Search Results (88)

Background: Hypoxic–ischemic encephalopathy (HIE) is a leading cause of severe neurological impairments in childhood. Therapeutic hypothermia (TH) is both safe and effective in neonates born at ≥36 weeks gestation with moderate to severe HIE. We aimed to evaluate short-term outcomes—including brain injury detected on magnetic resonance imaging (MRI)—in infants born at 34–35 weeks of gestation drawing on our clinical experience with neonates under 36 weeks of gestational age (GA). Methods: In this retrospective cohort study, 20 preterm infants with a GA of 34 to 35 weeks and a matched cohort of 80 infants with a GA of ≥36 weeks who were diagnosed with moderate to severe HIE and underwent TH were included. Infants were matched in a 1:4 ratio based on the worst base deficit in blood gas and sex. Maternal and neonatal characteristics, brain MRI findings and short term outcomes were compared. Results: Infants with a GA of 34–35 weeks had a lower birth weight and a higher rate of caesarean delivery (both p < 0.001). Apgar scores, sex, intubation rate in delivery room, blood gas pH, base deficit and lactate were comparable between the groups. Compared to infants born at ≥36 weeks of GA, preterm neonates were more likely to receive inotropes, had a longer time to achieve full enteral feeding, and experienced a longer hospital stay. The mortality rate was 10% in the 34–35 weeks GA group. Neuroimaging revealed injury in 66.7% of infants born at 34–35 weeks of gestation and in 58.8% of those born at ≥36 weeks (p = 0.56). Injury was observed across multiple brain regions, with white matter being the most frequently affected in the 34–35 weeks GA group. Thalamic and cerebellar abnormal signal intensity or diffusion restriction, punctate white matter lesions, and diffusion restriction in the corpus callosum and optic radiations were more frequently detected in infants born at 34–35 weeks of gestation. Conclusions: Our study contributes to the growing body of literature suggesting that TH may be feasible and tolerated in late preterm infants. Larger randomized controlled trials focused on this vulnerable population are necessary to establish clear guidelines regarding the safety and efficacy of TH in late preterm infants. Full article

Background/Objectives: Although there is a critical need for timely, accurate recognition of infants with hypoxic ischemic encephalopathy (HIE) eligible for therapeutic hypothermia (TH), there is little published literature that comprehensively validates strategies to achieve this. For the Mater Mothers’ Hospital, a screening protocol combining use of umbilical cord gases according to obstetric criteria and other evidence of depression at birth with a decision aid (the HIE Trigger Tool (TT)) for at-risk infants was developed. We audited whether the protocol supported appropriate clinical decisions. Methods: Obstetric records were searched from 1 January 2016 to 31 July 2022 for eligible infants. Neonatal records were examined to assess usage, determine outcomes (diagnosis of HIE or other neurological conditions, use of TH, mortality and neurodevelopmental outcomes) and detect any additional HIE cases. Results: Of 64,055 live births ≥35 weeks, 35.4% had cord gases taken. Of 580 eligible infants, the TT was applied to 498 (86.3%), 155 of whom screened positive for HIE (any severity). Of 76 infants with moderate or severe encephalopathy, 69 received TH. The other seven had contraindications to TH (n = 2), late presentations without any depression at birth (>6 h, n = 3) or other causes of their encephalopathy (n = 2). The TT (which per instructions was commenced by one hour of age) was used to identify 61 of the infants with moderate/severe encephalopathy, while 15 were diagnosed before it was applied. No infants who screened negative using the TT presented later with seizures or any other signs of moderate or severe HIE. Conclusions: The protocol including cord gases and the HIE TT is an effective method of screening for acute HIE needing TH. Full article

Prognostication of neurodevelopmental outcomes for neonates with hypoxic–ischemic encephalopathy (HIE) is primarily reliant on structural assessment using conventional brain magnetic resonance imaging in the clinical setting. Diffuse optical tomography (DOT) can provide complementary information on brain function at the bedside, further enhancing prognostic accuracy. The predictive accuracy and generalizability of DOT-based neuroimaging markers are unknown. This study aims to test the feasibility of prospectively recruiting and retaining neonates for 12 months in a larger study that investigates the prognostic utility of DOT-based biomarkers of HIE. The study will recruit 25 neonates with HIE over one year and follow them beyond NICU discharge at 6 and 12 months of age. Study subjects will undergo resting-state DOT measurement within 7 days of life for a 30–45-min period without sedation. A customized neonatal cap with 10 sources and eight detectors per side will be used to quantify cortical functional connectivity and to generate brain networks using MATLAB-based software (version 24.2). The Ages and Stages Questionnaires—3rd edition will be used for standardized developmental assessments at follow-up. This feasibility study will help refine the design and sample-size calculation for an adequately powered larger study that determines the clinical utility of DOT-based neuroimaging in perinatal brain injury. Full article

