CXCL10 is a crucial chemoattractant for efficient intranasal delivery of mesenchymal stem cells to the neonatal hypoxic-ischemic brain.

BACKGROUND: Hypoxic-Ischemic Encephalopathy (HIE) is a leading cause of mortality and morbidity in newborns. Recent research has shown promise in using intranasal mesenchymal stem cell (MSC) therapy if administered within 10 days after Hypoxia-Ischemia (HI) in neonatal mice. MSCs migrate from the nasal cavity to the cerebral lesion in response to chemotactic cues. Which exact chemokines are crucial for MSC guidance to the HI lesion is currently not fully understood. This study investigates the role of CXCL10 in MSC migration towards the HI-injured brain. METHODS: HI was induced in male and female 9-day-old C57BL/6 mice followed by intranasal MSC treatment at day 10 or 17 post-HI. CXCL10 protein levels, PKH26-labeled MSCs and lesion size were assessed by ELISA, immunofluorescent imaging and MAP2 staining respectively. At day 17 post-HI, when CXCL10 levels were reduced, intracranial CXCL10 injection and intranasal PKH26-labeled MSC administration were combined to assess CXCL10-guided MSC migration. MSC treatment efficacy was evaluated after 18 days, measuring lesion size, motor outcome (cylinder rearing task), glial scarring (GFAP staining) and neuronal density (NeuN staining) around the lesion. Expression of the receptor for CXCL10, i.e. CXCR3, on MSCs was confirmed by qPCR and Western Blot. Moreover, CXCL10-guided MSC migration was assessed through an in vitro transwell migration assay. RESULTS: Intranasal MSC treatment at day 17 post-HI did not reduce lesion size in contrast to earlier treatment timepoints. Cerebral CXCL10 levels were significantly decreased at 17 days versus 10 days post-HI and correlated with reduced MSC migration towards the brain. In vitro experiments demonstrated that CXCR3 receptor inhibition prevented CXCL10-guided migration of MSCs. Intracranial CXCL10 injection at day 17 post-HI significantly increased the number of MSCs reaching the lesion which was accompanied by repair of the HI lesion as measured by reduced lesion size and glial scarring, and an increased number of neurons around the lesion. CONCLUSIONS: This study underscores the crucial role of the chemoattractant CXCL10 in guiding MSCs to the HI lesion after intranasal administration. Strategies to enhance CXCR3-mediated migration of MSCs may improve the efficacy of MSC therapy or extend its regenerative therapeutic window.

Whole-Body Hypothermia vs Targeted Normothermia for Neonates With Mild Encephalopathy: A Multicenter Pilot Randomized Clinical Trial.

Importance: Although whole-body hypothermia is widely used after mild neonatal hypoxic-ischemic encephalopathy (HIE), safety and efficacy have not been evaluated in randomized clinical trials (RCTs), to our knowledge. Objective: To examine the effect of 48 and 72 hours of whole-body hypothermia after mild HIE on cerebral magnetic resonance (MR) biomarkers. Design, Setting, and Participants: This open-label, 3-arm RCT was conducted between October 31, 2019, and April 28, 2023, with masked outcome analysis. Participants were neonates at 6 tertiary neonatal intensive care units in the UK and Italy born at or after 36 weeks' gestation with severe birth acidosis, requiring continued resuscitation, or with an Apgar score less than 6 at 10 minutes after birth and with evidence of mild HIE on modified Sarnat staging. Statistical analysis was per intention to treat. Interventions: Random allocation to 1 of 3 groups (1:1:1) based on age: neonates younger than 6 hours were randomized to normothermia or 72-hour hypothermia (33.5 °C), and those 6 hours or older and already receiving whole-body hypothermia were randomized to rewarming after 48 or 72 hours of hypothermia. Main Outcomes and Measures: Thalamic N-acetyl aspartate (NAA) concentration (mmol/kg wet weight), assessed by cerebral MR imaging and thalamic spectroscopy between 4 and 7 days after birth using harmonized sequences. Results: Of 225 eligible neonates, 101 were recruited (54 males [53.5%]); 48 (47.5%) were younger than 6 hours and 53 (52.5%) were 6 hours or older at randomization. Mean (SD) gestational age and birth weight were 39.5 (1.1) weeks and 3378 (380) grams in the normothermia group (n = 34), 38.7 (0.5) weeks and 3017 (338) grams in the 48-hour hypothermia group (n = 31), and 39.0 (1.1) weeks and 3293 (252) grams in the 72-hour hypothermia group (n = 36). More neonates in the 48-hour (14 of 31 [45.2%]) and 72-hour (13 of 36 [36.1%]) groups required intubation at birth than in the normothermic group (3 of 34 [8.8%]). Ninety-nine neonates (98.0%) had MR imaging data and 87 (86.1%), NAA data. Injury scores on conventional MR biomarkers were similar across groups. The mean (SD) NAA level in the normothermia group was 10.98 (0.92) mmol/kg wet weight vs 8.36 (1.23) mmol/kg wet weight (mean difference [MD], -2.62 [95% CI, -3.34 to -1.89] mmol/kg wet weight) in the 48-hour and 9.02 (1.79) mmol/kg wet weight (MD, -1.96 [95% CI, -2.66 to -1.26] mmol/kg wet weight) in the 72-hour hypothermia group. Seizures occurred beyond 6 hours after birth in 4 neonates: 1 (2.9%) in the normothermia group, 1 (3.2%) in the 48-hour hypothermia group, and 2 (5.6%) in the 72-hour hypothermia group. Conclusions and Relevance: In this pilot RCT, whole-body hypothermia did not improve cerebral MR biomarkers after mild HIE, although neonates in the hypothermia groups were sicker at baseline. Safety and efficacy of whole-body hypothermia should be evaluated in RCTs. Trial Registration: ClinicalTrials.gov Identifier: NCT03409770.

