Severe Hypoxic-ischemic Encephalopathy Research Articles

Effects of Therapeutic Hypothermia and Minimal Enteral Nutrition on Short-Term Outcomes in Neonates with Hypoxic–Ischemic Encephalopathy: A 10-Year Experience from Oman

Background: Therapeutic hypothermia (TH) is the standard treatment for moderate to severe hypoxic–ischemic encephalopathy (HIE) in developed countries, but data on its safety and efficacy in low-middle-income countries are limited and often conflicting. The impact of enteral feeding during TH remains inadequately explored. We aimed to examine TH’s effects on mortality and brain injury and evaluate the safety and effectiveness of minimal enteral feeding during TH. Here, we report our single-center experience with TH over a 10-year period”. Methods: A total of 187 neonates with moderate to severe HIE who underwent cooling were included in this retrospective study. Post-rewarming MRI scans were scored using a validated MRI scoring system. The primary outcomes were mortality and composite outcomes of mortality and brain injury. Results: The mortality rate was 3% in moderate and 25% in severe cases (p < 0.001). Overall, 85% (160/187) of neonates received minimal enteral nutrition. Multivariate regression analysis revealed that the severity of HIE at admission (OR 3.4 (1.03–11.6); p < 0.04) and gestational age (OR: 0.624 (0.442–0.882); p < 0.008) were independent predictors of composite outcomes of death and brain injuries. MRI score was a strong predictor of mortality (AUC: 0.89; p < 0.001) and of ability to orally feed at discharge (AUC: 0.73; p < 0.001). Conclusions: Mortality rates associated with TH in infants with moderate–severe HIE align with those in high-income countries, and minimal enteral feeding during TH is safe. The severity of HIE, MRI scores, and feeding status are important predictors of outcomes.

Uneven Distribution of Purkinje Cell Injury in the Cerebellar Vermis of Term Neonates with Hypoxic-Ischemic Encephalopathy.

In term neonates with hypoxic-ischemic encephalopathy (HIE), cerebellar injury is becoming more and more acknowledged. Animal studies demonstrated that Purkinje cells (PCs) are especially vulnerable for hypoxic-ischemic injury. In neonates, however, the extent and pattern of PC injury has not been investigated. The aim of this study was to characterize the morphology and distribution of PCs in the cerebellar vermis of term born neonates with HIE. Twenty-two term born neonates with severe HIE, several of which received therapeutic hypothermia, who underwent post-mortem autopsy of the brain including cerebellar vermis within three to five days after birth were included. Haematoxylin & Eosin (H&E) stained sections of the vermis were used to determine total PC count and morphology (normal, abnormal or non-classified) at the bases and crowns of the folia and of the lobules in both the anterior and posterior lobes. Differences in PC count and PC morphology between the anterior and posterior lobe and between the bases and crowns were compared. The total number of PCs was significantly higher at the crowns compared to the bases (p < 0.001) irrespective of the precise location. Besides, PCs at the bases more often had an abnormal morphology. Also, a significant difference between the injury in the anterior and posterior lobe was observed,notably at specific microscopic locations with more abnormal PCs in the posterior lobe. The number of PCs scored as abnormal was increased in the bases compared to the crowns, which might resemble supratentorial ulegyria.

Acupuncture for hypoxic ischemic encephalopathy in neonates.

