Una década después de la implantación en España de la hipotermia terapéutica en el recién nacido con encefalopatía hipóxico-isquémica perinatal / Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain

Introducción: Se cumple ahora más de una década del inicio de la hipotermia terapéutica (HT)en Espa ̃na, la única intervención neuroprotectora que ha venido a ser práctica estándar en eltratamiento de la encefalopatía hipóxico-isquémica perinatal (EHI). El objetivo de este artículoes ofrecer un panorama actual y presentar las controversias surgidas alrededor de la aplicaciónde esta terapia. Desarrollo: En esta década se ha implantado con éxito la HT en la gran mayoría de los hospitalesterciarios de Espa ̃na y más del 85% de los recién nacidos con EHI moderada-grave reciben estaterapia. Entre los aspectos que pueden mejorar la eficacia de la HT están su inicio precoz dentrode las primeras 6 h de vida y el control de factores comórbidos asociados a la asfixia perinatal. En los pacientes con EHI moderada el inicio después de las 6 h parece mantener cierta eficacianeuroprotectora. Una duración de la HT mayor de 72 horas o un enfriamiento más profundo noofrecen mayor eficacia neuroprotectora y aumentan el riesgo de efectos adversos. Aspectosno bien aclarados aún son la sedación durante la HT y la aplicación de esta intervención a losneonatos con EHI leve y en otros escenarios. La información pronóstica y su marco temporal esuno de los aspectos más desafiantes. Conclusiones: La HT es universal en países con recursos económicos, aunque existen puntos de controversia no resueltos. Si bien es un tratamiento generalizado en nuestro país, falta disponerde dispositivos para el traslado de estos pacientes y su centralización.(AU)

Introduction: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice inthe treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to providea current picture of the technique and to address the controversies surrounding its use. Development: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severeHIE currently receive the treatment. The factors that can improve the efficacy of TH includeearly treatment onset (first 6 hours of life) and the control of comorbid factors associated withperinatal asphyxia. In patients with moderate HIE, treatment onset after 6 hours seems to havesome neuroprotective efficacy. TH duration longer than 72 hours or deeper hypothermia do notoffer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Unclarified aspects are the sedation of patients during TH, the application of the treatment in infantswith mild HIE, and its application in other scenarios. Prognostic information and time frame areone of the most challenging aspects. Conclusions: TH is universal in countries with sufficient economic resources, although certainunresolved controversies remain. While the treatment is widespread in Spain, there is a needfor cooling devices for the transfer of these patients and their centralisation.(AU)

Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain.

INTRODUCTION: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. DEVELOPMENT: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6 h of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6 h seems to have some neuroprotective efficacy. TH duration longer than 72 h or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Controversy persists around the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. CONCLUSIONS: TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for devices for the transfer of these patients and their centralisation.

Bedside and laboratory neuromonitoring in neonatal encephalopathy.

Several bedside and laboratory neuromonitoring tools are currently used in neonatal encephalopathy (NE) to assess 1) brain function [amplitude-integrated electroencephalogram (aEEG) and EEG], 2) cerebral oxygenation delivery and consumption [near-infrared spectroscopy (NIRS)] and 3) blood and cerebrospinal fluid biomarkers. The aim of the review is to provide the role of neuromonitoring in understanding the development of brain injury in these newborns and better predict their long-term outcome. Simultaneous use of these monitoring modalities may improve our ability to provide meaningful prognostic information regarding ongoing treatments. Evidence will be summarized in this review for each of these modalities, by describing (1) the methods, (2) the clinical evidence in context of NE both before and with hypothermia, and (3) the research and future directions.

Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain. / Una década después de la implantación en España de la hipotermia terapéutica en el recién nacido con encefalopatía hipóxico-isquémica perinatal.

INTRODUCTION: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. DEVELOPMENT: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6hours of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6hours seems to have some neuroprotective efficacy. TH duration longer than 72hours or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Unclarified aspects are the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. CONCLUSIONS: TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for cooling devices for the transfer of these patients and their centralisation.

Infratentorial congenital glioblastoma multiforme. A rare tumour with a still unknown biology. / Glioblastoma multiforme congenito infratentorial. Un tumor excepcional con una biologia aun desconocida.