Quality improvement and outcomes for neonates with hypoxic-ischemic encephalopathy: obstetrics and neonatal perspectives.

Despite significant improvement in perinatal care and research, hypoxic ischemic encephalopathy (HIE) remains a global healthcare challenge. From both published research and reports of QI initiatives, we have identified a number of distinct opportunities that can serve as targets of quality improvement (QI) initiatives focused on reducing HIE. Specifically, (i) implementation of perinatal interventions to anticipate and timely manage high-risk deliveries; (ii) enhancement of team training and communication; (iii) optimization of early HIE diagnosis and management in referring centers and during transport; (iv) standardization of the approach when managing neonates with HIE during therapeutic hypothermia; (v) and establishment of protocols for family integration and follow-up, have been identified as important in successful QI initiatives. We also provide a framework and examples of tools that can be used to support QI work and discuss some of the perceived challenges and future opportunities for QI targeting HIE.

Cerebral rScO2 Measured by Near-Infrared Spectroscopy (NIRS) During Therapeutic Hypothermia in Neonates with Hypoxic-Ischemic Encephalopathy: A Systematic Review.

INTRODUCTION: Perinatal asphyxia, a leading cause of neonatal mortality and neurological sequelae, necessitates early detection of pathophysiological neurologic changes during hypoxic-ischaemic encephalopathy (HIE). This study aimed to review published data on rScO2 monitoring during hypothermia treatment in neonates with perinatal asphyxia to predict short- and long-term neurological injury. METHODS: A systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Study identification was performed through a search between November and December 2021 in the electronic databases PubMed, Embase, Lilacs, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL). The main outcome was short-term (Changes in brain magnetic resonating imaging) and long-term (In neurodevelopment) neurological injury. The study protocol was registered in PROSPERO (International Prospective Register of Systematic Reviews) with CRD42023395438. RESULTS: 380 articles were collected from databases in the initial search. Finally, 15 articles were selected for extraction and analysis of the information. An increase in rScO2 measured by NIRS (Near-infrared spectroscopy) at different moments of treatment predicts neurological injury. However, there exists a wide variability in the methods and outcomes of the studies. CONCLUSION: High rScO2 values were found to predict negative outcomes, with substantial discord among studies. NIRS is proposed as a real-time bedside tool for predicting brain injury in neonates with moderate to severe HIE.

Human Placenta-Derived Mesenchymal Stem Cells Improve Neurological Function in Rats with Intrauterine Hypoxic-Ischaemic Encephalopathy by Reducing Apoptosis and Inflammatory Reactions.

