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Aim Methods Results Conclusion Immune dysregulation and delayed onset of sleep wake cycling (SWC) are associated with worse outcome in neonatal encephalopathy (NE), however the association between sleep and immune dysfunction in NE remains unclear. Aimed to evaluate association of sleep and systemic inflammation with outcomes in NE.Amplitude‐integrated electroencephalography (aEEG) recordings were collected on infants undergoing therapeutic hypothermia (TH). Duration to onset of (SWC) and sleep quality (SQ) were examined. Blood samples collected during the first 2 days of life. Thirteen pro‐ and anti‐inflammatory serum cytokines were quantified. Adverse outcome defined as death or abnormal MRI brain.Earlier onset of SWC and better SQ had less adverse outcomes. SQ provided better prognostic value and showed better interobserver agreement compared to duration to SWC. Better SQ associated with lower cytokines EPO and interleukin (IL)‐1β. In infants with unfavourable outcome, shorter duration to SWC was associated with higher EPO and better SQ was associated with lower TNF‐α.Earlier onset of SWC or better SQ showed less systemic inflammation and fewer adverse outcomes. SQ during TH provided better prognostic information than time of onset of SWC. Modulation of circadian rhythm in infants with NE may have an immunomodulatory role, leading to improved outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Blood lactate levels in neonates with hypoxic-ischemic encephalopathy (HIE) vary, and their impact on neurodevelopmental outcome is unclear. We assessed blood lactate course over time in neonates with HIE during therapeutic hypothermia (TH) and investigated if blood lactate values were associated with neurodevelopmental outcome at 2 years of age. Methods: This is a retrospective cohort study of neonates with HIE born between 2013 and 2019, treated at the University Children's Hospital Zurich. We recorded blood lactate values over time and calculated time until lactate was ≤2 mmol/L. Neurodevelopmental outcome was assessed at 18–24 months of age using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), and categorized as favorable or unfavorable. We investigated associations between blood lactate values and outcome using logistic regression and adjusted for Sarnat stage. Results: 33/45 neonates (69%) had a favorable and 14 (31%) an unfavorable neurodevelopmental outcome. Mean initial lactate values were lower in the favorable (13.9 mmol/L, standard deviation [SD]: 2.9) versus unfavorable group (17.1 mmol/L, SD 3.2; p = 0.002). Higher initial and maximal blood lactate levels were associated with unfavorable outcome, also when adjusted for Sarnat stage (adjusted odds ratio [aOR]: 1.37, 95% CI: 1.01–1.88, p = 0.046, and aOR: 1.35, 95% CI: 1.01–1.81, p = 0.041, respectively). Conclusion: In neonates with HIE receiving TH, initial and maximal blood lactate levels were associated with neurodevelopmental outcome at 18–24 months of age, also when adjusted for Sarnat stage. Further investigations to analyze blood lactate as a biomarker for prognostic value are needed. [ABSTRACT FROM AUTHOR]

Background: Quantitative EEG is frequently used to monitor children affected by acute encephalopathy (AE), with the expectation of providing comprehensive insights into continuous EEG monitoring. However, the potential of quantitative EEG for estimating outcomes in this context remains unclear. We sought reliable prognostic markers within the color density spectral array (CDSA) of the continuous EEG for AE-affected children undergoing therapeutic hypothermia (TH). Methods: This retrospective study analyzed CDSA data from eight scalp electrodes of 15 AE-affected children undergoing TH. Two CDSA features were investigated—high-frequency lines (HFLs) and periodic elevation in the low frequency band (PLFB)—along with the corresponding EEG characteristics. The inter-rater reliability for CDSA was assessed by four pediatric neurologists. Outcomes were grouped into either no/mild or severe decline in motor and cognitive functions, then compared with CDSA features. Results: The median EEG recording time was 114 (81–151) h per child. While at least 41 % of HFLs corresponded to typical sleep spindles, 94 % of PLFB aligned with cyclic changes in the amplitude of delta/theta waves on the raw EEG. Inter-rater reliability was higher for HFLs than for PLFB (kappa values: 0.69 vs. 0.46). HFLs were significantly more prevalent in children with no/mild decline than in children with severe decline (p = 0.017), whereas PLFB did not differ significantly (p = 0.33). Conclusions: This study provides preliminary evidence that reduced HFLs on CDSA predict unfavorable outcomes in AE-affected children undergoing TH. This suggests that maintaining high-frequency waves is critical for optimal brain function. [ABSTRACT FROM AUTHOR]

Background: Acute ischemic stroke remains a major contributor to mortality and disability worldwide. The use of hypothermia has emerged as a promising neuroprotective strategy, with proven effectiveness in cardiac arrest and neonatal hypoxic-ischemic injury. Summary: This review explores the therapeutic potential of hypothermia in ischemic stroke by examining its impact on poststroke inflammatory responses. We synthesized evidence from basic and clinical studies to illustrate the inhibitory effects of hypothermia on poststroke brain inflammation. The underlying mechanisms include modulation of microglial activation and polarization; downregulation of key inflammatory pathways such as MAPKs, NF-KB, and JAK/STAT; protection of the blood-brain barrier integrity; and reduction of immune cell infiltration into the brain. We also discuss the current limitations of hypothermia treatment in clinical practice and highlight future research directions for optimizing protocols and evaluating its clinical efficacy in stroke patients. Key Messages: Therapeutic hypothermia (TH) has evolved significantly with advancements in medical technologies, especially with the introduction of automated cooling devices, both intravascular and surface based. However, a refined, highly individualized, and effective hypothermia protocol may stand robust against the devastating consequences of ischemic stroke, and we think it should become the future development goal. [ABSTRACT FROM AUTHOR]

Objective: In this study, we aimed to evaluate the relationship between the level of improvement in blood gas parameters in the first hours of age and normal and diffusion-restriction brain magnetic resonance imaging (MRI). Materials and Methods: The study is a retrospective cohort study. Cases of the diagnosis of hypoxic-ischemic encephalopathy (HIE) who received therapeutic hypothermia in our unit between January 2022 and January 2024 were included in the study. Clinical findings, blood gas values (first, cord; second, first hours of age; third, 24th hour of age), and MRI results were recorded from the case files and compared between normal and diffusion-restricted brain MRI groups. Results: Diffusion-restricted brain MRI was detected in 10 out of a total of 19 cases. The 5-minute Apgar score was lower (p=0.038) and mechanical ventilator support was higher (P=.003) in the diffusion-restricted MRI group than in the normal MRI group. The relationship was shown between high base excess (P=.022) in cord blood gas, low HCO3 (p=0.025) in the 24th hour blood gas, and convulsion (P=.033) in the diffusion-restricted MRI group. Additionally, it was found that only the improvement level of the pH value in the first hour of age was significant (P=.025) in the diffusion-restricted brain MRI group than in the normal MRI group. Conclusion: We showed that there was a relationship between diffusion-restricted brain MRI and the improvement level in the pH value in the first hours of age of patients diagnosed with HIE who received treatment for therapeutic hypothermia [ABSTRACT FROM AUTHOR]

Serial neonatal encephalopathy (NE) examinations are difficult to perform in rural community hospitals as on-site experts are not readily available. We implemented a synchronous, acute care model of teleconsultation—the Maine Neonatal Encephalopathy Teleconsultation program (Maine NET)—to provide remote, joint assessment of NE by pediatric neurology and neonatology at nine community hospitals and one tertiary care center. We performed a qualitative study to interview clinicians about their experience of this program. From April 2018 to October 2022, we employed a semistructured interview format with 16 clinicians representing all participating hospitals. We utilized deductive analysis to assign a set of predefined codes to the transcribed interviews. Thematic analysis supported the anticipated benefits of Maine NET, demonstrating that clinicians felt resource utilization, collaborative decision making, communication, and continuity of care were improved. Clinicians overwhelmingly supported the program: "This program has truly saved babies' lives and future function. I have not met any parents through this journey, who aren't incredibly grateful for the care that is provided" and emphasized the benefit of collaboration between all care team members. Teleconsultation was felt to be "more than adequate to [assess] NE." Connectivity issues were cited as a limitation. Maine NET has positively impacted care delivery for newborns with clinical concerns for NE. Additionally, the program has improved resource allocation, collaborative decision making, communication, and equity of care. Addressing technological challenges will be vital to the success and sustainability of the planned Maine NET expansion. [ABSTRACT FROM AUTHOR]

Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. As perinatal asphyxia and TH impact neonatal physiology, this could also influence enzyme functionality. Therefore, this study aimed to unravel the impact of age, hypothermia and hypoxia on porcine hepatic cytochrome P450 (CYP) gene expression, protein abundance and activity. Hepatic CYP expression, protein abundance and activity were assessed in naive adult and neonatal Göttingen minipigs, alongside those from an (non‐survival) in vivo study, where four conditions—control (C), therapeutic hypothermia (TH), hypoxia (H), hypoxia and TH (H + TH)—were examined. Naive neonatal Göttingen minipigs exhibited 75% lower general CYP activity and different gene expression patterns than adults. In vitro hypothermia (33°C) decreased general CYP activity in adult liver microsomes by 36%. Gene expression was not different between TH and C while hypoxia up‐regulated several genes (i.e., CYP3A29 [expression ratio; ER = 5.1472] and CYP2C33 [ER = 3.2292] in the H group and CYP2C33 [ER = 2.4914] and CYP2C42 [ER = 4.0197] in the H + TH group). The medical treatment and the interventions over 24 h, along with hypoxia and TH, affected the protein abundance. These data on CYP expression, abundance and activity in young animals can be valuable in building physiologically‐based pharmacokinetic models for neonatal drug dose predictions. [ABSTRACT FROM AUTHOR]

