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.

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.

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.

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.

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.

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.

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.

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.

Therapeutic hypothermia as a neuroprotective strategy in newborns with perinatal asphyxia-case report.

Background: Perinatal asphyxia is a public health problem and the third major cause of death among children under 5 years. Objective: Two clinical cases of newborns with perinatal asphyxia submitted to therapeutic hypothermia and the follow-up of their motor development after hospital discharge have been reported. Methods: This retrospective case report study included two newborns with hypoxic-ischemic encephalopathy due to perinatal asphyxia who received a hypothermia protocol at the neonatal intensive care unit (NICU). The two newborns and their families were followed up at the outpatient clinic and assessed using the Hammersmith Child Neurological Examination, Alberta Child Motor Scale, and Denver Developmental Screening Test-II. Results: The newborns were submitted to a 72-hour hypothermia protocol. One newborn remained for 13 days in the NICU, while the other remained for 22 days. According to the multidisciplinary team, both cases presented with typical motor development with no cerebral palsy during the follow-up. Conclusion: Both cases showed positive results and a good prognostic for motor development. Therapeutic hypothermia may be a strategy to prevent neurologic sequelae in newborns with perinatal asphyxia, including cerebral palsy.

Hemodynamic Changes with Umbilical Cord Milking in Nonvigorous Newborns: A Randomized Cluster Cross-over Trial.

OBJECTIVE: To assess the hemodynamic safety and efficacy of umbilical cord milking (UCM) compared with early cord clamping (ECC) in nonvigorous newborn infants enrolled in a large multicenter randomized cluster-crossover trial. STUDY DESIGN: Two hundred twenty-seven nonvigorous term or near-term infants who were enrolled in the parent UCM vs ECC trial consented for this substudy. An echocardiogram was performed at 12 ± 6 hours of age by ultrasound technicians blinded to randomization. The primary outcome was left ventricular output (LVO). Prespecified secondary outcomes included measured superior vena cava (SVC) flow, right ventricular output (RVO), peak systolic strain, and peak systolic velocity by tissue Doppler examination of the RV lateral wall and the interventricular septum. RESULTS: Nonvigorous infants receiving UCM had increased hemodynamic echocardiographic parameters as measured by higher LVO (225 ± 64 vs 187 ± 52 mL/kg/min; P < .001), RVO (284 ± 88 vs 222 ± 96 mL/kg/min; P < .001), and SVC flow (100 ± 36 vs 86 ± 40 mL/kg/min; P < .001) compared with the ECC group. Peak systolic strain was lower (-17 ± 3 vs -22 ± 3%; P < .001), but there was no difference in peak tissue Doppler flow (0.06 m/s [IQR, 0.05-0.07 m/s] vs 0.06 m/s [IQR, 0.05-0.08 m/s]). CONCLUSIONS: UCM increased cardiac output (as measured by LVO) compared with ECC in nonvigorous newborns. Overall increases in measures of cerebral and pulmonary blood flow (as measured by SVC and RVO flow, respectively) may explain improved outcomes associated with UCM (less cardiorespiratory support at birth and fewer cases of moderate-to-severe hypoxic ischemic encephalopathy) among nonvigorous newborn infants.

Evaluación renal y multiorgánica en el paciente con encefalopatía hipóxico-isquémica / Renal and multiorgan evaluation in infants with post-asphyxial hypoxic-ischaemic encephalopathy

Resumen Introducción: La encefalopatía hipóxico-isquémica (EHI) moderada-grave secundaria a asfixia perinatal puede afectar a cualquier órgano, empeorando el pronóstico. Objetivo: Evaluar la afectación renal y multiorgánica de estos pacientes. Material y método: Se incluyó a recién nacidos > 35 semanas con EHI moderada-grave tratados con hipotermia activa entre 2010 y 2020. Se evaluó la creatinina en tres periodos: 48-72 horas de vida, entre el 3.o y 7.o día de vida y del 7.o al 28.o día de vida. Resultados: Se incluyeron 135 pacientes: 112 con EHI moderada y 23 con EHI grave. Al comparar ambos grupos, se obtuvieron diferencias significativas a las 48-72 horas y entre 3.o-7.o día de vida. No hubo diferencias al comparar el método de hipotermia. Los pacientes con EHI grave presentaron mayor afectación hemodinámica, respiratoria y hepática. Conclusiones: Neonatos con EHI grave presentan aumento de los niveles de creatinina sérica y mayor afectación multiorgánica respecto a aquellos con EHI moderada.