BACKGROUND: Hypoxic-ischaemic encephalopathy (HIE) is a major cause of neonatal disability and mortality. Although hypothermia therapy offers some neuroprotection, the recovery of neurological function is limited. Therefore, new synergistic therapies are necessary to improve the prognosis. Mesenchymal stem cell-based therapy is emerging as a promising treatment option for HIE. In this study, we studied the therapeutic efficacy of human placenta-derived mesenchymal stem cells (PD-MSCs) in the HIE rat model and analyzed the underlying therapeutic mechanisms. METHODS: Rats were divided into 6 groups (n = 9 for each) as follows: control, HIE model, HIE + normal saline, and HIE + PD-MSC transplantation at days 7, 14 and 28 postpartum. Following PD-MSC transplantation, neurological behavior was evaluated using rotarod tests, traction tests, and the Morris water maze test. The degree of brain tissue damage was assessed by histological examination and Nissl staining. Expression levels of apoptosis-related proteins and inflammatory factors were quantified by Western blotting and enzyme-linked immunosorbent assays. Immunofluorescence was used to investigate the ability of PD-MSCs to repair the morphology and function of hippocampal neurons with hypoxic-ischaemic (HI) injury. RESULTS: PD-MSC transplantation enhanced motor coordination and muscle strength in HIE rats. This treatment also improved spatial memory ability by repairing pathological damage and preventing the loss of neurons in the cerebral cortex. The most effective treatment was observed in the HIE + PD-MSC transplantation at day 7 group. Expression levels of microtubule-associated protein-2 (MAP-2), B-cell lymphoma-2 (BCL-2), interleukin (IL)-10, and transforming growth factor (TGF -ß1) were significantly higher in the HIE + PD-MSC treatment groups compared to the HIE group, whereas the levels of BCL-2-associated X protein (BAX), BCL-2-associated agonist of cell death (BAD), IL-1ß and tumour necrosis factor α (TNF-α) were significantly lower. CONCLUSIONS: We demonstrated that intravenous injection of PD-MSC at 7, 14 and 28 days after intrauterine HI damage in a rat model could improve learning, memory, and motor function, possibly by inhibiting apoptosis and inflammatory damage. These findings indicate that autologous PD-MSC therapy could have potential application for the treatment of HIE.

Hypoxic-ischaemic encephalopathy code: A systematic review for resource-limited settings.

It is estimated that 96% of infants with hypoxic-ischaemic encephalopathy (HIE) are born in resource-limited settings with no capacity to provide the standard of care that has been established for nearly 15 years in high-resource countries, which includes therapeutic hypothermia (TH), continuous electroencephalographic monitoring and magnetic resonance imaging (MRI) in addition to close vital signs and haemodynamic monitoring. This situation does not seem to be changing; however, even with these limitations, currently available knowledge can help improve the care of HIE patients in resource-limited settings. The purpose of this systematic review was to provide, under the term "HIE Code", evidence-based recommendations for feasible care practices to optimise the care of infants with HIE and potentially help reduce the risks associated with comorbidity and improve neurodevelopmental outcomes. The content of the HIE code was grouped under 9 headings: (1) prevention of HIE, (2) resuscitation, (3) first 6h post birth, (4) identification and grading of encephalopathy, (5) seizure management, (6) other therapeutic interventions, (7) multiple organ dysfunction, (8) diagnostic tests and (9) family care.

Clinical-functional correlation with brain volumetry in severe perinatal asphyxia: a case report.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) appears in neurological conditions where some brain areas are likely to be injured, such as deep grey matter, basal ganglia area, and white matter subcortical periventricular áreas. Moreover, modeling these brain areas in a newborn is challenging due to significant variability in the intensities associated with HIE conditions. This paper aims to evaluate functional measurements and 3D machine learning models of a given HIE case by correlating the affected brain areas with the pathophysiology and clinical neurodevelopmental. CASE PRESENTATION: A comprehensive analysis of a term infant with perinatal asphyxia using longitudinal 3D brain information from Machine Learning Models is presented. The clinical analysis revealed the perinatal asphyxia diagnosis with APGAR <5 at 5 and 10 minutes, umbilical arterial pH of 7.0 BE of -21.2 mmol / L), neonatal seizures, and invasive ventilation mechanics. Therapeutic interventions: physical, occupational, and language neurodevelopmental therapies. Epilepsy treatment: vagus nerve stimulation, levetiracetam, and phenobarbital. Furthermore, the 3D analysis showed how the volume decreases due to age, exhibiting an increasing asymmetry between hemispheres. The results of the basal ganglia area showed that thalamus asymmetry, caudate, and putamen increase over time while globus pallidus decreases. CLINICAL OUTCOMES: spastic cerebral palsy, microcephaly, treatment-refractory epilepsy. CONCLUSIONS: Slight changes in the basal ganglia and cerebellum require 3D volumetry for detection, as standard MRI examinations cannot fully reveal their complex shape variations. Quantifying these subtle neurodevelopmental changes helps in understanding their clinical implications. Besides, neurophysiological evaluations can boost neuroplasticity in children with neurological sequelae by stimulating new neuronal connections.