INTRODUCTION: Congenital glioblastoma multiforme represents only 3% of congenital central nervous system tumours and an infratentorial location is unusual. CASE REPORT: A newborn with congenital glioblastoma multiforme with no mutation in the TP53 gene or p53 nuclear immunoreactivity that infiltrated practically the whole brainstem and also invaded supratentorial structures. CONCLUSIONS: As far as we know, only four cases with an infratentorial location have been reported previously, three in the cerebellum and one in the brainstem. The biology of congenital glioblastoma multiforme is not well known and, unlike glioblastoma multiforme in adults and children, mutations in the TP53 gene are uncommon. However, this is not associated with a more favourable prognosis. These observations suggest that specific biological processes underlie fetal glioblastoma multiforme development.

TITLE: Glioblastoma multiforme congenito infratentorial. Un tumor excepcional con una biologia aun desconocida.Introduccion. El glioblastoma multiforme congenito representa solo el 3% de los tumores congenitos del sistema nervioso central, y su ubicacion infrantentorial es excepcional. Caso clinico. Recien nacido con un glioblastoma multiforme congenito sin mutacion en el gen TP53 ni inmunorreactividad nuclear p53, que infiltraba practicamente todo el tronco cerebral e invadia tambien estructuras supratentoriales. Conclusiones. Hasta donde sabemos, solo se han referido previamente cuatro casos de localizacion infratentorial, tres en el cerebelo y uno en el tronco del encefalo. La biologia del glioblastoma multiforme congenito no se conoce bien y, a diferencia del glioblastoma multiforme en la edad adulta, las mutaciones en el gen TP53 son poco frecuentes, sin que eso parezca implicar un mejor pronostico. Estas observaciones sugieren que el glioblastoma multiforme con origen en la vida fetal tiene una biologia diferente del que se presenta en otras etapas de la vida.

Duración de la reanimación en neonatos con Apgar a los 10 min menor de 3 en la era de la hipotermia / Duration of resuscitation in neonates with Apgar scores at 10 minutes of less than 3 in the hypothermia era

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Programa multicéntrico para la atención integral del recién nacido con agresión hipóxico-isquémica perinatal (ARAHIP) / Multicenter program for the integrated care of newborns with perinatal hypoxic-ischemic insult (ARAHIP)

INTRODUCCIÓN: El recién nacido con indicadores de potencial evento hipóxico-isquémico perinatal precisa de una atención integral que detecte precozmente si necesita tratamiento con hipotermia y el control de los factores agravantes del da˜no cerebral en las primeras 6 h de vida. PACIENTES Y MÉTODOS: Aplicación de un programa prospectivo de ámbito poblacional que ordena y sistematiza la atención durante las primeras 6 h de vida en los ≥ 35 semanas nacidos con indicadores de agresión hipóxico-isquémica perinatal. El programa involucra 12 hospitales (91.217 m2), 7 de nivel asistencial i-ii y 5 de nivel III. Se establecen 4 protocolos: a) detección del recién nacido con potencial agresión hipóxico-isquémica; b) vigilancia de la repercusión neurológica y en otros órganos; c) control y tratamiento de complicaciones, y d) vigilancia y acciones durante el transporte. RESULTADOS: Entre junio del 2011 y junio del 2013, de 32.325 recién nacidos ≥ 35 semanas, 213 cumplieron criterios de potencial agresión hipóxico-isquémica perinatal (7,4 por 1.000). El 92% siguió la monitorización establecida en el programa; 33 recién nacidos tuvieron encefalopatía hipóxico-isquémica moderada-grave (1 por 1.000) y 31/33 (94%) recibieron tratamiento con hipotermia. CONCLUSIONES: El programa Atención integral al Recién nacido con Agresión Hipóxico-Isquémica Perinatal ha permitido ofrecer atención integral al recién nacido con indicadores de agresión hipóxico-isquémica perinatal. Se han controlado factores comórbidos agravantes de la lesión cerebral y se han detectado aquellos con encefalopatía hipóxico-isquémica moderadagrave, permitiendo iniciar la hipotermia dentro de las primeras 6 h de vida. Programas de ámbito poblacional son cruciales para disminuir la morbimortalidad asociada a la encefalopatía hipóxico-isquémica

