Epidural Analgesia During Labor and Neonatal Hypoxic-Ischemic Encephalopathy.

Importance: Epidural analgesia is used by approximately 70% of birthing persons in the US to alleviate labor pain and is a common cause of elevated temperature in the birthing parent during labor, which, in turn, is associated with adverse neonatal outcomes such as hypoxic-ischemic encephalopathy (HIE). Objective: To determine whether epidural analgesia is associated with increased risk of HIE after adjusting for the birthing person's maximal temperature before epidural placement and for the propensity to get an epidural. Design, Setting, and Participants: This retrospective, population-based cohort study was conducted at 15 Kaiser Permanente Northern California hospitals. Participants included singleton neonates born at 35 weeks' or later gestational age between 2012 and 2019. Elective cesarean deliveries and deliveries within 2 hours of hospital admission were excluded. Data analysis was performed from November 2022 to June 2024. Exposure: The primary exposure was epidural analgesia during labor. Main Outcomes and Measures: The primary outcome was HIE, defined as the presence of both neonatal acidosis (ie, pH <7 or base deficit ≥10) and encephalopathy. The presence and timing of epidural analgesia and demographic, pregnancy, and labor characteristics were extracted from electronic medical records. A propensity score for receiving epidural analgesia was created including demographic variables and comorbidities predating epidural placement. Logistic regression was used to evaluate the association between epidural analgesia and HIE, adjusting for maximal birthing parent's temperature before epidural placement and the propensity for receiving an epidural. Results: Among 233 056 infants born at 35 weeks' or later gestational age by vaginal or unplanned cesarean delivery after at least 2 hours of in-hospital labor, 177 603 (76%) were exposed to epidural analgesia and 439 (0.19%) had HIE. On unadjusted analysis, epidural analgesia was associated with an increased risk of maximal temperature greater than 38 °C during labor (risk ratio [RR], 8.58; 95% CI, 8.06-9.14). Each degree increase in maximal temperature during labor was associated with nearly triple the odds of HIE (odds ratio [OR], 2.82; 95% CI, 2.51-3.17). However, there was no significant association between epidural analgesia and the risk of HIE either on crude (RR, 1.21; 95% CI, 0.96-1.53) or adjusted (adjusted OR, 0.93; 95% CI, 0.73-1.17) analyses. Conclusions and Relevance: In this cohort study including more than 230 000 parent-infant dyads, epidural analgesia was associated with increased maximal temperature during labor, a known risk factor for HIE. However, epidural analgesia was not associated with increased odds of HIE.

Activation of the Nrf2/Keap1 signaling pathway mediates the neuroprotective effect of Perillyl alcohol against cerebral hypoxic-ischemic damage in neonatal rats.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe disease with a poor prognosis, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. Perillyl alcohol (POH), a natural monoterpene found in various plant essential oils, has shown neuroprotective properties, though its effects on HIE are not well understood. This study investigates the neuroprotective effects of POH on HIE both in vitro and in vivo. We established an in vitro model using glucose deprivation and hypoxia/reperfusion (OGD/R) in PC12 cells, alongside an in vivo model via the modified Rice-Vannucci method. Results indicated that POH acted as an indirect antioxidant, reducing inducible nitric oxide synthase and malondialdehyde production, maintaining content of antioxidant molecules and enzymes in OGD/R-induced PC12 cells. In vivo, POH remarkably lessened infarct volume, reduced cerebral edema, accelerated tissue regeneration, and blocked reactive astrogliosis after hypoxic-ischemic brain injury. POH exerted antiapoptotic activities through both the intrinsic and extrinsic apoptotic pathways. Mechanistically, POH activated Nrf2 and inactivated its negative regulator Keap1. The use of ML385, a Nrf2 inhibitor, reversed these effects. Overall, POH mitigates neuronal damage in HIE by combating oxidative stress, reducing inflammation, and inhibiting apoptosis via the Nrf2/Keap1 pathway, suggesting its potential for HIE treatment.