Respiratory Distress Syndrome (RDS) in Newborns with Hypoxic-Ischemic Encephalopathy (HIE).

Respiratory distress syndrome (RDS) and hypoxic-ischemic encephalopathy (HIE) are frequent causes of death and disability in neonates. This study included newborns between January 2021 and July 2022 at the University Clinic for Gynecology and Obstetrics, Skopje. Up to date criteria for HIE/RDS for term and for preterm infants as well for the severity of HIE/RDS were used in a comprehensive analysis of cranial ultrasonography, neurological status, neonatal infections, Apgar score, bradycardia and hypotension, X-ray of the lungs, FiO2, acid-base status, assisted ventilation and use of surfactant. Three groups were created: HIE with RDS (42 babies), HIE without RDS (30 babies) and RDS without HIE in 38 neonates. All newborns with severe (third) degree of HIE died. Intracranial bleeding was found in 35.7% in the first group and 30% in the second group, and in the third group in 53.3%. The need for surfactant in the HIE group with RDS is 59.5%, and in the RDS group without HIE 84.2%. DIC associated with sepsis was found in 13.1-50% in those groups. In newborns with HIE and bradycardia, the probability of having RDS was on average 3.2 times higher than in those without bradycardia. The application of the surfactant significantly improved the pH, pO2, pCO2, BE and chest X-ray in children with RDS. An Apgar score less than 6 at the fifth minute increases the risk of RDS by 3 times. The metabolic acidosis in the first 24 hours increases the risk of death by 23.6 times. The combination of HIE/ RDS significantly worsens the disease outcome. The use of scoring systems improved the early detection of high risk babies and initiation of early treatment increased the chances for survival without disabilities.

General movement assessment efficacy for assessment of nervous system integrity in children after hypoxic-ischemic encephalopathy in middle income countries.

BACKGROUND: Many infants who survive hypoxic-ischemic encephalopathy (HIE) face long-term complications like epilepsy, cerebral palsy, and developmental delays. Detecting and forecasting developmental issues in high-risk infants is critical. AIM: This study aims to assess the effectiveness of standardized General Movements Assessment (GMA) and Hammersmith Infant Neurological Examinations (HINE) in identifying nervous system damage and predicting neurological outcomes in infants with HIE. DESIGN: Prospective. SUBJECTS AND MEASURES: We examined full-term newborns with perinatal asphyxia, classifying them as Grade 2 HIE according to Sarnat and Sarnat. The study included 31 infants, with 14 (45.2 %) receiving therapeutic hypothermia (Group 1) and 17 (54.8 %) not (Group 2). We evaluated general movements during writhing and fidgety phases and conducted neurological assessments using the HINE. RESULTS: All infants exhibited cramped-synchronized - like movements, leading to cerebral palsy (CP) diagnosis. Three children in Group 1 and four in Group 2 lacked fidgety movements. During active movements, HINE and GMA showed high sensitivity and specificity, reaching 96 % and 100 % for all children. The ROC curve's area under the curve (AUC) was 0.978. CONCLUSION: Our study affirms HINE and GMA as effective tools for predicting CP in HIE-affected children. GMA exhibits higher sensitivity and specificity during fidgety movements. However, study limitations include a small sample size and data from a single medical institution, necessitating further research.

The role of the sensory input intervention in recovery of the motor function in hypoxic ischemic encephalopathy rat model.

