Comparison between selective head cooling and whole-body cooling in neonatal therapeutic hypothermia / Comparação entre resfriamento seletivo da cabeça e resfriamento de corpo inteiro na hipotermia terapêutica neonatal

INTRODUCTION: Experimental evidence, as well as improved clinical studies of the reduction of brain injury and, improves the neurological outcome, in newborns with hypoxic-ischemic encephalopathy (HIE) occurring in therapeutic hypothermia (TH). OBJECTIVE: To verify the potential of hypothermic hypoxic-ischemic encephalopathy (HIE) therapy in neonatal asphyxia, based on literature data, comparing the benefits between selective head cooling (SHC) and whole-body cooling (WBC), see that the use of TH as a standard treatment in newborns with moderate or severe HIE has been adopted. METHODS: A search was performed in the PubMed and SciELO databases of human studies, using the keywords "Therapeutic Hypothermia", "Induced Hypothermia", and "Hypoxic-Ischemic Encephalopathy", "Selective cooling of the head", "Total body cooling" and its variables. RESULTS: Eleven articles were selected to compose the review, after detailed reading. There is a consensus, that the reduction of the risk of death or disability at 18 months of life in neonates with moderate to severe HIE, occurs to TH through the techniques of WBC or SHC. It was found in the studies that there is no difference in terms of adverse effects between the two methods. As for radiological changes, such as hypoxic-ischemic injuries and the incidence of seizures after cooling, they are more frequent with SHC. CONCLUSION: Both WBC and SHC demonstrated neuroprotective properties, although WBC provides a broader area of brain protection. However, no significant differences were found between the methods in terms of adverse effects and beneficial short or long-term results.

INTRODUÇÃO: Evidências experimentais, assim como estudos clínicos, sugerem a redução da lesão cerebral e melhora do desfecho neurológico, em recém-nascidos com encefalopatia isquêmica hipóxica (EHI) submetidos à hipotermia terapêutica (HT). OBJETIVO: Verificar a potencialidade da terapia hipotérmica de encefalopatia hipóxico-isquêmica (EHI) na asfixia neonatal, com base em dados da literatura, comparando os benefícios entre o resfriamento seletivo da cabeça (RSC) e o resfriamento de corpo inteiro (RCI), visto que o uso de hipotermia terapêutica (HT) como tratamento padrão em recém-nascidos com EHI moderada ou grave tem sido amplamente adotada. MÉTODOS: Foi realizada uma busca nas bases de dados PubMed e SciELO de estudos em humanos, utilizando-se as palavras-chave "Therapeutic Hypothermia", "Induced Hypothermia", "Hypoxic-Ischemic Encephalopathy", "selective head cooling", "whole body cooling" e suas respectivas variáveis. RESULTADOS: Foram selecionados 11 artigos para compor a revisão, após leitura detalhada. É consenso, a redução do risco de morte ou incapacidade aos 18 meses de vida nos neonatos com EHI moderado a grave, submetidos à HT através das técnicas de RCI ou RSC. Constatou-se diante dos estudos que não há diferença em termos de efeitos adversos entre os dois métodos. Quanto às alterações radiológicas, as lesões hipóxico-isquêmicas e incidência de convulsões após o resfriamento são mais frequentes com o RSC. CONCLUSÃO: Tanto RCI quanto o RSC demonstraram propriedades neuroprotetoras, embora o RCI proporcione uma área de proteção cerebral mais ampla. No entanto, não foram constatadas diferenças significativas entre os métodos quanto a efeitos adversos e a resultados benéficos em curto e longo prazo.

Hipomagnesemia en recién nacidos con encefalopatía hipóxico isquémica en hipotermia corporal total / Hypomagnesemia in newborns with hypoxic ischemic encephalopathy and whole-body hypothermia

Resumen: Introducción: En recién nacidos (RN) con encefalopatía hipóxico isquémica (EHI) en hipotermia se describen alte raciones metabólicas que se asocian a pronóstico neurológico. La hipomagnesemia ha sido reportada en la literatura, pero no es medida ni corregida en todos los centros de atención neonatal. Objeti vo: Evaluar la frecuencia de hipomagnesemia e hipocalcemia en RN con EHI en tratamiento con hipotermia corporal total y evaluar la respuesta al aporte de sulfato de magnesio. Pacientes y Méto do: Estudio prospectivo, observational y descriptivo en RN con EHI sometidos a hipotermia corporal total, hospitalizados entre los años 2016-2017. Se realizó medición seriada en sangre de magnesemia (Mg) y calcemia (Ca). Con Mg menor o igual de 1,8 mg/dl se administró suplemento como sulfato de Mg para mantener niveles entre 1,9 y 2,8 mg/dl. Se describió la frecuencia de hipomagnesemia e hipocalcemia y su presentación en el tiempo. Se realizó registro prospectivo de evolución clínica. Se hizo un análisis estadístico descriptivo, con medidas de tendencia central. Resultados: Se incluyeron 16 pacientes. Presentaron hipomagnesemia 13/16 (81,3%), la que fue precoz (6-36 h de vida), nor malizándose con aporte de sulfato de magnesio, requiriendo 2a dosis 4 de ellos. Presentaron hipo- calcemia 6/16 (37,5%). Conclusiones: La hipomagnesemia es frecuente (80%), similar a lo descrito en la literatura. Dado su importancia fisiológica debe controlarse y corregirse, de igual manera que el calcio.

