Hipotermia terapéutica: estudio descriptivo de una cohorte de 10 años en un hospital público de alta complejidad / Therapeutic hypothermia: A descriptive, cohort study conducted over 10 years at a tertiary care public hospital

Introducción. La hipotermia terapéutica (HT) reduce el riesgo de muerte o discapacidad en niños con encefalopatía hipóxico-isquémica (EHI) moderada-grave. Objetivo. Describir una población de pacientes con EHI que requirió HT y su evolución hasta el alta hospitalaria. Población y métodos. Estudio descriptivo de cohorte retrospectivo. Se analizaron todos los pacientes que ingresaron a HT entre 2013 y 2022. Se evaluaron datos epidemiológicos, clínicos, de monitoreo, tratamiento, estudios complementarios y condición al alta. Se compararon los factores de riesgo entre pacientes fallecidos y sobrevivientes, y de estos, los que requirieron necesidades especiales al alta (NEAS). Resultados. Se incluyeron 247 pacientes. Mortalidad: 11 %. Evento centinela más frecuente: período expulsivo prolongado (39 %). Inicio del tratamiento: mediana 5 horas de vida. Convulsiones: 57 %. Eritropoyetina intravenosa: 66,7 %. Patrón anormal de monitoreo de función cerebral: 52 %. Normalización del monitoreo: mediana 24 horas. Resonancia magnética patológica: 42 %. Variables predictoras de mortalidad: Sarnat y Sarnat grave, y ecografía patológica al ingreso. Conclusión. La mortalidad global fue del 11 %. Las derivaciones aumentaron en forma más evidente a partir del año 2018. El horario de inicio de HT fue más tardío que en reportes anteriores. Los signos neurológicos de gravedad según la escala de Sarnat y Sarnat y la ecografía cerebral basal patológica fueron predictores independientes de mortalidad al alta. Los pacientes con NEAS presentaron normalización del trazado del electroencefalograma de amplitud integrada más tardío. El hallazgo más frecuente en la resonancia fue la afectación de los ganglios basales. No se encontraron diferencias clínicas ni de complicaciones estadísticamente significativas entre los pacientes que recibieron eritropoyetina.

Introduction. Therapeutic hypothermia (TH) reduces the risk of death or disability in children with moderate to severe hypoxic ischemic encephalopathy (HIE). Objective. To describe a population of patients with HIE that required TH and their course until discharge. Population and methods. Retrospective, descriptive, cohort study. All patients admitted to TH between 2013 and 2022 were studied. Epidemiological, clinical, monitoring, and treatment data were assessed, together with supplementary tests and condition at discharge. Risk factors were compared between deceased patients and survivors; and, among the latter, those requiring special healthcare needs (SHCN) at discharge. Results. A total of 247 patients were included. Mortality: 11%. Most common sentinel event: prolonged second stage of labor (39%). Treatment initiation: median of 5 hours of life. Seizures: 57%. Intravenous erythropoietin: 66.7%. Abnormal pattern in brain function monitoring: 52%. Normalization of monitoring: median of 24 hours. Pathological magnetic resonance imaging: 42%. Predictor variables of mortality: severe Sarnat and Sarnat staging and pathological ultrasound upon admission. Conclusion. The overall mortality rate was 11%. Referrals increased more markedly since 2018. The time of TH initiation was later than in previous reports. Severe neurological signs as per the Sarnat and Sarnat staging and a pathological baseline cranial ultrasound were independent predictors of mortality at discharge. Patients with SHCN at discharge showed a normalized tracing in the amplitude-integrated electroencephalography performed later. The most common finding in the magnetic resonance imaging was basal ganglia involvement. No statistically significant differences were observed in terms of clinical characteristics or complications among patients who received erythropoietin.

p75ECD-Fc reverses neonatal hypoxic-ischemic encephalopathy-induced neurological deficits and inhibits apoptosis associated with Nestin.

