Hipotermia terapéutica: estudio descriptivo de una cohorte de 10 años en un hospital público de alta complejidad / Therapeutic hypothermia: A descriptive, cohort study conducted over 10 years at a tertiary care public hospital

Introducción. La hipotermia terapéutica (HT) reduce el riesgo de muerte o discapacidad en niños con encefalopatía hipóxico-isquémica (EHI) moderada-grave. Objetivo. Describir una población de pacientes con EHI que requirió HT y su evolución hasta el alta hospitalaria. Población y métodos. Estudio descriptivo de cohorte retrospectivo. Se analizaron todos los pacientes que ingresaron a HT entre 2013 y 2022. Se evaluaron datos epidemiológicos, clínicos, de monitoreo, tratamiento, estudios complementarios y condición al alta. Se compararon los factores de riesgo entre pacientes fallecidos y sobrevivientes, y de estos, los que requirieron necesidades especiales al alta (NEAS). Resultados. Se incluyeron 247 pacientes. Mortalidad: 11 %. Evento centinela más frecuente: período expulsivo prolongado (39 %). Inicio del tratamiento: mediana 5 horas de vida. Convulsiones: 57 %. Eritropoyetina intravenosa: 66,7 %. Patrón anormal de monitoreo de función cerebral: 52 %. Normalización del monitoreo: mediana 24 horas. Resonancia magnética patológica: 42 %. Variables predictoras de mortalidad: Sarnat y Sarnat grave, y ecografía patológica al ingreso. Conclusión. La mortalidad global fue del 11 %. Las derivaciones aumentaron en forma más evidente a partir del año 2018. El horario de inicio de HT fue más tardío que en reportes anteriores. Los signos neurológicos de gravedad según la escala de Sarnat y Sarnat y la ecografía cerebral basal patológica fueron predictores independientes de mortalidad al alta. Los pacientes con NEAS presentaron normalización del trazado del electroencefalograma de amplitud integrada más tardío. El hallazgo más frecuente en la resonancia fue la afectación de los ganglios basales. No se encontraron diferencias clínicas ni de complicaciones estadísticamente significativas entre los pacientes que recibieron eritropoyetina.

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. / Células autólogas de sangre de cordón umbilical y placenta para la encefalopatía hipóxico isquémica: estudio exploratorio de seguridad y factibilidad.

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.

Introducción. La encefalopatía hipóxico-isquémica (EHI) causada por la falta de oxígeno y/o perfusión al cerebro puede provocar daño neurológico agudo en el recién nacido. La hipotermia terapéutica (HT) es el tratamiento más eficaz y seguro. Sin embargo, la mortalidad sigue siendo alta y con numerosas secuelas a largo plazo. Las terapias celulares y, en particular, la sangre de cordón umbilical (SCU) se estudian como terapias alternativas. El objetivo de este trabajo es evaluar la factibilidad y seguridad de la infusión de células autólogas de la sangre de cordón junto con la hipotermia moderada. Población y métodos. Se incorporaron 12 bebés de 36 semanas o más de gestación con diagnóstico de EHI moderada o grave y que contaban con colecta de SCU. La SCU se redujo en volumen y se obtuvieron hasta 4 dosis, que fueron infundidas en las primeras 72 horas posnatales. Se evaluó el tiempo a la primera infusión y posibles reacciones adversas a la infusión. Resultados. Entre los años 2014 y 2019, 12 bebés fueron incluidos en el protocolo (HT + SCU), 9 con diagnóstico de EHI moderada y 3 con EHI grave. En todos los casos, se obtuvo al menos 1 dosis de SCU para infundir. En todos los casos, fue posible infundir la primera dosis antes de las 24 horas y no hubo reacciones adversas atribuibles a la infusión. Conclusiones. La colecta, preparación e infusión de sangre de cordón umbilical autóloga fresca para su uso en recién nacidos con EHI es factible y segura en nuestras condiciones.

Prognostic Indicators of Reorientation of Care in Perinatal Hypoxic-Ischemic Encephalopathy Spectrum.