Motor disturbances predominantly characterize hypoxic-ischemic encephalopathy (HIE). Among its intervention methods, environmental enrichment (EE) is strictly considered a form of sensory intervention. However, limited research uses EE as a single sensory input intervention to validate outcomes postintervention. A Sprague-Dawley rat model subjected to left common carotid artery ligation and exposure to oxygen-hypoxic conditions is used in this study. EE was achieved by enhancing the recreational and stress-relief items within the cage, increasing the duration of sunlight, colorful items exposure, and introducing background music. JZL184 (JZL) was administered as neuroprotective drugs. EE was performed 21 days postoperatively and the rats were randomly assigned to the standard environment and EE groups, the two groups were redivided into control, JZL, and vehicle injection subgroups. The Western blotting and behavior test indicated that EE and JZL injections were efficacious in promoting cognitive function in rats following HIE. In addition, the motor function performance in the EE-alone intervention group and the JZL-alone group after HIE was significantly improved compared with the control group. The combined EE and JZL intervention group exhibited even more pronounced improvements in these performances. EE may enhance motor function through sensory input different from the direct neuroprotective effect of pharmacological treatment.NEW & NOTEWORTHY Rarely does literature assess motor function, even though it is common after hypoxia ischemic encephalopathy (HIE). Previously used environmental enrichment (EE) components have not been solely used as sensory inputs. Physical factors were minimized in our study to observe the effects of purely sensory inputs.

Neuroprotective efficacy of hypothermia and Inter-alpha Inhibitor Proteins after hypoxic ischemic brain injury in neonatal rats.

Therapeutic hypothermia is the standard of care for hypoxic-ischemic (HI) encephalopathy. Inter-alpha Inhibitor Proteins (IAIPs) attenuate brain injury after HI in neonatal rats. Human (h) IAIPs (60 â€‹mg/kg) or placebo (PL) were given 15 â€‹min, 24 and 48 â€‹h to postnatal (P) day-7 rats after carotid ligation and 8% oxygen for 90 â€‹min with (30 â€‹°C) and without (36 â€‹°C) exposure to hypothermia 1.5 â€‹h after HI for 3 â€‹h. Hemispheric volume atrophy (P14) and neurobehavioral tests including righting reflex (P8-P10), small open field (P13-P14), and negative geotaxis (P14) were determined. Hemispheric volume atrophy in males was reduced (P â€‹< â€‹0.05) by 41.9% in the normothermic-IAIP and 28.1% in the hypothermic-IAIP compared with the normothermic-PL group, and in females reduced (P â€‹< â€‹0.05) by 30.3% in the normothermic-IAIP, 45.7% in hypothermic-PL, and 55.2% in hypothermic-IAIP compared with the normothermic-PL group after HI. Hypothermia improved (P â€‹< â€‹0.05) the neuroprotective effects of hIAIPs in females. The neuroprotective efficacy of hIAIPs was comparable to hypothermia in female rats (P â€‹= â€‹0.183). Treatment with hIAIPs, hypothermia, and hIAIPs with hypothermia decreased (P â€‹< â€‹0.05) the latency to enter the peripheral zone in the small open field test in males. We conclude that hIAIPs provide neuroprotection from HI brain injury that is comparable to the protection by hypothermia, hypothermia increases the effects of hIAIPs in females, and hIAIPs and hypothermia exhibit some sex-related differential effects.

The effect of hypoxic ischemic encephalopathy towards multi-organ complications and its early outcome at a Malaysian district hospital.

INTRODUCTION: Hypoxic ischemic encephalopathy (HIE) is a clinically defined syndrome of disturbed neurologic function in the newborn with evidence of perinatal asphyxia. Stages of HIE are categorised into mild, moderate or severe based on the Sarnat classification. Neurological dysfunction constitutes a part of the wide spectrum of hypoxic ischemic insult as affected infants can have co-existing multi-organ dysfunction which further contributes to morbidities and mortality. This study aims to determine the relationship between the severity of HIE with multi-organ complications and early clinical outcomes. MATERIALS AND METHODS: All neonates who were admitted to the NICU at Hospital Sultan Abdul Halim between January 2018 to December 2022, who fulfilled the inclusion criteria were included. Demographic data, clinical course and investigation results were retrospectively obtained from the medical records. RESULTS: From a total of 90 infants (n = 90) who fulfilled our inclusion criteria, 31 (34%) were mild, 31 (34%) were moderate and 28 (31%) were severe HIE. The mean maternal age was 27 years. Common antenatal issues include diabetes mellitus (37.8%) and anaemia (22.2%). The Apgar scores at 1 and 5 minutes, initial resuscitation requiring intubation, chest compression and adrenaline were associated with higher severity of HIE (p < 0.05). Coagulation dysfunction was the most common complication (79.7%), followed by respiratory dysfunction (33.3%), cardiac dysfunction (28.9%), renal dysfunction (16.1%), haematological dysfunction (15.6%) and hepatic dysfunction (12%). Respiratory and haematological dysfunctions were significantly associated with higher mortality (p < 0.05). There was a significant longer hospital stay (p = 0.023), longer duration of ventilation (p < 0.001) and increase in frequency of seizures (p < 0.001) when comparing moderate and severe HIE patients to mild HIE patients. With increasing severity of HIE, there was also statistically significant higher mortality (p < 0.001). CONCLUSIONS: There is a significant relationship between multiorgan dysfunction, the severity of HIE and mortality. Early anticipation of multi-organ injury is crucial for optimal early management which would reduce the mortality and improve the neurological outcome of the patients.