Abstract: Introduction: In newborns with the diagnosis of hypoxic-ischemic encephalopathy (HIE) treated with hypother mia, metabolic alterations are observed, which are associated with neurological prognosis. Hypo magnesemia has been reported frequently in the literature in these patients, but it is not measured or corrected in all neonatal healthcare centers. Objective: To evaluate the frequency of hypomag nesemia and hypocalcemia in newborns with HIE treated with whole-body hypothermia and to evaluate the response to the magnesium sulfate administration. Patients and Method: Prospective, observational and descriptive study in hospitalized newborns with the diagnosis of HIE and trea ted with whole-body hypothermia between the years 2016 and 2017. Serial blood measurement of magnesemia (Mg) and calcemia (Ca) was performed. When presenting an Mg level < 1.8 mg/dl, supplementation with magnesium sulfate was administered to maintain levels between 1.9 and 2.8 mg/dl. The frecuency of hypomagnesemia, hypocalcemia and clinical evolution was registered. A descriptive statistical analysis was performed, with central tendency measures. Results: Sixteen ca ses were included, 13 of them presented hypomagnesemia (81.3%), with early-onset (6-36 hours of life), which was normalized with magnesium sulfate treatment, receiving a second dose 4 patients. Six of 16 patients presented hypocalcemia (37.5 %). Conclusions: Hypomagnesemia is frequent (80%), similar to that described in the literature, and should be controlled and corrected early, given its physiological role, in the same way that calcium is controlled.

Hipotermia neuroprotetora tardia / Late hypothermic neuroprotection

A parada cardiorrespiratória é um evento de alta mortalidade. A isquemia cerebral difusa relacionada ao hipofluxo cerebral frequentemente leva à injúria neurológica grave e ao desenvolvimento de estado vegetativo persistente. A hipotermia terapêutica representa um importante avanço no tratamento da encefalopatia anóxica pós-parada cardíaca. Seus efeitos neuroprotetores têm sido amplamente demonstrados em várias situações de isquemia neuronal. Apesar de ser um procedimento associado com redução de mortalidade nestes pacientes, a hipotermia ainda é um tratamento subutilizado no manejo da síndrome pós-ressuscitação. Nosso objetivo foi demonstrar que a hipotermia neuroprotetora tem efeito benéfico mesmo realizada tardiamente naqueles pacientes comprovadamente encefalopatas como consequência de baixo fluxo cerebral devido à parada cardiorrespiratória que mantém um nível neurológico baixo (Glasgow abaixo de 8). Este fato é demonstrado pelo não uso de substâncias neurodepressoras nas últimas 48 horas, e o ganho para o paciente seria maior que os prováveis riscos que a hipotermia pode ocasionar. Este relato mostra os efeitos benéficos no paciente submetido ao tratamento da hipotermia neuroprotetora tardiamente, evoluindo satisfatoriamente, visto que foi devolvido à sociedade em Glasgow 14 e com independência suficiente para atender suas necessidades humanas básicas. Era um paciente do sexo masculino, 25 anos, pardo, solteiro, imigrante ilegal oriundo da Bolívia, auxiliar de costura, com história de mal súbito enquanto praticava futebol com amigos em quadra ao ar livre. Deu entrada no pronto-socorro em parada cardiorrespiratória por taquicardia ventricular. Foram realizadas manobras de reanimação com cardioversão elétrica e massagem cardíaca e não houve relato do tempo de parada cardíaca. Foi transferido para a unidade de terapia intensiva adulto com hipótese diagnóstica de encefalopatia anóxica pós-parada cardiorrespiratória sem uso de drogas vasoativas em Glasgow 6.(AU)

Cardiac arrest is a high-mortality event. Brain hypoflow-related diffuse cerebral ischemia often leads to severe neurological injury, and to the development of a persistent vegetative state. Therapeutic hypothermia is an important advance in the treatment of anoxic encephalopathy after cardiac arrest. Its neuroprotective effects have been widely demonstrated in several situations of neuronal ischemia. Although the procedure is associated with reduced mortality, hypothermia is still an underused treatment in the management of post-resuscitation syndrome. Our goal was to demonstrate that neuroprotective hypothermia is effective even when performed late in patients with encephalopathies from brain hypoflow due to cardiac arrest with a low neurological level (Glasgow below 8). This is demonstrated by the lack of neurodepressant substances in the previous 48 hours, and patient benefit would be higher than the probable risks that hypothermia could cause. This report shows the beneficial effects in the patient undergoing delayed neuroprotective hypothermia, who progressed satisfactorily, since taken back to Glasgow 13 with sufficient independence to meet basic human needs. The patient was a male of 25 years old, dark-skinned, single, an illegal immigrant from Bolivia, sewing assistant, with a history of sudden cardiac arrest, which occured while playing soccer outdoors. He was admitted to the emergency room in cardiopulmonary arrest (CPA) due to ventricular tachycardia. Resuscitation maneuvers with electrical cardioversion and cardiac massage were performed, and there is no reported time of cardiac arrest. He was transferred to the Adult Intensive Care Unit with a diagnosis hypothesis of anoxic encephalopathy after cardiac arrest, with no use of vasoactive drugs in Glasgow 6.(AU)