Gender-specific association of multiple risk factors with neonatal moderate or severe hypoxic ischemic encephalopathy: a cross-sectional study.

BACKGROUND: Neonatal hypoxic ischemic encephalopathy (HIE) leads to different degrees of neurological sequelae. The incidence of HIE is relatively high, and the causal pathways leading to HIE are still controversial. This study aimed to investigate the risk factors associated with HIE comparing differences between genders. METHODS: A cross-sectional study of 196 neonates diagnosed with HIE was conducted. Based on the severity of clinical findings, HIE was classified as mild, moderate or severe. For mild HIE, the outcomes were relatively less severe, whereas moderate to severe HIE could suffer serious consequences, including death, cerebral palsy, epilepsy. T-test, chi-square test and logistic regression were used to analyze data. RESULTS: Among the 196 neonatal HIE, 39 (19.9%) had mild HIE,157 (80.1%) had moderate or severe HIE. The logistic regression analysis showed that gender was a specific stratified characteristic of moderate or severe HIE. In the male neonates group, emergency cesarean section, abnormal labor stage and amniotic fluid contamination were associated with an increased risk of moderate or severe HIE, where the adjusted odds ratios (ORs) were 4.378 (95% confidence intervals (CI):2.263-6.382), 2.827 (95% CI:1.743-5.196) and 2.653 (95%CI:1.645-3.972), respectively. As expected, a significant additive effect was found in the interactions between emergency cesarean section and abnormal labor stage, as well as between emergency cesarean section and amniotic fluid contamination, where the relative excess risk of interaction was 2.315(95%CI:1.573-3.652) and 1.896(95%CI: 1.337-3.861) respectively. CONCLUSION: Emergency cesarean section, abnormal labor stage and amniotic fluid contamination were risk factors of moderate or severe HIE in neonates, and the associations were significantly correlated with male gender. Notably, coinciding incidences of emergency cesarean section with abnormal labor stage, or emergency cesarean section with amniotic fluid contamination were possibly synergistic in increasing the risk of moderate or severe HIE. These findings may assist clinicians in strengthening their awareness on risks affecting HIE and help reduce the incidence of moderate or severe HIE in clinical practice.

Constraint-Induced Movement Therapy (CIMT) and Neural Precursor Cell (NPC) Transplantation Synergistically Promote Anatomical and Functional Recovery in a Hypoxic-Ischemic Mouse Model.

Cerebral palsy (CP) is a common neurodevelopmental disorder characterized by pronounced motor dysfunction and resulting in physical disability. Neural precursor cells (NPCs) have shown therapeutic promise in mouse models of hypoxic-ischemic (HI) perinatal brain injury, which mirror hemiplegic CP. Constraint-induced movement therapy (CIMT) enhances the functional use of the impaired limb and has emerged as a beneficial intervention for hemiplegic CP. However, the precise mechanisms and optimal application of CIMT remain poorly understood. The potential synergy between a regenerative approach using NPCs and a rehabilitation strategy using CIMT has not been explored. We employed the Rice-Vannucci HI model on C57Bl/6 mice at postnatal day (PND) 7, effectively replicating the clinical and neuroanatomical characteristics of hemiplegic CP. NPCs were transplanted in the corpus callosum (CC) at PND21, which is the age corresponding to a 2-year-old child from a developmental perspective and until which CP is often not formally diagnosed, followed or not by Botulinum toxin injections in the unaffected forelimb muscles at PND23, 26, 29 and 32 to apply CIMT. Both interventions led to enhanced CC myelination and significant functional recovery (as shown by rearing and gait analysis testing), through the recruitment of endogenous oligodendrocytes. The combinatorial treatment indicated a synergistic effect, as shown by newly recruited oligodendrocytes and functional recovery. This work demonstrates the mechanistic effects of CIMT and NPC transplantation and advocates for their combined therapeutic potential in addressing hemiplegic CP.