A recent study has introduced a recombinant fusion protein, consisting of the extracellular domain (ECD) of p75 and the Fc fragment of human immunoglobulin IgG1 (p75ECD-Fc), as a multifaceted agent within the nervous system. This research aimed to assess the effects of p75ECD-Fc on neuronal growth and the restoration of neurological functions in rats afflicted with neonatal hypoxic-ischemic encephalopathy (NHIE). In vitro analyses revealed that 1 µM p75ECD-Fc treatment markedly increased cell viability and facilitated neurite outgrowth in neurons exposed to oxygen-glucose deprivation (OGD). Subsequent in vivo studies determined that a dose of 78.6 µg/3 µl of p75ECD-Fc significantly mitigated brain damage and both acute and long-term neurological impairments, outperforming the therapeutic efficacy of hypothermia, as evidenced through behavioral assessments. Additionally, in vivo immunostaining showed that p75ECD-Fc administration enhanced neuronal survival and regeneration, and reduced astrocytosis and microglia activation in the cortex and hippocampus of NHIE rats. A noteworthy shift from A1 to A2 astrocyte phenotypes and from M1 to M2 microglia phenotypes was observed after p75ECD-Fc treatment. Furthermore, a co-expression of the p75 neurotrophin receptor (p75NTR) and Nestin was identified, with an overexpression of Nestin alleviating the neurological dysfunction induced by NHIE. Mechanistically, the neuroprotective effects of p75ECD-Fc, particularly its inhibition of neuronal apoptosis post-OGD, may be attributed to Nestin. Taken together, these results highlight the neuroprotective and anti-inflammatory effects of p75ECD-Fc treatment through the modulation of glial cell phenotypes and the Nestin-mediated inhibition of neuronal apoptosis, positioning it as a viable therapeutic approach for NHIE.

Genistein-3'-sodium sulfonate enhances neurological function in neonatal rats with hypoxia-ischemia during the recovery period.

Hypoxic-ischemic (HI) can cause neonatal brain damage leading to disability. Patients with HI experience long-term neurological issues impacting quality of life. Limited clinical treatments are available despite extensive research on HI's molecular mechanisms. Genistein-3'-sodium sulfonate (GSS), a phytoestrogen, has been found to improve acute brain injury in neonatal rats caused by hypoxic-ischemia, but its potential for chronic stage neurological recovery in HI is unknown. HI neonatal rats were treated with 1 mg/kg GSS once a day for 21 days. Then, a series of behavioral experiments was performed to evaluate the learning, memory, cognition, anxiety level and depression-like behaviors of the rats. GSS treatment reduced neuronal loss, enhanced learning, memory and cognitive function while also alleviated anxiety and depression-like behaviors in HI rats during the recovery period. These findings indicated that GSS exerted enhance neurological function in HI rats during the chronic stage, prompting further research on how it works to potentially develop new therapies.

Identification of Novel Biomarkers Using Serum and Urinary Proteomics for Early Detection of Hypoxic Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a severe birth complication affecting neonates. Around 40-60% of affected neonates die by two years of age or have severe disabilities and neurodevelopmental delays. The early assessments of brain injury using traditional clinical and biochemical indicators do not always align with its severity and recovery. This delays identifying neonates who may benefit from adjuvant therapeutic strategies and monitoring therapy response. Our aim was to identify specific proteins using proteomic approach to predict the severity of neonatal asphyxia so that its outcome can also be prevented. To achieve this goal a case-control study was conducted on 38 neonates, and serum and urine samples were collected within 24 h of life. Clinical findings, biochemical parameters, and outcomes of the neonates were recorded. A tandem mass spectrometry-based quantitative proteomics approach was used to identify proteins in the serum and urine of HIE neonates. Bioinformatics analyses were performed to assess the potential features and competence of the identified differentially expressed proteins. This resulted in identification of 51 differentially expressed proteins which were found common to both serum and urine proteomic data. Some of the promising biomarkers found were APOD, ORM1, SOD1, and FABP1. These proteins were associated with the pathways like Amyloid fiber formation, diseases of programmed cell death, detoxification of reactive oxygen species, and neurodegenerative diseases. This study will pave the way for identifying the biomarkers (proteins) that can screen neonates for brain injury and monitor the disease progression, which may reduce mortality and neurodevelopmental impairment. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-023-01143-2.

A Systematic Review of the Relationship Between Neonatal Hypoxic-Ischemic Encephalopathy and Long-Term Cognitive Outcomes: Where Do We Stand?

This study aims to systematically review the existing literature on long-term cognitive outcomes in neonates with hypoxic-ischemic encephalopathy (HIE). A thorough search of PubMed, MEDLINE, and Embase was conducted to find studies that satisfied the inclusion requirements. Rayyan (Qatar Computing Research Institute, Doha, Qatar) was utilized during the whole operation. Our results included seven studies with a total of 521 patients and 247 (47.4%) were females. All of the included participants were assessed for the incidence of cognitive functions following hypothermia therapy. Newborns with significant HIE are at high risk for neurodevelopmental complications even in the absence of magnetic resonance imagining (MRI) abnormalities, such as poor performance score and hearing-language score, functional status, delayed language skills, emotional processing, sensory movement, learning, and memory. Independent of motor deficits, participants with a history of HIE are susceptible to issues with cognition and executive function during late childhood and adolescence. It is crucial to keep an eye on their intellectual development after infancy since cognitive dysfunction and memory problems might manifest subtly or not at all in the early years of life, but they can cause problems in later childhood and adolescence. Long-term follow-up research is also required to ascertain whether the enhanced cognitive outcomes will continue throughout adolescence. Even in cases where overt neuromotor abnormalities are not evident, children with watershed injuries on brain MRIs should be closely monitored to evaluate cognitive function, particularly language development.