Peripartum asphyxia affects three to five per 1000 live births, with moderate or severe hypoxic ischemic encephalopathy (HIE) occurring in 0.5 to 1 per 1000 live births, and is associated with high mortality and morbidity. Therapeutic hypothermia is an effective treatment, but alternative therapies such as acupuncture are also used. To determine the benefits and harms of acupuncture (e.g. needle acupuncture with or without electrical stimulation; laser acupuncture; non-penetrating types of manual or embedded acupressure) on mortality and morbidity in neonates with HIE, compared with 1) no treatment, 2) placebo or sham treatment, 3) any pharmacologic treatment, or 4) different types of acupuncture. We searched CENTRAL, PubMed, Embase, ClinicalTrials.gov, and the WHO ICTRP in March 2023. We conducted a search of the grey literature to identify reports of trials conducted by or referenced in research by CORDIS EU, National Institute for Health and Care Excellence (NICE), and NHSGGC Paediatrics for Health Professionals. We also checked the reference lists of relevant articles to identify additional studies. We included randomized controlled trials (RCTs) or quasi-RCTs and cluster-randomized trials. We included studies where participants were term infants (37 weeks or greater) and late preterm infants (34 + 0 to 36 + 6 weeks' gestation) 10 days of age or less, with evidence of peripartum asphyxia. We included studies on acupuncture (e.g. needle acupuncture with or without electrical stimulation; laser acupuncture; non-penetrating types of manual or embedded acupressure). We included studies where acupuncture was compared with: 1) no treatment; 2) placebo or sham treatment; 3) any pharmacologic treatment; or 4) different types of acupuncture. We used standard Cochrane methods. Our primary outcomes were all-cause mortality at the latest follow-up, major neurodevelopmental disability in children aged 18 to 24 months and aged 3 to 5 years, adverse events until hospital discharge, and length of hospital stay. We included four studies (enrolling 464 infants) that compared acupuncture with no treatment. The studies ranged in size from 60 to 200 infants. Three studies were conducted in China and one in Russia. None of the four studies reported on any of the prespecified outcomes of our review. We did not identify any ongoing studies. There is limited availability of studies addressing this specific population. The included studies did not assess mortality, long-term neurodevelopmental outcomes, or adverse effects of acupuncture. We are unable to draw any conclusions about the benefits and harms of acupuncture for HIE in neonates. In light of the current limitations, clinicians are urged to approach the use of acupuncture in neonates with HIE cautiously, as there is no evidence to support its routine application. The available trials assessed surrogate outcomes that have a relatively small impact on newborns, and failed to report important outcomes such as mortality and long-term neurodevelopmental outcomes. Other available trials were performed on older infants who had experienced neonatal HIE. Given the lack of available evidence, well-designed randomized controlled trials with relevant outcomes such as mortality and neurodevelopmental outcomes are essential to evaluate the efficacy and safety of acupuncture for HIE in neonates.

Predictors of Death or Severe Impairment in Neonates With Hypoxic-Ischemic Encephalopathy

Outcomes after hypoxic-ischemic encephalopathy (HIE) are variable. Predicting death or severe neurodevelopmental impairment (NDI) in affected neonates is crucial for guiding management and parent communication. To predict death or severe NDI in neonates who receive hypothermia for HIE. This prognostic study included participants enrolled in a large US clinical trial conducted in US neonatal intensive care units who were born between January 2017 and October 2019 and followed up to age 2 years. Eligible participants were neonates with moderate-severe HIE born at 36 weeks or more gestation and with 2-year outcome data. Data were analyzed June 2023. External validation was performed with a UK cohort. Clinical, electroencephalography (EEG), and magnetic resonance imaging (MRI) variables were curated and examined at 24 hours and following cooling. Death or severe NDI at age 2 years. Severe NDI was defined as Bayley Scales of Infant Toddler Development cognitive score below 70, Gross Motor Function Classification System score of 3 or higher, or quadriparesis. Model performance metrics were derived from training, internal, and external validation datasets. Among 424 neonates (mean [SD] gestational age, 39.1 [1.4] weeks; 192 female [45.3%]; 28 Asian [6.6%], 50 Black [11.8%], 311 White [73.3%]), 105 (24.7%) had severe encephalopathy at enrollment. Overall, 59 (13.9%) died and 46 (10.8%) had severe NDI. In the 24-hour model, the combined presence of 3 clinical characteristics-(1) severely abnormal EEG, (2) pH level of 7.11 or below, and (3) 5-minute Apgar score of 0-had a specificity of 99.6% (95% CI, 97.5%-100%) and a positive predictive value (PPV) of 95.2% (95% CI, 73.2%-99.3%). Validation model metrics were 97.9% (95% CI, 92.7%-99.8%) for internal specificity, with a PPV of 77.8% (95% CI, 43.4%-94.1%), and 97.6% (95% CI, 95.1%-99.0%) for external specificity, with a PPV of 46.2% (95% CI, 23.3%-70.8%). In the postcooling model, specificity for T1, T2, or diffusion-weighted imaging (DWI) abnormality in at least 2 of 3 deep gray regions (ie, thalamus, caudate, putamen and/or globus pallidus) plus a severely abnormal EEG within the first 24 hours was 99.1% (95% CI, 96.8%-99.9%), with a PPV of 91.7% (95% CI, 72.8%-97.8%). Internal specificity in this model was 98.9% (95% CI, 94.1%-100%), with a PPV of 92.9% (95% CI, 64.2%-99.0%); external specificity was 98.6% (95% CI, 96.5%-99.6%), with a PPV of 83.3% (95% CI, 64.1%-93.4%). In this prognostic study of neonates with moderate or severe HIE who were treated with therapeutic hypothermia, simple models using readily available clinical, EEG, and MRI results during the hospital admission had high specificity and PPV for death or severe NDI at age 2 years.