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OBJECTIVES: To investigate the efficacy of therapeutic hypothermia on mild neonatal hypoxic-ischemic encephalopathy (HIE). METHODS: A prospective study was performed on 153 neonates with mild HIE who were born from September 2019 to September 2023. These neonates were randomly divided into two groups: therapeutic hypothermia (n=77) and non-therapeutic hypothermia group (n=76). The short-term clinical efficacy of the two groups were compared. Barkovich scoring system was used to analyze the severity of brain injury shown on magnetic resonance imaging (MRI) between the two groups. RESULTS: There were no significant differences in gestational age, gender, birth weight, mode of birth, and Apgar score between the therapeutic hypothermia and non-therapeutic hypothermia groups (P>0.05). There were no significant differences in the incidence rates of sepsis, arrhythmia, persistent pulmonary hypertension and pulmonary hemorrhage and the duration of mechanical ventilation within the first 72 hours after birth between the two groups. The therapeutic hypothermia group had longer prothrombin time within the first 72 hours after birth and a longer hospital stay (P<0.05). Compared with the non-therapeutic hypothermia group, the therapeutic hypothermia group had lower incidence rates of MRI abnormalities (30% vs 57%), moderate to severe brain injury on MRI (5% vs 28%), and watershed injury (27% vs 51%) (P<0.05), as well as lower medium watershed injury score (0 vs 1) (P<0.05). CONCLUSIONS: Therapeutic hypothermia can reduce the incidence rates of MRI abnormalities and watershed injury, without obvious adverse effects, in neonates with mild HIE, suggesting that therapeutic hypothermia may be beneficial in neuroprotection in these neonates.

Oxidative and Antioxidative Biomarker Profiles in Neonatal Hypoxic-Ischemic Encephalopathy: Insights for Pathophysiology and Treatment Strategies.

BACKGROUND Neonatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of perinatal and postnatal morbidity and mortality worldwide. Catalase (CAT) activity detection is used to determine levels of inflammation and oxidative stress. Glutathione (GSH) is the most critical non-enzymatic endogenous antioxidant. Lipid peroxidation levels marked after hypoxia can be detected based on the level of malondialdehyde (MDA). Ischemia-modified albumin (IMA) is considered a biomarker for cardiac ischemia and is known to increase in the liver, brain, and kidney in states of insufficient oxygenation. We aimed to explain the results and relations between the oxidant and antioxidants to detail oxidant-antioxidant balance and cellular mechanisms. MATERIAL AND METHODS Serum levels of IMA and MDA, as an oxidative stress marker, and CAT and GSH, as antioxidant enzymes, were measured in first blood samples of 59 neonates diagnosed with HIE, with pH <7, base excess >12, and APGAR scores. RESULTS Neonates who were ≥37 weeks of gestation and had hypoxia were included. Compared with healthy newborns (n=32), CAT was statistically significantly lower in the hypoxia group (P=0.0001), while MDA serum levels were significantly higher in neonates with hypoxia (P=0.01). There was no difference between hypoxic and healthy neonates in GSH and IMA measurements (P=0.054, P=0.19 respectively). CONCLUSIONS HIE pathophysiology involves oxidative stress and mitochondrial energy production failure. Explaining the pathways between oxidant-antioxidant balance and cell death, which explains the pathophysiology of HIE, is essential to develop treatment strategies that will minimize the effects of oxygen deprivation on other body organs, especially the brain.

Therapeutic hypothermia for neonates with hypoxic-ischaemic encephalopathy in low- and lower-middle-income countries: a systematic review and meta-analysis.

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, I2 = 85%). Neonatal mortality rate did not differ significantly between cooling therapy and standard care (RR 0.92, 95% CI 0.76-1.13, I2 = 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, I2 = 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.

Neocortical cholinergic pathology after neonatal brain injury is increased by Alzheimer's disease-related genes in mice.