Amide proton transfer and apparent diffusion coefficient analysis reveal susceptibility of brain regions to neonatal hypoxic-ischemic encephalopathy.

Purpose: To identify brain regions affected by Hypoxic-Ischemic Encephalopathy (HIE) in neonates using Amide Proton Transfer (APT) imaging and Apparent Diffusion Coefficient (ADC). Materials and methods: Twenty neonates were divided into HIE and control groups. All neonates were undergoing MRI, including APT and DWI. Imaging analysis was performed using SPM12. The independent-samples t-test was used to analyze the difference in APTw values and ADC values between the mild HIE neonates and the control group. The receiver operating characteristic (ROC) curves were established to assess the diagnostic values of APTw and ADC values in different brain regions for HIE. Pearson's correlation analysis was used to analyze the correlation between APTw values and ADC values for each region. Results: APTw values were significantly higher in 26 regions of the HIE group. ADC values were lower in the right anterior temporal lobe and higher in bilateral Subthalamic nucleus in HIE. The APTw values of 22 regions showed very high area under the curve (AUC), whereas the AUC of ADC values in right anterior temporal lobe and right subthalamic nucleus were both 0.802. Notably, the right anterior temporal lobe exhibited significant differences in both APTw and ADC values between the HIE and control groups, additionally, APTw value was significant positive correlated with ADC values in right anterior temporal lobe. Conclusion: APTw and ADC are effective in detecting HIE, with APTw being more sensitive. The right anterior temporal lobe is particularly affected by HIE, with significant changes in APTw and ADC values and a positive correlation between them. This suggests that temporal lobe damage may be critical in the long-term neurological consequences of HIE.

Prediction of feeding difficulties in neonates with hypoxic-ischemic encephalopathy using magnetic resonance imaging-derived radiomics features.

BACKGROUND: The mechanisms behind brain and spinal cord injuries in hypoxic-ischemic encephalopathy (HIE) and associated feeding difficulties are unclear, with previous magnetic resonance imaging (MRI) attempts yielding inconclusive results. OBJECTIVE: We aim to evaluate an MRI radiomics model for predicting feeding difficulties in HIE infants. Additionally, we investigate changes in predictive capability after incorporating the duration of mechanical ventilation and the timing of MRI examination. MATERIALS AND METHODS: Retrospective study with 151 HIE infants (January 2013 to December 2021), randomly divided into training and validation sets. Radiomics features extracted from basal ganglia-thalamus and brainstem in T1-weighted and T2-weighted MRI. Established single-modality, single-site, and multimodality/multisite models. Receiver operating characteristic analysis and area under the curve evaluated models. Decision curve analysis assessed changes in predictive capability. RESULTS: The combined radiomics model of the basal ganglia-thalamus and brainstem regions on the T2-weighted imaging demonstrated superior performance (area under the curve: 0.958 and 0.875 for training and validation, respectively). Combining scores with duration of mechanical ventilation and MRI examination time in a calibration plot model improved and stabilized performance, showing high fitting and clinical utility. Decision curve analysis favored the combined calibration plot model. CONCLUSION: The MRI-based radiomics model predicts feeding difficulties in HIE infants, with basal ganglia-thalamus and brainstem as relevant factors. The combined calibration plot model exhibits the highest clinical predictive efficacy.

Genetic Diagnosis in Neonatal Encephalopathy With Hypoxic Brain Damage Using Targeted Gene Panel Sequencing.