In-Hospital Outcomes of Neonates with Hypoxic-Ischemic Encephalopathy Receiving Sedation-Analgesia during Therapeutic Hypothermia.

This study aimed to compare magnetic resonance imaging (MRI) severity scores and in-hospital outcomes among neonates with perinatal hypoxic-ischemic encephalopathy (HIE) with and without exposure to sedation-analgesia (SA) during therapeutic hypothermia (TH). A single-center, retrospective cohort study of neonates with perinatal HIE undergoing TH between January 2010 and December 2020. Demographics, clinical characteristics, MRI scores, and in-hospital outcomes were compared between patients without SA exposure and those with SA use. Of the 131 neonates, 55 (42%) did not have SA exposure, and 76 (58%) had SA during TH. Groups were similar in birth weight, gestational age, and severity of HIE. A higher proportion of neonates in the SA group received inhaled nitric oxide (iNO, 39.4% vs. 2%, p < 0.001) and vasopressors (41% vs. 20%, p = 0.012) compared to no SA group. There was no difference in median MRI severity scores for neither T1 (2 [2, 4.25] vs. 3 [2, 6], p = 0.295), T2 (2 [0, 3] vs. 3 [1.5, 5.5], p = 0.088) nor diffusion-weighted images (0 [0, 2] vs. 0 [0, 4.25], p = 0.090) between SA and no SA groups, respectively. In-hospital outcomes were similar between groups except for lower survival to discharge (87% vs. 98%, p = 0.020) in the SA group compared to those without SA. A regression analysis showed death was associated with the concomitant use of iNO (p < 0.001) and inotropes (p < 0.001). SA during TH for perinatal HIE did not alter early MRI severity scores. A lower survival to discharge in the SA group may be related to illness severity rather than SA use alone. · Conflicting studies exist regarding the efficacy of SA use during TH.. · SA use during TH did not alter in-hospital MRI severity scores.. · SA use was associated with a lower survival to discharge, correlated to the severity of illness rather than SA use alone..

Risk Factors and Predictors of Outcomes in Hypoxic-Ischemic Encephalopathy in Neonates.

Background Hypoxic-ischemic encephalopathy (HIE) in neonates results from oxygen deprivation at birth, often leading to long-term neurological issues like cerebral palsy. Early detection is key to improving outcomes, but HIE remains a significant cause of neonatal complications. Here we aimto study the risk factors and predictors of outcome in moderate to severe HIE in inborn Term babies in the neonatal intensive care unit (NICU) Methods This prospective observational study was conducted in the NICUat a tertiary care center between August 2022 and July 2024. Forty term neonates diagnosed with moderate to severe HIE based on clinical and MRI findings were included. The study recorded antepartum, intrapartum, and postnatal risk factors, and neonatal outcomes were followed up. Results In this study of 40 term neonates with HIE, 27 (67.5%) were male, 30 (75%) had a birth weight <2.5 kg, and 27 (67.5%) were delivered by cesarean section. Socioeconomic analysis revealed that 17 (42.5%) were from poor backgrounds. Of the mothers, 12 (30%) were over 30 years oldand 19 (47.5%) used medications. Intrapartum factors included oligohydramnios in 13 (32.5%) and pregnancy-induced hypertension in 10 (25%). Postnatally, 28 (70%) required resuscitation, and 32 (80%) had a cord blood pH ≤7.0. MRI patterns showed 18 (45%) with basal ganglia/thalamus involvement and 22 (55%) with watershed lesions. At discharge, 39 (97.5%) were sent home, with 5 (12.5%) needing anti-seizure medications. No significant associations were found between MRI patterns and muscle tone or seizure activity. Conclusion This study highlights the complex interplay of maternal, intrapartum, and neonatal factors in the development of HIE.Identifying early risk factors is crucial for developing preventive and therapeutic strategies to reduce the burden of HIE-associated disabilities.