In the present study, we investigated the neuroprotective effects of local therapeutic hypothermia (LTH) in a model of focal ischemia induced by epipial application of Endothelin-1 to the somatosensory cortex of the rat brain by morphometric analysis of ischemic foci formed 3 hours after Endothelin-1 application. The size of ischemic foci was measured in serial coronal brain slices after staining with 2,3,5-triphenyltetrazolium chloride (TTC). It was found that cooling the cortical surface to 28°C using a subdural Peltier element at 0, 10 and 60 minutes delay after Endothelin-1 application, caused a significant reduction in the size of ischemic focus compared to normothermic conditions. The neuroprotective effects of LTH were inversely correlated with the delay of LTH onset from the time of Endothelin-1 application and were most pronounced with LTH initiated with the shortest (0 and 10 minutes) delay after Endothelin-1 application. The size of the ischemic focus was also found to correlate significantly with the degree of electrical activity suppression analyzed in parallel paper. Taken together, the results of morphological and electrophysiological analysis indicate pronounced neuroprotective effects of surface LTH, particularly significant at minimal LTH latency after ischemic onset, in a model of Endothelin-1-induced focal ischemia in the rat cerebral cortex. [ABSTRACT FROM AUTHOR]

Local therapeutic hypothermia (LTH) is one of the most promising methods for neuroprotection in cerebral ischemia. However, the efficacy of superficial LTH at clinically relevant delays after the onset of ischemic attack remains poorly understood. In the present study, we investigated the neuroprotective effects of LTH in a model of focal ischemia induced by epipial application of the vasoconstrictor Endothelin-1 in the somatosensory cortex region of the rat brain. The neuroprotective effects of LTH were assessed by the level of spontaneous and sensory-evoked electrical activity at different cortical depths using linear electrode arrays. We found that cooling the cortical surface to 28°C using a Peltier element starting from 0, 10, and 60 minutes after Endothelin-1 application caused a significant reduction in the degree of suppression of electrical activity in the ischemic focus formed in the cerebral cortex 3 hours after Endothelin-1 application. The neuroprotective effects of LTH were manifested by a higher level of spontaneous multiunit activity, higher power of the local field potential oscillations in theta, alpha and beta bands, as well in a greater amplitude and higher multiunit activity during sensory evoked responses. The neuroprotective effects of LTH were inversely correlated with the delay of LTH onset and were most pronounced with LTH initiated with minimal (0 and 10 minutes) delay after Endothelin-1 application. We also found that only LTH initiated simultaneously with Endothelin-1 application delayed the onsets of spreading depolarization waves and that LTH did not affect the amplitude of negative ultraslow potentials evoked by Endothelin-1. Taken together, the results of the electrophysiological analysis suggest neuroprotective effects of surface LTH, which are particularly pronounced when LTH is minimally delayed from the onset of the ischemic insult in the Endothelin-1-induced focal ischemia model. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress-related diseases in newborns arise from pro-oxidant/antioxidant imbalance in both term and preterm neonates. Pro-oxidant/antioxidant imbalance has shown to be present in different pathological conditions such as hypoxic ischemic encephalopathy (HIE), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and patent ductus arteriosus (PDA). Methods and Results: We performed a narrative review according to the most recent available literature (2012–2024), using Scopus and PubMed as electronic databases. Many observational and experimental studies in vitro and in vivo have evaluated the effectiveness of antioxidant therapies such as melatonin, erythropoietin (EPO), allopurinol, N-acetylcisteine (NAS), and nitric oxide synthase (NOS) inhibitors in these diseases. Perinatal asphyxia is one of the most important causes of mortality and morbidity in term and near-term newborns. Therapeutic hypothermia (TH) is the gold standard treatment for neonates with moderate-severe perinatal asphyxia, resulting in a reduction in the mortality and neurodevelopmental disability rates. Conclusions: According to the most recent literature and clinical trials, melatonin, allopurinol, NAS, NOS inhibitors, magnesium sulfate, and stem cells stand out as promising as both adjuvants and future probable alternatives to TH in the treatment of HIE. [ABSTRACT FROM AUTHOR]

Background/Objective: It is difficult to predict perinatal brain injury, and performing brain magnetic resonance imaging (MRI) based on suspected injury remains a clinical challenge. Therefore, we aimed to develop a reliable method for predicting perinatal brain injury using a machine learning model with early birth data. Methods: Neonates admitted to our institution from January 2017 to June 2024 with a gestational age of ≥36 weeks, a birth weight of ≥1800 g, admission within 6 h of birth, and who underwent brain MRI to confirm perinatal brain injury were included. Various machine learning models, including gradient boosting, were trained using early birth data to predict perinatal brain injury. Synthetic minority over-sampling and adaptive synthetic sampling (ADASYN) were applied to address class imbalance. Model performance was evaluated using accuracy, F1 score, and ROC curves. Feature importance scores and Shapley additive explanations (SHAP) values were also calculated. Results: Among 179 neonates, 39 had perinatal brain injury. There were significant differences between the injury and non-injury groups in mode of delivery, Apgar scores, capillary pH, lactate dehydrogenase (LDH) levels, and whether therapeutic hypothermia was performed. The gradient boosting model with the ADASYN method achieved the best performance. In terms of feature importance scores, the 1 min Apgar score was the most influential predictor. Additionally, SHAP analysis showed that LDH levels had the highest SHAP values. Conclusion: the gradient boosting model with ADASYN oversampling effectively predicts perinatal brain injury, potentially improving early detection for predicting long-term outcomes, reducing unnecessary MRI scans, and lowering healthcare costs. [ABSTRACT FROM AUTHOR]

Hypoxic–ischemic encephalopathy (HIE) is a perinatal brain injury that is the leading cause of cerebral palsy, developmental delay, and poor cognitive outcomes in children born at term, occurring in about 1.5 out of 1000 births. The only proven therapy for HIE is therapeutic hypothermia. However, despite this treatment, many children ultimately suffer disability, brain injury, and even death. Barriers to implementation including late diagnosis and lack of resources also lead to poorer outcomes. This demonstrates a critical need for additional treatments for HIE, and to facilitate this, we need translational models that accurately reflect risk factors and interactions present in HIE. Maternal or amniotic infection is a significant risk factor and possible cause of HIE in humans. Maternal immune activation (MIA) is a well-established model of maternal infection and inflammation that has significant developmental consequences largely characterized within the context of neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. MIA can also lead to long-lasting changes within the neuroimmune system, which lead to compounding negative outcomes following a second insult. This supports the importance of understanding the interaction of maternal inflammation and hypoxic–ischemic outcomes. Animal models have been invaluable to understanding the pathophysiology of this injury and to the development of therapeutic hypothermia. However, each model system has its own limitations. Large animal models such as pigs may more accurately represent the brain and organ development and complexity in humans, while rodent models are more cost-effective and offer more possible molecular techniques. Recent studies have utilized MIA or direct inflammation prior to HIE insult. Investigators should thoughtfully consider the risk factors they wish to include in their HIE animal models. In the incorporation of MIA, investigators should consider the type, timing, and dose of the inflammatory stimulus, as well as the timing, severity, and type of hypoxic insult. Using a variety of animal models that incorporate the maternal–placental–fetal system of inflammation will most likely lead to a more robust understanding of the mechanisms of this injury that can guide future clinical decisions and therapies. [ABSTRACT FROM AUTHOR]

Introduction: Eleclazine is a highly selective late sodium current inhibitor, possibly effective in reducing ventricular fibrillation (VF) in heart failure (HF) with ischemia-reperfusion (IR) injury. The electrophysiological effects of eleclazine at therapeutic hypothermia (TH) are unknown. We investigated the effects of eleclazine in suppressing VF in failing rabbit hearts with IR injury undergoing TH. Method: HF was induced by right ventricular pacing. An IR model was created using coronary artery ligation for 60 min, followed by reperfusion for 30 min. Hearts were excised and Langendorff-perfused for optical mapping and electrophysiological studies. Electrophysiological studies were repeated after TH (33°C) for 30 min or eleclazine (1 μm) infusion for 20 min. Results: In failing IR-injured hearts, eleclazine reduced action potential duration (APD) dispersion and accelerated intracellular Ca2+ uptake to suppress arrhythmogenic alternans but also exacerbated rate-dependent conduction slowing, resulting in neutral effects on VF inducibility at normothermia. TH increased VF severity. Eleclazine after TH ameliorated TH-induced APD dispersion and further depressed conduction to reduce VF inducibility and severity. TH after eleclazine also slowed conduction to a greater extent to reduce VF inducibility and severity by extrastimulus pacing. In control IR-injured hearts, eleclazine increased VF severity by dynamic pacing at normothermia, which was counteracted by TH. Conclusions: Eleclazine does not prevent VF at normothermia but reduces VF inducibility and severity by extrastimulus pacing at TH in isolated failing hearts with regional IR injury. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion CoolCuddle, enabling parents to cuddle their babies with neonatal encephalopathy (NE) during therapeutic hypothermia and intensive care (TH), was developed in research settings. To determine the impact of implementing CoolCuddle in usual care in six diverse neonatal intensive care units on the cooling process and intensive care.This vital sign cohort study embedded within the CoolCuddle implementation study enrolled 36 infants receiving TH for NE. Nurses received training on CoolCuddle and a standard operating procedure using an instruction video. After consenting, parents experienced up to 2 h of CoolCuddle with 30 min of pre‐ and post‐cuddle observation. We used multilevel, clustered linear modelling to assess the physiological stability in temperature, cardio‐respiratory and neurophysiology across the CoolCuddle.In 60 CoolCuddles over 93.12 h, respiratory parameters, heart rate or neurological function did not vary between the epochs (p > 0.05). During cuddle, sleep–wake cycling on amplitude‐integrated EEG increased (p = 0.008) and there was weak evidence of lower pain scores (p = 0.08). No adverse effects were observed.Implementing CoolCuddle with support in usual practice maintained physiological stability and did not significantly affect the cooling process or intensive care, and may improve infant comfort. Ongoing monitoring of adverse effects when implementing CoolCuddle is recommended. [ABSTRACT FROM AUTHOR]