Abstract Background: Hypoxic-ischemic encephalopathy (HIE) secondary to perinatal asphyxia can affect any organ, worsening the prognosis. Objective: To describe renal and multiorgan involvement in moderate-severe HIE. Material and method: Newborns > 35 weeks diagnosed with moderate-severe HIE who required active hypothermia between 2010-2020 were included. To assess renal involvement, serum creatinine was measured in three different periods: at 48-72 hours, between the 3rd and the 7th day, and from the 7th to the 28th day. Results: A total of 135 patients were included, 112 (83%) with moderate and 23 (17%) with severe HIE. Significant differences were obtained when comparing median creatinine levels at 48-72 hours and between 3-7 days in both groups. There were no differences in creatinine according to the hypothermia method. Patients with severe HIE presented greater hemodynamic, respiratory, and hepatic involvement. Conclusions: Neonates with severe HIE present increased serum creatinine levels and greater multi-organ involvement than those with moderate HIE.

Lesión cerebral post paro cardiaco: aspectos médicos, éticos y legales / Brain injury after cardiac arrest: Medical, ethical and legal issues disorder

RESUMEN Los sobrevivientes de la reanimación cardiopulmonar posterior a un paro cardiaco pueden tener un amplio rango de desenlaces y van desde recuperación neurológica completa, estado de vigilia sin respuesta, compromiso cognoscitivo diverso o la muerte. La lesión del tejido cerebral se presenta inmediatamente después del paro cardíaco, durante la reanimación y al retornar la circulación espontánea. La severidad y duración de la noxa isquémica determinarán el devenir neurológico. El examen clínico es el punto de partida en el abordaje multimodal del neuropronóstico. Se debe complementar con electroencefalograma, potenciales evocados somatosensoriales, neuroimágenes y biomar-cadores séricos. Entre un 10 a 15% de los pacientes con lesión cerebral posterior al paro cardiaco evolucionan hacia muerte por criterios neurológicos y son potenciales candidatos a la donación de órganos. Un retiro temprano de las terapias de sostenimiento de vida puede malograr la posibilidad de un potencial donante de órganos. Se puede estimar de manera temprana qué pacientes tienen mayor riesgo de evolucionar a muerte por criterios neurológicos. El neurólogo tiene un papel protagónico en el manejo de pacientes con lesión cerebral post paro cardiaco y sus decisiones tienen implicaciones éticas y legales.

ABSTRACT People who survive cardiopulmonary resuscitation (CPR) after cardiac arrest, have a wide range of outcomes including complete neurological recovery, coma, compromised cognitive function and death. Injury of the brain parenchyma starts immediately after a cardiac arrest, during CPR and return of spontaneous circulation. The severity of the ischemic injury will define the neurological outcome. The first step needed to determine a neurological prognosis is the clinical exam, with the help of electroencephalography, somatosensory evoked potentials, neuroimaging, and serum biomarkers. Between 10 and 15% of patients with brain injury after a cardiac arrest, develop brain death and become potential candidates for organ donation. A premature withdrawal of vital support can hamper the possibility of organ donation. The patients with higher risk of developing brain death can be identified early based on neurological criteria. The neurologist has a major role in the approach of patients with brain injury after cardiac arrest and the decision making with legal and ethical consequences.

Potential pharmacological target of tight junctions to improve the BBB permeability in neonatal Hypoxic-Ischemic encephalopathy Diseases.

Neonatal encephalopathy (NE) is a pathological condition that describes a neurocognitive malfunction in the newborn that arises from fetal, peripartum, or intrapartum events of multifactorial nature, having a poor prognosis and accounting for an incidence of 5-8 per 1000 live births. Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most studied paradigms of NE, caused by a scarce cerebral perfusion and oxygen supply during perinatal life. The cerebral hypoxic-ischemic insult promotes a loss of permeability of the blood-brain barrier (BBB), an essential structural intermediary of blood-brain communication. This permeability disruption is associated with an increase in inflammatory cytokines, an increase of adhesion molecules, and oxidative stress which disturb the tight junction (TJ) performance and enable transcytosis and paracellular leakage, ultimately leading to death from brain cells. In this context, TJs proteins are essential to preserving the barrier mechanical stability and signaling that modulates the brain-blood vessel multicellular domains, known as neurovascular units (NVU). Recent studies have proposed different strategies with neuroprotective effects that allow for maintaining or restoring the integrity and permeability of the BBB. This review identifies and discusses regulator mechanisms and novel aspects of TJs in the BBB disruption induced by cerebral hypoxic insults during the perinatal period, evaluating potential pharmacological strategies to safeguard BBB integrity.

