Neonatal Outcomes in Hypoxic Ischemic Encephalopathy Exposed to Chorioamnionitis, a Retrospective Cohort Study.

Comparison of the outcomes of targeted temperature management for the cardiac arrest patients with and without diabetes mellitus: The TIMECARD study.

Temperature management in malignant infarction requiring decompressive craniectomy: real-world experience and hemorrhagic outcomes.

Hypoxic-ischemic brain damage (HIBD) is a primary cause of neonatal neurological dysfunction, such as cerebral palsy, characterized by complex cascades of neuronal death. Despite the urgent need, effective therapeutic strategies are scarce, and the efficacy of standard interventions, such as therapeutic hypothermia, remains limited. Astragaloside IV (AS-IV), a promising neuroprotective agent, is hindered from wide clinical applications by poor permeability across the blood-brain barrier (BBB) and low bioavailability. To overcome this bottleneck, we developed a novel targeted delivery system based on neural stem cell-derived extracellular vesicle, designated AS-EV, which efficiently deliver AS-IV to the HIBD-affected brain region. AS-EV were successfully prepared via ultracentrifugation and sonication-loading, exhibiting typical exosomal characteristics, and favorable drug-loading efficiency. In vivo experiments confirmed that AS-EV effectively crossed the BBB to accumulate in the injured brain region with satisfying biocompatibility. Mechanistic investigation using primary cortical neurons revealed that the core therapeutic mechanism of AS-EV is mediated by mTOR activation, which consequently suppressed HIBD-induced neuronal apoptosis, an effect that was abrogated by mTOR inhibition. Furthermore, functional and histological assessments demonstrated that AS-EV intervention significantly promoted neurological function recovery, alleviated brain tissue pathology, protected white matter integrity, facilitated neural structural remodeling, and inhibited glial scar proliferation in neonatal HIBD rats. In conclusion, NSC-EV-mediated delivery of AS-IV exerts multifaceted neuroprotective and reparative effects by activating the mTOR pathway, offering a promising therapeutic strategy for HIBD.

To evaluate the association of neonatal magnetic resonance imaging (MRI) and Child Opportunity Index (COI) with 4-year cognitive outcomes after neonatal encephalopathy. This was a cross-sectional analysis of 4-year outcomes (interquartile range [IQR]=48-52 months) in a single-center prospective cohort of term neonatal encephalopathy (1993-2017). Therapeutic hypothermia began in 2007. Watershed and basal ganglia/thalamus injury was scored on day-4 MRI (IQR=3-6) by a blinded pediatric neuroradiologist. Zip code at birth determined the COI composite and subscores (0-100). The primary outcome was 4-year full-scale, verbal, and performanceIQ on the Wechsler Preschool & Primary Scale of Intelligence, Third Edition. Among 149 children (77 males, 72 females) with neonatal encephalopathy, the median full-scale4-year IQ was 101 (IQR=81-112), verbalIQ was 97 (IQR=79-112), and performanceIQ was 100 (IQR=84-112). Basal ganglia/thalamus injury was associated with lower full-scale, verbal, and performance IQ, adjusting for therapeutic hypothermia and birth characteristics. An increasing composite COI was associated with higher full-scale and verbal IQ adjusting for MRI injury, therapeutic hypothermia, and birth characteristics. Every 10-point increase in COI was independently associated with a 2-point increase in full-scale IQ (95% confidence interval [CI]=0.8-3.2, p=0.002) and 2.6-point increase in verbal IQ (95% CI=1.3-3.8, p < 0.001). Neighborhood-level social drivers of health are associated with cognition after neonatal encephalopathy, regardless of MRI findings. These data highlight modifiable opportunities after hospital discharge.