Introduction: Hypoxic-ischemic encephalopathy (HIE) affects 1–2 per 1,000 births and is associated with mortality and long-term neurodevelopmental challenges. At present, therapeutic hypothermia (TH) is the only neuroprotective intervention for these infants. This study examines whether HIE severity, clinical management during TH, and post-rewarming outcomes have changed since its introduction 15 years ago. Methods: Neonatal characteristics, HIE severity, management during TH, and post-rewarming MRI of all infants with HIE undergoing TH between 2008 and 2023 were compared across three five-year epochs. Linear regression was used to estimate annual changes over time. Results: In total, 252 infants underwent TH. Median gestational age (39.5 weeks), birth weight (3,376 g), and time to start TH (4.25 h) remained stable over time. Apgar score at 5 min (p = 0.031) and lowest pH <1 h postpartum (p = 0.020) increased over time. Thompson score at 1–3 h decreased across epochs (p = 0.046). There was an increase in percentage with normal-mild aEEG background patterns on admission (p = 0.041) and a decrease in aEEG-confirmed seizures (p < 0.001) and antiseizure medication (p < 0.001). Inotropic support decreased (p = 0.007), and use of invasive mechanical ventilation decreased over the last 5 years. Mortality (28.6%) and post-rewarming composite adverse outcome (i.e., neonatal mortality and/or adverse MRI score) (37.9%) remained unchanged. Number of infants seen at 2-year follow-up increased (p < 0.001). Conclusion: Over the last 15 years, we treated more infants with milder HIE, as indicated by lower Thompson and milder aEEG scores, and the need for invasive cardiorespiratory support declined. However, there were no improvements in composite adverse outcome (mortality and/or adverse MRI score). [ABSTRACT FROM AUTHOR]

Cesarean section for breech presentation is often recommended. However, cesarean section affects future reproduction. The aim of this study was to assess the effect of mode of the first birth in breech on outcomes of the second birth and the two births together. This is a register-based nationwide cohort study including 23 062 women with a first singleton birth in breech ≥ 34 gestational weeks and a subsequent singleton birth in Sweden 2000–2019. Exposure was mode of first delivery. Main maternal outcome was a composite of fourth-degree perineal injury, postpartum hemorrhage requiring blood transfusion, hysterectomy, or death. Main infant outcome was a composite of stillbirth, extremely preterm birth (< 28 weeks), moderate to severe hypoxic ischemic encephalopathy, therapeutic hypothermia, or death. Outcomes were analyzed using multivariable logistic regression. In the first birth, the infant composite outcome affected < 1% in both groups but the risk was higher in the vaginal breech group (13/1525), compared with the breech CS group (27/21 537), aOR 7.06, 95% CI 2.91–17.1. In the second birth, the infant composite outcome affected < 1% in both groups but the risk was lower for the first vaginal breech group (3/1525) compared with the first breech CS group (152/21 537), aOR 0.26, 95% CI 0.08–0.84. There was no significant difference between the groups in risk of composite infant outcome in the two births assessed together, or in risk of composite maternal outcome. In total, the chance of a two-children family without maternal or infant severe adverse composite outcome was high and similar regardless mode of the breech first birth. [ABSTRACT FROM AUTHOR]

Aims and hypothesis: Hypoxic-ischemic encephalopathy (HIE) remains an important cause of death and disability in newborns. Mild therapeutic hypothermia (TH) is safe and effective; however, there are no tissue biomarkers available at the bedside to select babies for treatment. The aim of this study was to show that it is feasible to study plasma neurofilament light (NfL) levels from newborns and to evaluate their temporal course. Hypothesis: Raised plasma NFL protein levels from newborns who undergo TH after HIE are associated with abnormal MRI outcomes. Methods: Between February 2014 and January 2016, term newborns with HIE treated with TH for 72 h had plasma samples taken at three time points: (i) after the infant had reached target temperature, (ii) prior to commencing rewarming, and (iii) after completing rewarming. Infants with mild HIE who did not receive TH had a single specimen taken. NfL protein was analyzed using an enzyme-linked immunosorbent assay. Results: Twenty-six newborns with moderate-severe HIE treated with TH were studied. Half of these had cerebral MRI predictive of an unfavorable outcome. Plasma NfL levels were significantly higher in the TH group with unfavorable outcome (median age 18 h) compared to levels from both the mild HIE group and TH group with favorable outcome (F = 25.83, p < 0.0001). Newborns who had MRIs predictive of unfavorable outcome had significantly higher NfL levels compared to those with favorable outcomes, at all three time points (mixed models, F = 27.63, p < 0.001). A cutoff NfL level >29 pg/mL at 24 h is predictive of an unfavorable outcome [sensitivity 77%, specificity 69%, positive predictive value (PPV) 67%, negative predictive value (NPV) 72%] with increasing predictive value until after rewarming (sensitivity 92%, specificity 92%, PPV 92%, NPV 86%). Interpretation of research: Plasma NfL protein levels may be a useful biomarker of unfavorable MRI outcomes in newborns with moderate-severe HIE and may assist in selecting newborns for adjunctive neuroprotective interventions. Larger studies with NfL testing at earlier time points are required. [ABSTRACT FROM AUTHOR]

Hypoxic-ischaemic encephalopathy (HIE) is a major cause of mortality and neurodevelopmental disability, especially in low-income countries. While therapeutic hypothermia has been shown to reduce morbidity and mortality in infants with HIE, some clinical trials in low-income countries have reported an increase in the risk of mortality. We conducted a systematic review and meta-analysis of all randomized and quasi-randomized controlled trials conducted in low-income and lower-middle-income countries that compared cooling therapy with standard care for HIE. Our primary outcome was composite of neonatal mortality and neurodevelopmental disability at 6 months or beyond. The review was registered with PROSPERO (CRD42022352728). Our review included 11 randomized controlled trials with 1324 infants with HIE. The composite of death or disability at 6 months or beyond was lower in therapeutic hypothermia group (RR 0.78, 95% CI 0.66–0.92, I 2 = 85%). Neonatal mortality rate did not differ significantly between cooling therapy and standard care (RR 0.92, 95% CI 0.76–1.13, I 2 = 61%). Additionally, the cooled group exhibited significantly lower rates of neurodevelopmental disability at or beyond 6 months (RR 0.34, 95%CI 0.22–0.52, I 2 = 0%). Our analysis found that neonatal mortality rate did not differ between cooled and noncooled infants in low- and lower-middle-income countries. Cooling may have a beneficial effect on neurodevelopmental disability and the composite of death or disability at 6 months or beyond. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to compare the achievement of target temperature and the short-term neurological outcome according to the use of servo-controlled hypothermia in transport. This is a monocentric retrospective observational before-and-after uncontrolled study of newborns transported for neonatal encephalopathy. The first group was transported from 01/01/2019 to 12/31/2019 in passive hypothermia and the second group from 01/01/2021 to 12/31/2021 in controlled hypothermia. We included patients who had a total of 72 h of servo-controlled therapeutic hypothermia (CTH). We excluded those who had no or less than 72 h of CTH. There were 33 children transported in passive hypothermia in 2019 and 23 children transported in CTH in 2021. There were 9/28 (32%) patients in 2019 who reached the target temperature on arrival at the NICU compared with 20/20 (100%) in 2021 (p value < 0.01). There was a trend towards earlier age of therapeutic hypothermia if started in transport: 3.1 h ± 1.0 vs 4.0 h ± 2.4 for passive hypothermia (p value 0.07). There was no difference in age of arrival in NICU (4.0 h ± 1.2 with CTH vs 3.8 h ± 2.2 without CTH). We found no difference in short-term outcome (survival, abnormal MRI, seizures on EEG) between the two groups. Conclusion: The use of servo-controlled therapeutic hypothermia makes it possible to reach the temperature target, without increasing the age of arrival in the NICU. What is Known: • CTH is rarely used during transport in France even if passive hypothermia rarely reaches temperature target, inducing overcooling and hyperthermia. What is New: • This study shows better temperature control on arrival in the NICU with CTH compared to passive hypothermia, with no increase in arrival time [ABSTRACT FROM AUTHOR]