Synergistic Clinico-Radiological Assessment of Term Newborns Afflicted by Birth Asphyxia in a Tertiary Medical Center: A Prospective Observational Study.

Background and objectives Hypoxic-ischemic encephalopathy (HIE) remains a critical concern in newborns, with therapeutic hypothermia (TH) serving as a key treatment strategy. However, assessing long-term outcomes requires a comprehensive approach, as children may develop neuropsychological and learning challenges even in the absence of noticeable motor impairments. This study aims to explore the correlation between electroencephalography (EEG) and neuroimaging findings with the clinical severity of HIE. Materials and methods This prospective observational study included a sample of 110 term neonates with birth asphyxia admitted to a medical college-affiliated hospital in Telangana, India. Data were collected on a predesigned Case Record Form by a single investigator through direct interviews with parents, caregivers, and other relevant individuals. Results Among the 110 neonates analyzed, most fell into HIE Grade II (49.1%), delivered predominantly via normal vaginal delivery (61.8%). Common risk factors included prolonged labor (57.3%) and meconium-stained amniotic fluid (42.7%). Serum parameters revealed variations, with significant associations between sodium, potassium, blood urea, blood culture, EEG, and magnetic resonance imaging (MRI) findings and HIE staging. Abnormal EEG (36.4%) and MRI (63.6%) findings correlated significantly with HIE severity. Conclusions The study provides valuable insights into clinico-radiological correlations in term newborns with birth asphyxia, highlighting the diagnostic value of EEG and neuroimaging modalities. Serum parameters and imaging findings showed significant associations with HIE severity, emphasizing the importance of comprehensive assessment in predicting neonatal outcomes. EEG and MRI demonstrated high sensitivity in predicting abnormal neurological conditions at discharge, suggesting their utility in prognostication.

Biochemical profile of term neonates with perinatal asphyxia and their correlation with severity of asphyxia.

Birth asphyxia is a major cause of neonatal mortality and neurological morbidity. This study was aimed to determine biochemical (sodium, potassium, and calcium) abnormalities and their correlation across different severities of perinatal asphyxia in term neonates. This observational analytical study was conducted in term neonates with perinatal asphyxia admitted at the neonatal intensive care unit of a tertiary care centre for a period of 18 months. Blood collection was done at baseline, 24 hours, and 48 hours of treatment to evaluate electrolyte abnormalities. The abnormality in serum electrolytes was correlated across different stages of hypoxic ischaemic encephalopathy (HIE) as per severity and at different time intervals. A total of 74 neonates were included in the study and classified into HIE stage 1 (n = 37), stage 2 (n = 18), and stage 3 (n = 19). At baseline, hyponatremia, hyperkalaemia, and hypocalaemia were observed in 36.5% (n = 27), 20.3% (n = 15), and 10.8% (n = 8), respectively. The difference between mean serum sodium (p: 0.007), potassium (P: 0.004), and calcium levels (p: 0.001) at baseline in stage 1 and stage 3 was statistically significant. The degree of hyponatremia and hyperkalaemia was more and statistically significant as per increasing severity of HIE. All the deaths (n = 6.8.1%) belonged to stage 3 of HIE. The degree of hyponatremia, hypocalaemia, and hyperkalaemia in the asphyxiated newborns correlated with the severity of birth asphyxia. The mortality rate was greater in asphyxiated neonates with severe HIE and electrolyte abnormality. Effective perinatal care and meticulous management of dyselectrolytemia are crucial for improving neonatal outcomes.

Neurodevelopment of Critical ILL Neonates at the Age of 12 Months.