OBJECTIVE: To investigate the clinical, electrographic, and neuroimaging characteristics in neonates with perinatal hypoxic-ischemic encephalopathy who underwent reorientation of care using standardized scoring systems. STUDY DESIGN: A nested observational substudy within a prospective hypoxic-ischemic encephalopathy cohort was conducted. Group 1 comprised infants whose parents received the medical recommendation for reorientation of care, while group 2 continued to receive standard care. Encephalopathy scores were monitored daily. Amplitude-integrated and continuous-video-integrated electroencephalogram during therapeutic hypothermia were analyzed. Standardized scoring systems for cranial ultrasonography and postrewarming brain magnetic resonance imaging were deployed. RESULTS: The study included 165 infants, with 35 in group 1 and 130 in Group 2. By day 3, all infants in group 1 were encephalopathic with higher Thompson scores (median 13 [IQR 10-19] vs 0 [IQR 0-3], P < .001). Electrographic background normalization within 48 hours occurred in 3% of group 1 compared with 46% of group 2 (P < .001). Sleep-wake cycling was not observed in group 1 and emerged in 63% of group 2 within the first 72 hours (P < .001). The number of antiseizure medications received was higher in group 1 (median 3 [IQR, 2-4] vs 0 [IQR, 0-1], respectively; P < .001). Group 1 had higher cranial ultrasound injury scores (median 4 [IQR 2-7] vs 1 [IQR 0-1], P < .001) within 48 hours and postrewarming brain magnetic resonance imaging injury scores (median 33 [range 20-51] vs 4 [range 0-28], P < .001). CONCLUSIONS: Neonates with perinatal hypoxic-ischemic encephalopathy who underwent reorientation of care presented with and maintained significantly more pronounced clinical manifestations, electrographic findings, and near-total brain injury as scored objectively on all modalities. TRIAL REGISTRATION: Registration of the study cohort: NCT04913324.

Hypoxic ischemic encephalopathy (HIE).

Introduction: The morbidity and mortality of acute ischemic hypoxic encephalopathy in newborns have not been dramatically modified over the last 20 years. The purpose of this review is to describe the use of hyperbaric oxygenation therapy (HBOT) in the management of acute ischemic hypoxic encephalopathy in newborns. Methods: A review of the medical literature was conducted on the use of HBOT in the pathophysiology of this condition and its impact on outcomes of patients treated at an early stage. Results: When HBOT is administered promptly, it can promote the survival of the penumbra, modulate the cytokine storm, modify inflammatory cascades, restore mitochondrial function, inhibit apoptosis, reinstate cellular communication and cytoskeleton function, reinstall the functioning of the kinase system, reduce cytotoxic and tissue edema, promote microcirculation, and provide an antioxidant effect. All these secondary mechanisms aid in saving, rescuing, and protecting the marginal tissue. Conclusion: When used promptly, HBOT is a non-invasive adjunct treatment that can preserve the marginal tissue affected by ischemia, hypoxia, meet the metabolic needs of the penumbra, reduce inflammatory cascades, prevent the extension of the damaged tissue, and modulate ischemia-reperfusion injury.

Practice Variations for Therapeutic Hypothermia in Neonates with Hypoxic-ischemic Encephalopathy: An International Survey.

OBJECTIVE: To evaluate variations in management of therapeutic hypothermia (TH) for neonatal hypoxic-ischemic encephalopathy (HIE) among international clinical sites and to identify areas for harmonization. STUDY DESIGN: An electronic survey was sent to Children's Hospitals Neonatal Consortium site sponsors, Canadian Neonatal Network site investigators, members of the Newborn Brain Society, and American Academy of Pediatrics Neonatology chiefs. RESULTS: One hundred five sites responded, with most from high-income regions (n = 95). Groupings were adapted from the United Nations regional groups: US (n = 52 sites); Canada (n = 20); Western Europe and other states excluding Canada and US Group (WEOG, n = 18); and non-WEOG (central and eastern Europe, Asia, Africa, Latin America, and Caribbean, n = 15). Regional variations were seen in the eligibility criteria for TH, such as the minimum gestational age, grading of HIE severity, use of electroencephalography, and the frequency of providing TH for mild HIE. Active TH during transport varied among regions and was less likely in smaller volume sites. Amplitude-integrated electroencephalogram and/or continuous electroencephalogram to determine eligibility for TH was used by most sites in WEOG and non-WEOG but infrequently by the US and Canada Groups. For sedation during TH, morphine was most frequently used as first choice but there was relatively high (33%) use of dexmedetomidine in the US Group. Timing of brain magnetic resonance imaging and neurodevelopmental follow-up were variable. Neurodevelopmental follow occurred earlier and more frequently, although for a shorter duration, in the non-WEOG. CONCLUSIONS: We found significant variations in practices for TH for HIE across regions internationally. Future guidelines should incorporate resource availability in a global perspective.