Early amplitude-integrated electroencephalography for monitoring neonates at high risk for brain injury / Eletroencefalograma de amplitude integrada precoce no monitoramento de neonatos com risco elevado de lesão cerebral

Abstract Objective: This study aimed to correlate amplitude-integrated electroencephalography findings with early outcomes, measured by mortality and neuroimaging findings, in a prospective cohort of infants at high risk for brain injury in this center in Brazil. Methods: This blinded prospective cohort study evaluated 23 preterm infants below 31 weeks of gestational age and 17 infants diagnosed with hypoxic-ischemic encephalopathy secondary to perinatal asphyxia, with gestational age greater than 36 weeks, monitored with amplitude-integrated electroencephalography in a public tertiary center from February 2014 to January 2015. Background activity (classified as continuous, discontinuous high-voltage, discontinuous low-voltage, burst-suppression, continuous low-voltage, or flat trace), presence of sleep-wake cycling, and presence of seizures were evaluated. Cranial ultrasonography in preterm infants and cranial magnetic resonance imaging in infants with hypoxic-ischemic encephalopathy were performed. Results: In the preterm group, pathological trace or discontinuous low-voltage pattern (p = 0.03) and absence of sleep-wake cycling (p = 0.019) were associated with mortality and brain injury assessed by cranial ultrasonography. In patients with hypoxic-ischemic encephalopathy, seizure patterns on amplitude-integrated electroencephalography traces were associated with mortality or brain lesion in cranial magnetic resonance imaging (p = 0.005). Conclusion: This study supports previous results and demonstrates the utility of amplitude-integrated electroencephalography for monitoring brain function and predicting early outcome in the studied groups of infants at high risk for brain injury.

Resumo Objetivo: Este estudo visou correlacionar os achados do eletroencefalograma de amplitude integrada (aEEG) com resultados precoces, medidos por mortalidade e achados de neuroimagem, em uma coorte prospectiva de neonatos com risco elevado de lesão cerebral em nosso centro no Brasil. Métodos: O estudo prospectivo de coorte cego avaliou 23 neonatos prematuros abaixo de 31 semanas de idade gestacional (IG) e 17 neonatos diagnosticados com encefalopatia hipóxico-isquêmica (EHI) secundária à asfixia perinatal, com IG superior a 36 semanas, monitorados com aEEG em um centro terciário público de fevereiro de 2014 a janeiro de 2015. Foram avaliadas a atividade de fundo (classificada como padrão contínuo, descontínuo de alta voltagem, descontínuo de baixa voltagem, supressão de explosão, contínuo de baixa voltagem ou traço plano), a presença de ciclo do sono-vigília e a presença de convulsões. Foram feitas a ultrassonografia craniana em prematuros e a ressonância magnética (RMI) craniana em neonatos com EHI. Resultados: No grupo de prematuros, o traço patológico ou padrão descontínuo de baixa voltagem (p = 0,03) e a ausência de ciclo do sono-vigília (p = 0,019) foram associados a mortalidade e lesão cerebral avaliada por ultrassonografia craniana. Em pacientes com EHI, os padrões de convulsão nos traços do aEEG foram associados a mortalidade ou lesão cerebral na RMI craniana (p = 0,005). Conclusão: Este estudo corrobora os resultados anteriores e demonstra a utilidade do aEEG no monitoramento da função cerebral e na predição de alterações precoces nos grupos de neonatos estudados com risco elevado de lesão cerebral.

Brain caspase-3 and intestinal FABP responses in preterm and term rats submitted to birth asphyxia

Neonatal asphyxia can cause irreversible injury of multiple organs resulting in hypoxic-ischemic encephalopathy and necrotizing enterocolitis (NEC). This injury is dependent on time, severity, and gestational age, once the preterm babies need ventilator support. Our aim was to assess the different brain and intestinal effects of ischemia and reperfusion in neonate rats after birth anoxia and mechanical ventilation. Preterm and term neonates were divided into 8 subgroups (n=12/group): 1) preterm control (PTC), 2) preterm ventilated (PTV), 3) preterm asphyxiated (PTA), 4) preterm asphyxiated and ventilated (PTAV), 5) term control (TC), 6) term ventilated (TV), 7) term asphyxiated (TA), and 8) term asphyxiated and ventilated (TAV). We measured body, brain, and intestine weights and respective ratios [(BW), (BrW), (IW), (BrW/BW) and (IW/BW)]. Histology analysis and damage grading were performed in the brain (cortex/hippocampus) and intestine (jejunum/ileum) tissues, as well as immunohistochemistry analysis for caspase-3 and intestinal fatty acid-binding protein (I-FABP). IW was lower in the TA than in the other terms (P<0.05), and the IW/BW ratio was lower in the TA than in the TAV (P<0.005). PTA, PTAV and TA presented high levels of brain damage. In histological intestinal analysis, PTAV and TAV had higher scores than the other groups. Caspase-3 was higher in PTAV (cortex) and TA (cortex/hippocampus) (P<0.005). I-FABP was higher in PTAV (P<0.005) and TA (ileum) (P<0.05). I-FABP expression was increased in PTAV subgroup (P<0.0001). Brain and intestinal responses in neonatal rats caused by neonatal asphyxia, with or without mechanical ventilation, varied with gestational age, with increased expression of caspase-3 and I-FABP biomarkers.