Critically ill neonates who survive are often left with dire consequences. Cerebral palsy, other neurological and motor deficiencies, intellectual disability, and various degrees of cognitive and behavioral deficiencies all result from neonatal critical diseases. We investigated psychomotor development in 20 children with hypoxic-ischemic encephalopathy (HIE), and as newborns often have multiple comorbidities, the following as well: HIE with respiratory distress syndrome (RDS), infections, hypo and hyperglycemia and hypocalcemia. Socio-demographic, pregnancy and delivery data together with appropriate staging tools in determining the severity of HIE or RDS were utilized in this evaluation. In addition, a physical examination, Apgar score, blood gas analyses, biochemical, microbiological and ultrasound data were also part of this study. A child's psychomotor development includes four main areas: motor skills, language, cognition, and social relationships. The Griffiths Mental Development Scale (GMDS) compares different developmental domains and enables early diagnosis of deficiencies and guidance for appropriate early intervention. Six children (30%) were diagnosed with cerebral palsy. GMDS showed that at the age of one year, 50% of the children had typical development, 5% had mild disability, 20% moderate disability and 25% had severe disability. The severity of HIE, Apgar score, weak muscle tone, seizures, disturbances in glucose homeostasis, comorbidities (sepsis, infection) statistically significantly impacted the outcome. Studies with a greater number of patients are needed to support these findings and enable early interventions to avoid severe consequences of critical illness neonates.

Fifteen Years of Neonatal Therapeutic Hypothermia: Clinical Trends Show Unchanged Post-Rewarming Outcomes despite Reduction in Hypoxic-Ischemic Encephalopathy Severity

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).

Incidence of Acute Kidney Injury in Asphyxiated Neonates and Its Relationship with Severity of Hypoxic-Ischemic Encephalopathy: Experience from a Medical College Hospital, Bangladesh.

Background: Perinatal asphyxia (PNA) is one of the leading causes of neonatal morbidity and mortality in Bangladesh. Among others, hypoxic-ischemic encephalopathy and acute kidney injury are two common complications of perinatal asphyxia. Morbidity and mortality increases when PNA is associated with these two complications. Objective: The objectives of the study were to determine the incidence of acute kidney injury (AKI) among asphyxiated neonates associated with various stages of hypoxic-ischemic encephalopathy (HIE) and to find out the relationship between AKI and HIE stages. Materials and Methods: This cross-sectional study was conducted in the neonatal unit of Jalalabad Ragib-Rabeya Medical College Hospital, Sylhet, between the periods of January 2018 and June 2018. A total of 130 newborns admitted in the neonatal ward within 24 hours of age with perinatal asphyxia and hypoxic-ischemic encephalopathy were included in the study by the consecutive sampling method. Serum creatinine level was measured at 24 hours after birth. AKI was considered if serum creatinine level was ³1.5 mg/dL. Result: Among 130 neonates, 35.4% had HIE stage-I, 56.1% had HIE stage-II and 8.5% had HIE stage-III. AKI was present in 12.3% of the asphyxiated neonates. There were no significant relationship between AKI and demographic variables like gender, birth weight, and place of delivery, mode of delivery and parity of the mothers. AKI was significantly associated with HIE stage-II and stage-III compared to HIE stage-I (p=0.02). The mean serum creatinine level was significantly higher in HIE stage-II and stage-III than HIE stage-I (p=0.001). Among the study neonates, 28.5% died. There was no significant relationship between death and AKI (p=0.74). The Pearson correlation test revealed no statistically significant relationship between serum creatinine levels and hospital stay. Conclusion: The incidence of acute kidney injury was 12.3% among asphyxiated newborn associated with HIE. Frequency of AKI significantly associated with severity of HIE. BANGLADESH J CHILD HEALTH 2023; VOL 47 (1) : 24-29

Early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy: a multicentre double-blind pilot randomised controlled trial

ObjectiveTo examine the feasibility of early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy (HIE).DesignDouble-blind pilot randomised controlled trial.SettingEight neonatal units in South Asia.PatientsNeonates (≥36 weeks) with moderate or severe...

If the first child is breech, overall outcomes for families with two children are similar regardless of the mode of the first birth

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.

Therapeutic hypothermia: A descriptive, cohort study conducted over 10 years at a tertiary care public hospital.