Nutrition of Newborns with Hypoxic-Ischaemic Encephalopathy during Therapeutic Hypothermia - A Survey of Practice in Polish Neonatal Care Units.

BACKGROUND: The nutritional practice for newborns with hypoxic-ischaemic encephalopathy during therapeutic hypothermia differs among Polish neonatal care units, as no guidelines are provided. We assessed the prevailing procedures. MATERIAL AND METHODS: Data was collected through an anonymous, web-based questionnaire. We surveyed aspects of the current nutritional practices and the reasoning behind the choice of the feeding strategy. RESULTS: Thirty-one responses were obtained (31/33, 94%). Based on participants' estimations, 342 newborns are diagnosed with hypoxic-ischaemic encephalopathy and qualified for therapeutic hypothermia annually. Among them, almost ⅓ is fed exclusively parenterally, while 71% both ways-parenterally and enterally. In the vast majority of units, the introduction of enteral nutrition takes place during the first 48 hours of therapeutic hypothermia, and breast milk is primarily provided, although with substantial first feeding volume differentiation (an average of 2,9 ml/kg (0,3 - 10ml/kg)). Adverse events, such as necrotising enterocolitis, sepsis, and glycemia level disturbances that derive from the initiation of enteral nutrition, are difficult to estimate as no official statistics are provided. CONCLUSIONS: The majority of newborns after hypoxic-ischaemic encephalopathy treated with therapeutic hypothermia are fed both parenterally and enterally during the procedure, predominantly with expressed or donor breast milk. However, due to the lack of nutritional guidelines, significant variability of nutritional strategies concerning initiation time, type and volume of enteral feeds given is noted. Therefore, further studies are required to clarify feeding recommendations.

Socioemotional and Psychological Outcomes of Hypoxic-Ischemic Encephalopathy: A Systematic Review.

BACKGROUND AND OBJECTIVES: Therapeutic hypothermia has reduced the risk of death or major disability following perinatal hypoxic-ischemic encephalopathy (HIE); however, many children who experience perinatal HIE still go on to develop personal and behavioral challenges, which can be difficult for caregivers and a public health burden for society. Our objective with this review is to systematically identify and synthesize studies that evaluate associations between perinatal HIE and socioemotional or psychological outcomes. METHODS: We screened all search-returned journal articles from Cochrane Library, Embase, Medline, PsycINFO, Scopus, and Web of Science from data inception through February 1, 2023. Keywords related to HIE (eg, neonatal encephalopathy, neonatal brain injury) and outcomes (eg, social*, emotion*, behav* problem, psycholog*, psychiatr*) were searched with a predefined search string. We included all observational human studies reporting socioemotional or psychological sequelae of term HIE. Study data were recorded on standardized sheets, and the Newcastle-Ottawa Scale was adapted to assess study quality. RESULTS: We included 43 studies documenting 3244 HIE participants and 2132 comparison participants. We found statistically significant associations between HIE and social and emotional, behavioral, and psychological and psychiatric deficits throughout infancy, childhood, and adolescence (19 studies). The authors of the included studies also report nonsignificant findings (11 studies) and outcomes without statistical comparison (25 studies). CONCLUSIONS: Perinatal HIE may be a risk factor for a range of socioemotional and psychological challenges in the short- and long-term. Routine screening, early intervention, and follow-up support may be particularly beneficial to this population.

Bone Marrow Nucleated Cells and Bone Marrow-Derived CD271+ Mesenchymal Stem Cell in Treatment of Encephalopathy and Drug-Resistant Epilepsy.