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

A practical magnetic-resonance imaging score for outcome prediction in comatose cardiac arrest survivors.

AIM: Magnetic Resonance Imaging (MRI) is an important prognostic tool in cardiac arrest (CA) survivors given its sensitivity for detecting hypoxic-ischemic brain injury (HIBI), however, it is limited by poorly defined objective thresholds. To address this limitation, we evaluated a qualitative MRI score for predicting neurological outcome in CA survivors. METHODS: Adult comatose CA survivors who underwent MRI were retrospectively identified at a single academic medical center. Two blinded neurointensivists qualitatively scored HIBI amongst 12 MRI brain regions. Scores were summated to form four distinct score groups: cortex, deep grey nuclei (DGN), cortex-DGN combined, and total (cortex, DGN, brainstem, and cerebellum). Poor neurological outcome was defined as Cerebral Performance Category (CPC) score 3-5 at hospital discharge. Inter-rater reliability was tested using intra-class correlation (ICC) and discrimination of poor neurological outcome assessed using area under the receiver operating curve (AUC). RESULTS: Our cohort included 219 patients with median time to MRI of 96 (IQR 81-110) hours. ICC (95% CI) was good to excellent across all MRI scores: cortex 0.92 (0.89-0.94), DGN 0.88 (0.80-0.92), cortex-DGN 0.94 (0.92-0.95), and total 0.93 (0.91-0.95). AUC (95% CI) for poor outcome was good across all MRI scores: cortex 0.84 (0.78-0.90), DGN 0.83 (0.77-0.89), cortex-DGN 0.83 (0.77-0.89), and total 0.83 (0.77-0.88). CONCLUSION: A simplified, qualitative MRI score had excellent reliability and good discrimination for poor neurologic outcome. Further work is necessary to externally validate our findings in an independent, ideally prospective, cohort.

Neuroprognostication, withdrawal of care and long-term outcomes after cardiopulmonary resuscitation.

PURPOSE OF REVIEW: Survivors of cardiac arrest often have increased long-term risks of mortality and disability that are primarily associated with hypoxic-ischemic brain injury (HIBI). This review aims to examine health-related long-term outcomes after cardiac arrest. RECENT FINDINGS: A notable portion of cardiac arrest survivors face a decline in their quality of life, encountering persistent physical, cognitive, and mental health challenges emerging years after the initial event. Within the first-year postarrest, survivors are at elevated risk for stroke, epilepsy, and psychiatric conditions, along with a heightened susceptibility to developing dementia. Addressing these challenges necessitates establishing comprehensive, multidisciplinary care systems tailored to the needs of these individuals. SUMMARY: HIBI remains the leading cause of disability among cardiac arrest survivors. No single strategy is likely to improve long term outcomes after cardiac arrest. A multimodal neuroprognostication approach (clinical examination, imaging, neurophysiology, and biomarkers) is recommended by guidelines, but fails to predict long-term outcomes. Cardiac arrest survivors often experience long-term disabilities that negatively impact their quality of life. The likelihood of such outcomes implements a multidisciplinary care an integral part of long-term recovery.

FTO-Mediated m6A Modification of FTH1 Inhibits Ferroptosis of Neurons in Neonatal Cerebral Hypoxic Ischemia.