In neonatal hypoxic-ischemic brain injury (HIBI), a common form of perinatal brain damage associated with mortality and neurological disability, the disruption of oxygen and nutrient supply severely impacts brain metabolism. Though therapeutic hypothermia reduces cerebral metabolic rate and improves outcomes, disruption of oxidative metabolism compromising neuronal survival often persists. The complex cerebral metabolic shifts in HIBI remain poorly understood. We directly analyzed the metabolome (LC-MS) of neonatal hypoxia-ischemia(HI)-affected brain tissue to gain further insight into HIBI pathophysiology, isolate the metabolic effects of ischemia and hypoxia,and identify potential therapeutic targets. Postnatal day 10 mice were subjected to five experimental conditions: HI (n = 9) by unilateral carotid artery ligation (UCAL) and hypoxia exposure; contralateral hemispheres; ischemia (UCAL, n = 8); hypoxia (n = 12); and naive (n = 9).Cerebral hemispheres were analyzed 24h post-HI to capture their acute metabolic state. HI resulted in marked alterations in energy production, amino acid and nucleotide metabolism, and pathways governing neuronal homeostasis. Metabolites and pathways linked to NAD⁺ signaling, glutamate regulation, PI3K/AKT signaling, arginine metabolism, neuroinflammation, and vascular regulation were significantly dysregulated. Importantly, these metabolic changes were largely reproduced by ischemia alone, revealing an ischemia-dominant metabolic phenotype. Overall, brain metabolomic profiling identified ischemia as a primary driver of metabolic dysfunction in neonatal HIBI and highlighted specific metabolic pathways involved in bioenergetic deficit, imbalance of neurodegenerative-neuroprotective mechanisms, inflammation, and vascular function, as candidate targets for future therapeutic strategies aimed at limiting secondary brain injury and mitigating neurodevelopmental sequelae.

The objective of this study was to determine the ability of pediatric emergency medicine (PEM) physicians to use cardiac POCUS for the evaluation of cardiac standstill by obtaining cardiac POCUS images on healthy model pediatric patients in ≤10 seconds before and after a brief training video and then interpreting prerecorded cardiac POCUS images for cardiac standstill versus organized cardiac activity as quickly as possible. This was a single-center, prospective, simulation-based study. During simulated pediatric cardiac arrest scenarios, PEM physicians performed cardiac POCUS, reviewed a training video, and then reperformed cardiac POCUS. Subjects then interpreted 12 prerecorded cardiac POCUS video images as cardiac activity or standstill. The time to perform cardiac POCUS and to interpret images was recorded. Twenty PEM physicians participated. There was no change in median time, 10 seconds, to obtain cardiac POCUS images before and after the training video ( P =0.44). When data were dichotomized by ≤10 or >10 seconds, the odds of obtaining the image in ≤10 seconds were 3.5 times higher after viewing the video (95% CI=0.7, 34.5). When interpreting cardiac images, 40% (n=8) interpreted all of the images correctly; however, only 10% (n=2) did so in ≤10 seconds. The majority of PEM physicians can obtain cardiac POCUS images for the evaluation of cardiac standstill in ≤10 seconds. The ability to interpret cardiac POCUS images for cardiac activity or standstill in ≤10 seconds is variable; further research is needed to determine whether additional training could improve overall precision and timeliness.

Therapeutic hypothermia (TH) decreases morbidity and mortality in neonates with perinatal asphyxia (PA) and moderate-to-severe hypoxic-ischaemic encephalopathy. Midazolam is an antiepileptic and substrate of CYP3A4. Drug metabolism during PA/TH remains partially characterized, and disentangling effects of PA and TH is difficult, making precision dosing challenging. The I-PREDICT project aims to develop a framework for drug disposition in PA/TH neonates, using physiologically based pharmacokinetic (PBPK) modelling. The predictive performance of the model was explored for midazolam and its active metabolites, 1'-hydroxymidazolam and 1'-hydroxymidazolam-O-glucuronide, in neonates with PA/TH. The model was established stepwise, starting with healthy adults, and extrapolated to paediatric (1month-18 years) and neonatal (0-27 days, non-asphyxiated) populations. Finally, PA/TH-related physiological and metabolic changes were incorporated. For each population, performance was verified using clinical data. Model predictive performance for midazolam and 1'-hydroxymidazolam was acceptable in adults and children, with AFE and AAFE values ranging from 0.87 to 1.22 and 1.15 to 1.23, respectively. The neonatal PA/TH PBPK model captured midazolam pharmacokinetics, with 71% of the observations within the 10th-90th percentiles and 46% within the 25th-75th percentiles of the prediction. Incorporating PA/TH physiology improved the neonatal PA/TH model by 6%-43% (within the 10th-90th percentiles), depending on the compound. This PA/TH-adjusted neonatal PBPK model may support future midazolam dose optimization through mechanistic understanding and provides a framework for other drugs in neonates with PA/TH. Future knowledge on the impact of TH on protein binding and renal clearance of 1'-hydroxymidazolam-O-glucuronide would further improve the model.