Oral Clonidine-Based Strategy to Reduce Opiate Use During Cooling for Neonatal Encephalopathy: An Observational Study.

OBJECTIVE: To determine whether an enteral, clonidine-based sedation strategy (CLON) during therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy would decrease opiate use while maintaining similar short-term safety and efficacy profiles to a morphine-based strategy (MOR). STUDY DESIGN: This was a single-center, observational study conducted at a level IV neonatal intensive care unit from January 1, 2017, to October 1, 2021. From April 13, 2020, to August 13, 2020, we transitioned from MOR to CLON. Thus, patients receiving TH for hypoxic-ischemic encephalopathy were grouped to MOR (before April 13, 2020) and CLON (after August 13, 2020). We calculated the total and rescue morphine milligram equivalent/kg (primary outcome) and frequency of hemodynamic changes (secondary outcome) for both groups. RESULTS: The MOR and CLON groups (74 and 25 neonates, respectively) had similar baseline characteristics and need for rescue sedative intravenous infusion (21.6% MOR and 20% CLON). Both morphine milligram equivalent/kg and need for rescue opiates (combined bolus and infusions) were greater in MOR than CLON (P < .001). As days in TH advanced, a lower percentage of patients receiving CLON needed rescue opiates (92% on day 1 to 68% on day 3). Patients receiving MOR received a greater cumulative dose of dopamine and more frequently required a second inotrope and hydrocortisone for hypotension. MOR had a lower respiratory rate during TH (P = .01 vs CLON). CONCLUSIONS: Our CLON protocol is noninferior to MOR, maintaining perceived effectiveness and hemodynamic safety, with an apparently reduced need for opiates and inotropes.

Defining the Typical Course of Persistent Pulmonary Hypertension of the Newborn: When to Think Beyond Reversible Causes.

OBJECTIVES: To describe the typical clinical course of reversible persistent pulmonary hypertension of the newborn (PPHN) from perinatal etiologies and compare that with the clinical course of PPHN due to underlying fetal developmental etiologies. STUDY DESIGN: This was a single-center, retrospective cohort study of liveborn newborns either born or transferred to our facility for higher level of care between 2015 and 2020 with gestational age ≥35 weeks and a clinical diagnosis of PPHN in the electronic health record. Newborns with complex congenital heart disease and congenital diaphragmatic hernia were excluded. Using all data available at time of collection, newborns were stratified into 2 groups by PPHN etiology - perinatal and fetal developmental causes. Primary outcomes were age at initiation, discontinuation, and total duration of extracorporeal life support, mechanical ventilation, supplemental oxygen, inhaled nitric oxide, inotropic support, and prostaglandin E1. Our secondary outcome was age at echocardiographic resolution of pulmonary hypertension. Groups were compared by t-test. Time-to-event Kaplan Meier curves described and compared (log-rank test) discontinuation of each therapy. RESULTS: Sixty-four (72%) newborns had perinatal etiologies whereas 24 (28%) had fetal developmental etiologies. The resolution of perinatal PPHN was more rapid compared with fetal developmental PPHN. By 10 days of age, more neonates were off inotropes (98% vs 29%, P < .01), decannulated from extracorporeal life support (100% vs 0%, P < .01), extubated (75% vs 37%, P < .01), and had echocardiographic resolution of PH (35% vs 7%, P = .02). CONCLUSIONS: An atypical PPHN course, characterized by persistent targeted therapies in the second week of life, warrants further work-up for fetal developmental causes.

Therapeutic hypothermia: A descriptive, cohort study conducted over 10 years at a tertiary care public hospital. / Hipotermia terapéutica: estudio descriptivo de una cohorte de 10 años en un hospital público de alta complejidad.

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.