INTRODUCTION: Newborns with perinatal indicators of a potential hypoxic-ischemic event require an integrated care in order to control the aggravating factors of brain damage, and the early identification of candidates for hypothermia treatment. PATIENTS AND METHODS: The application of a prospective, populational program that organizes and systematizes medical care during the first 6 hours of life to all newborns over 35 weeks gestational age born with indicators of a perinatal hypoxic-ischemic insult. The program includes 12 hospitals (91,217 m2); two level I centers, five level II centers, and five level III hospitals. The program establishes four protocols: a) detection of the newborn with a potential hypoxic-ischemic insult, b) surveillance of the neurological repercussions and other organ involvement, c) control and treatment of complications, d) procedures and monitoring during transport. RESULTS: From June 2011 to June 2013, 213 of 32325 newborns above 35 weeks gestational age met the criteria of a potential hypoxic-ischemic insult (7.4/1000), with 92% of them being cared for following the program specifications. Moderate-severe hypoxic-ischemic encephalopathy was diagnosed in 33 cases (1/1,000), and 31 out of the 33 received treatment with hypothermia (94%). CONCLUSIONS: The program for the Integrated Care of Newborns with Perinatal Hypoxic-Ischemic Insult has led to providing a comprehensive care to the newborns with a suspected perinatal hypoxic-ischemic insult. Aggravators of brain damage have been controlled, and cases of moderate-severe hypoxic-ischemic encephalopathy have been detected, allowing the start of hypothermia treatment within the first six hours of life. Populational programs are fundamental to reducing the mortality and morbidity of hypoxic-ischemic encephalopathy

Sedación en los recién nacidos a término o casi a término con encefalopatía hipóxico-isquémica que requieren hipotermia terapéutica / Sedation in term or near-term newborns with hypoxic-ischemic encephalopathy who require therapeutic hypothermia

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[Multicenter program for the integrated care of newborns with perinatal hypoxic-ischemic insult (ARAHIP)]. / Programa multicéntrico para la atención integral del recién nacido con agresión hipóxico-isquémica perinatal (ARAHIP).

INTRODUCTION: Newborns with perinatal indicators of a potential hypoxic-ischemic event require an integrated care in order to control the aggravating factors of brain damage, and the early identification of candidates for hypothermia treatment. PATIENTS AND METHODS: The application of a prospective, populational program that organizes and systematizes medical care during the first 6 hours of life to all newborns over 35 weeks gestational age born with indicators of a perinatal hypoxic-ischemic insult. The program includes 12 hospitals (91,217 m(2)); two level i centers, five level ii centers, and five level iii hospitals. The program establishes four protocols: a) detection of the newborn with a potential hypoxic-ischemic insult, b) surveillance of the neurological repercussions and other organ involvement, c) control and treatment of complications, d) procedures and monitoring during transport. RESULTS: From June 2011 to June 2013, 213 of 32325 newborns above 35 weeks gestational age met the criteria of a potential hypoxic-ischemic insult (7.4/1000), with 92% of them being cared for following the program specifications. Moderate-severe hypoxic-ischemic encephalopathy was diagnosed in 33 cases (1/1,000), and 31 out of the 33 received treatment with hypothermia (94%). CONCLUSIONS: The program for the Integrated Care of Newborns with Perinatal Hypoxic-Ischemic Insult has led to providing a comprehensive care to the newborns with a suspected perinatal hypoxic-ischemic insult. Aggravators of brain damage have been controlled, and cases of moderate-severe hypoxic-ischemic encephalopathy have been detected, allowing the start of hypothermia treatment within the first six hours of life. Populational programs are fundamental to reducing the mortality and morbidity of hypoxic-ischemic encephalopathy.