Neuroprotective body hypothermia among newborns with hypoxic ischemic encephalopathy: three-year experience in a tertiary university hospital. A retrospective observational study / Hipotermia corpórea neuroprotetora em recém-nascidos com encefalopatia hipóxico-isquêmica: três anos de experiência em hospital universitário terciário. Um estudo observacional retrospectivo

CONTEXT AND OBJECTIVE:Neonatal hypoxic-ischemic encephalopathy is associated with high morbidity and mortality. Studies have shown that therapeutic hypothermia decreases neurological sequelae and death. Our aim was therefore to report on a three-year experience of therapeutic hypothermia among asphyxiated newborns.DESIGN AND SETTING:Retrospective study, conducted in a university hospital.METHODS:Thirty-five patients with perinatal asphyxia undergoing body cooling between May 2009 and November 2012 were evaluated.RESULTS:Thirty-nine infants fulfilled the hypothermia protocol criteria. Four newborns were removed from study due to refractory septic shock, non-maintenance of temperature and severe coagulopathy. The median Apgar scores at 1 and 5 minutes were 2 and 5. The main complication was infection, diagnosed in seven mothers (20%) and 14 newborns (40%). Convulsions occurred in 15 infants (43%). Thirty-one patients (88.6%) required mechanical ventilation and 14 of them (45%) were extubated within 24 hours. The duration of mechanical ventilation among the others was 7.7 days. The cooling protocol was started 1.8 hours after birth. All patients showed elevated levels of creatine phosphokinase, creatine phosphokinase- MB and lactate dehydrogenase. There was no severe arrhythmia; one newborn (2.9%) presented controlled coagulopathy. Four patients (11.4%) presented controlled hypotension. Twenty-nine patients (82.9%) underwent cerebral ultrasonography and 10 of them (34.5%) presented white matter hyper-echogenicity. Brain magnetic resonance imaging was performed on 33 infants (94.3%) and 11 of them (33.3%) presented hypoxic-ischemic changes. The hospital stay was 23 days. All newborns were discharged. Two patients (5.8%) needed gastrostomy.CONCLUSION:Hypothermia as therapy for asphyxiated newborns was shown to be safe.

CONTEXTO E OBJETIVO:A encefalopatia hipóxico-isquêmica neonatal apresenta alta morbi-mortalidade. Estudos com hipotermia comprovam diminuição de sequelas neurológicas e morte. Nosso objetivo foi então relatar experiência de três anos da hipotermia terapêutica em recém-nascidos (RN) asfixiados.TIPO DE ESTUDO E LOCAL:Estudo restrospectivo, conduzido em hospital universitário.MÉTODOS:Trinta e cinco pacientes com asfixia perinatal submetidos a resfriamento corporal entre maio de 2009 e novembro de 2012 foram avaliados.RESULTADOS:Trinta e nove RN preencheram os critérios do protocolo de hipotermia. Quatro RN foram excluídos devido a choque séptico refratário, não manutenção da temperatura e coagulopatia grave. A mediana do Apgar de 1 e 5 minutos foi de 2 e 5. A maior complicação foi infecção, diagnosticada em sete mães (20%) e 14 RN (40%). Convulsão ocorreu em 15 RN (43%). 31 pacientes (88,6%) necessitaram da ventilação mecânica e 14 (45%) foram extubados em 24 horas. O tempo de ventilação mecânica dos demais foi de 7,7 dias. O início do resfriamento ocorreu com 1,8 horas de vida. Todos os pacientes apresentaram níveis elevados de creatinofosfoquinase, creatinofosfoquinase-MB e desidrogenase lática. Não se observou arritmia grave; um RN (2,9%) apresentou coagulopatia controlada. Quatro pacientes (11,4%) tiveram hipotensão controlada. Realizou-se ultrassonografia cerebral em 29 pacientes (82,9%), 10 (34,5%) com hiperecogenicidade da substância branca. 33 RN (94,3%) fizeram ressonância magnética cerebral, 11 (33,3%) com alterações hipóxico-isquêmicas. O tempo de internação foi de 23 dias e todos receberam alta. Dois pacientes (5,8%) necessitaram de gastrostomia.CONCLUSÃO:A hipotermia como terapêutica para RN asfixiados demonstrou ser segura.

Hipoxia perinatal y su impacto en el neurodesarrollo / Perinatal hypoxia and its impact on neurodevelopment

Durante el periodo perinatal el cerebro puede quedar privado de oxígeno por dos mecanismos importantes: la hipoxemia y la isquemia. El primero consiste en una disminución de la concentración de oxígeno en sangre y el segundo en la cantidad de sangre que riega al cerebro. Clínicamente se le conoce como encefalopatía hipoxia-isquémica al síndrome caracterizado por la suspensión o grave disminución del intercambio gaseoso a nivel de la placenta o de los pulmones, que resulta en hipoxemia, hipercapnia e hipoxia tisular con acidosis metabólica. Los cambios metabólicos resultantes provocan a corto plazo daño necrótico y a largo plazo daño apoptótico. Las principales lesiones neurológicas que se presentan son la necrosis neuronal selectiva, la lesión cerebral parasagital y la leucomalacia periventricular, provocando secuelas como la parálisis cerebral, epilepsia, problemas en el habla y el lenguaje, auditivos y neuropsicológicos, siendo los procesos, atencionales, mnémicos, y visuoespaciales los más representativos en este rubro. En México se reporta una incidencia de 14.6 por cada 1,000 recién nacidos vivos, con una letalidad del 8.5 por ciento y un índice de secuelas de 3.6 por ciento. A pesar de la gran cantidad de estos estudios sobre secuelas de la hipoxia perinatal aún son pocos los programas a nivel institucional enfocados en el diagnóstico y tratamiento temprano.