Introducción. La hipotermia terapéutica (HT) reduce el riesgo de muerte o discapacidad en niños con encefalopatía hipóxico-isquémica (EHI) moderada-grave. Objetivo. Describir una población de pacientes con EHI que requirió HT y su evolución hasta el alta hospitalaria. Población y métodos. Estudio descriptivo de cohorte retrospectivo. Se analizaron todos los pacientes que ingresaron a HT entre 2013 y 2022. Se evaluaron datos epidemiológicos, clínicos, de monitoreo, tratamiento, estudios complementarios y condición al alta. Se compararon los factores de riesgo entre pacientes fallecidos y sobrevivientes, y de estos, los que requirieron necesidades especiales al alta (NEAS). Resultados. Se incluyeron 247 pacientes. Mortalidad: 11 %. Evento centinela más frecuente: período expulsivo prolongado (39 %). Inicio del tratamiento: mediana 5 horas de vida. Convulsiones: 57 %. Eritropoyetina intravenosa: 66,7 %. Patrón anormal de monitoreo de función cerebral: 52 %. Normalización del monitoreo: mediana 24 horas. Resonancia magnética patológica: 42 %. Variables predictoras de mortalidad: Sarnat y Sarnat grave, y ecografía patológica al ingreso. Conclusión. La mortalidad global fue del 11 %. Las derivaciones aumentaron en forma más evidente a partir del año 2018. El horario de inicio de HT fue más tardío que en reportes anteriores. Los signos neurológicos de gravedad según la escala de Sarnat y Sarnat y la ecografía cerebral basal patológica fueron predictores independientes de mortalidad al alta. Los pacientes con NEAS presentaron normalización del trazado del electroencefalograma de amplitud integrada más tardío. El hallazgo más frecuente en la resonancia fue la afectación de los ganglios basales. No se encontraron diferencias clínicas ni de complicaciones estadísticamente significativas entre los pacientes que recibieron eritropoyetina.

Involvement of SIRT1 and SIRT3 in Effects of Hypoxic Hypobaric Preconditioning on Hippocampal Damage Induced by Chronic Cerebral Hypoperfusion in C57/6j and a7nAchRs(-/-) Mice / Participación de SIRT1 y SIRT3 en los Efectos del Precondicionamiento Hipobárico Hipóxico sobre el Daño del Hipocampo Inducido por Hipoperfusión Cerebral Crónica en Ratones C57/6j y a7nAchRs (-/-)

SUMMARY: Hypoxic preconditioning is known to induce neuroprotection, but its effects and pathways in chronic brain pathology still unknown. The aim was to establish an involvement of a7 subunit of nicotinic acetylcholine receptors (a7nAchRs), and sirtuins of 1 (SIRT1) and 3 (SIRT3) types in the effects of hypoxic hypobaric preconditioning on brain damage in mice with chronic cerebral hypoperfusion caused by the left common carotid artery occlusion. The male C57/6j (C57, wild type) and a7nAchRs(-/-) mice were divided to six experimental groups (10 mice per group): sham-operated C57, C57 with chronic cerebral hypoperfusion, C57 with hypoxic hypobaric preconditioning and chronic cerebral hypoperfusion, sham-operated a7nAchRs(-/-) mice, a7nAchRs(-/-) with chronic cerebral hypoperfusion, a7nAchRs(-/-) with hypoxic hypobaric preconditioning and chronic cerebral hypoperfusion. For preconditioning, mice were exposed to hypoxia by "lifting" in barochamber to simulated altitude of 5600 m a.s.l. for 1 h/day on 3 consecutive days before surgical manipulation. Expressions of SIRT1, SIRT3 in brain tissue, and histopathological changes of the hippocampi were examined. It was shown that 8-week chronic hypoperfusion of the brain, caused by unilateral occlusion of the common carotid artery, was accompanied by injury to the neurons of the hippocampi of both hemispheres, which was more pronounced on the side of the occlusion. This damage, as well as the mechanisms of neuroprotection induced by hypoxic preconditioning, were maintained for at least 8 weeks by mechanisms mediated through a7nAChRs. Deficite of a7nAChRs was accompanied with reduction of neuronal damage caused CCH in 8 weeks, as well as preconditioning effects, and lead to compensatory activation of regulatory and protective mechanisms mediated by SIRT1, in normal conditions and in CCH. In wild-type (C57) mice, protective mechanisms in CCH were realized to a greater extent by increased expression of SIRT3 in both hemispheres of the brain.