Novedades en Pediatría por pediatras leoneses de prestigio El pronóstico en el neonato con encefalopatía hipóxico-isquémica neonatal / The prognosis in the newborn with neonatal hypoxic ischemic encephalopathy

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Rombencefalosinapsis, una rara alteración del desarrollo del cerebelo de fácil diagnóstico / Rhombencephalosynapsis, a rare congenital abnormality easy to diagnose

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Seguimiento de los recién nacidos con encefalopatía hipóxico-isquémica / Follow-up of newborns with hypoxic-ischaemic encephalopathy

La introducción del tratamiento con hipotermia para la encefalopatía hipóxicoisquémica neonatal ha conseguido reducir el número de niños con esta enfermedad que fallecen o que sobreviven con secuelas neurológicas. A pesar de la generalización de esta terapia, la encefalopatía hipóxico-isquémica continúa siendo una causa importante de mortalidad y de discapacidad neurológica. Las consecuencias de esta enfermedad sobre el neurodesarrollo y la calidad de vida del recién nacido justifican que estos pacientes sean incluidos en programas de seguimiento específicos con el fin de identificar y tratar precozmente los problemas que puedan surgir, así como de ofrecer orientación y apoyo a las familias. En este artículo se describen las complicaciones más importantes que presentan los niños con encefalopatía hipóxico-isquémica después del alta hospitalaria y se propone un programa de seguimiento basado en el pronóstico neurológico, establecido este a partir del estado clínico del recién nacido y de otros indicadores pronósticos, principalmente los estudios de neuroimagen. Se exponen también brevemente algunos aspectos sociales de importancia durante el seguimiento

Hypothermia treatment for newborn infants with hypoxic-ischemic encephalopathy reduces the number of neonates who die or have permanent neurological deficits. Although this therapy is now standard of care, neonatal hypoxic-ischaemic encephalopathy still has a significant impact on the child’s neurodevelopment and quality of life. Infants with hypoxic-ischaemic encephalopathy should be enrolled in multidisciplinary follow-up programsin order to detect impairments, to initiate early intervention, and to provide counselling and support for families. This article describes the main neurodevelopmental outcomes after term neonatal hypoxic ischaemic encephalopathy. We offer recommendations for follow-up based on the infant’s clinical condition and other prognostic indicators, mainly neonatal neuroimaging. Other aspects, such as palliative care and medico-legal issues, are also briefly discussed

Treatment with bisphosphonates in severe hypercalcemia due to subcutaneous fat necrosis in an infant with hypoxic-ischemic encephalopathy.

Subcutaneous fat necrosis (SCFN) is a rare entity that occurs generally in term or post-term newborns exposed to perinatal stressing factors. These cutaneous lesions appear during the first weeks of life and their potential complications, such as hypercalcemia, determine the prognosis. We present a full-term newborn with SCFN lesions that appeared at the age of 12 days and who, 1 week later, developed moderate hypercalcemia. In our patient, the standard treatment was not enough to normalize calcemia and, in order to prevent secondary effects, etidronate therapy was initiated and it successfully normalized calcium levels. When SCFN is diagnosed, it is important to detect early hypercalcemia and treat it aggressively. This case provides further evidence of etidronate as an alternative and effective treatment for moderate-severe hypercalcemia.

[Follow-up of newborns with hypoxic-ischaemic encephalopathy]. / Seguimiento de los recién nacidos con encefalopatía hipóxico-isquémica.

Hypothermia treatment for newborn infants with hypoxic-ischemic encephalopathy reduces the number of neonates who die or have permanent neurological deficits. Although this therapy is now standard of care, neonatal hypoxic-ischaemic encephalopathy still has a significant impact on the child's neurodevelopment and quality of life. Infants with hypoxic-ischaemic encephalopathy should be enrolled in multidisciplinary follow-up programs in order to detect impairments, to initiate early intervention, and to provide counselling and support for families. This article describes the main neurodevelopmental outcomes after term neonatal hypoxic-ischaemic encephalopathy. We offer recommendations for follow-up based on the infant's clinical condition and other prognostic indicators, mainly neonatal neuroimaging. Other aspects, such as palliative care and medico-legal issues, are also briefly discussed.

Anthropogenic impact and lead pollution throughout the Holocene in Southern Iberia.