Introduction. Therapeutic hypothermia (TH) reduces the risk of death or disability in children with moderate to severe hypoxic ischemic encephalopathy (HIE). Objective. To describe a population of patients with HIE that required TH and their course until discharge. Population and methods. Retrospective, descriptive, cohort study. All patients admitted to TH between 2013 and 2022 were studied. Epidemiological, clinical, monitoring, and treatment data were assessed, together with supplementary tests and condition at discharge. Risk factors were compared between deceased patients and survivors; and, among the latter, those requiring special healthcare needs (SHCN) at discharge. Results. A total of 247 patients were included. Mortality: 11%. Most common sentinel event: prolonged second stage of labor (39%). Treatment initiation: median of 5 hours of life. Seizures: 57%. Intravenous erythropoietin: 66.7%. Abnormal pattern in brain function monitoring: 52%. Normalization of monitoring: median of 24 hours. Pathological magnetic resonance imaging: 42%. Predictor variables of mortality: severe Sarnat and Sarnat staging and pathological ultrasound upon admission. Conclusion. The overall mortality rate was 11%. Referrals increased more markedly since 2018. The time of TH initiation was later than in previous reports. Severe neurological signs as per the Sarnat and Sarnat staging and a pathological baseline cranial ultrasound were independent predictors of mortality at discharge. Patients with SHCN at discharge showed a normalized tracing in the amplitude-integrated electroencephalography performed later. The most common finding in the magnetic resonance imaging was basal ganglia involvement. No statistically significant differences were observed in terms of clinical characteristics or complications among patients who received erythropoietin.

Using autologous umbilical cord blood and placental cells for hypoxic-ischemic encephalopathy: an exploratory safety and feasibility study.

Introduction. Hypoxic-ischemic encephalopathy (HIE) caused by lack of oxygen and perfusion to the brain can lead to acute neurological damage in newborns. Therapeutic hypothermia (TH) is the most effective and safest treatment. However, mortality remains high with numerous long-term sequelae. Cellular therapies, particularly umbilical cord blood (UCB), are being studied as alternative therapies. The aim of this study is to assess the feasibility and safety of combining autologous cord blood cell infusion with moderate hypothermia. Population and methods. Twelve infants of 36 weeks gestational age or older, diagnosed with moderate or severe HIE and with umbilical cord blood (UCB) collected were included. UCB was volume-reduced, and up to four doses were obtained. These doses were infused within the first 72 postnatal hours. Time to the first infusion and possible adverse reactions to the infusion were evaluated. Results. Between 2014 and 2019, 12 infants were included in the protocol (TH + UCB), 9 with a diagnosis of moderate HIE and 3 with severe HIE. In all cases, at least one dose of UCB was obtained for infusion. In all cases, the first dose was infused within 24 hours in every case, and no adverse reactions attributable to the infusion were observed. Conclusions. The collection, processing, and infusion of fresh autologous umbilical cord blood for use in newborns with HIE are feasible and safe under our conditions.

Clinical and prognostic significance of neurosonography of lateral ventricles for infants treated with therapeutic hypothermia during the early neonatal period

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 &gt; 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 &lt; 0.05, Fisher’s exact test). Significant correlations (p &lt; 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.

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

BackgroundNeonatal 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.MethodsA 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.ResultsAmong 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.ConclusionEmergency 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.

LOX-mediated ECM mechanical stress induces Piezo1 activation in hypoxic-ischemic brain damage and identification of novel inhibitor of LOX