Se sabe que el precondicionamiento hipóxico induce neuroprotección, pero aún se desconocen sus efectos y vías en la patología cerebral crónica. El objetivo fue establecer la participación de la subunidad a7 de los receptores nicotínicos de acetilcolina (a7nAchR) y las sirtuinas de tipo 1 (SIRT1) y 3 (SIRT3) en los efectos del precondicionamiento hipóxico hipobárico sobre el daño cerebral en ratones con hipoperfusión cerebral crónica causada por la oclusión de la arteria carótida común izquierda. Los ratones macho C57/6j (C57, tipo salvaje) y a7nAchRs(-/-) se dividieron en seis grupos experimentales (10 ratones por grupo): C57 con operación simulada, C57 con hipoperfusión cerebral crónica, C57 con precondicionamiento hipobárico hipóxico y crónica. hipoperfusión cerebral, ratones a7nAchRs(-/-) operados de forma simulada, a7nAchRs(-/-) con hipoperfusión cerebral crónica, a7nAchRs(-/-) con precondicionamiento hipobárico hipóxico e hipoperfusión cerebral crónica. Para el preacondicionamiento, los ratones fueron expuestos a hipoxia "levantándolos" en una cámara de barro a una altitud simulada de 5600 m s.n.m. durante 1 h/día durante 3 días consecutivos antes de la manipulación quirúrgica. Se examinaron las expresiones de SIRT1, SIRT3 en tejido cerebral y los cambios histopatológicos de los hipocampos. Se demostró que la hipoperfusión cerebral crónica de 8 semanas, causada por la oclusión unilateral de la arteria carótida común, se acompañaba de lesión de las neuronas del hipocampo de ambos hemisferios y que era más pronunciada en el lado de la oclusión. Este daño, así como los mecanismos de neuroprotección inducidos por el precondicionamiento hipóxico, se mantuvieron durante al menos 8 semanas mediante mecanismos mediados por a7nAChR. El déficit de a7nAChR se acompañó de una reducción del daño neuronal causado por CCH en 8 semanas, así como de efectos de precondicionamiento, y condujo a una activación compensatoria de mecanismos reguladores y protectores mediados por SIRT1, en condiciones normales y en CCH. En ratones de tipo salvaje (C57), los mecanismos de protección en CCH se realizaron en mayor medida mediante una mayor expresión de SIRT3 en ambos hemisfe- rios del cerebro.

Quality assessment of clinical practice guidelines on hypoxic-ischaemic encephalopathy in newborns using the AGREE II tool: a systematic review.

INTRODUCTION: Hypoxic-ischaemic encephalopathy is a clinical syndrome of neurological dysfunction that occurs immediately after birth following an episode of perinatal asphyxia. We conducted a scoping review to assess the methodological quality of clinical practice guidelines that address this condition. METHODOLOGY: We conducted the evaluation using the AGREE II tool. High methodological quality was defined as a score greater than 70% in every domain. RESULTS: The analysis included three clinical practice guidelines; the highest scores were in the scope and purpose domain (84.26%; SD, 14.25%) and the clarity of presentation domain (84.26%; SD, 17.86%), while the lowest score corresponded to the applicability domain (62.50%; SD, 36.62%). Two guidelines were classified as high quality and one guideline as low-quality. CONCLUSIONS: Two of the assessed guidelines were classified as being of high quality; however, the analysis identified shortcomings in the applicability domain, in addition to methodological variation between guidelines developed in middle- or low-income countries versus high-income countries. Efforts are needed to make high-quality guidelines available to approach the management of hypoxic-ischaemic encephalopathy in newborns.

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.

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.

Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication.

OBJECTIVE: To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pretreatment maximal hourly seizure burden and total seizure duration with successful response to initial antiseizure medication (ASM). STUDY DESIGN: This was a retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between January 25, 2017, and October 9, 2019. We evaluated a cohort of neonates born at ≥36 weeks of gestation with moderate-to-severe HIE who underwent continuous electroencephalogram monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1) pretreatment maximal hourly seizure burden, (2) pretreatment total seizure duration, (3) time from first seizure to initial ASM, and (4) successful response to initial ASM. RESULTS: Among 39 neonates meeting inclusion criteria, greater pretreatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pretreatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (relative risk 1.007, 95% CI 1.003-1.010). CONCLUSIONS: Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

Early Hyperoxemia and 2-year Outcomes in Infants with Hypoxic-ischemic Encephalopathy: A Secondary Analysis of the Infant Cooling Evaluation Trial.