• We use qEEG analysis to mimic a visual EEG analysis approach in neonatal hypoxic-ischemic encephalopathy. • Machine learning models were developed and validated on two independent EEG datasets. • The proposed model is effective in discriminating neonates requiring therapeutic hypothermia in the first 6 h of life. The study aimed to address the challenge of early assessment of neonatal hypoxic-ischemic encephalopathy (HIE) severity to identify candidates for therapeutic hypothermia (TH). The objective was to develop an automated classification model for neonatal EEGs, enabling accurate HIE severity assessment 24/7. EEGs recorded within 6 h of life after perinatal anoxia were visually graded into 3 severity groups (HIE French Classification) and quantified using 6 qEEG markers measuring amplitude, continuity and frequency content. Machine learning models were developed on a dataset of 90 EEGs and validated on an independent dataset of 60 EEGs. The selected model achieved an overall accuracy of 80.6% in the development phase and 80% in the validation phase. Notably, the model accurately identified 28 out of 30 children for whom TH was indicated after visual EEG analysis, with only 2 cases (moderate EEG abnormalities) not recommended for cooling. The combination of clinically relevant qEEG markers led to the development of an effective automated EEG classification model, particularly suited for the post-anoxic latency phase. This model successfully discriminated neonates requiring TH. The proposed model has potential as a bedside clinical decision support tool for TH. [ABSTRACT FROM AUTHOR]

Background: The main focus of traumatic brain injury (TBI) management is prevention of secondary injury. Therapeutic hypothermia (TH), the induction of a targeted low core body temperature, has been explored as a potential neuroprotectant in TBI. The aim of this article is to synthesize the available clinical data comparing the use of TH with the use of normothermia in TBI. Methods: A systematic search was conducted through MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for randomized clinical trials including one or more outcome of interest associated with TH use in TBI. Independent reviewers evaluated quality of the studies and extracted data on patients with TBI undergoing TH treatment compared with those undergoing normothermia treatment. Pooled estimates, confidence intervals (CIs), and risk ratios (RRs) or odds ratios were calculated for all outcomes. Results: A total of 3,909 patients from 32 studies were eligible for analysis. Pooled analysis revealed a significant benefit of TH on mortality and functional outcome (RR 0.81, 95% CI 0.68–0.96, I2 = 41%; and RR 0.77; 95% CI 0.67–0.88, I2 = 68%, respectively). However, subgroup analysis based on risk of bias showed that only studies with a high risk of bias maintained this benefit. When divided by cooling method, reduced poor functional outcome was seen in the systemic surface cooling and cranial cooling groups (RR 0.68, 95% CI 0.59–0.79, I2 = 35%; and RR 0.44, 95% CI 0.29–0.67, I2 = 0%), and no difference was seen for the systemic intravenous or gastric cooling group. Reduced mortality was only seen in the systemic surface cooling group (RR 0.63, 95% CI 0.53–0.75, I2 = 0%,); however, this group had mostly high risk of bias studies. TH had an increased rate of pneumonia (RR 1.24, 95% CI 1.10–1.40, I2 = 32%), coagulation abnormalities (RR 1.63, 95% CI 1.09–2.44, I2 = 55%), and cardiac arrhythmias (RR 1.78, 95% CI 1.05–3.01, I2 = 21%). Once separated by low and high risk of bias, we saw no difference in these complications in the groups with low risk of bias. Overall quality of the evidence was moderate for mortality, functional outcome, and pneumonia and was low for coagulation abnormalities and cardiac arrhythmias. Conclusions: With the addition of several recent randomized clinical trials and a thorough quality assessment, we have provided an updated systematic review and meta-analysis that concludes that TH does not show any benefit over normothermia in terms of mortality and functional outcome. [ABSTRACT FROM AUTHOR]

Hypoxic‐ischemic encephalopathy (HIE) is a common neurological syndrome in newborns with high mortality and morbidity. Therapeutic hypothermia (TH), which is standard of care for HIE, mitigates brain injury by suppressing anaerobic metabolism. However, more than 40% of HIE neonates have a poor outcome, even after TH. This study aims to provide metabolic biomarkers for predicting the outcomes of hypoxia‐ischemia (HI) after TH using hyperpolarized [1‐13C] pyruvate magnetic resonance spectroscopy. Postnatal day 10 (P10) mice with HI underwent TH at 1 h and were scanned at 6–8 h (P10), 24 h (P11), 7 days (P17), and 21 days (P31) post‐HI on a 14.1‐T NMR spectrometer. The metabolic images were collected, and the conversion rate from pyruvate to lactate and the ratio of lactate to pyruvate in the injured left hemisphere (kPL(L) and Lac/Pyr(L), respectively) were calculated at each timepoint. The outcomes of TH were determined by the assessments of brain injury on T2‐weighted images and behavioral tests at later timepoint. kPL(L) and Lac/Pyr(L) over time between the good‐outcome and poor‐outcome groups and across timepoints within groups were analyzed. We found significant differences in temporal trends of kPL(L) and Lac/Pyr(L) between groups. In the good‐outcome group, kPL(L) increased until P31 with a significantly higher value at P31 compared with that at P10, while the level of Lac/Pyr(L) at P31 was notably higher than those at all other timepoints. In the poor‐outcome group, kPL(L) and Lac/Pyr(L) increased within 24 h. The kPL(L) value at P11 was considerably higher compared with P10. Discrete temporal changes of kPL(L) and Lac/Pyr(L) after TH between the good‐outcome and poor‐outcome groups were seen as early as 24 h after HI, reflecting various TH effects on brain anaerobic metabolism, which may provide insights for early screening for response to TH. [ABSTRACT FROM AUTHOR]

Background: To prevent hypoxic–ischemic brain damage in patients with post-cardiac arrest syndrome (PCAS), international guidelines have emphasized performing targeted temperature management (TTM). However, the most optimal targeted core temperature and cooling duration reached no consensus to date. This study aimed to clarify the optimal targeted core temperature and cooling duration, selected according to the time interval from collapse to return of spontaneous circulation (ROSC) in patients with PCAS due to cardiac etiology. Methods: Between 2014 and 2020, the targeted core temperature was 34 °C or 35 °C, and the cooling duration was 24 h. If the time interval from collapse to ROSC was within 20 min, we performed the 35 °C targeted core temperature (Group A), and, if not, we performed the 34 °C targeted core temperature (Group B). Between 2009 and 2013, the targeted core temperature was 34 °C, and the cooling duration was 24 or 48 h. If the interval was within 20 min, we performed the 24 h cooling duration (Group C), and, if not, we performed the 48 h cooling duration (Group D). Results: The favorable neurological outcome rates at 30 days following cardiac arrest were 45.7% and 45.5% in Groups A + B and C + D, respectively (p = 0.977). In patients with ROSC within 20 min, the favorable neurological outcome rates at 30 days following cardiac arrest were 75.6% and 86.4% in Groups A and C, respectively (p = 0.315). In patients with ROSC ≥ 21 min, the favorable neurological outcome rates at 30 days following cardiac arrest were 29.3% and 18.2% in Groups B and D, respectively (p = 0.233). Conclusions: Selecting the optimal target core temperature and the cooling duration for TTM, according to the time interval from collapse to ROSC, may be helpful in patients with PCAS due to cardiac etiology. [ABSTRACT FROM AUTHOR]

BackgroundTherapeutic hypothermia improves outcomes in experimental stroke models, especially after ischemia-reperfusion injury. In recent years, the safety and efficacy of hypothermia combining thrombolysis or mechanical thrombectomy have attracted widespread attention. The primary objective of the study was to evaluate the effectiveness and safety of hypothermia by combining reperfusion therapy in acute ischemic stroke patients.MethodsA systematic search was performed in PubMed, EMBASE, Cochrane Library, and the Clinical Trial Registries on articles published until May 2024. The full-text articles were thoroughly reviewed, and relevant information regarding study characteristics and outcomes was extracted. Mantel–Haenszel (M–H) random-effects model was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). In addition, subgroup analyses were performed focusing on the different hypothermia modalities and duration.ResultsAfter screening 2,265 articles, 10 studies were included in the present analysis with a total sample size of 785. Forest plots of clinical outcomes were as follows: modified Rankin Scale (mRS) ≤2 at 3 months (RR = 1.28, 95% CI 1.01–1.61, p = 0.04), mortality within 3 months (RR = 0.95, 95% CI 0.69–1.29, p = 0.73), total complications (RR = 1.02, 95% CI 0.89–1.16, p = 0.77) and pneumonia (RR = 1.35, 95% CI 0.76–2.40, p = 0.31). Subgroup analyses indicated a mild protective effect of selective cerebral hypothermia; however, the difference in mortality between the hypothermia and control groups was not statistically significant (RR = 0.88, 95% CI 0.57–1.35, p = 0.55). Patients undergoing hypothermia for 24–48 h experienced a higher rate of overall complications (RR = 1.37, 95% CI 1.01–1.86, p = 0.04) and pneumonia (RR = 2.84, 95% CI 1.05–7.66, p = 0.04).ConclusionThe preliminary evidence supports the safety and feasibility of hypothermia combined with reperfusion therapy, which should be further investigated in randomized controlled studies.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024556625.