BACKGROUND AND PURPOSE: Neonatal encephalopathy (NE) is a neurological syndrome that presents with severe neurological impairments and complications. Hypoxic-ischemic encephalopathy is a major contributor to poor outcomes, being responsible for 50%-80% of admissions to neonatal intensive care units. However, some cases of NE accompanied by hypoxic brain damage cannot be solely attributed to hypoxia-ischemia. We aimed to identify diverse pathogenic genetic variations that may be associated with cases of NE accompanied by hypoxic brain damage rather than hypoxia-ischemia. METHODS: We collected data from 34 patients diagnosed with NE accompanied by hypoxic brain damage over a 10-year period. Patients with the following specific conditions were excluded: 1) premature birth (<32 weeks), 2) no history of hypoxic events, 3) related anomalies, 4) neonatal infections, 5) antenatal or perinatal obstetrical complications, 6) severe hypoxia due to other medical conditions, and 7) early death (within 1 week). A comprehensive review of clinical and radiological features was conducted. RESULTS: A genetic diagnosis was made in 11 (32.4%) patients, with pathogenic variants being identified in the following 9 genes: CACNA1A (n=2), KCNQ2 (n=2), SCN2A (n=1), SCN8A (n=1), STXBP1 (n=1), NSD1 (n=1), PURA (n=1), ZBTB20 (n=1), and ENG (n=1). No specific treatment outcomes or clinical features other than preterm birth were associated with the results of the genetic analyses. Personalized treatments based on the results of genetic tests were attempted, such as the administration of sodium-channel blockers in patients with KCNQ2 or SCN8A variants and the implementation of a ketogenic diet in patients with STXBP1 or SCN2A mutations, which demonstrated some degree of effectiveness in these patients. CONCLUSIONS: Genetic analyses may help in diagnosing the underlying etiology of NE and concurrent hypoxic brain damage, irrespective of the initial clinical features.

Amplitude-Integrated Electroencephalography: A Readily Available Tool for Neonatologists.

Hypoxic-ischemic encephalopathy (HIE) is a common condition occurring at birth, impairing central nervous system function. Therapeutic hypothermia is beneficial for suspected HIE as it reduces mortality and disability in survivors but not for other types of encephalopathy (e.g., metabolic). Amplitude-integrated electroencephalography (aEEG) complements limited resource Neonatal Intensive Care Units as a screening tool that can provide information regarding the degree of encephalopathy and electrographic seizures. Patients with HIE are at increased risk for seizures, which are subclinical in half of the cases. The aEEG emphasizes electroencephalographic amplitude differences, whereas continuous video electroencephalography (cEEG) provides a high-resolution picture of cerebral electrical activity, making it the most accurate method for detecting subclinical seizures. Still, its interpretation demands extensive training beyond the scope of neonatologists. Any infant in whom aEEG is suspicious for seizures should undergo cEEG to confirm the findings because even very low-amplitude artifacts might be misdiagnosed as seizures. We report a case and review the utility of aEEG in detecting subclinical seizures in neonates with HIE during therapeutic hypothermia while cEEG is not available.

Inhibition of cGAS attenuates neonatal hypoxic-ischemic encephalopathy via regulating microglia polarization and pyroptosis.

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is a condition causing brain injury in newborns with unclear pathogenesis. Cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway and NOD-like receptor protein 3 (NLRP3) mediated pyroptosis are thought to be involved in the pathological process of HIE, but whether these two mechanisms act independently is still unknown. Therefore, we aim to clarify whether there is any interaction between these two pathways and thus synergistically affects the progression of HIE. Methods: The HIE model of neonatal rats was established using the Rice-Vannucci method. The potential therapeutic effect of RU.521 targeting cGAS on HIE was explored through rescue experiment. Twenty-four hours after modeling was selected as observation point, sham + vehicle group, HIE + vehicle group and HIE + RU.521 group were established. A complete medium of BV2 cells was adjusted to a glucose-free medium, and the oxygen-glucose deprivation model was established after continuous hypoxia for 4 hours and reoxygenation for 12 to 24 hours. 2,3,5-triphenyl tetrazolium chloride staining was employed to detect ischemic cerebral infarction in rat brain tissue, and hematoxylin and eosin staining was used to observe tissue injury. Immunofluorescence was applied to monitor the expression of cGAS. Real-time quantitative polymerase chain reaction and western blot were utilized to detect the expression of messenger RNA and protein. Results: cGAS expression was increased in brain tissues of neonatal rats with HIE, and mainly localized in microglia. RU.521 administration reduced infarct size and pathological damage in rat HIE. Moreover, blocking cGAS with RU.521 significantly reduced inflammatory conditions in the brain by down-regulating STING expression, decreasing NLRP3 inflammasome activation and reducing microglial pyroptosis both in vivo and in vitro. Besides, RU.521 promoted the switching of BV2 cells towards the M2 phenotype. Conclusions: This study revealed a link between the cGAS/STING pathway and the NLRP3/GSDMD/pyroptosis pathway in neonatal HIE. Furthermore, the small molecule compound RU.521 can negatively regulate cGAS/STING/NLRP3/pyroptosis axis and promote M2 polarization in microglia, which provides a potential therapeutic strategy for the treatment of neuroinflammation in HIE.