OBJECTIVE: To determine the causal relationship between exposure to early hyperoxemia and death or major disability in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: We analyzed data from the Infant Cooling Evaluation (ICE) trial that enrolled newborns ≥35 weeks' gestation with moderate-severe HIE, randomly allocated to hypothermia or normothermia. The primary outcome was death or major sensorineural disability at 2 years. We included infants with arterial pO2 measured within 2 hours of birth. Using a directed acyclic graph, we established that markers of severity of perinatal hypoxia-ischemia and pCO2 were a minimally sufficient set of variables for adjustment in a regression model to estimate the causal relationship between arterial pO2 and death/disability. RESULTS: Among 221 infants, 116 (56%) had arterial pO2 and primary outcome data. The unadjusted analysis revealed a U-shaped relationship between arterial pO2 and death or major disability. Among hyperoxemic infants (pO2 100-500 mmHg) the proportion with death or major disability was 40/58 (0.69), while the proportion in normoxemic infants (pO2 40-99 mmHg) was 20/48 (0.42). In the adjusted model, hyperoxemia increased the risk of death or major disability (adjusted risk ratio 1.61, 95% CI 1.07-2.00, P = .03) in relation to normoxemia. CONCLUSION: Early hyperoxemia increased the risk of death or major disability among infants who had an early arterial pO2 in the ICE trial. Limitations include the possibility of residual confounding and other causal biases. Further work is warranted to confirm this relationship in the era of routine therapeutic hypothermia.

Use of Inter-Effort Recovery Hypoxia as a New Approach to Improve Anaerobic Capacity and Time to Exhaustion.

Putti, Germano Marcolino, Gabriel Peinado Costa, Matheus Silva Norberto, Carlos Dellavechia de Carvalho, Rômulo Cássio de Moraes Bertuzzi, and Marcelo Papoti. Use of inter-effort recovery hypoxia as a new approach to improve anaerobic capacity and time to exhaustion. High Alt Med Biol. 25:68-76, 2024. Background: Although adding hypoxia to high-intensity training may offer some benefits, a significant problem of this training model is the diminished quality of the training session when performing efforts in hypoxia. The purpose of this study was to investigate the effects of training and tapering combined with inter-effort recovery hypoxia (IEH) on anaerobic capacity, as estimated by alternative maximum accumulated oxygen deficit (MAODALT) and time to exhaustion (TTE). Methods: Twenty-four amateur runners performed, for 5 weeks, 3 sessions per week of training consisted of ten 1-minute bouts at 120% (weeks 1-3) and 130% (weeks 4 and 5) of maximum velocity (VMAX) obtained in graded exercise test, separated by a 2-minute interval in IEH (IEH, n = 11, FIO2 = 0.136) or normoxia (NOR, n = 13, fraction of inspired oxygen = 0.209). Before training, after training, and after 1 week of tapering, a graded exercise test and a maximal effort to exhaustion at 120% of VMAX were performed to determine TTE and MAODALT. The results were analyzed using generalized linear mixed models, and a clinical analysis was also realized by the smallest worthwhile change. Results: MAODALT increased only in IEH after training (0.8 ± 0.5 eq.lO2) and tapering (0.8 ± 0.5 eq.lO2), with time x group interaction. TTE increased for the pooled groups after taper (23 ± 11 seconds) and only for IEH alone (29 ± 16 seconds). Clinical analysis revealed a small size increase for NOR and a moderate size increase for IEH. Conclusions: Although the effects should be investigated in other populations, it can be concluded that IEH is a promising model for improving anaerobic performance and capacity. World Health Organization Universal Trial Number: U1111-1295-9954. University's ethics committee registration number: CAAE: 32220020.0.0000.5659.

Neonatal Hypoxic-Ischemic Encephalopathy Spectrum: Severity-Stratified Analysis of Neuroimaging Modalities and Association with Neurodevelopmental Outcomes.

OBJECTIVE: To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. STUDY DESIGN: This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and postrewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18 months of age. RESULTS: Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48 hours after birth were more common in the severe HIE group than the mild HIE group (81% vs 39% and 50% vs 0%, respectively; P < .001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted P < .001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (OR: 19.9, 95% CI: 4.0-98.1; P < .001). CONCLUSION: The present study shows the complementary utility of cUS in the first 48 hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.

Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Effects of Different Protocols of Moderate-Intensity Intermittent Hypoxic Training on Mental Health and Quality of Life in Brazilian Adults Recovered from COVID-19: The AEROBICOVID Double-Blind Randomized Controlled Study.