ObjectiveTo evaluate the association between admission blood gas parameters, particularly pH and base excess (BE), and serial amplitude-integrated electroencephalography (aEEG) background patterns, and to determine whether these early metabolic markers are associated with MRI-defined brain injury severity in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH).MethodsThis retrospective study included 80 neonates (gestational age ≥35 weeks) with moderate-to-severe HIE treated with TH. Admission pH and BE values were recorded. Serial aEEG monitoring was performed at 6, 24, 48, and 72 h of life, and background patterns were classified according to Hellström-Westas criteria. aEEG recordings were independently interpreted by two reviewers blinded to the clinical and MRI data. Brain MRI was performed in 74 neonates at a median postnatal age of 5 days and was evaluated by a blinded pediatric neuroradiologist.ResultsAdmission BE was significantly associated with aEEG background patterns at all evaluated time points (6 h: p = 0.001; 24 h: p = 0.003; 48 h: p = 0.034; 72 h: p = 0.005). Infants with more severely depressed aEEG patterns had more negative admission BE values. In contrast, neither admission pH nor BE was significantly associated with MRI-defined brain injury severity. Overall mortality was 7.5%.ConclusionAdmission metabolic derangement, particularly BE, is associated with early electrocortical depression on serial aEEG but not with MRI-defined structural brain injury severity in neonates with HIE treated with TH. These findings support a dissociation between early metabolic acidosis and established structural brain injury and underscore the importance of multimodal prognostic assessment in early clinical decision-making.

The aim was to synthesize current evidence on nutritional management in adult patients after cardiac arrest (CA) and to develop a structured framework for clinical practice in the absence of CA-specific nutritional guidelines. Post-cardiac arrest syndrome is characterized by systemic ischemia-reperfusion injury, metabolic stress, and organ dysfunction. Although nutritional support is an integral component of critical care, randomized controlled trials specifically evaluating nutritional strategies in patients after CA are lacking. Current practice therefore relies largely on extrapolation from general intensive care unit (ICU) guidelines, with additional uncertainty during targeted temperature management (TTM, a controlled medical therapy designed to actively lower or regulate a patient's core body temperature to improve neurological outcomes after CA). A narrative review of international guideline recommendations, randomized controlled trials in critically ill populations, CA-specific observational studies, and relevant mechanistic data was conducted. Evidence was interpreted using a hierarchical approach to distinguish high-certainty guideline-supported practices from lower-certainty observational and hypothesis-generating findings. High-level evidence from ICU guidelines supports early enteral nutrition (EN), hypocaloric feeding during the acute phase, and individualized protein provision. Observational studies in CA cohorts suggest that early EN is feasible during targeted temperature management and may be associated with improved neurological outcomes, although causality remains unproven. Temperature management reduces energy expenditure and alters substrate utilization, necessitating appropriate adjustment of caloric targets. Biomarkers such as glycemic variability, triglyceride levels, triglyceride-glucose index, and protein-related indices demonstrate prognostic associations but have not been validated as guides for nutritional prescription. In the absence of CA-specific interventional trials, nutritional management after CA should be grounded in established ICU principles and adapted according to physiological context and metabolic tolerance. The framework presented herein aims to support structured clinical decision-making while underscoring the need for prospective studies to define evidence-based, population-specific nutritional strategies.