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal death and neurodevelopmental disorders, and its pathological mechanisms are closely related to disturbed energy metabolism and lipid remodeling. Exploring the spatial heterogeneity of metabolomics is essential to analyze the pathological process of HIE. Methods: In this study, we established a neonatal mouse hypoxic-ischemic brain damage (HIBD) model by the modified Rice method, and analyzed various metabolic pathways such as the tricarboxylic acid (TCA) cycle, purine metabolism, and lipid metabolism in the ischemic edema area, with contralateral and control brain tissues using matrix-assisted laser desorption mass spectrometry imaging (MALDI-MSI) with a spatial resolution of 50 μm. Results: In the HIBD model, key metabolites of the tricarboxylic acid (TCA) cycle (citrate, succinate, L-glutamate, glucose, aspartate, and glutamine) were significantly enriched in the edematous area compared with the control (fold change: 1.52–2.82), which suggests a blockage of mitochondrial function; ATP/ADP/AMP levels were reduced by 53–73% in the edematous area, and xanthine was abnormally accumulated in the hippocampus of the affected side, suggesting energy depletion and altered purine metabolism; lipid remodeling showed regional specificity: some unsaturated fatty acids, such as docosahexaenoic acid, were abnormally accumulated in the hippocampus. In contrast, pentadecanoic acid levels were reduced across the entire brain in the HIBD model, with a more pronounced decrease in the ipsilateral hippocampus, suggesting impaired membrane stability. Conclusions: The neonatal mouse HIBD model exhibits reprogramming of energy metabolism, characterized by a blockage in the tricarboxylic acid (TCA) cycle and ATP depletion, along with an abnormal spatial distribution of lipids. By targeting xanthine metabolic pathways, restoring mitochondrial function, and intervening in region-specific lipid remodeling, brain energy homeostasis may be improved and neurological damage attenuated. Further studies should validate the clinical feasibility of xanthine and lipid imbalance as diagnostic markers of HIBD and explore the critical time window for metabolic intervention to optimize therapeutic strategies. Full article

Background and Objective: This study aims to investigate the clinical significance and risk factors of retinal hemorrhages (RH) and white-centered retinal hemorrhages (Roth spots, RS) in neonates with hypoxic-ischemic encephalopathy (HIE), as well as their long-term ophthalmologic outcomes. Materials and Methods: Neonates diagnosed with HIE were classified into three stages according to the Sarnat classification. A comprehensive ophthalmologic assessment was performed within the first three days of life and at two years of age. Retinal hemorrhages were staged based on the Egge classification, and the presence of RS was also documented. The clinical characteristics and risk factors associated with RH and RS were systematically recorded. Results: Retinal hemorrhages were identified in 178 eyes (42.3%), and RS were observed in 180 eyes (42.8%). The prevalence of both RH and RS was significantly higher in neonates with Stage 2 and Stage 3 HIE (p < 0.001). The resolution time for both RH and RS was significantly prolonged in neonates with Stage 3 HIE compared to those with lower grades (p < 0.001). Furthermore, the frequency of grade 3 RH increased with advancing HIE stages (p < 0.001). Logistic regression analysis revealed that Stage 2 HIE (OR: 5.41, 95% CI: 1.19–24.54, p = 0.03) and Stage 3 HIE (OR: 27.17, 95% CI: 5.38–137.25, p < 0.001) were significantly associated with RS. Similarly, Stage 2 HIE (OR: 4.54, 95% CI: 1.00–20.68, p = 0.05) and Stage 3 HIE (OR: 40.88, 95% CI: 7.75–215.68, p < 0.001) were significantly associated with RH. At the age of two, strabismus was identified in 34 (18.4%) patients, while refractive errors were detected in 68 (37.4%) patients. Conclusions: The prevalence of RH and RS increases in correlation with the severity of HIE. While these hemorrhages generally resolve spontaneously, the risk of refractive errors and strabismus remains elevated. Full article

