OBJECTIVE: To investigate the efficacy of therapeutic hypothermia on mild neonatal hypoxic-ischemic encephalopathy (HIE).
METHODS: A prospective study was performed on 153 neonates with mild HIE who were born from September 2019 to September 2023. These neonates were randomly divided into two groups: therapeutic hypothermia (n=77) and non-therapeutic hypothermia group (n=76). The short-term clinical efficacy of the two groups were compared. Barkovich scoring system was used to analyze the severity of brain injury shown on magnetic resonance imaging (MRI) between the two groups.
RESULTS: There were no significant differences in gestational age, gender, birth weight, mode of birth, and Apgar score between the therapeutic hypothermia and non-therapeutic hypothermia groups (P>0.05). There were no significant differences in the incidence rates of sepsis, arrhythmia, persistent pulmonary hypertension and pulmonary hemorrhage and the duration of mechanical ventilation within the first 72 hours after birth between the two groups. The therapeutic hypothermia group had longer prothrombin time within the first 72 hours after birth and a longer hospital stay (P<0.05). Compared with the non-therapeutic hypothermia group, the therapeutic hypothermia group had lower incidence rates of MRI abnormalities (30% vs 57%), moderate to severe brain injury on MRI (5% vs 28%), and watershed injury (27% vs 51%) (P<0.05), as well as lower medium watershed injury score (0 vs 1) (P<0.05).
CONCLUSIONS: Therapeutic hypothermia can reduce the incidence rates of MRI abnormalities and watershed injury, without obvious adverse effects, in neonates with mild HIE, suggesting that therapeutic hypothermia may be beneficial in neuroprotection in these neonates.
目的: 探讨亚低温对新生儿轻度缺氧缺血性脑病（hypoxic-ischemic encephalopathy, HIE）的治疗效果。方法: 前瞻性纳入2019年9月—2023年9月出生的153例轻度HIE新生儿，随机分为亚低温组（77例）和非亚低温组（76例），比较两组的短期临床效果，并采用Barkovich评分系统分析两组患儿磁共振成像（magnetic resonance imaging, MRI）上脑损伤的严重程度。结果: 亚低温组和非亚低温组胎龄、性别、出生体重、Apgar评分等基线资料的比较差异无统计学意义（P>0.05）。两组生后72 h内败血症、心律失常、持续性肺动脉高压、肺出血的发生率及机械通气时间的比较差异无统计学意义（P>0.05）。亚低温组住院时间及生后72 h内凝血酶原时间长于非亚低温组（P<0.05）。与非亚低温组相比，亚低温组MRI异常发生率（30% vs 57%）、MRI中重度脑损伤发生率（5% vs 28%）、分水岭损伤发生率（27% vs 51%）及中位分水岭损伤评分（0 vs 1）均较低（P<0.05）。结论: 新生儿轻度HIE患儿进行亚低温治疗可降低MRI异常发生率和分水岭损伤发生率，且未见明显不良反应，提示新生儿轻度HIE患儿进行亚低温治疗可能在神经保护方面获益。.

OBJECTIVE: To assess the merit of clinical assessment tools in a neurocognitive screening following out-of-hospital cardiac arrest (OHCA).
METHODS: The neurocognitive screening that was evaluated included the performance-based Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT), the patient-reported Two Simple Questions (TSQ) and the observer-reported Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest (IQCODE-CA). These instruments were administered at 6-months in the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. We used a comprehensive neuropsychological test battery from a TTM2 trial sub-study as a gold standard to evaluate the sensitivity and specificity of the neurocognitive screening.
RESULTS: In our cohort of 108 OHCA survivors (median age = 62, 88% male), the most favourable cut-off scores were: MoCA <26; SDMT z ≤-1; IQCODE-CA ≥3.04. The MoCA (sensitivity 0.64, specificity 0.85) and SDMT (sensitivity 0.59, specificity 0.83) had a higher classification accuracy than the TSQ (sensitivity 0.28, specificity 0.74) and IQCODE-CA (sensitivity 0.42, specificity 0.60). When using the cut-points for MoCA or SDMT in combination to identify neurocognitive impairment, sensitivity improved (0.74, specificity 0.81), area under the curve = 0.77, 95% CI [0.69, 0.85]. The most common unidentified impairments were within the episodic memory and executive functions domains, with fewer false negative cases on the MoCA or SDMT combined.
CONCLUSIONS: The MoCA and SDMT have acceptable diagnostic accuracy for screening for neurocognitive impairment in an OHCA population, and when used in combination the sensitivity improves. Patient and observer-reports correspond poorly with neurocognitive performance.
RESULTS: gov Identifier: NCT03543371.