Abstract Background Post-cardiac arrest syndrome (PCAS) presents a multifaceted challenge in clinical practice, characterized by severe neurological injury and high mortality rates despite advancements in management strategies. One of the important critical aspects of PCAS is post-arrest lung injury (PALI), which significantly contributes to poor outcomes. PALI arises from a complex interplay of pathophysiological mechanisms, including trauma from chest compressions, pulmonary ischemia–reperfusion (IR) injury, aspiration, and systemic inflammation. Despite its clinical significance, the pathophysiology of PALI remains incompletely understood, necessitating further investigation to optimize therapeutic approaches. Methods This review comprehensively examines the existing literature to elucidate the epidemiology, pathophysiology, and therapeutic strategies for PALI. A comprehensive literature search was conducted to identify preclinical and clinical studies investigating PALI. Data from these studies were synthesized to provide a comprehensive overview of PALI and its management. Results Epidemiological studies have highlighted the substantial prevalence of PALI in post-cardiac arrest patients, with up to 50% of survivors experiencing acute lung injury. Diagnostic imaging modalities, including chest X-rays, computed tomography, and lung ultrasound, play a crucial role in identifying PALI and assessing its severity. Pathophysiologically, PALI encompasses a spectrum of factors, including chest compression-related trauma, pulmonary IR injury, aspiration, and systemic inflammation, which collectively contribute to lung dysfunction and poor outcomes. Therapeutically, lung-protective ventilation strategies, such as low tidal volume ventilation and optimization of positive end-expiratory pressure, have emerged as cornerstone approaches in the management of PALI. Additionally, therapeutic hypothermia and emerging therapies targeting mitochondrial dysfunction hold promise in mitigating PALI-related morbidity and mortality. Conclusion PALI represents a significant clinical challenge in post-cardiac arrest care, necessitating prompt diagnosis and targeted interventions to improve outcomes. Mitochondrial-related therapies are among the novel therapeutic strategies for PALI. Further clinical research is warranted to optimize PALI management and enhance post-cardiac arrest care paradigms. Graphical Abstract

Abstract Background Cerebral blood flow dynamics can be explored through analysis of endothelial frequencies. Our hypothesis posits a disparity in endothelial activity among neonates with perinatal asphyxia, stratified by the presence or absence of neuronal lesions. Methods We conducted a retrospective longitudinal study involving newborns treated with hypothermia for moderate to severe asphyxia. Participants were grouped based on the presence or absence of neuronal damage to investigate temporal endothelial involvement in cerebral blood flow regulation. Regional cerebral oxygen saturation (rScO2) was measured using near-infrared spectroscopy (NIRS), and temporal series were analyzed in the frequency domain, utilizing the original frequency of the INVOS™ device. Results The study included 88 patients, with 53% (47/88) being male and 33% (29/88) demonstrating brain lesions on magnetic resonance imaging. Among them, 86% (76/88) had a gestational age exceeding 37 weeks according to the Ballard scale, and 81% (71/88) had a birth weight exceeding 2500 g. Cohen’s d effect size was calculated to assess differences in endothelial frequency between groups, indicating a small effect size based on cerebral MRI findings (Cohen’s d values for Day 2 = 0.2351 and Day 3 = 0.2325). Conclusion NIRS represents a valuable tool for monitoring cerebral autoregulation in neonates affected by perinatal asphyxia, underscoring the utility of assessing endothelial frequency or energy on rScO2 measured by NIRS using the original INVOS™ device frequency.

The goal of this study was to assess the therapeutic potential of a 5-hour local spinal cord (SC) hypothermia by 4 °C saline on preservation of SC tissue at the injury epicentre and 3 cranial and caudal 10 mm long SC segments in a porcine experimental model of spinal cord injury (SCI). The SCI was inflicted through L3 laminectomy by a metallic rod moved by a velocity of 30 mm.sec−1, and operated by a computer-controlled apparatus. A group of 15 female minipigs 5‒8-month-old weighing 28‒35 kg was randomly divided into 5 subgroups (each composed of 3 animals): 1) sham controls; 2) SCI by force 8N; 3) SCI by force 8N, 5-hour hypothermia; 4) SCI by force 15N; 5) SCI by force 15N, 5-hour hypothermia. After a 9-week survival period, the minipigs were in deep general anaesthesia transcardially perfused by 5000 ml of saline and fixed by 5000 ml 4 % neutral paraformaldehyde. White and grey SC matter damage was evaluated in specimens cut from the epicentre of injury as well as 3 cranial and 3 caudal 10 mm long SC blocks dyed according to Luxol fast blue (LFB) with cresyl violet (CV) protocol for light microscopic observations. The percentage of preserved SC white and grey matter was assessed in microphotographs and compared with data from sham controls (considered 100 %). The data were statistically evaluated by ANOVA test, the difference P ˂ 0.05 was considered significant. Results of the study suggest that 5-hour local cooling of the epicentre of SCI is well tolerated and facilitates the preservation of SC tissue integrity. Additional experimental and preclinical studies are necessary before introducing the method in practice.

Aim: Neonatal encephalopathy remains one of the most significant causes of neonatal morbidity and mortality. The present study compared the risk factors, demographic data, laboratory and imaging findings, and short-term outcomes of two groups of patients. Materials and Methods: A retrospective analysis was conducted on 45 patients who had undergone therapeutic hypothermia (TH) between January 1st, 2021, and August 31st, 2023. According to blood gas parameters; Group 1 (32 patients) met the criteria (pH ≤7.0 and/or base excess BE ≤-16) for TH, while Group 2 (13 patients) did not (pH >7.0, BE >-16, and with an absence of clinical findings). Results: A comparison of the demographic data revealed higher incidences of birth trauma (p=0.046) and neonatal risk (p=0.026) in Group 1 than in Group 2, with no other significant differences. Severe amplitude electroencephalogram (aEEG) abnormalities were more common in Group 1 but one patient of Group 2 displayed moderate abnormality during follow-up. A comparison of all imaging findings [aEEG, transfontanelle ultrasonography (USG), abdominal USG, cranial magnetic resonance imaging, echocardiography] revealed no significant differences (p=0.45). At the end of the follow-up period, 35 patients (77.7%) were discharged, while two (4.4%) patients did not survive (both in Group 1). Upon discharge, all patients in Group 2 exhibited normal neurological examination findings. Conclusion: Re-evaluating the existing criteria for the identification of those infants who may benefit from TH, but who are often deemed ineligible due to incomplete adherence to the treatment criteria, could significantly reduce the mortality and morbidity associated with birth asphyxia.

Background. Currently, therapeutic hypothermia (TH) is the only approved method for treating hypoxic-ischemic encephalopathy (HIE) that helps improve outcomes. However, it also has significant drawbacks, including the necessity for expensive equipment and treatment technologies, poorly understood pathophysiological mechanisms, and, most importantly, not always well-understood long-term results. Numerous scientific studies report the potential benefits of TH, but the actual risk/benefit ratio is still unknown. The results of long-term follow-up of children who underwent TH and did not have serious neuromotor or intellectual disorders are variable. It is believed that the correlation between neonatal neuroimaging and the degree of nervous system impairment remains poorly defined. Chronic brain injuries diagnosed after the neonatal period, such as parenchymal volume loss, appear to be more prognostically significant, which may be reflected by moderate enlargement of the ventricular system of the brain. The method for determining the size of the ventricular system using ultrasound can be accessible for infants of the first year of life who had HIE but do not have direct indications for magne­tic resonance imaging. Therefore, this study aimed to explore the characteristics of the cerebral ventricular system in infants of the first year of life who suffered severe asphyxia at birth, depen­ding on the method of post-resuscitation care (with or without TH). Materials and ­methods. The study examined the results of neurosonographic examinations of 309 infants during their first year of life. Inclusion criteria were gestational age at birth ≥ 36 weeks and birth weight ≥ 2000 g, manifestations of HIE in the early neonatal period without adverse short-term outcomes (at the time of discharge from the neonatal hospital, the children showed no signs of destructive hypoxic-ischemic lesions of the central nervous system (CNS), seizures, or pathological muscle tone, and had full oral feeding). Exclusion criteria were diagnosed congenital CNS abnormalities, neuroinfections, psychomotor development delay of more than 3 months during the first years of life, progressive obstructive ventriculomegaly or ventriculomegaly associated with non-atrophic subarachnomegaly. The children were divided into three groups: hypothermia group — 19 infants who underwent TH after birth; normothermia group — 14 children who conditio­nally had indications for TH but did not undergo it; comparison group — 276 children in their first year of life who did not require TH (Apgar score > 5 at 10 minutes of life, manifestations of mild or moderate HIE (according to the Sarnat scale) during the first days of life). Neurosonographic examinations were conducted at the age of 2–7 months (mean of 2.12 ± 0.07 months). The sizes of the lateral ventricles were assessed in comparison with the results from the control group of infants of the same age (34 healthy children with no recorded factors of complicated perinatal period, no signs of neurological dysfunction during the neonatal period, and the seven-month observation). Enlargement of the lateral ventricles was recorded when the size of the anterior horn or body of the ventricle in the parasagittal projection exceeded the 95th percentile of the corresponding measurements from the control group. Results. Enlargement of the lateral ventricles during the neurosonographic examination was detected in 36.8 % of children in the hypothermia group, 14.3 % in the normothermia group, and 8.0 % of children in the comparison group. Significant differences were registered only when comparing the results of the hypothermia group with the comparison group (p < 0.05, Fisher’s exact test). Significant correlations (p < 0.05) were found between the size of the lateral ventricles and clinical signs such as sleep disturbances, decreased muscle tone in the arms, increased tendon reflexes, delayed motor development, increased muscle tone in a pyramidal pattern, and diffuse muscle hypotonia. Conclusions. Thus, infants who had severe asphyxia at birth and underwent TH significantly more often had enlargement of the cerebral ventri­cular system (versus the comparison group). Therefore, although therapeutic hypothermia improves outcomes for the development of the nervous system in children who have moderate and severe hypoxic-ischemic encephalopathy, brain morphology (particularly the state of the ventricular system) may still be altered in infants during the first year of life. And the presence of significant correlations between the size of the lateral ventricles and clinical signs of neurological dysfunction argues for further clinical monitoring of children after therapeutic hypothermia throughout the first years of life and in the absence of short-term adverse outcomes of HIE or significant delays in psychomotor development during the first year of life.

