed vasopressors or inhaled nitric oxide, or had persistent feeding difficulty, or remained intubated following cooling. However, median LOS did not differ between the infants with and without MRI pattern of severe injury (15 days, interquartile range [IQR]: 9-28 vs. 12 days, IQR: 10-20; p = 0.4294). On multivariate linear regression analysis, only persistent feeding difficulty (β coefficient = 11, p = 0.001; or LOS = 11 days longer if had feeding difficulty) and ventilator days (β coefficient 1.7, p < 0.001; or LOS increased 1.7 times for each day of ventilator support) but not the severity of brain injury predicted LOS. Unlike neurodevelopmental outcome, LOS is not related to severity of brain injury as defined by the NICHD. · The NICHD pattern of brain injury on MRI predicts neurodevelopmental outcome following hypothermia treatment for neonatal HIE.. · LOS did not differ between the infants with and without MRI patterns of severe injury.. · The severity of brain injury as defined by the NICHD was not predictive of the LOS following therapeutic hypothermia..

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.