UNASSIGNED: To determine cardiotocographic patterns in newborns with metabolic acidosis, based on clinical signs of neurological alteration (NA) and the need for hypothermic treatment.
UNASSIGNED: All term newborns with metabolic acidosis in a single center from 2016 to 2020 were included in the study. Three segments of intrapartum CTG (cardiotocography) were considered (first 30 min of active labor, 90 to 30 min before birth, and last 30 min before delivery) and a longitudinal analysis of CTG pattern was performed according to the 2015 FIGO classification.
UNASSIGNED: Three hundred and twenty-four neonates with metabolic acidosis diagnosed at birth were divided into three groups: the first group included all neonates with any clinical sign of neurological alteration, requiring hypothermia according to the recommendation of the Italian Society of Neonatology (group TNA-Treated neurological Alteration, n = 17), the second encompassed neonates with any clinical sign of neurological alteration not requiring hypothermia (group NTNA-Not Treated neurological Alteration, n = 83), and the third enclosed all neonates without any sign of clinical neurological involvement (group NoNA-No neurological Alteration, n = 224). The most frequent alterations of CTG in TNA group were late decelerations, reduced variability, bradycardia, and tachysystole. Unexpectedly, from the longitudinal analysis of the CTG, 49% of all cases with metabolic acidosis never showed a pathological CTG with normal trace at the beginning of labor followed by normal or suspicious trace in the final part of labor, the same as in TNA and NTNA groups (10 and 39%, respectively).
UNASSIGNED: CTG has limited specificity in identifying cases of acidosis at birth, even in babies who will develop NA.

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer\'s disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aβ plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aβ deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

The objective of this review is to ascertain the advantages and disadvantages of several treatments and therapeutic protocols that have been used for the prevention and treatment of perinatal asphyxia in human neonates and in different animal models. Perinatal asphyxia is one of the main causes of mortality worldwide and is an important factor in triggering physio-metabolic disorders that result in serious neurological consequences and learning disorders not only in human foetuses and neonates, but also in animals. In recent years, the search for new pharmacological protocols to prevent and reverse physio-metabolic disorders and brain damage derived from perinatal asphyxia has been and continues to be the subject of intense research. Currently, within these pharmacological protocols, therapeutic strategies have been evaluated that use respiratory and hormonal stimulants, as well as hypothermic therapies in combination with other putative neuroprotective agents. Similarly, energy supplements have been evaluated with the objective of preventing perinatal asphyxia and treating new-borns with this condition, and to decrease the incidence of neonatal and foetal deaths associated with it. However, despite these promising advances, this pathology has persisted, since the administration of these therapies in low doses may not exert a neuroprotective effect or, in high doses, can trigger adverse effects (such as reduced cardiac contractility, reduced cerebral blood flow, poor perfusion, sympathetic and neuroendocrine stimulation, and increased blood viscosity) in human foetuses and neonates as well as in different animal models (rats, piglets, sheep and rabbits). Therefore, it is important to determine the minimum effective dose with which these therapies exert a neuroprotective effect, as well as the mode of administration, the duration of therapy, etc. Therefore, until a powerful strategy is found to improve the consequences of suffocation, this topic will continue to be the subject of intensive research in the future.

Historically, neonatal neuroscience boasted a robust and successful preclinical pipeline for therapeutic interventions, in particular for the treatment of hypoxic-ischemic encephalopathy (HIE). However, since the successful translation of therapeutic hypothermia (TH), several high-profile failures of promising adjunctive therapies, in addition to the lack of benefit of TH in lower resource settings, have brought to light critical issues in that same pipeline. Using recent data from clinical trials of erythropoietin as an example, the authors highlight several key challenges facing preclinical neonatal neuroscience for HIE therapeutic development and propose key areas where model development and collaboration across the field in general can ensure ongoing success in treatment development for HIE worldwide.

This article summarizes the current evidence regarding inflammatory biomarkers (placental and postnatal) and provides a comprehensive understanding of their roles: (1) diagnostic accuracy to predict the severity of hypoxic-ischemia encephalopathy (HIE), (2) value in assessing treatment responses, and (3) prediction of both short- and long-term neurodevelopmental outcomes. In the early critical stages of perinatal asphyxia, inflammatory biomarkers may guide clinical decision-making. Additional research is required to increase our understanding of the optimal utility of biomarkers to predict the severity, evolution, and developmental outcomes after exposure to HIE.

Multiple randomized controlled trials of hypothermia for moderate or severe neonatal hypoxic-ischemic encephalopathy (HIE) have uniformly demonstrated a reduction in death or disability at early childhood evaluation. These initial trials along with other smaller studies established hypothermia as a standard of care in the neonatal community for moderate or severe HIE. The results of the initial trials have identified gaps in knowledge. This article describes 3 randomized controlled trials of hypothermia (second-generation trials) to address refinement of hypothermia therapy (longer and/or deeper cooling), late initiation of hypothermia (after 6 hours following birth), and use of hypothermia in preterm newborns.

Therapeutic hypothermia is now well established to improve neurodevelopmental outcomes after hypoxic-ischemic encephalopathy (HIE). Although the overall principles of treatment are now well established, many smaller questions are unclear. The potential impact of reversal of hypothermia therapy and the effect of high temperatures on recovery of the neurovascular unit after therapeutic hypothermia for HIE has received relatively little attention. This article will address the effects of hypoxia-ischemia and rewarming and increased temperatures on the neurovascular unit in preclinical and clinical models.

Reproductive, pregnancy, and placental exposomes influence the fetal neural exposome through toxic stressor interplay, impairing the maternal-placental-fetal (MPF) triad. Neonatal encephalopathy represents different clinical presentations based on complex time-dependent etiopathogenetic mechanisms including hypoxia-ischemia that challenge diagnosis and prognosis. Reproductive, pregnancy, and placental exposomes impair the fetal neural exposome through toxic stressor interplay within the MPF triad. Long intervals often separate disease onset from phenotype. Interdisciplinary fetal-neonatal neurology training, practice, and research closes this knowledge gap. Maintaining reproductive health preserves MPF triad health with life-course benefits.