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.

[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.

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.

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

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. RESULTS: During 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<.0001). Re-warming took a median time of 10.5 hours. 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.

[Neuroprotection with hypothermia in the newborn with hypoxic-ischaemic encephalopathy. Standard guidelines for its clinical application]. / Neuroprotección con hipotermia en el recién nacido con encefalopatía hipóxico-isquémica. Guía de estándares para su aplicación clínica.

Standardisation of hypothermia as a treatment for perinatal hypoxic-ischaemic encephalopathy is supported by current scientific evidence. The following document was prepared by the authors on request of the Spanish Society of Neonatology and is intended to be a guide for the proper implementation of this therapy. We discuss the difficulties that may arise when moving from the strict framework of clinical trials to clinical daily care: early recognition of clinical encephalopathy, inclusion and exclusion criteria, hypothermia during transport, type of hypothermia (selective head or systemic cooling) and side effects of therapy. The availability of hypothermia therapy has changed the prognosis of children with hypoxic-ischaemic encephalopathy and our choices of therapeutic support. In this sense, it is especially important to be aware of the changes in the predictive value of the neurological examination and the electroencephalographic recording in cooled infants. In order to improve neuroprotection with hypothermia we need earlier recognition of to recognise earlier the infants that may benefit from cooling. Biomarkers of brain injury could help us in the selection of these patients. Every single infant treated with hypothermia must be included in a follow up program in order to assess neurodevelopmental outcome.

[Neonatal hypoxic-ischemic encephalopathy: Incidence and prevalence in the first decade of the 21st century]. / Incidencia y prevalencia de la encefalopatía hipoxico-isquémica en la primera década del siglo xxi.

AIM: To examine the incidence and the prevalence of neonatal hypoxic-ischemic encephalopathy (HIE) in a tertiary Spanish center over a 9-year period, before the implementation of a hypothermia program. METHODS: All infants > or =34 weeks gestation, born between 2000 and 2008 with evidence of perinatal asphyxia and neonatal encephalopathy were identified. HIE was classified as mild, moderate or severe. Joinpoint regression model was used to identify changes in the trends of HIE incidences. RESULTS: A total of 90,963 live infants were born in La Paz Hospital between 2000 and 2008, and 23.3% of them (21.228) were admitted to the Neonatal Unit. In addition, 200 infants were referred from other centers. A total of 110 infants had HIE, of which 90% were inborn. The overall incidence of HIE was 1.088 per 1,000 live births, and the incidence of clinically significant HIE (moderate and severe grades) was 0.49 per 1,000 live births. The incidence of HIE showed a linear downward trend throughout the study period (slope=-5.37; P<0.05). Fifty-two neonates had moderate or severe HIE, this represents a prevalence of 2.42 per 1,000 infants admitted to the Neonatal Unit and means that 5-6 infants a year would have been candidates for therapeutic hypothermia. CONCLUSIONS: Neonatal HIE, and in particular significant HIE, is an infrequent condition. The low prevalence of HIE requires that these infants are referred to regional centers with sufficient experience in the use of therapeutic hypothermia, and in the management of all the medical problems associated with HIE.

[A guide to the clinical diagnosis and urgent treatment of neonatal hyperammonaemia]. / Guía clínica de diagnóstico y tratamiento urgente de hiperamonemia neonatal.

Symptomatic hyperammonaemia in newborn is a medical emergency that should be recognised in its early stages, specifically diagnosed and aggressively treated to improve the immediate and long-term prognosis of these children. The paediatrician and the neonatal doctor should have a diagnosis-therapy scheme for its urgent management.

[Impact of cardiopulmonary resuscitation on extremely low birth weight infants]. / Impacto de la reanimación cardiopulmonar avanzada en recién nacidos pretérmino de extremado bajo peso.

OBJECTIVE: To examine whether extremely low birth weight (ELBW) infants who undergo Cardiopulmonary Resuscitation (CPR) in the delivery room present poorer survival and greater short-term neurological and general morbidity than those who do not. METHODS: In a retrospective cohort of 150 ELBW infants born at our hospital between 2000 and 2004, those who needed CPR and those who did not were compared for mortality and short-term general and neurological morbidity. Infants with major birth defects, suspicion of genetic disease and those without a proactive perinatal attitude in the delivery room were excluded. CPR was defined as the administration of chest compressions and/or epinephrine in the delivery room. RESULTS: 150 infants were included, with gestational ages of 23-27 weeks (mean 25.6+/-1.2), birth weight of 425-995 grams (mean 745.2+/-132). Delivery room CPR was given to 32 infants (21.4%). No differences in perinatal characteristics were found except for lower pH and Apgar score and a higher SNAPPE score in infants who underwent CPR. Survival at discharge was similar (62.5% vs 76.3% for those without CPR). Infants who received CPR needed more surfactant, oxygen and higher median airway pressure than infants who did not. Air leaks and coagulopathy were more frequent in CPR infants (p<0.01). Prevalence of bronchopulmonary dysplasia, necrotizing enterocolitis and retinopathy was similar in the two groups. No statistical differences between ELBW infants who needed CPR and those who did not were found in prevalence of intraventricular haemorrhage (IVH) (62.5% vs 52.5%), IVH III (31.2% vs 17.7%), periventricular haemorrhagic infarction (PHI) (18.7% vs 11%) or cystic periventricular leucomalacia (PVL) (15.6% vs 11%). However, in a combined analysis of neurological morbidity (IVH III and/or PVL and/or PHI), significant differences between the two groups were found (46.7% vs 21.6%; p=0.01). CONCLUSION: This study does not support poorer survival or significant non-neurological morbidity during the neonatal period in ELBW infants who receive CPR. Although the prevalence of individual neurological problems was similar in the two groups, CPR was associated with a clear increase in general neurological morbidity, with a three-times greater risk of brain damage.

[Clinical guide to the management of patients with Beckwith-Wiedemann syndrome]. / Guía clínica para el seguimiento de pacientes con síndrome de Beckwith-Wiedemann.

Beckwith-Wiedemann syndrome (BWS) is characterized by congenital overgrowth, macroglossia and omphalocele or umbilical hernia. Children with BWS may also have all or some of the following features: asymmetry (hemihypertrophy) of the limbs, torso or face, hypoglycemia, organomegaly, ear pits or creases, and embryonal tumors. The frequency of BWS is approximately 1:14,000 births. We present a guide for the management of children with BWS aimed at helping pediatricians and general practitioners or specialists in the clinical follow-up of these patients. This guide has been structured according to different age groups and is based on published evidence.