Hypoxic–Ischemic Encephalopathy (HIE) occurs in patients who experience a decreased flow of blood and oxygen to the brain, with the optimal window for effective treatment being within the first six hours of life. This puts a significant demand on medical professionals to accurately and effectively grade the severity of the HIE present, which is a time-consuming and challenging task. This paper proposes a novel workflow for background EEG grading, implementing a blend of Digital Signal Processing (DSP) and Machine-Learning (ML) techniques. First, the EEG signal is transformed into an amplitude and frequency modulated audio spectrogram, which enhances its relevant signal properties. The difference between EEG Grades 1 and 2 is enhanced. A convolutional neural network is then designed as a regressor to map the input image into an EEG grade, by utilizing an optimized rounding module to leverage the monotonic relationship among the grades. Using a nested cross-validation approach, an accuracy of 89.97% was achieved, in particular improving the AUC of the most challenging grades, Grade 1 and Grade 2, to 0.98 and 0.96. The results of this study show that the proposed representation and workflow increase the potential for background grading of EEG signals, increasing the accuracy of grading background patterns that are most relevant for therapeutic intervention, across large windows of time. Full article

Background/Objectives: Hypoxic–ischemic encephalopathy (HIE), affecting 1.3–1.7/1000 live births, is treated with conventional therapeutic hypothermia (TH) but carries significant mortality and neurological impairment. Here, we compared intravascular cooling with extracorporeal membrane oxygenation (ECMO) and conventional TH in neonates with moderate to severe HIE. Methods: We retrospectively analyzed single-center neonates born in 2000–2022. Neonates with a 10 min Apgar score ≤ 3 or umbilical artery pH ≤ 6.7, along with persistent pulmonary hypertension of the newborn and an oxygenation index of ≥25 to <40, were divided into ECMO (n = 17) and conventional TH (n = 18) groups and administered the Kyoto Scale of Psychological Development at 18 months. Results: Neonatal and maternal characteristics were similar between the groups. A significantly higher proportion of the ECMO group (70.6% vs. 33.3%) achieved a developmental quotient ≥ 70. Conclusions: Intravascular cooling with ECMO may improve the neurodevelopmental outcomes of neonates with HIE, severe acidosis, and low Apgar scores. Full article

Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article

Background/Objectives: The Hammersmith Infant Neurological Examination (HINE) is a standardized neurologic exam for infants between 2 and 24 months. Scores can be compared to optimality cutoffs as one component to support an early diagnosis of cerebral palsy (CP). Some prognosis is also possible for infants diagnosed with CP. We aimed to understand the longitudinal trajectories of HINE scores in infants who were ultimately diagnosed with CP. Methods: Clinical records were reviewed for children who were diagnosed with CP in two high-risk infant follow-up clinics with HINE scores from at least two visits between the corrected ages of 3 months and 2 years. Trajectories were calculated individually and by group for infants in four categories—term neonatal hypoxic ischemic encephalopathy (HIE), term perinatal arterial ischemic stroke (PAIS), premature infants with brain injury, and “Other” (term infants with congenital malformations and/or congenital hydrocephalus). The changes in HINE scores between clinic visits were compared using linear mixed-effect models with a random intercept, pulling data by diagnostic group across visits and accounting for within-child correlations of scores over the follow-up time. Results: The changes in HINE scores for sixty children (twenty-five with prematurity, eighteen with HIE, seven with PAIS, and ten in the other category) were assessed. The linear mixed-effect models indicated that the infants with PAIS had an estimated 10.8-point increase in total HINE scores after 9 months of age compared to earlier assessments (95% CI [2.5, 19.2]. There was no statistically significant improvement in the scores among the infants in the other brain injury groups. The infants with PAIS had an estimated 2.9-point increase in HINE asymmetry scores after 9 months of age compared to prior visits (95% CI [0.7, 5.1]). None of the other diagnostic categories had statistically significant increases in asymmetry scores over time. Conclusions: The children with PAIS with resultant hemiplegia showed increasing HINE scores throughout the first two years of life. In contrast, the HINE scores remained stable for those children with term HIE, prematurity-associated brain injury, and congenital malformations and/or congenital hydrocephalus diagnosed with CP. Tracking individual changes (or stability) in HINE scores can aid diagnosis, inform prognosis, and guide the design of clinical trials targeting neurologic injury. Full article