Objective Hypoxic–ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in neonates. Therapeutic hypothermia (TH) has improved outcomes and mortality in infants with >36 weeks' gestational age (GA) with moderate-to-severe HIE. There are limited data on the safety and efficacy of TH in preterm infants with HIE. This study describes our experience and examines the safety of TH in neonates with <36 weeks' GA. Study Design A single-center, retrospective study of preterm neonates born at <36 weeks' GA with moderate-to-severe HIE and treated with TH, compared to a cohort of term neonates with HIE (≥37 weeks' GA), was conducted. The term cohort was matched for degree of background abnormality on electroencephalogram, sex, inborn versus outborn status, and birth year. Medical records were reviewed for pregnancy and delivery complications, need for transfusion, sedation and antiseizure medications, electroencephalography and imaging findings, and in-hospital mortality. Results Forty-two neonates born at <36 weeks' GA with HIE received TH between 2005 and 2022. Data from 42 term neonates were analyzed for comparison. The average GA of the preterm cohort was 34.6 weeks and 39.3 weeks for the term cohort. Apgar scores, degree of acidosis, and need for blood product transfusions were similar between groups. Preterm infants were more likely to require inotropic support (55 vs. 29%, p = 0.026) and hydrocortisone (36 vs. 12%, p = 0.019) for hypotension. The proportion of infants without evidence of injury on magnetic resonance imaging was similar in both groups: 43 versus 50% in preterm and term infants, respectively. No significant difference was found in mortality between groups. Conclusion In this single-center cohort, TH in preterm infants appears to be as safe as in term infants, with no significant increase in intracranial bleeds or mortality. Preterm infants more frequently required inotropes and steroids for hypotension. Further research is needed to determine efficacy of TH in preterm infants. Key Points TH is used off-protocol in preterm infants. Preterm and term infants have similar mortality. Preterm cohort required more inotropic support. [ABSTRACT FROM AUTHOR]

Clinical trials of hypothermia after pediatric cardiac arrest (CA) have not seen robust improvement in functional outcome, possibly because of the long delay in achieving target temperature. Previous work in infant piglets showed that high nasal airflow, which induces evaporative cooling in the nasal mucosa, reduced regional brain temperature uniformly in half the time needed to reduce body temperature. Here, we evaluated whether initiation of hypothermia with high transnasal airflow provides neuroprotection without adverse effects in the setting of asphyxic CA. Anesthetized piglets underwent sham-operated procedures (n = 7) or asphyxic CA with normothermic recovery (38.5°C; n = 9) or hypothermia initiated by surface cooling at 10 (n = 8) or 120 (n = 7) min or transnasal cooling initiated at 10 (n = 7) or 120 (n = 7) min after resuscitation. Hypothermia was sustained at 34°C with surface cooling until 20 h followed by 6 h of rewarming. At 4 days of recovery, significant neuronal loss occurred in putamen and sensorimotor cortex. Transnasal cooling initiated at 10 min significantly rescued the number of viable neurons in putamen, whereas levels in putamen in other hypothermic groups remained less than sham levels. In sensorimotor cortex, neuronal viability in the four hypothermic groups was not significantly different from the sham group. These results demonstrate that early initiation of high transnasal airflow in a pediatric CA model is effective in protecting vulnerable brain regions. Because of its simplicity, portability, and low cost, transnasal cooling potentially could be deployed in the field or emergency room for early initiation of brain cooling after pediatric CA. NEW & NOTEWORTHY: The onset of therapeutic hypothermia after cardiac resuscitation is often delayed, leading to incomplete neuroprotection. In an infant swine model of asphyxic cardiac arrest, initiation of high transnasal airflow to maximize nasal evaporative cooling produced hypothermia sufficient to provide neuroprotection that was not inferior to body surface cooling. Because of its simplicity and portability, this technique may be of use in the field or emergency room for rapid brain cooling in pediatric cardiac arrest victims. [ABSTRACT FROM AUTHOR]

To investigate the prevalence and associated outcomes of glucose abnormalities in infants with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Glucose values were reviewed in all HIE infants. Pearson's correlation was used to assess the association of hypo- and hyperglycemic episodes with neonatal brain MRI and neurodevelopmental outcomes (NDO) at 12 & 24 months. Of 153 infants included, 31, 56 and 43 had episodes of hypo-, hyperglycemia and combined, respectively. Hyperglycemia and combined hypo/hyper had higher mortality (p = 0.035), seizures (p = 0.009), and longer hospitalization (p = 0.023). Hypo- and hyperglycemia were associated with parenchymal hemorrhages (p = 0.028 & p = 0.027, respectively). Hypoglycemia was associated with restricted diffusion (p = 0.014), while hyperglycemia was associated with cortical injuries (p = 0.045). Each hour of hyper- or hypoglycemia was associated with 5.2–5.8 times unfavorable outcomes (p < 0.001). Blood glucose aberrations were detrimental in HIE infants treated with TH. Optimizing glucose management is crucial in this setting. [ABSTRACT FROM AUTHOR]

Introduction: Numerous nonpharmacological interventions are being investigated for cardioprotective effects among individuals with acute myocardial infarction (MI) who underwent revascularization. However, results of these trials are contradictory. This review aimed to explore the emerging nonpharmacological interventions to prevent myocardial reperfusion injury (RI). Materials and Methods: This review followed Introduction, Methods, Results, Discussion pattern for nonsystematic reviews. Article published form 2015 to November 2023 were retrieved from PubMed, Science direct, and Scopus. Population, Intervention, Comparator, Outcomes, Study design format was used to assess the eligibility of articles where population was ST elevated MI; Intervention was any nonpharmacological interventions such as ischemic postconditioning, therapeutic hypothermia, low level laser therapy (LLLT), remote ischemic conditioning (RIC), and therapeutic hyperoxemia; Comparator can be placebo/sham or control groups, Outcomes were infarct size and cardiac biomarkers and study design can be randomized clinical trials, pre–post experimental studies, etc. Results: 15,889 articles were identified and after duplicate removal and assessing eligibility criteria, 27 articles were included in this review. Out of 27, 7 studies used ischemic post conditioning where only 3 studies revealed improvements in ejection fraction and reduction in cardiac biomarkers; 12 studies employed RIC in which only 2 studies showed improvements in ejection fraction whereas 5 showed reduction in peak cardiac biomarkers, 7 experimental studies used therapeutic hypothermia in which only 1 study showed reduction in infract size postintervention, and one study used LLLT where reduction in cardiac biomarkers was seen postintervention. Conclusion: Ischemic postconditioning and RIC showed significant results on myocardial RI whereas therapeutic hypothermia revealed nonsignificant results in most of the trials and failed to prove its efficacy in preventing Myocardial RI. However, a new intervention LLLT proved to be significantly effective in preventing myocardial RI in one human clinical trial. [ABSTRACT FROM AUTHOR]

Background: Post-cardiac arrest syndrome (PCAS) presents a multifaceted challenge in clinical practice, characterized by severe neurological injury and high mortality rates despite advancements in management strategies. One of the important critical aspects of PCAS is post-arrest lung injury (PALI), which significantly contributes to poor outcomes. PALI arises from a complex interplay of pathophysiological mechanisms, including trauma from chest compressions, pulmonary ischemia–reperfusion (IR) injury, aspiration, and systemic inflammation. Despite its clinical significance, the pathophysiology of PALI remains incompletely understood, necessitating further investigation to optimize therapeutic approaches. Methods: This review comprehensively examines the existing literature to elucidate the epidemiology, pathophysiology, and therapeutic strategies for PALI. A comprehensive literature search was conducted to identify preclinical and clinical studies investigating PALI. Data from these studies were synthesized to provide a comprehensive overview of PALI and its management. Results: Epidemiological studies have highlighted the substantial prevalence of PALI in post-cardiac arrest patients, with up to 50% of survivors experiencing acute lung injury. Diagnostic imaging modalities, including chest X-rays, computed tomography, and lung ultrasound, play a crucial role in identifying PALI and assessing its severity. Pathophysiologically, PALI encompasses a spectrum of factors, including chest compression-related trauma, pulmonary IR injury, aspiration, and systemic inflammation, which collectively contribute to lung dysfunction and poor outcomes. Therapeutically, lung-protective ventilation strategies, such as low tidal volume ventilation and optimization of positive end-expiratory pressure, have emerged as cornerstone approaches in the management of PALI. Additionally, therapeutic hypothermia and emerging therapies targeting mitochondrial dysfunction hold promise in mitigating PALI-related morbidity and mortality. Conclusion: PALI represents a significant clinical challenge in post-cardiac arrest care, necessitating prompt diagnosis and targeted interventions to improve outcomes. Mitochondrial-related therapies are among the novel therapeutic strategies for PALI. Further clinical research is warranted to optimize PALI management and enhance post-cardiac arrest care paradigms. [ABSTRACT FROM AUTHOR]