During the perinatal period the brain can be deprived of oxygen by two major mechanisms, hypoxemia and ischemia. The first consists in a decrease in blood oxygen concentration and the second in the amount of blood that irrigates the brain. Clinically, it is known as hypoxic-ischemic encephalopathy; a syndrome characterized by severe suspension or decreased gas exchange in the placenta or lungs, resulting in hypoxemia, hypercapnia and tissue hypoxia with metabolic acidosis. A metabolic short-term change causes necrotic damage and long-term change causes apoptotic damage. The main neurological injuries that occur are selective neuronal necrosis, parasagittal brain injury and periventricular leukomalacia, causing sequelae such as cerebral palsy, epilepsy, speech and language disorders, lost hearing and neuropsychological deficits, especially in attentional, mnemonic, and visuospatial proceses. In our country, an incidence of 14.6 per 1,000 live births, with a mortality rate of 8.5 percent and 3.6 sequels index percent are reported. Despite the large number of studies about consequences of perinatal hipoxia are still few institutional level programs focused on early diagnosis and treatment.

Inibição do receptor de glutamato do tipo NMDA em um modelo de hipóxia-isquemia prenatal: avaliação morfofuncional do cerebelo / Inhibition of glutamate NMDA receptor in a prenatal hipoxia-ischemia model: morphofunctional analises of cerebellum

Lesões sistêmicas peri e pré-natais alteram o desenvolvimento do SNC, levando a problemas cognitivos e motores em crianças que podem perdurar por toda a vida. Um tipo particular de lesão é a hipóxia-isquemia (HI), caracterizada pela interrupção momentânea ou permanente do fluxo sanguíneo. Um dos mecanismos propostos para as lesões decorrentes da HI é a excitotoxicidade glutamatérgica. O uso de inibidores da neurotransmissão glutamatérgica tem sido estudados em diversos modelos de HI. Neste trabalho, avaliamos os efeitos morfofuncionais da administração de um antagonista não-competitivo do receptor de glutamato NMDA sobre o desenvolvimento do cerebelo. Ratas no 18º dia de gestação foram anestesiadas, os cornos uterinos expostos e as 4 artérias uterinas obstruídas por 45 minutos (Grupo H). Animais controle tiveram os úteros expostos, sem a obstrução (Grupo S). Após a cirurgia a gestação prosseguiu. Somente animais nascidos a termo foram utilizados. Um dia após o nascimento, metade de cada ninhada foi designada para receber MK801, 0,3mg/kg/dia, (grupos SM e HM) e a outra metade recebeu solução salina (grupos SS e HS), por 5 dias. Após anestesia e perfusão-fixação com paraformaldeído 4% aos 9, 23, 30 e 60 dias pós-natais, cortes parassagitais do cerebelo foram obtidos em criótomo e submetidos à imunohistoquímica para calbindina, GFAP, GLAST, PDGFRα e MBP. A partir de 45 dias de vida, os animais foram testados em vários de testes comportamentais: labirinto em cruz elevado (LCE), campo vazado (CV), ROTAROD, teste de caminhada sobre barras (ladder test) e teste do comprimento da passada (stride length). Aos 9 dias, a espessura da árvore dendrítica era menor nos animais SM, HS/HM, demonstrando efeitos deletérios tanto do MK801 quanto da HI. Menor número de células PDGFRα+ foi observado nos animais HS/HM, sem efeitos da administração de MK801. Aos 23 dias, maior número de células PDGFRα+ foi observado nos animais HM comparado aos outros 3 grupos, indicando efeito ...

Peri and prenatal systemic lesions alter CNS development leading to motor and cognitive problems in children that might persist throughout life. A particular kind of injury, the hypoxic ischemic (HI), is characterized by a permanent or temporary blockage of blood flow. One of the proposed mechanisms downstream from a HI event is called glutamatergic excitotoxicity. The administration of glutamate inhibitors has been studied in HI models for several years. In this work, we evaluated the effects of administration of a non-competitive antagonist of glutamate receptor, NMDA, on cerebellar development and behavioral tests of HI animals. Pregnant rats in the 18th gestational day were anesthetized, the uterine horns were exposed and the four uterine arteries were clamped for 45 minutes (group H). Sham controls had the uterine horns exposed, but no arteries were clamped (group S). Gestation proceeded after surgery. Only full term animals were used. One day after birth half the animals was assigned to receive either SALINE (groups SS and HS) or MK801 (groups SM and HM). Animals were anesthetized and perfused with 4% paraformaldehyde at 9, 23, 30 and 60 days of age. Parasagittal cerebellar sections were submitted to Calbindin, GFAP, GLAST, PDGFRα and MBP immunohistochemistry. Beginning at P45 animals were subjected to a battery of behavioral tests: elevated plus maze (EPM), hole board (HB), ROTAROD, ladder test and stride length. At P9 the dendritic tree of Purkinje cells were thinner in SM, HS/HM animals, indicating that both HI and MK801 are deleterious regarding this Purkinje cell differentiation. A lower number of PDGFRα+ cells was observed in HS/HM animals, with no effects of MK801 administration. At P23 a greater number of PDGFRα+ cells was found in HM animals when compared to the other 3 groups, demonstrating a neuroprotector effect of MK801. A lower number of myelinated fibers (MBP+) was observed in HS animals at P9, and MK801 administration reverse this ...