FTO alpha-ketoglutarate dependent dioxygenase (FTO) is aberrantly expressed in brain disorders. However, the roles of FTO in neonatal hypoxic-ischemic brain injury (HIE) are still unclear. This study aims to investigate the potential of FTO in neonatal HIE. Oxygen-glucose deprivation (OGD) was used to establish HIE in vitro. mRNA levels were detected by real-time reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Protein expression was detected by Western blot. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), ferrous iron (Fe2+) and glutathione (GSH) was detected by specific kit. m6A sites were analyzed using SRAMP and further verify by methylated RNA immunoprecipitation (MeRIP) assay. Cell proliferation was determined by Cell Counting Kit-8 (CCK-8) assay. Cell death was determined by propidium iodide (PI) staining. FTO was downregulated in patients with neonatal HIE and OGD-treated neurons. Moreover, FTO mRNA expression was decreased in ferroptosis inducer, especially ferric ammonium citrate (FAC). However, overexpression of FTO inhibited the ferroptosis of neurons. Moreover, FTO-mediated N6-methyladenosine (m6A) modification of ferritin heavy chain 1 (FTH1) suppressed its mRNA expression and stability, inhibiting its protein expression. However, overexpression of FTH1 abrogated the effects of FTO and promoted the ferroptosis of neurons. In summary, FTO functions as a protective role in neonatal HIE via inhibiting FTH1 signaling. Thence, targeting may be a promising strategy for FTO neonatal HIE.

Burst-Suppression EEG Reactivity to Photic Stimulation-A Translational Biomarker in Hypoxic-Ischemic Brain Injury.

The reactivity of an electroencephalogram (EEG) to external stimuli is impaired in comatose patients showing burst-suppression (BS) patterns following hypoxic-ischemic brain injury (HIBI). We explored the reactivity of BS induced by isoflurane in rat models of HIBI and controls using intermittent photic stimulation (IPS) delivered to one eye. The relative time spent in suppression referred to as the suppression ratio (SR) was measured on the contralateral fronto-occipital cortical EEG channel. The BS reactivity (BSR) was defined as the decrease in the SR during IPS from the baseline before stimulation (SRPRE). We found that BSR increased with SRPRE. To standardize by anesthetic depth, we derived the BSR index (BSRi) as BSR divided by SRPRE. We found that the BSRi was decreased at 3 days after transient global cerebral ischemia in rats, which is a model of brain injury after cardiac arrest. The BSRi was also reduced 2 months after experimental perinatal asphyxia in rats, a model of birth asphyxia, which is a frequent neonatal complication in humans. Furthermore, Oxytocin attenuated BSRi impairment, consistent with a neuroprotective effect in this model. Our data suggest that the BSRi is a promising translational marker in HIBI which should be considered in future neuroprotection studies.

2,3-Diphosphoglyceric Acid Alleviating Hypoxic-Ischemic Brain Damage through p38 MAPK Modulation.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a critical condition characterized by significant brain damage due to insufficient blood flow and oxygen delivery at birth, leading to high rates of neonatal mortality and long-term neurological deficits worldwide. 2,3-Diphosphoglyceric acid (2,3-DPG), a small molecule metabolite prevalent in erythrocytes, plays an important role in regulating oxygen delivery, but its potential neuroprotective role in hypoxic-ischemic brain damage (HIBD) has yet to be fully elucidated. Our research reveals that the administration of 2,3-DPG effectively reduces neuron damage caused by hypoxia-ischemia (HI) both in vitro and in vivo. We observed a notable decrease in HI-induced neuronal cell apoptosis, attributed to the downregulation of Bax and cleaved-caspase 3, alongside an upregulation of Bcl-2 expression. Furthermore, 2,3-DPG significantly alleviates oxidative stress and mitochondrial damage induced by oxygen-glucose deprivation/reperfusion (OGD/R). The administration of 2,3-DPG in rats subjected to HIBD resulted in a marked reduction in brain edema and infarct volume, achieved through the suppression of neuronal apoptosis and neuroinflammation. Using RNA-seq analysis, we validated that 2,3-DPG offers protection against neuronal apoptosis under HI conditions by modulating the p38 MAPK pathway. These insights indicated that 2,3-DPG might act as a promising novel therapeutic candidate for HIE.

Dried Blood Spot Metabolome Features of Ischemic-Hypoxic Encephalopathy: A Neonatal Rat Model.

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.

Histone modifications in hypoxic ischemic encephalopathy: Implications for therapeutic interventions.