Brain Injury in Infants Evaluated for, But Not Treated with, Therapeutic Hypothermia.

Defining neonatal encephalopathy clinically to qualify for therapeutic hypothermia is challenging. This study examines magnetic resonance imaging outcomes of 39 infants who were evaluated and not cooled using criteria inclusive of mild encephalopathy. Infants evaluated for therapeutic hypothermia are at risk for brain injury and may benefit from neuroimaging and follow-up.

Adición de melatonina a terapia con hipotermia para encefalopatía hipóxico-isquémica neonatal / Addition of melatonin to hypothermia therapy for neonatal hypoxic-ischemic encephalopathy

Introducción La encefalopatía hipóxico-isquémica neonatal es una patología caracterizada por una disfunción neurológica aguda, de severidad variable, causada por un episodio asfíctico perinatal. Se presenta en uno a seis de cada 1000 recién nacidos de término, asociándose a una alta morbimortalidad neonatal y a desenlaces neurológicos adversos. El uso de hipotermia es considerado como la terapia estándar para esta condición. Sin embargo, debido a su limitada eficacia clínica, se han propuesto diferentes opciones terapéuticas adyuvantes, incluyendo el uso de fármacos como la melatonina. Existe controversia sobre si la terapia combinada con melatonina es superior a la monoterapia con hipotermia. Métodos Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el tamizaje de múltiples fuentes de información, incluyendo MEDLINE/PubMed, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un meta-análisis y preparamos una tabla de resumen de los resultados utilizando el método Grading of Recommendations Assessment, Development and Evaluation, GRADE Resultados Identificamos dos revisiones sistemáticas que en conjunto incluyeron dos estudios primarios, ambos ensayos aleatorizados. Se incluyeron los dos ensayos aleatorizados en el análisis del presente trabajo. Conclusiones No es posible establecer con claridad si la adición de melatonina disminuye la mortalidad o la probabilidad de presentar alteraciones reflejadas en la resonancia magnética cerebral, debido a que la certeza de la evidencia existente ha sido evaluada como muy baja. Por otro lado, adicionar melatonina a la terapia con hipotermia, comparado con la monoterapia con hipotermia, podría aumentar la probabilidad de que el examen neurológico sea normal a los seis meses, y que la cognición sea normal a los 18 meses. Finalmente, la adición de melatonina a la terapia con hipotermia probablemente disminuya la probabilidad de presentar convulsiones.

Introduction Neonatal hypoxic-ischemic encephalopathy is caused by perinatal asphyxia, resulting in an acute neurological dysfunction of variable severity. It occurs in one to six of every 1000 full-term newborns and is associated with high neonatal morbimortality and adverse neurological outcomes. The use of hypothermia is considered the standard therapy for this condition. However, different adjuvant therapeutic options have been proposed due to limited clinical efficacy, including drugs like melatonin. There is controversy about whether combined therapy with melatonin is superior to monotherapy with hypothermia. Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, and Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of the findings table using the GRADE approach. Results We identified two systematic reviews that included two primary studies, both randomized trials. The two randomized trials were included in the analysis of the present work. Conclusion It is not possible to establish whether the addition of melatonin decreases mortality or the probability of alterations in brain magnetic resonance imaging because the certainty of the existing evidence has been assessed as very low. On the other hand, the addition of melatonin to hypothermia therapy, compared to hypothermia monotherapy, may increase the probability of normal neurological examination at six months and the probability of normal cognition at 18 months. Finally, adding melatonin to hypothermia therapy likely reduces the probability of seizures.

Pathophysiology of Perinatal Asphyxia in Humans and Animal Models.

Perinatal asphyxia is caused by lack of oxygen delivery (hypoxia) to end organs due to an hypoxemic or ischemic insult occurring in temporal proximity to labor (peripartum) or delivery (intrapartum). Hypoxic-ischemic encephalopathy is the clinical manifestation of hypoxic injury to the brain and is usually graded as mild, moderate, or severe. The search for useful biomarkers to precisely predict the severity of lesions in perinatal asphyxia and hypoxic-ischemic encephalopathy (HIE) is a field of increasing interest. As pathophysiology is not fully comprehended, the gold standard for treatment remains an active area of research. Hypothermia has proven to be an effective neuroprotective strategy and has been implemented in clinical routine. Current studies are exploring various add-on therapies, including erythropoietin, xenon, topiramate, melatonin, and stem cells. This review aims to perform an updated integration of the pathophysiological processes after perinatal asphyxia in humans and animal models to allow us to answer some questions and provide an interim update on progress in this field.