Status epilepticus and capillary leak syndrome in a neonate related to perinatal hypoxic-ischemic encephalopathy.

Hypoxic-ischemic cerebral injury that occurs during the perinatal period is one of the most commonly recognized cause of long-term neurological deficit in children, often referred to as cerebral palsy. We describe a case with capillary leak syndrome and seizures to co-morbid status epilepticus related to perinatal hypoxicischemic encephalopathy in newborn period.

Efeitos da hipóxia-isquemia perinatal sobre o comportamento motor, distribuição da Tirosina Hidroxilase na substância negra e da NADPH diaforase no hipocampo durante o desenvolvimento em ratos / Effects of hypoxia-ischemia under motor behavior, tyrosine hydroxylase distribution in the nigra substantia and the diaphorase NADPH in hippocampus in rats

A hipóxia isquemia (HI) pré-natal é uma das principais causas de mortalidade e doenças neurológicas crônicas em neonatos, que podem apresentar déficits remanentes como: retardamento, paralisia cerebral, dificuldade de aprendizado ou epilepsia. Estes prejuízos, provavelmente, estão relacionados com o atraso no desenvolvimento neural, astrogliose e com a perda de neurônios e oligodendrócitos. Déficits funcionais e cognitivos estão associados à degeneração de vias dopaminérgicas e de estruturas hipocampais. A enzima tirosina hidroxilase (TH) é a enzima limitante na síntese de dopamina e seus níveis são alterados em eventos de HI. O óxido nítrico (NO) é um gás difusível que atua modulando diferentes sistemas, participando de eventos como plasticidade sináptica e neuromodulação no sistema nervoso central e é produzido em grandes quantidades em eventos de injúria e inflamação, como é o caso da HI. O presente estudo teve por objetivos avaliar, utilizando o modelo criado por Robinson e colaboradores em 2005, os efeitos da HI sobre o comportamento motor e avaliar o desenvolvimento de estruturas encefálicas relacionadas a este comportamento como a substância negra (SN) e o complexo hipocampal. A HI foi induzida a partir do clampeamento das artérias uterinas da rata grávida, por 45 minutos no décimo oitavo dia de gestação (grupo HI). Em um grupo de fêmeas a cirurgia foi realizada, mas não houve clampeamento das artérias (grupo SHAM). A avaliação do comportamento motor foi realizada com os testes ROTAROD e de campo aberto em animais de 45 dias. Os encéfalos foram processados histologicamente nas idades de P9, P16, P23 e P90, sendo então realizada imunohistoquímica para TH e histoquímica para NADPH diaforase (NADPH-d), para avaliação do NO. Nossos resultados demonstraram redução da imunorreatividade para a TH em corpos celulares na SN aos 16 dias no grupo HI e aumento na imunorreatividade das fibras na parte reticulada aos 23 dias, com a presença de corpos celulares...

Perinatal hypoxia-ischemia (HI) is one of the major causes of mortality and chronic neurological diseases in newborns that can show permanent effects such as mental retardation, cerebral palsy, learning difficulty and epilepsy. It is probable that these impairs may be related to a delay in the neural development, astrogliosis and to the death of neurons and oligodendrocytes. Cognitive and functional deficits are related to degeneration of dopaminergic pathways and hippocampus. The enzyme tyrosine hydroxylase (TH) is a limiting step in the dopamine synthesis and its levels are impaired in HI insults. Nitric oxide (NO) is a diffusible gas that acts by modulating different systems and participates in several phenomena such as synaptic plasticity and neuromodulation in the central nervous system and is produced in higher levels in events of injury and inflamation as in the case of HI. This study aimed to evaluate the effects of HI on the motor behavior and to evaluate the development of brain structures related to this behavior as the substantia nigra (SN) and the hippocampal complex, using the model developed by Robinson and colleagues in 2005. HI was induced by clamping the uterine arteries of pregnant rats, for 45 minutes, on the eighteenth day of gestation (group HI). In a group of females, the surgery was performed, but no clamping of the arteries (group SHAM) was made. Assessment of motor behavior was performed with the ROTAROD test and open field test in animals of 45 days (P45) of age. The brains were processed histologically at ages P9, P16, P23 and P90, and then submitted to immunohistochemistry for TH and NADPH diaphorase (NADPH-d) histochemistry for evaluation of NOS. Our results demonstrated an apparent decrease in TH immunoreactivity in cell bodies in the SN at P16 in the HI group and an increase in immunoreactivity of the fibers in the SN pars reticulata at P23 with the presence of TH immunoreactive cell bodies at this same region in the HI group...