The broad spectrum of brain injuries in preterm newborns and the plasticity of the central nervous system prompts us to seek solutions for neurodegeneration to prevent the consequences of prematurity and perinatal problems. The study aimed to evaluate the safety and efficacy of the implantation of autologous bone marrow nucleated cells and bone marrow mesenchymal stem cells in different schemes in patients with hypoxic-ischemic encephalopathy and immunological encephalopathy. Fourteen patients received single implantation of bone marrow nucleated cells administered intrathecally and intravenously, followed by multiple rounds of bone marrow mesenchymal stem cells implanted intrathecally, and five patients were treated only with repeated rounds of bone marrow mesenchymal stem cells. Seizure outcomes improved in most cases, including fewer seizures and status epilepticus and reduced doses of antiepileptic drugs compared to the period before treatment. The neuropsychological improvement was more frequent in patients with hypoxic-ischemic encephalopathy than in the immunological encephalopathy group. Changes in emotional functioning occurred with similar frequency in both groups of patients. In the hypoxic-ischemic encephalopathy group, motor improvement was observed in all patients and the majority in the immunological encephalopathy group. The treatment had manageable toxicity, mainly mild to moderate early-onset adverse events. The treatment was generally safe in the 4-year follow-up period, and the effects of the therapy were maintained after its termination.

Esophageal Versus Rectal Temperature Monitoring During Whole-Body Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy: Association with Short- and Long-Term Outcomes.

OBJECTIVE: To compare the short- and long-term outcomes of infants with hypoxic-ischemic encephalopathy (HIE) treated with whole-body therapeutic hypothermia (TH), monitored by esophageal vs rectal temperature. STUDY DESIGN: We conducted a secondary analysis of the multicenter High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial. All infants had moderate or severe HIE and were treated with whole-body TH. The primary outcome was death or neurodevelopmental impairment (NDI) at 22-36 months of age. Secondary outcomes included seizures, evidence of brain injury on magnetic resonance imaging, and complications of hypothermia. Logistic regression was used with adjustment for disease severity and site as clustering variable because cooling modality differed by site. RESULTS: Of the 500 infants who underwent TH, 294 (59%) and 206 (41%) had esophageal and rectal temperature monitoring, respectively. There were no differences in death or NDI, seizures, or evidence of injury on magnetic resonance imaging between the 2 groups. Infants treated with TH and rectal temperature monitoring had lower odds of overcooling (OR 0.52, 95% CI 0.34-0.80) and lower odds of hypotension (OR 0.57, 95% CI 0.39-0.84) compared with those with esophageal temperature monitoring. CONCLUSIONS: Although infants undergoing TH with esophageal monitoring were more likely to experience overcooling and hypotension, the rate of death or NDI was similar whether esophageal monitoring or rectal temperature monitoring was used. Further studies are needed to investigate whether esophageal temperature monitoring during TH is associated with an increased risk of overcooling and hypotension.

Altered resting-state functional connectivity in newborns with hypoxic ischemic encephalopathy assessed using high-density functional near-infrared spectroscopy.

Hypoxic-ischemic encephalopathy (HIE) results from a lack of oxygen to the brain during the perinatal period. HIE can lead to mortality and various acute and long-term morbidities. Improved bedside monitoring methods are needed to identify biomarkers of brain health. Functional near-infrared spectroscopy (fNIRS) can assess resting-state functional connectivity (RSFC) at the bedside. We acquired resting-state fNIRS data from 21 neonates with HIE (postmenstrual age [PMA] = 39.96), in 19 neonates the scans were acquired post-therapeutic hypothermia (TH), and from 20 term-born healthy newborns (PMA = 39.93). Twelve HIE neonates also underwent resting-state functional magnetic resonance imaging (fMRI) post-TH. RSFC was calculated as correlation coefficients amongst the time courses for fNIRS and fMRI data, respectively. The fNIRS and fMRI RSFC maps were comparable. RSFC patterns were then measured with graph theory metrics and compared between HIE infants and healthy controls. HIE newborns showed significantly increased clustering coefficients, network efficiency and modularity compared to controls. Using a support vector machine algorithm, RSFC features demonstrated good performance in classifying the HIE and healthy newborns in separate groups. Our results indicate the utility of fNIRS-connectivity patterns as potential biomarkers for HIE and fNIRS as a new bedside tool for newborns with HIE.