Present day lead pollution is an environmental hazard of global proportions. A correct determination of natural lead levels is very important in order to evaluate anthropogenic lead contributions. In this paper, the anthropogenic signature of early metallurgy in Southern Iberia during the Holocene, more specifically during the Late Prehistory, was assessed by mean of a multiproxy approach: comparison of atmospheric lead pollution, fire regimes, deforestation, mass sediment transport, and archeological data. Although the onset of metallurgy in Southern Iberia is a matter of controversy, here we show the oldest lead pollution record from Western Europe in a continuous paleoenvironmental sequence, which suggests clear lead pollution caused by metallurgical activities since ~3900 cal BP (Early Bronze Age). This lead pollution was especially important during Late Bronze and Early Iron ages. At the same time, since ~4000 cal BP, an increase in fire activity is observed in this area, which is also coupled with deforestation and increased erosion rates. This study also shows that the lead pollution record locally reached near present-day values many times in the past, suggesting intensive use and manipulation of lead during those periods in this area.

Hipotermia cerebral moderada en la encefalopatía hipóxico-isquémica. Experiencia en el primer año de su puesta en marcha / Moderate cerebral hypothermia in hypoxic-ischaemic encephalopathy: Experience after one year

Introducción: La hipotermia cerebral moderada ha probado ser una intervención eficaz para reducir la mortalidad y la discapacidad mayor en los neonatos con encefalopatía hipóxico-isquémica (EHI) moderada-grave. Objetivos: Describir la experiencia en el primer año de su utilización y valorar la factibilidad y seguridad de esta intervención. Métodos: Revisión de los 20 pacientes con EHI moderada-grave tratados con hipotermia corporal total en la Agrupación Sanitaria Hospital Sant Joan de Déu-Hospital Clínic, entre enero de 2009 y junio de 2010. Resultados: Durante este periodo ingresaron 50 neonatos con EHI perinatal, en 26 de ellos moderada-grave. Un total de 20 neonatos recibieron hipotermia (13 con EHI grave y 7 moderada). En todos ellos se encontró un antecedente de riesgo de hipoxia-isquemia perinatal y algún signo clínico de EHI. Quince neonatos presentaron convulsiones clínicas y/o en el registro electroencefalográfico. La temperatura rectal se mantuvo en 33,5±0,5°C en el 76,5% de las determinaciones para los neonatos con control manual de la temperatura y en el 93,6% para los manejados con servocontrol (p<0,0001). El recalentamiento se realizó en una mediana de 10,5 horas. No se produjo ninguna complicación potencialmente grave relacionada con la hipotermia. Fallecieron 7 neonatos (35%), todos ellos con EHI grave. Conclusiones: No se han apreciado dificultades en ninguna de las fases de esta intervención terapéutica ni se ha registrado ninguna complicación potencialmente grave relacionada con ella. Tanto el control manual de la temperatura como su servocontrol son eficaces para mantener la temperatura diana, pero esta muestra una menor variabilidad con el equipo servocontrolado(AU)

Introduction: Moderate cerebral hypothermia has been shown to be an effective intervention in decreasing mortality and major disabilities in infants with moderate-severe hypoxic-ischaemic encephalopathy (HIE). Objectives: To describe our experience within the first year of implementation, and to evaluate the feasibility and safety of this intervention. Methods: Retrospective study of 20 patients with moderate-severe HIE treated with whole body hypothermia in the Agrupación Sanitaria Hospital Sant Joan de Déu-Hospital Clínic, between January 2009 and June 2010.ResultsDuring this period, 50 patients with perinatal HIE, 26 of them moderate- severe, were admitted to our units. Twenty patients received hypothermia (13 with severe and 7 with moderate HIE). All of them had at least one risk factor for perinatal hypoxia-ischaemia, and clinical signs of HIE. Fifteen had clinical and/or EEG seizures. Core temperature was maintained at 33.5±0.5°C in 76.5% of determinations for infants cooled with a manual control device, and in 93.6% for those cooled with a servo-controlled device (P<0,0001). Re-warming took a median time of 10.5hours. No potentially severe complications related to hypothermia were observed. Seven patients (35%) died, all of them with severe HIE. Conclusions: There were no difficulties in any of the steps of this intervention, and no potentially severe complications related to it were recorded. Both manual and servo-control methods are equally effective on maintaining the target temperature, although temperature shows less variability using the servo-controlled equipment(AU)