Neuropatía auditiva, diagnóstico y manejo audiológico / Auditory neuropathy / dyssychrony, assessment and audiologic management

Los hallazgos clínicos que definen una neuropatía/des sincronía (NA/DA) son la integridad de las células ciliadas evidenciado, mediante la presencia de emisiones otoacústicas evocadas (EOAe) y/o la presencia de potenciales microfónicos cocleares (PMIC), junto con la ausencia de actividad neural evocada a nivel del VIII par craneano (potencial de acción compuesto) y tronco cerebral (potencial evocado auditivo de tronco (PEAT)). Las condiciones clínicas relacionadas con una NA/DA incluyen a la hiperbilirrubinemia, enfermedades neurovegetativas (ejemplo ataxia de Friedreich), síndrome de Charcot-Marie-Tooth así como otras neuropatías sensoriomotoras, desórdenes mitocondriales y neuropatías isquémica-hipóxicas como resultados de asfixia. El desarrollo de las habilidades auditivas y comunicacionales pueden estar comprometidas en forma importante en los niños con aparición prelingual de una NA/DA, mayor es aún este compromiso al no existir un perfil pronóstico preestablecido del desarrollo y resultados en el tratamiento de este desorden. En la actualidad existen múltiples estudios en donde se ha observado que hasta 50 por ciento de los pacientes con NA/DA presentan algún grado de beneficio al usar audífonos por lo que se sugiere que sistemas de amplificación como los audífonos o incluso implante coclear deberían ser el primer paso en el proceso de (re)habilitación.

The clinical findings that define an auditory neuropathy/dyssynchrony (AN/Dys) are the integrity of the outer hair cells demonstrated by the presence of evoked otoacoustics emissions (OAEe) and/or the presence of cochlear microphonic potential (CMP) along with the absence of neural activity evoked at level of VIII nerve (action potential compound) and brainstem (Auditory Brainstem Response, ABR). The clinical conditions related to an AN they include hiperbilirrubinemia, neurodegenerative diseases (eg ataxia of Friedreich), Charcot-Marie-Tooth syndrome as well as other sensoriomotor neuropathies, mitocondrial disorders and hypoxic neuropathy as perinatal asphyxia. The development of the auditory and communicational abilities can be compromise in children with prelingual onset of an AN/Dys, the development and results of treatment of this disorder is still this commitment when not existing a profile prognosis. At the present time multiple studies have been observed that until a 50 percent of the patients with AN present some degree of benefit using hearing aids, reason why it suggests amplification systems as the hearing aids or even cochlear implant would have to be the first step in the process of (re) habilitation of these patients.

Tratamiento del estado epiléptico refractario con topiramato oral / Treatment of refractory status epilepticus with topiramate: report of three cases

Refractory status epilepticus is a catastrophic illness of the central nervous system, with a mortality rate that reaches 50 percent. We report three patients admitted with refractory status epilepticus: a 24 year-old male that discontinued antiepileptic medications, a 46 year-old male with a focal epilepsy secondary to an encephalitis that discontinued medications due to gastrointestinal problems and a 59 year-old male with an ischemic encephalopathy AH were treated with topiramate, delivered through a nasogastric tube with a good response.

Leucoencefalopatía hipóxico-isquémica retardada: caso clínico y revisión de la literatura / Hypoxic-ischemic delayed leukoencephalopathy: case report and review of the literature

Delayed Hypoxic-isquemic Leucoencephalopathy described in 1976 by Ginsberg is a brain white matter demyelinization phenomenon that occurred days or weeks after a hypoxic-isquemic injury followed by a complete recovery of the episode. The pathogenesis process remains unknown. We describe a 48 year old woman with cervico-uterine cancer in palliative treatment with opoids. She enters the emergency room with a respiratory depression, a prolonged hypotension and confusion, that it was recovered. At admission exhibits a recurrent pneumonia. Two weeks later, in conditions of discharge, initiates with agitation in context with rapidly progressive decline cognition, with concordant lesions of Leucoencephalopathy defined in the Magnetic Resonance (MR) study The metabolic profile, the cerebrospinal fluid and the electroencephalogram allowed dismissing other etiologic hypothesis. In front to the suspicious of Ginsberg syndrome, she had normal levels of Arylsulfatase. This acute post-hypoxic demyelinization process has been pathogenic interpreted as an arylsulfatase deficiency. Although numerous cases develop with normal arylsulfatase and the experimental studies of hypoxia, has support the hypothesis of a central hypoxic axonopathy due to failing in axonal transport as the base of the demyelinization phenomenal.

La leucoencefalopatía hipóxico-isquémica retardada (EHIR), descrita por Ginsberg en el año 1976, es un fenómeno desmielinizante de la sustancia blanca cerebral, que se origina días o semanas después de un daño hipóxico-isquémico que había sido seguido de una recuperación completa del episodio. La patogenia del proceso no está completamente establecida. Se presenta una mujer de 48 años portadora de cáncer cérvicouterino, en tratamiento paliativo con opiáceos. Ingresa al Servicio de Urgencia por una depresión respiratoria, hipotensión prolongada y compromiso de conciencia, donde es recuperada. Se hospitaliza por una neumopatía intercúrrente. Dos semanas más tarde, estando en condiciones de alta, se inicia agitación psicomotora en el contexto de un deterioro cognitivo rápidamente progresivo, que el estudio de Resonancia Magnética (RM) definió como lesiones concordantes con una leucoencefalopatía. El perfil metabólico, el líquido cefalorraquídeo y el electroencefalograma, permitieron descartar otras hipótesis etiológicas. Frente a la sospecha de un síndrome de Ginsberg, los niveles de arilsulfatasa fueron normales. Este proceso desmielinizante agudo post-hipóxico, ha sido interpretado patogénicamente como un déficit de arilsulfatasa. Sin embargo, la existencia de numerosos casos que cursan con arilsulfatasa normal y los estudios experimentales de hipoxia, ha avalado la hipótesis de una axonopatía central hipóxica, atribuible a fallas del transporte axoplásmico, como base para el fenómeno desmielinizante.