Association Between Seizures and Neurodevelopmental Outcome at Two and Five Years in Asphyxiated Newborns With Therapeutic Hypothermia.

OBJECTIVE: To investigate the association between the presence and severity of seizures in asphyxiated newborns and their neurodevelopmental outcome at ages two and five years. METHODS: Retrospective data analysis from a prospectively collected multicenter cohort of 186 term-born asphyxiated newborns undergoing therapeutic hypothermia (TH) in 11 centers in the Netherlands and Belgium. Seizures were diagnosed by amplitude-integrated electroencephalography (EEG) and raw EEG signal reading up to 48 hours after rewarming. Neurodevelopmental outcome was assessed by standardized testing at age two and five years. Primary outcome was death or long-term neurodevelopmental impairment (NDI) including cerebral palsy. Associations were calculated using univariate and multivariate logistic regression analyses adjusting for Thompson score and a validated brain magnetic resonance imaging (MRI) score. RESULTS: Seventy infants (38%) had seizures during TH or rewarming, and 44 (63%) of these needed two or more antiseizure medications (ASMs). Overall mortality was 21%. Follow-up data from 147 survivors were available for 137 infants (93%) at two and for 94 of 116 infants (81%) at five years. NDI was present in 26% at two and five years. Univariate analyses showed a significant association between seizures and death or NDI, but this was no longer significant after adjusting for Thompson and MRI score in the multivariate analysis; this was also true for severe seizures (need for two or more ASMs) or seizures starting during rewarming. CONCLUSION: The presence or severity of seizures in newborns undergoing TH for hypoxic-ischemic encephalopathy was not independently associated with death or NDI up to age five years after adjusting for several confounders.

Asphyxia, Therapeutic Hypothermia, and Pulmonary Hypertension.

Neonates with a perinatal hypoxic insult and subsequent neonatal encephalopathy are at risk of acute pulmonary hypertension (aPH) in the transitional period. The phenotypic contributors to aPH following perinatal asphyxia include a combination of hypoxic vasoconstriction of the pulmonary vascular bed, right heart dysfunction, and left heart dysfunction. Therapeutic hypothermia is the standard of care for neonates with moderate-to-severe hypoxic ischemic encephalopathy. This review summarizes the underlying risk factors, causes of aPH in neonates with perinatal asphyxia, discusses the unique phenotypical contributors to disease, and explores the impact of the initial insult and subsequent therapeutic hypothermia on aPH.

Motor, cognitive and behavioural outcomes after neonatal hypoxic-ischaemic encephalopathy.

INTRODUCTION: The current neurodevelopmental status of patients with neonatal hypoxic-ischaemic encephalopathy (HIE) in Spain is unknown. Recent European studies highlight a shift of severe pathology towards mild motor disorders and emotional problems. The aim of this study was to analyse neurodevelopmental outcomes in a cohort of neonates with HIE at age 3 years. PATIENTS AND METHOD: Multicentre observational study of neonates born at 35 or more weeks of gestation with moderate to severe HIE in 2011-2013 in 12 hospitals in a large Spanish region (91 217 m2), with the recruitment extended through 2017 in the coordinating hospital. We analysed the findings of neonatal neuroimaging and neurodevelopmental test scores at 3 years (Bayley-III, Peabody Picture Vocabulary Test and Child Behavior Checklist). The sample included 79 controls with no history of perinatal asphyxia. RESULTS: Sixty-three patients were recruited, of whom 5 (7.9%) were excluded due to other pathology and 14 (24%) died. Of the 44 survivors, 42 (95.5%) were evaluated. Of these 42, 10 (24%) had adverse outcomes (visual or hearing impairment, epilepsy, cerebral palsy or developmental delay). Other detected problems were minor neurological signs in 6 of the 42 (14%) and a higher incidence of emotional problems compared to controls: introversion (10.5% vs. 1.3%), anxiety (34.2% vs. 11.7%) and depression (28.9% vs. 7.8%) (P < .05). The severity of the lesions on neuroimaging was significantly higher in patients with motor impairment (P = .004) or who died or had an adverse outcome (P = .027). CONCLUSION: In addition to classical sequelae, the followup of patients with neonatal HIE should include the diagnosis and treatment of minor motor disorders and social and emotional problems.