Hypoxic-ischemic encephalopathy (HIE) poses a significant challenge in neonatal medicine, often resulting in profound and lasting neurological deficits. Current therapeutic strategies for hypoxia-ischemia brain damage (HIBD) remain limited. Ferroptosis has been reported to play a crucial role in HIE and serves as a potential therapeutic target. However, the mechanisms underlying ferroptosis in HIBD remain largely unclear. In this study, we found that elevated lysyl oxidase (LOX) expression correlates closely with the severity of HIE, suggesting LOX as a potential biomarker for HIE. LOX expression levels and enzymatic activity were significantly increased in HI-induced neuronal models both in vitro and in vivo. Notably, we discovered that HI-induced brain tissue injury results in increased stiffness and observed a selective upregulation of the mechanosensitive ion channel Piezo1 in both brain tissue of HIBD and primary cortex neurons. Mechanistically, LOX increases its catalytic substrates, the Collagen I/III components, promoting extracellular matrix (ECM) remodeling and possibly mediating ECM cross-linking, which leads to increased stiffness at the site of injury and subsequent activation of the Piezo1 channel. Piezo1 senses these stiffness stimuli and then induces neuronal ferroptosis in a GPX4-dependent manner. Pharmacological inhibition of LOX or Piezo1 ameliorated brain neuronal ferroptosis and improved learning and memory impairments. Furthermore, we identified traumatic acid (TA) as a novel LOX inhibitor that effectively suppresses LOX enzymatic activity, mitigating neuronal ferroptosis and promoting synaptic plasticity. In conclusion, our findings elucidate a critical role for LOX-mediated ECM mechanical stress-induced Piezo1 activation in regulating ferroptotic cell death in HIBD. This mechanistic insight provides a basis for developing targeted therapies aimed at ameliorating neurological outcomes in neonates affected by HIBD.

Persistent pulmonary hypertension and short-term neurological outcomes in infants with moderate to severe hypoxic ischemic encephalopathy.

Our aim was to investigate the relationship between persistent pulmonary hypertension of the newborn (PPHN), short-term brain injury or death, and clinical parameters in infants with moderate to severe hypoxic ischemic encephalopathy (HIE). Retrospective single-center cohort study of 274 HIE infants, 230 underwent Therapeutic Hypothermia (TH). Primary outcome was severe HIE brain injury on MRI and/or death within the first month of life in relation to presence and severity of PPHN (clinical or echocardiographic). Secondary outcomes were HIE brain injury pattern, abnormal electroencephalogram (EEG), seizures, clinical, and laboratory differences. A logistic regression model was performed to evaluate PPHN presence and severity as risk factor for brain injury or death. The combined outcome of severe brain injury or death was higher in the clinical PPHN group vs non-PPHN (32.6 vs 22.8%, p = 0.014). There was no difference in brain injury, seizure burden or EEG abnormalities associated with PPHN, despite those with PPHN being sicker with higher ventilation needs and worse laboratory values than those without. Mortality had a strong correlation with echocardiographic PPHN with the highest incidence in severe (36%) vs moderate (7.7%) vs mild PPHN (10%, p = 0.002). Highest mortality had those with 'early exit' who did not complete 72 hours of TH (71.4%). In infants with HIE, PPHN was not associated with increased risk of brain injury as evident on MRI, nor seizure burden, despite being sicker with worse laboratory values. However, mortality rates were higher the worse the PPHN, especially with early exit from TH.

Serum calcium and glucose level in asphyxiated neonates: a prospective study

Background: Birth asphyxia is the primary cause of both mortality and death in newborns. Neonates that experience birth asphyxia are more likely to develop hypocalcemia and hypoglycemia. The primary objective of this study was to assess the calcium and glucose in newborns who had asphyxia and compare with the hypoxic-ischemic encephalopathy (HIE) severity. Methods: This prospective observational study conducted on 75 asphyxiated neonates admitted to NICU. The serum calcium, ionized calcium and glucose level were measured using standard biochemical methods. The severity of HIE was assessed using the Sarnat and Sarnat staging system. The calcium and glucose level were compared across different stages of HIE using one-way ANOVA. Results: The mean total calcium level was 7.87±1.87 mg/dl, mean ionized calcium level was 3.27±0.76 mg/dl and mean serum glucose level was 44.43±6.5 mg/dl respectively. Out of 75 neonates, majority 32 (42.7%) were in were in HIE stage II moderate risk. There was a significant decline in calcium level among the neonate in HIE stage III severe risk when compared to HIE stage II (3.65±0.97 vs 4.05±1.06) and HIE stage I (3.65±0.97 vs 5.76±1.32). The mean serum glucose level was significantly (p=0.001) lower in HIE stage III severe risk when compared to HIE stage II (38.12±4.65 vs 44.76±5.45) and HIE stage I (38.12±4.65 vs 50.43±6.28). Conclusions: The ionic calcium and glucose levels were decreased in asphyxiated neonates and early intervention is required to reduce the neonatal mortality.