Hypoxic-ischemic encephalopathy (HIE) is a common cause of significant neonatal morbidity and mortality. The stronghold of the treatment for moderate-to-severe HIE is therapeutic hypothermia (TH) which provides a neuroprotective effect. However, it also is associated with pain and stress. Moreover, neonates with HIE are subjected to a significant number of painful procedures. Untreated pain during the early neonatal period may entail future challenges such as impaired brain growth and development as well as impaired pain sensitivity later in life. Hereby, the provision of adequate sedation and alleviation of pain and discomfort is essential. There are currently no universally accepted guidelines for sedation and pain management for this patient population. In this review, we highlight non-pharmacologic and pharmacologic methods currently in use to provide comfort and sedation to patients with HIE undergoing TH. Full article

Background/Objectives: Neonatal hypoxic-ischemic encephalopathy (HIE) due to perinatal complications remains an important pathology with a significant burden for neonates, families, and the healthcare system. Resuscitation and simulation team training are key elements in increasing patient safety. In this retrospective cohort study, we evaluated whether regular constant training of all personnel working in delivery rooms in South Tyrol improved the outcome of neonates with HIE. Methods: We retrospectively analyzed three groups of neonates with moderate to severe HIE who required therapeutic hypothermia. The first group included infants born before the systematic introduction of training and was compared to the second group, which included infants born after three years of regular training. A third group, which included infants born after the SARS-CoV-2 pandemic, was compared with the previous two to evaluate retention of skills and the long-term effect of our training program. Results: Over the three study periods, mortality decreased from 41.2% to 0% and 14.3%, respectively. There was also a significant reduction of patients with subclincal seizures detected only through EEG, from 47.1% in the first period to 43.7% and 14.3% in the second and third study periods, respectively. Clinical manifestations of seizures decreased significantly from 47.1% to 37.5% and 10.7%, respectively, as well as severe brain lesions in ultrasound (US) and MRI. Conclusions: In this study, constant and regular simulation training for all birth attendants significantly decreases mortality and improves the outcome in neonates with moderate to severe HIE. This positive effect seems to last even after a one-year period during which training sessions could not be performed due to the COVID-19 pandemic. Full article

Background/Objectives: Hypoxic-ischemic encephalopathy (HIE) in late preterm and term neonates accounts for neonatal mortality and unfavorable neurodevelopmental outcomes in survivors despite therapeutic hypothermia (TH) for neuroprotection. The circumstances of death in neonates with HIE, including involvement of neonatal palliative care (NPC) specialists and neurodevelopmental follow-up at 18–24 months in survivors, warrant further evaluation. Methods: A retrospective multicenter cohort study including neonates ≥ 35 weeks gestational age with moderate to severe HIE receiving TH, registered in the Swiss National Asphyxia and Cooling Register between 2011 and 2021. Neurodevelopmental follow-up at 18–24 months in survivors was assessed. The groups of survivors and deaths were compared regarding perinatal demographic and HIE data. Prognostic factors leading to redirection of care (ROC) were depicted. Results: A total of 137 neonates were included, with 23 (16.8%) deaths and 114 (83.2%) survivors. All but one death (95.7%) occurred after ROC, with death on a median of 3.5 (2–6) days of life. Severe encephalopathy was indicated by a Sarnat score of 3 on admission, seizures were more frequent, and blood lactate values were higher on postnatal days 1 to 4 in neonates who died. Lactate in worst blood gas analysis (unit-adjusted odds ratio 1.25, 95% CI 1.02–1.54, p = 0.0352) was the only variable independently associated with ROC. NPC specialists were involved in one case. Of 114 survivors, 88 (77.2%) had neurodevelopmental assessments, and 21 (23.9%) of those had unfavorable outcomes (moderate to severe disability). Conclusions: Death in neonates with moderate to severe HIE receiving TH almost exclusively occurred after ROC. Parents thus had to make critical decisions and accompany their neonate at end-of-life within the first week of life. Involvement of NPC specialists is encouraged in ROC so that there is continuity of care for the families whether the neonate survives or not. Full article