Hypoxic-ischemic encephalopathy (HIE) is a brain injury induced by many causes of cerebral tissue ischemia and hypoxia. Although HIE may occur at many ages, its impact on the neonatal brain is greater because it occurs during the formative stage. Recent research suggests that histone modifications may occur in the human brain in response to acute stress events, resulting in transcriptional changes and HIE development. Because there are no safe and effective therapies for HIE, researchers have focused on HIE treatments that target histone modifications. In this review, four main histone modifications are explored, histone methylation, acetylation, phosphorylation, and crotonylation, as well as their relevance to HIE. The efficacy of histone deacetylase inhibitors in the treatment of HIE is also explored. In conclusion, targeting histone modifications may be a novel strategy for elucidating the mechanism of HIE, as well as a novel approach to HIE treatment.

Subcortical white matter differences according to presence of disorders of consciousness in hypoxic-ischemic brain injury: a tract-based spatial statistics study.

We investigated differences in subcortical white matter according to the presence disorders of consciousness (DOC) in patients with hypoxic-ischemic brain injury (HI-BI), using tract-based spatial statistics (TBSS). Thirty-two consecutive patients with HI-BI were recruited. The patients were assigned in group A [preserved consciousness (Glasgow Coma Scale: 15 and Coma Recovery Scale-revised (CRS-R): 23, 9 patients)] or group B [DOC present (Glasgow Coma Scale <15 and CRS-R < 23, 20 patients)]. Voxel-wise statistical analysis of fractional anisotropy data was performed by using TBSS as implemented in the FMRIB Software Library. We calculated mean fractional anisotropy values across the white matter skeleton and within 48 regions of interest (ROIs) based on intersections between the skeleton and the probabilistic Johns Hopkins University white matter atlases. Among the 48 ROIs examined, the fractional anisotropy values of two ROIs (the left superior corona radiata, and left tapetum) were significantly lower in group B than in group A ( P  < 0.05). No significant differences were observed, however, in the other 46 ROIs ( P  > 0.05). Our results suggest that abnormalities of the superior corona radiata and tapetum may be critical for DOC presence in patients with HI-BI.

Early automated classification of neonatal hypoxic-ischemic encephalopathy - An aid to the decision to use therapeutic hypothermia.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SIGNIFICANCE: The proposed model has potential as a bedside clinical decision support tool for TH.

Lactate administration causes long-term neuroprotective effects following neonatal hypoxia-ischemia.

Neonatal hypoxia-ischemia (HI) is one of the main causes of mortality and long-term disabilities in newborns, and the only clinical approach to treat this condition is therapeutic hypothermia, which shows some limitations. Thus, putative neuroprotective agents have been tested in animal models of HI. Lactate is a preferential metabolic substrate of the neonatal brain and has already been shown to produce beneficial neuroprotective outcomes in neonatal animals exposed to HI. Here, we administered lactate as a treatment in neonatal rats previously exposed to HI and evaluated the impact of this treatment in adulthood. Seven-day-old (P7) male and female Wistar rats underwent permanent common right carotid occlusion combined with an exposition to a hypoxic atmosphere (8% oxygen) for 60 min. Animals were assigned to one of four experimental groups: HI, HI+LAC, SHAM, SHAM+LAC. Lactate was administered intraperitoneally 30 min and 2 h after hypoxia in HI+LAC and SHAM+LAC groups, whereas HI and SHAM groups received vehicle. Animals were tested in the behavioral tasks of negative geotaxis and righting reflex (P8), cylinder test (P24), and the modified neurological severity score was calculated (P25). Open field (OF), and novel object recognition (NOR) were evaluated in adulthood. Animals were killed at P60, and the brains were harvested and processed to evaluate the volume of brain injury. Our results showed that lactate administration reduced the volume of brain lesion and improved sensorimotor and cognitive behaviors in neonatal, juvenile, and adult life in HI animals from both sexes. Thus, lactate administration might be considered as a potential neuroprotective strategy for the treatment of neonatal HI, which is a prevalent disorder affecting newborns.