Decentralised implementation of therapeutic hypothermia (TH) for neonatal hypoxic-ischaemic encephalopathy (HIE) in Germany historically caused heterogeneous clinical practices. The aim of this study was to assess the impact of the German Hypothermia Registry on clinical standardisation and confidence in neonatal HIE care since its initiation in 2022. We conducted a nationwide, two-phase, web-based survey in 2022 (n = 66) and 2025 (n = 222). A longitudinal subgroup analysis included physicians participating in both surveys (n = 30). Outcomes included guideline adherence, subjective diagnostic and therapeutic confidence, and perceived needs for further standardisation. From 2022 to 2025, clinician confidence improved across most domains. Complete confidence in diagnosing HIE increased from 42.4% to 80.0% in the longitudinal subgroup, while confidence in performing TH rose from 53.0% to 86.7%. Clarity regarding inclusion criteria reached 100% among longitudinal participants. In contrast, complete confidence in neurological assessment (36.7%) and amplitude-integrated electroencephalography (aEEG) interpretation (60.0%) remained comparatively lower in 2025. The German Hypothermia Registry markedly improved standardisation and clinician confidence in neonatal HIE care. However, neurological assessment and aEEG interpretation remain key areas requiring targeted educational support.

Neonatal hypoxia-ischemia (HI) remains a major cause of perinatal morbidity and mortality, leading to lifelong neurological sequelae. Therapeutic hypothermia is the current standard of care but provides only partial protection and must be applied within a narrow therapeutic window. Complementary or preventive neuroprotective strategies are therefore needed. Maternal supplementation with plant-derived polyphenols has shown promising effects in reducing oxidative stress, neuroinflammation, and neuronal loss in experimental models of neonatal HI. Passion fruit extract, rich in stilbenes such as piceatannol, represents a potential neuroprotective candidate, yet its compatibility with post-HI hypothermia has not been systematically evaluated. Pregnant rats received oral supplementation with a passion fruit extract of defined polyphenolic composition during the last week of gestation and the first week of lactation. Neonatal HI was induced at postnatal day 7, followed by therapeutic hypothermia (2 h, 32 °C) in selected groups. All experimental groups were compared versus sham (controls) group. Brain injury was assessed using MRI and histology, while behavioral outcomes were evaluated from the neonatal to juvenile period (50 days old). Maternal supplementation with passion fruit extract significantly reduced lesion volumes, attenuated oxidative and inflammatory markers, and improved sensorimotor and cognitive performance. When combined with hypothermia, structural protection was further enhanced, although passion fruit extract alone sometimes provided superior benefit in specific behavioral tests, suggesting possible overlapping or modulatory mechanisms. Maternal supplementation with passion fruit extract offers robust neuroprotection against neonatal HI and is compatible with post-HI therapeutic hypothermia. This combined preventive and therapeutic approach may represent a scalable, low-risk, and cost-effective adjunct strategy to enhance outcomes in neonatal HI.

Low-frequency TMS ameliorates neonatal hypoxia-ischemia injury by normalizing glutamatergic transmission in penumbra.

Uterine incision-to-delivery interval and neonatal outcomes among nonurgent, term, cesarean deliveries.

Mild hypothermia alleviates post-resuscitation cerebral injury in rats via modulating the balance of the renin-angiotensin system.

Impaired renal function (IRF), defined as the rate of decline in serum creatinine levels during the week after birth, frequently affects neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, its clinical relevance in this vulnerable population requires further investigation. This study aimed to evaluate the association between IRF and brain injury severity in neonates with HIE. This retrospective single-center study included neonates treated with therapeutic hypothermia for moderate or severe HIE. A multivariable logistic regression analysis evaluated the association between IRF and the combined outcomes of early death or severe brain injury (ED/SevereBI). Of the 147 included neonates, 67 (45.6%) had IRF and 32 (22%) had ED/SevereBI. Those with ED/SevereBI were more likely to have a lower 5-min Apgar score (median [interquartile range]: 4 [2-5] vs. 2 [1-3], P<0.01), have a higher initial blood lactate level (mean cord blood lactate level, +34%, P<0.05), be intubated in the delivery room (50% vs. 75%, P=0.01), and have IRF (39% vs. 69%, P<0.01). After the adjustment for neonatal characteristics and perinatal asphyxia parameters, neonates with IRF had a 2- to 3-fold higher odds of ED/SevereBI than those without IRF (adjusted odds ratio [95% confidence interval]: 2.66 [1.09-6.84], P=0.03). In neonates treated with therapeutic hypothermia for HIE, IRF can be used as a marker of adverse outcomes. Further studies are required to evaluate its long-term prognostic value.

Combined short- and mid-latency SSEP amplitudes for early prediction of favorable neurological recovery after cardiac arrest.