The aim of this study was to investigate the effects of different protocols of moderate-intensity intermittent hypoxic training in patients who had recovered from COVID-19 on quality of life (QoL) and mental health. The sample of this clinical trial-controlled double-blind study consisted of 67 participants aged 30-69 years, who were organized randomly according to Normoxia, Hypoxia, Hypoxia Recovery or Control Group. Eight weeks of cycle ergometer training were performed with a frequency of three training sessions per week in normoxic or hypoxic conditions (with or without hypoxic recovery). Health-related QoL and Mental Health Status were evaluated by 12-Item Short Form Survey and Depression Anxiety and Stress Scale instruments, respectively. All training groups improved the QoL's physical dimensions (Baseline-Post: Normoxia Group 42.1 (11.0)-48.7 (7.0), Hypoxia Group 46.9 (11.8)-53.5 (6.6) and Hypoxia Recovery Group 45.8 (9.2)-51.1 (5.3)) and mental dimensions (Baseline-Post: Normoxia Group 48.8 (7.9)-54.6 (4.6), Hypoxia Group 45.2 (7.7)-53.2 (3.8) and Hypoxia Recovery Group 46.5 (9.7)-52.0 (9.9)). Regarding mental health outcomes, all training groups decreased depressive symptoms (66.7% Normoxia, 31.2% Hypoxia Recovery and 31% Hypoxia groups), anxiety symptoms (46.5% Normoxia, 45.9% Hypoxia Recovery and 39.5% in the Hypoxia groups) and stress symptoms (40.6% Normoxia, 36.3% Hypoxia Recovery and 22.1% Hypoxia groups). Significant statistical difference was not found between groups. Normoxic and hypoxic training showed a similar effect on QoL and the mental health of Brazilian adults who had recovered from COVID-19.

Effect of Leuprolide Acetate, a GnRH Agonist, on Neuroinflammation and Anxiety-Like Behavior after Mild Hypoxic-Ischemic Encephalopathy in Rat Model.

BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is a condition that predisposes to negative outcomes such as neuroanatomical injury, mood disorders, and motor or cognitive disabilities. The neuroinflammation plays an important role in the neurological damage; therefore, reducing it could provide neuroprotection. The leuprolide acetate (LA) has shown to have neuroregenerative and immunomodulator properties in other nervous system injuries. OBJECTIVE: The aim of this study was to evaluate the immunomodulatory effect of LA in the acute phase of mild HIE and its effects in motor activity and behavior in a subacute phase. METHOD: Forty-five Wistar rats on postnatal day 7 were divided into Sham, HIE treated with saline solution (HIE-SS), and HIE-LA. The HIE was performed cutting of the right carotid artery followed by 60 min of hypoxia. The expression of the inflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and the chemokine CXCL-1 were evaluated 72 h after HIE by RT-qPCR and the motor activity and behavior were evaluated by open field test at postnatal day 33. RESULTS: HIE-SS animals showed increased expression of IL-1ß, TNF-α, IFN-γ, and CXCL-1 genes in injured tissue. However, the HIE-LA group exhibited similar expression levels of IL-1ß and TNF-α to the Sham group, while IFN-γ and CXCL-1 mRNA expression were attenuated with LA treatment. LA treatment also prevented anxiety-like behavior in the open field test. CONCLUSION: Treatment with LA partially reverses HIE-induced neuroinflammation and prevents anxiety-like behavior in neonatal rats.

Short-term neurological injury in newborns infants with overcooling in passive hypothermia and transferred to reference hospital in Colombia.

AIM: The aim of the study was to determine whether overcooling (temperature <33°C) during passive hypothermia when transporting neonates with perinatal asphyxia increased the risk of short-term neurological injury. METHODS: A retrospective observational study was performed. Newborns transferred to the LaCardio neonatal unit between January 2021 and April 2022 with moderate and severe perinatal asphyxia and who received passive hypothermia during transport were included. A temperature of <33°C was considered overcooling. A composite outcome of neurological injury was defined by the presence of abnormalities on brain magnetic resonance imaging, video telemetry, seizure before discharge or both. RESULTS: The study included 101 newborns. A total of 18 neonates had a temperature <33°C after transportation. Neurological injuries were present in 21.8% of the temperature <33°C group and 78.2% of the temperature ≥33°C group. Temperature <33°C at the end of transport (aOR 9.2, 95% CI 1.1-77.3) were associated with neurological injury before discharge from the unit. CONCLUSION: During transportation, overcooling in neonates with asphyxia increases the risk of neurological injury before discharge from the neonatal unit. It is important to qualify the transport team with adequate training and equipment for therapeutic hypothermia.