Aim: Neonatal encephalopathy remains one of the most significant causes of neonatal morbidity and mortality. The present study compared the risk factors, demographic data, laboratory and imaging findings, and short-term outcomes of two groups of patients. Materials and Methods: A retrospective analysis was conducted on 45 patients who had undergone therapeutic hypothermia (TH) between January 1st, 2021, and August 31st, 2023. According to blood gas parameters; Group 1 (32 patients) met the criteria (pH ≤7.0 and/or base excess BE ≤-16) for TH, while Group 2 (13 patients) did not (pH >7.0, BE >-16, and with an absence of clinical findings). Results: A comparison of the demographic data revealed higher incidences of birth trauma (p=0.046) and neonatal risk (p=0.026) in Group 1 than in Group 2, with no other significant differences. Severe amplitude electroencephalogram (aEEG) abnormalities were more common in Group 1 but one patient of Group 2 displayed moderate abnormality during follow-up. A comparison of all imaging findings [aEEG, transfontanelle ultrasonography (USG), abdominal USG, cranial magnetic resonance imaging, echocardiography] revealed no significant differences (p=0.45). At the end of the follow-up period, 35 patients (77.7%) were discharged, while two (4.4%) patients did not survive (both in Group 1). Upon discharge, all patients in Group 2 exhibited normal neurological examination findings. Conclusion: Re-evaluating the existing criteria for the identification of those infants who may benefit from TH, but who are often deemed ineligible due to incomplete adherence to the treatment criteria, could significantly reduce the mortality and morbidity associated with birth asphyxia. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia is the standard treatment for hypoxic-ischemic encephalopathy (HIE), but despite its widespread use, the rates of mortality and neurodevelopmental impairment for moderate to severe HIE remain around 30%. Methylxanthines, such as caffeine and aminophylline, have potential neuroprotective effects in the setting of hypoxic-ischemic injury. However, data on the safety and efficacy of methylxanthines in the setting of therapeutic hypothermia for HIE are limited. This retrospective multicenter study examined in-hospital outcomes in 52 infants with HIE receiving methylxanthines and therapeutic hypothermia. The frequency of mortality and in-hospital morbidities were similar to those of infants enrolled in clinical trials undergoing therapeutic hypothermia without adjunctive therapies. Clinical trials of methylxanthines for neuroprotection in HIE are needed to determine safety and efficacy and should explore optimal dosing and timing of methylxanthine administration. [ABSTRACT FROM AUTHOR]

Hypoxic–ischemic encephalopathy (HIE) is a severe neurological disorder caused by perinatal asphyxia with significant consequences. Early recognition and intervention are crucial, with therapeutic hypothermia (TH) being the primary treatment, but its efficacy depends on early initiation of treatment. Accurately assessing the HIE severity in neonatal care poses challenges, but omics approaches have made significant contribution to understanding its complex pathophysiology. Our study further explores the impact of HIE on the blood metabolome over time and investigated changes associated with hypothermia's therapeutic effects. Using a rat model of hypoxic–ischemic brain injury, we comprehensively analyzed dried blood spot samples for fat-soluble compounds using HPLC-MS. Our research shows significant changes in the blood metabolome after HIE, with a particularly rapid recovery of lipid metabolism observed. Significant changes in lipid metabolites were observed after 3 h of HIE, including increases in ceramides, carnitines, certain fatty acids, phosphocholines, and phosphoethanolamines, while sphingomyelins and N-acylethanolamines (NAEs) decreased (p < 0.05). Furthermore, NAEs were found to be significant features in the OPLS-DA model for HIE diagnosis, with an area under the curve of 0.812. TH showed a notable association with decreased concentrations of ceramides. Enrichment analysis further corroborated these observations, showing modulation in several key metabolic pathways, including arachidonic acid oxylipin metabolism, eicosanoid metabolism via lipooxygenases, and leukotriene C4 synthesis deficiency. Our study reveals dynamic changes in the blood metabolome after HIE and the therapeutic effects of hypothermia, which improves our understanding of the pathophysiology of HIE and could lead to the development of new rapid diagnostic approaches for neonatal HIE. [ABSTRACT FROM AUTHOR]

• Early measurement of GWR values using HCT could predict neurologic outcomes in OHCA survivors. • GWR values show variations in predicting neurologic outcomes based on HIBI severity. • GWR in the moderate group was associated with poor neurologic outcomes. • Early prediction of neurologic outcomes can guide treatment decisions. • GWR measurement is a noninvasive and cost-effective method to predict neurologic outcomes. Hypoxic-ischemic brain injury (HIBI) is a common complication of out-of-hospital cardiac arrest (OHCA). We investigated whether grey-to-white matter ratio (GWR) values, measured using early head computed tomography (HCT), were associated with neurologic outcomes based on the severity of HIBI in survivors of OHCA. This retrospective multicenter study included adult comatose OHCA survivors who underwent an HCT scan within 2 h after the return of spontaneous circulation. HIBI severity was assessed using the revised post-Cardiac Arrest Syndrome for Therapeutic hypothermia (rCAST) scale (low, moderate, and severe). Poor neurologic outcomes were defined as Cerebral Performance Categories 3 to 5 at 6 months after OHCA. Among 354 patients, 27% were women and 224 (63.3%) had poor neurologic outcomes. The distribution of severity was 19.5% low, 47.5% moderate, and 33.1% severe. The area under the receiver operating curves of the GWR values for predicting rCAST severity (low, moderate, and severe) were 0.52, 0.62, and 0.79, respectively. The severe group had significantly higher predictive performance than the moderate group (p = 0.02). Multivariate logistic regression analysis revealed a significant association between GWR values and poor neurologic outcomes in the moderate group (adjusted odds ratio = 0.012, 95% CI 0.0–0.54, p = 0.02). In this cohort study, GWR values measured using early HCT demonstrated variations in predicting neurologic outcomes based on HIBI severity. Furthermore, GWR in the moderate group was associated with poor neurologic outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Therapeutic hypothermia (TH) is widely acknowledged as one of the interventions for preventing hypoxic ischemic brain injury in comatose patients following cardiac arrest (CA). Despite its recognized efficacy, recent debates have questioned its effectiveness. This preclinical study evaluated the impact of TH on brain glucose metabolism, utilizing fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a rat model of CA. Methods: Asphyxia CA was induced in Sprague-Dawley rats using vecuronium. Brain PET images using 18F-FDG were obtained from 21 CA rats, who were randomized to receive either TH or no intervention. Of these, 9 rats in the TH group received hypothermia under general anesthesia and mechanical ventilation for eight hours, while the remaining 12 rats in the non-TH group were observed without intervention. We conducted regional and voxel-based analyses of standardized uptake values relative to the pons (SUVRpons) to compare the two groups. Results: Survival rates were identical in both the TH and non-TH groups (67%). There was no discernible difference in the SUVRpons across the brain cortical regions between the groups. However, in a subgroup analysis of the rats that did not survive (n = 7), those in the TH group (n = 3) displayed significantly higher SUVRpons values across most cortical regions compared to those in the non-TH group (n = 4), with statistical significance after false-discovery rate correction (p < 0.05). Conclusions: The enhancement in SUVRpons due to TH intervention was only observed in the cortical regions of rats with severe encephalopathy that subsequently died. These findings suggest that the beneficial effects of TH on brain glucose metabolism in this asphyxia CA model may be confined to cases of severe ischemic encephalopathy. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) was suggested as a potential target for intervention to mitigate brain injury. However, its neuro-protective effect in post-resuscitation care has not been proven. We investigated the time-course of changes in IL-6 and its association with other markers (systemic inflammation and myocardial and neuronal injury), according to the injury severity of the cardiac arrest. This retrospective study analyzed IL-6 and other markers at baseline and 24, 48, and 72 h after the return of spontaneous circulation. The primary outcome was the association of IL-6 with injury severity as assessed using the revised Post-Cardiac Arrest Syndrome for Therapeutic Hypothermia scoring system (low, moderate, and high severity). Of 111 patients, 22 (19.8%), 61 (55.0%), and 28 (25.2%) had low-, moderate-, and high-severity scores, respectively. IL-6 levels were significantly lower in the low-severity group than in the moderate- and high-severity groups at baseline and at 24 h and 72 h (p < 0.005). While IL-6 was not independently associated with neuronal injury markers in the low-severity group, it was demonstrated to be associated with it in the moderate-severity (β [95% CI] = 4.3 [0.1–8.6], R2 = 0.11) and high-severity (β [95% CI] = 7.9 [3.4–12.5], R2 = 0.14) groups. IL-6 exhibits distinct patterns across severity and shows differential associations with systemic inflammation or neuronal injury. [ABSTRACT FROM AUTHOR]