To investigate whether early lactate dehydrogenase (LDH) and amplitude-integrated electroencephalography (aEEG) improve the prediction of outcome in outborn infants transported for therapeutic hypothermia. Secondary analysis of a randomised controlled trial (2016-2019) including 113 asphyxiated newborn infants randomised to transport with a phase-change material mattress or standard care. The analysis included 81 infants with available aEEG, of whom 50 had LDH measured on admission. Outcome at 18 months was categorised as good, defined as normal development or mild delay, or poor, defined as moderate or severe impairment or death. Mean (SD) rectal temperature on admission was lower in the PCM group (34.6 [1.1]°C vs. 35.2 [1.1]°C, p = 0.027), but the proportion within target temperature did not differ (39.5% vs. 25.6%, p = 0.235). Clinical characteristics, LDH, aEEG and outcomes were similar between groups. Poor outcome was predicted by LDH > 1000 U/L (89% sensitivity and 61% specificity), severely depressed aEEG within 12 h (87% sensitivity and 47% specificity) and the combination of both (91% sensitivity, 62% specificity and accuracy 81%). Combined LDH and aEEG provide a strong early prediction of outcome in encephalopathic infants.

Introduction: This study explored how illness severity scores correspond to hypoxic-ischemic brain injury (HIBI) after cardiac arrest. Methods: This study included cardiac arrest survivors with sufficient data to calculate the Pittsburgh Cardiac Arrest Category (PCAC) and revised post-cardiac arrest syndrome for therapeutic hypothermia (rCAST) scores who underwent brain magnetic resonance imaging and cerebrospinal fluid neuron–specific enolase (CSF-NSE) measurement within 6 h after return of spontaneous circulation. The primary outcome was the association of PCAC and rCAST with quantitative brain injury markers assessed using whole brain mean apparent diffusion coefficient (mean ADC), low ADC volume fractions (PV600, 650, and 700), and CSF-NSE. Results: In total, 81 patients were included. PCAC was not significantly associated with CSF-NSE, mean ADC, or PVs. The rCAST score was significantly associated with higher CSF-NSE, lower mean ADC, and higher PV700. The neurologic sub-score of PCAC was independently associated with all evaluated brain injury markers, whereas the systemic sub-score was not. Of the individual rCAST components, anoxic time was independently associated with CSF-NSE, whereas no other single component was associated with these markers. Conclusions: rCAST was significantly associated with degree of HIBI, whereas PCAC was not. The neurologic sub-score of PCAC showed independent associations with HIBI.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a common form of acute infection-triggered encephalopathy in children. This study aimed to evaluate the safety and feasibility of remote ischaemic postconditioning (RIPoC) as an adjunct to therapeutic hypothermia in patients with AESD. In this prospective, non-randomised study, patients treated in January 2021-July 2024 were compared with a historical control group treated in January 2017-December 2020. RIPoC (four cycles of 5-min inflation and 5-min deflation) was applied to the lower extremity at the initiation of therapeutic hypothermia. Adverse events were assessed between the RIPoC group (n = 15) and patients with therapeutic hypothermia in the control groups (n = 12). Neurological outcomes at 6-18 months post-onset were compared between the RIPoC group (n = 12) and patients with/without therapeutic hypothermia in the control groups (n = 13). Multivariate analyses were performed to identify predictors of favourable neurological outcomes. While the comparison of adverse events and neurological outcomes between groups did not show significant differences, multiple analysis suggested associations between a lower Tada score or RIPoC treatment and better outcomes. RIPoC combined with therapeutic hypothermia appears safe and feasible in patients with AESD. Remote ischaemic postconditioning (RIPoC) was safely combined with hypothermia in paediatric patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). No coagulation, hemodynamic complications, or adverse events were observed. Multiple linear regression analysis suggested associations between a lower Tada score or RIPoC treatment and better outcomes in patients with AESD. This is the first report to examine the feasibility and safety of the RIPoC in paediatric central nervous system disease not directly related to ischaemia-reperfusion injury. Findings support future randomised controlled studies to confirm RIPoC as a possible adjunctive neuroprotective therapy in paediatric brain injury, particularly AESD.