Background: Therapeutic hypothermia (TH) is the standard treatment for moderate to severe hypoxic–ischemic encephalopathy (HIE) in developed countries, but data on its safety and efficacy in low-middle-income countries are limited and often conflicting. The impact of enteral feeding during TH remains inadequately explored. We aimed to examine TH’s effects on mortality and brain injury and evaluate the safety and effectiveness of minimal enteral feeding during TH. Here, we report our single-center experience with TH over a 10-year period”. Methods: A total of 187 neonates with moderate to severe HIE who underwent cooling were included in this retrospective study. Post-rewarming MRI scans were scored using a validated MRI scoring system. The primary outcomes were mortality and composite outcomes of mortality and brain injury. Results: The mortality rate was 3% in moderate and 25% in severe cases (p < 0.001). Overall, 85% (160/187) of neonates received minimal enteral nutrition. Multivariate regression analysis revealed that the severity of HIE at admission (OR 3.4 (1.03–11.6); p < 0.04) and gestational age (OR: 0.624 (0.442–0.882); p < 0.008) were independent predictors of composite outcomes of death and brain injuries. MRI score was a strong predictor of mortality (AUC: 0.89; p < 0.001) and of ability to orally feed at discharge (AUC: 0.73; p < 0.001). Conclusions: Mortality rates associated with TH in infants with moderate–severe HIE align with those in high-income countries, and minimal enteral feeding during TH is safe. The severity of HIE, MRI scores, and feeding status are important predictors of outcomes. Full article

Background: Vasoactive inotrope score, renal score, fibrosis-5 index, and lactate-albumin ratio have not been investigated before in determining multiple organ dysfunctions accompanying infants with hypoxic–ischemic encephalopathy (HIE) in neonatal intensive care units (NICUs). The aim of this study was to determine whether multiple organ dysfunctions that may accompany HIE in infants are correlated with vasoactive inotrope score (VIS), renal score (RS), fibrosis-5 index (FIB-5), and lactate-albumin ratio (LAR), and whether these parameters can predict morbidity and mortality. Methods: This is a retrospective study, and 106 newborns diagnosed with HIE and treated with hypothermia were included in the study. Vasoactive inotrope score for cardiac dysfunction, renal score for renal dysfunction, fibrosis-5 index, and lactate/albumin ratio for hepatic dysfunction were evaluated. Results: We found that the vasoactive inotrope score, renal score, fibrosis-5 index, and lactate-albumin ratio values of infants diagnosed with HIE are associated with cardiac, renal, and hepatic dysfunction. These values, calculated on the 2nd postnatal day, are particularly linked to prolonged hospital stay and mortality, which are key prognostic factors. Conclusions: Our study is the first to combine vasoactive inotrope score, renal score, fibrosis-5 index, and lactate-albumin ratio parameters in determining organ dysfunction in newborns with hypoxic–ischemic encephalopathy and to reveal their prognostic and mortality prediction values. Therefore, although it offers new perspectives, new studies are needed. Full article

Hypoxic-ischemic encephalopathy (HIE) is a brain injury condition that poses a significant risk to newborns, potentially causing varying degrees of damage to the central nervous system. Its clinical manifestations include respiratory distress, cardiac dysfunction, hypotension, muscle weakness, seizures, and coma. As HIE represents a progressive brain injury, early identification of the extent of the damage and the implementation of appropriate treatment are crucial for reducing mortality and improving outcomes. HIE patients may face long-term complications such as cerebral palsy, epilepsy, vision loss, and developmental delays. Therefore, prompt identification and treatment of hypoxic-ischemic symptoms can help reduce the risk of severe sequelae in patients. Currently, hypothermia therapy is one of the most effective treatments for HIE patients. However, not all newborns with HIE are suitable for this therapy, making rapid and accurate assessment of the extent of brain injury critical for treatment. Among HIE patients, hypothermia therapy has shown better efficacy in those diagnosed with moderate to severe HIE within 6 h of birth, establishing this time frame as the golden period for treatment. During this golden period, an accurate assessment of HIE severity is essential for formulating appropriate treatment strategies and predicting long-term outcomes for the affected infants. This study proposes a method for addressing data imbalance and noise interference through data preprocessing techniques, including filtering and SMOTE. It then employs EEGNet, a deep learning model specifically designed for EEG classification, combined with a Transformer model featuring an attention mechanism that excels at capturing long-term sequential features to construct the Trans-EEGNet model. This model outperforms previous methods in computation time and feature extraction, enabling rapid classification and assessment of HIE severity in newborns. Full article