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The close interaction between neurons and astrocytes has been extensively studied. However, the specific behavior of these cells after ischemia-reperfusion injury and hypothermia remains poorly characterized. A growing body of evidence suggests that mitochondria function and putative transference between neurons and astrocytes may play a fundamental role in adaptive and homeostatic responses after systemic insults such as cardiac arrest, which highlights the importance of a better understanding of how neurons and astrocytes behave individually in these settings. Brain injury is one of the most important challenges in post-cardiac arrest syndrome, and therapeutic hypothermia remains the single, gold standard treatment for neuroprotection after cardiac arrest. In our study, we modeled ischemia-reperfusion injury by using in vitro enhanced oxygen-glucose deprivation and reperfusion (eOGD-R) and subsequent hypothermia (HPT) (31.5 °C) to cell lines of neurons (HT-22) and astrocytes (C8-D1A) with/without hypothermia. Using cell lysis (LDH; lactate dehydrogenase) as a measure of membrane integrity and cell viability, we found that neurons were more susceptible to eOGD-R when compared with astrocytes. However, they benefited significantly from HPT, while the HPT effect after eOGD-R on astrocytes was negligible. Similarly, eOGD-R caused a more significant reduction in adenosine triphosphate (ATP) in neurons than astrocytes, and the ATP-enhancing effects from HPT were more prominent in neurons than astrocytes. In both neurons and astrocytes, measurement of reactive oxygen species (ROS) revealed higher ROS output following eOGD-R, with a non-significant trend of differential reduction observed in neurons. HPT after eOGD-R effectively downregulated ROS in both cells; however, the effect was significantly more effective in neurons. Lipid peroxidation was higher after eOGD-R in neurons, while in astrocytes, the increase was not statistically significant. Interestingly, HPT had similar effects on the reduction in lipoperoxidation after eOGD-R with both types of cells. While glutathione (GSH) levels were downregulated after eOGD-R in both cells, HPT enhanced GSH in astrocytes, but worsened GSH in neurons. In conclusion, neuron and astrocyte cultures respond differently to eOGD-R and eOGD-R + HTP treatments. Neurons showed higher sensitivity to ischemia-reperfusion insults than astrocytes; however, they benefited more from HPT therapy. These data suggest that given the differential effects from HPT in neurons and astrocytes, future therapeutic developments could potentially enhance HPT outcomes by means of neuronal and astrocytic targeted therapies. [ABSTRACT FROM AUTHOR]

Fever control is essential in patients with severe traumatic brain injury (TBI). The efficacy of therapeutic hypothermia (TH) in severe TBI has been investigated over the last few decades; however, in contrast to experimental studies showing benefits, no evidence of efficacy has been demonstrated in clinical practice. In this review, the mechanisms and history of hypothermia were briefly outlined, while the results of major randomized controlled trials (RCTs) and meta-analyses investigating TH for adult TBI were introduced and discussed. The retrieved meta-analyses showed conflicting results, with a limited number of studies indicating the benefits of TH. Some studies have shown the benefits of long-term TH compared with short-term TH. Although TH is effective at lowering elevated intracranial pressure (ICP), reduced ICP does not lead to favorable outcomes. Low-quality RCTs overestimated the benefits of TH, while high-quality RCTs showed no difference or worse outcomes with TH. RCTs assessing standardized TH quality demonstrated the benefits of TH. As TBI has heterogeneous and complicated pathologies, applying a uniform treatment may not be ideal. A meta-analysis of young patients who underwent early cooling and hematoma removal showed better TH results. TH should not be abandoned, and its optimal usage should be advocated on an individual basis. [ABSTRACT FROM AUTHOR]

Therapeutic measures aimed at optimising organ function prior to transplantation—whether by conditioning the donor after determination of brain death or by improving organ preservation after kidney removal—have the potential to enhance outcomes after transplantation. The particular advantage is that, unlike any optimised immunosuppressive therapy, a favourable effect can be achieved without side effects for the organ recipient. In recent years, several such measures have been tested in controlled clinical trials on large patient cohorts following kidney transplantation. Hypothermic pulsatile machine perfusion, in particular, has become the focus of interest, but interventions in the donor prior to organ removal, such as the administration of low-dose dopamine until the start of cold perfusion as an example of conditioning antioxidant therapy and therapeutic donor hypothermia in the intensive care unit after brain death confirmation, have also significantly reduced the frequency of dialysis after transplantation with far less effort and cost. With regard to benefits for graft survival, the database for all procedures is less clear and controversial. The aim of this review article is to re-evaluate the available clinical evidence from large multicentre controlled trials, which have also significantly influenced later meta-analyses, and to assess the significance for use in routine clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To determine the factors associated with the procalcitonin levels in newborns with hypoxic-ischemic encephalopathy (HIE) who received therapeutic hypothermia (TH). Materials and Methods: The neonates, who had moderate/severe HIE and were treated with TH, were included. The neonates were arranged into 2 groups by procalcitonin (PCT) level after rewarming was completed. The neonates who had a procalcitonin level of < 2.5 ng/ml constituted Group 1 and the ones who had a procalcitonin level of ≥ 2.5 ng/ml constituted Group 2. Univariate and multivariate logistic regression was used to assess the factors related with PCT level. Results: The first group included 123 (87.9%) neonates and the second group included 17 (12.1%) neonates. The median gestational age was 38 (36-39) weeks and the mean birth weight was 3081.7 ± 552.8 grams. In group 2, the rates for severe HIE, cesarean section, antibiotic switch, convulsion, inotrope use and mortality were higher, and duration of hospitalization was longer, whereas Apgar scores were lower (P < .05). The risk of a high procalcitonin level was found to be 6-fold (95% CI 1.9-19.1) higher in severe HIE and 5.2-fold higher (95% CI 1.7-16) in cesarean delivery. Conclusion: In neonates with HIE/TH, high post-rewarming procalcitonin levels were related with severe HIE and cesarean delivery. Some other clinical and laboratory findings, which may reflect worse clinical status, were also associated with high procalcitonin levels. [ABSTRACT FROM AUTHOR]

We aimed to develop a risk scoring system as a predictor of 24-month neurodevelopmental outcomes (cognitive, language, and motor) for neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE). This was a chart review of infants with HIE treated with therapeutic hypothermia who were admitted to the Neonatal Intensive Care Unit (NICU) at the University of Michigan between 2009 and 2019 and followed in the neonatal developmental clinic until 24 months of age. We examined bivariate associations between the neonatal characteristics and Bayley-III scores. We then performed stepwise logistic regression. To create the risk scores, a participant was given one point for each of the factors included in the final model. Fifty-five infants were included. The final model for Bayley cognitive abnormality included abnormal neonatal neurologic exam (p < 0.0001), white matter/watershed MRI abnormality (p = 0.01), 5-min Apgar score (p = 0.02), and EEG-confirmed seizures (p = 0.04). The model for language abnormality included abnormal neurologic exam (p = 0.0002), seizures (p = 0.007), clinical severity of HIE (p = 0.06), and basal ganglia/thalamus MRI abnormality (p = 0.17). The model for motor abnormality included seizures (p = 0.03), abnormal neurologic exam (p = 0.06) and basal ganglia/thalamus MRI abnormality (p = 0.02). The positive predictive values for the risk scores were 60 %, 85 % and 71 %, respectively, for the Bayley-III cognitive, language and motor domains. Our study identifies early clinical features that differentially predict domains of neurodevelopmental outcome and associated risk scores that may be of value to both clinicians and families. This novel scoring system should next be validated in a larger, prospective study. [ABSTRACT FROM AUTHOR]

The only current treatment for neonatal hypoxia-ischemia (HI) is therapeutic hypothermia (TH), which still shows some limitations. Specific effects of TH in the several processes involved in brain injury progression remain unclear. In this study, the effects of TH treatment on developmental parameters, behavioral outcomes, and peripheral leukocytes were evaluated in neonatal male and female rats. In P7, animals were submitted to right common carotid artery occlusion followed by hypoxia (8% oxygen). TH was performed by reducing the animal scalp temperature to 32°C for 5 h. Behavioral parameters and developmental landmarks were evaluated. Animals were euthanized at P9 or P21, and cerebral hemispheres, spleen, and thymus were weighed. White blood cells (WBCs) were counted in blood smears. There was a reduction in the weight of the brain hemisphere ipsilateral to the carotid occlusion in HI and TH groups, as well as a reduction in body weight gain and a delay in the opening of the ipsilateral eye. Latency in negative geotaxis was increased by HI at P12. TH did not prevent brain weight loss, developmental impairments, or WBC number changes but prevented negative geotaxis impairment and spleen weight reduction. These data reinforce that a better understanding of the events that occur after HI and TH in both males and females is necessary and would allow the development of more adequate and sex-specific therapeutic approaches. [ABSTRACT FROM AUTHOR]