Neonatal hypoglycemic brain - injury a common cause of infantile onset remote symptomatic epilepsy.

OBJECTIVES: To study the etiology of remote symptomatic epilepsy with onset in the first 3 years of life. Patients with neonatal hypoglycemic brain injury (NHBI), were further studied for risk factors and clinical features. METHODS: The study was conducted at a tertiary pediatric neurology service between May-August 2004. Consecutive patients were recruited prospectively. The probable etiological diagnoses were based primarily on cranial imaging. Two radiologists, blinded to the etiological diagnosis, reviewed the cranial imaging and suggested the likely etiology based on published imaging criteria. There were three categories i.e, (i) perinatal encephaloclastic conditions (PEC) e.g., hypoxic ischemic encephalopathy (HIE) etc, (ii) developmental (DV) e.g., tuberous sclerosis, etc and (iii) postnatal (PN) e.g., trauma, etc. Three risk factors (birth weight, type of delivery, feeding difficulty) were compared between NHBI and developmental etiology (DV) groups. Neurological findings were compared between the NHBI vs the other perinatal groups. Seizure details were studied only in the NHBI group. RESULTS: 63 boys and 37 girls were recruited. Mean age of seizure onset was 13.9 months. PEC were seen in 50 patients, DV in 28 patients and PN in 5. NHBI was seen in 23 patients and was the most frequent cause of epilepsy. Low birth weight (LBW), neonatal feeding difficulties and cesarean delivery were significant risk factors for NHBI vis a vis the DV group. Microcephaly, autism, visual impairment and apraxia of hand use were common while spasticity or dystronia were rare in NHBI. Spasms were the commonest seizure type. CONCLUSION: Neonatal hypoglycemia is the most common etiology of remote symptomatic infantile onset epilepsy. LBW, poor neonatal feeding and cesarean delivery are significant clinical correlates.

Effect of an isolated mild to moderate ischemic brain injury in the gastric emptying of liquids in rats / Efeito de lesão cerebral hipóxico-isquêmica isolada no esvaziamento gástrico de uma solução salina em ratos

PURPOSE: To evaluate the effect of hypoxic-ischemic brain injury over the gastric emptying of liquids in rats. METHODS: Fifty-two Wistar rats aged six weeks and weighing between 100g and 150g were divided in three groups. A Control group (C), a Sham group (S) undergoing sham procedure, and a Hypoxic-ischemic group (HI) consisting of 18 animals undergoing surgical ligature of the left carotid artery and exposure to hypoxic environment for three hours. Half of the animals were studied in the third day post-HI procedure (Early) and nine in the 14th day post-HI procedure (Late). Gastric emptying was evaluated by an infusion technique using fenolsulftalein as a marker. RESULTS: After the HI procedure, all animals displayed left eyelid ptosis, and six animals showed minor sideway gait. Histological examination confirmed de brain injury in all animals from the HI group. There was no statistical significant difference among the mean gastric retention values of the three groups neither in the Early nor in the Late evaluation. CONCLUSION: Isolated HI brain injury was not associated with delayed gastric emptying.

OBJETIVO: Avaliar o efeito de lesão cerebral hipoxico-isquêmica sobre esvaziamento gástrico (EG) de líquidos em ratos. MÉTODOS: Cinqüenta e dois ratos Wistar com seis semanas de idade e pesando entre 100g e 150g foram divididos em três grupos. Um grupo Controle (C), um grupo Sham (S) de 18 animais submetidos a manipulação da artéria carótida esquerda sem ligadura e um grupo Hipoxico-isquêmico (HI) que consistiu de 18 animais submetidos a ligadura cirúrgica da artéria carótida esquerda e exposição a ambiente hipóxico por três horas. Metade dos animais foi estudada no terceiro dia pós-procedimento (Precoce) e a outra metade no 14º dia pós-procedimento (Tardio). O EG de uma solução salina foi avaliado por uma técnica de infusão usando a fenolsulftaleína como um marcador. RESULTADOS: Após o procedimento de HI, todos os animais apresentaram ptose palpebral à esquerda e seis animais mostraram leve desvio da marcha. O exame histológico do cérebro confirmou lesão cerebral em todos os animais do grupo HI. Não foi observada diferença estatística significativa entre os valores médios da retenção gástrica dos três grupos nem nas observações Precoces nem nas Tardias. CONCLUSÃO: A lesão cerebral difusa isolada provocada por um episódio HI não esta associada com retarde de esvaziamento gástrico de uma refeição líquida não calórica.

Seizures in the newborn.

Seizures in the newborn period constitute a medical emergency. Subtle seizures are the commonest type of neonatal seizures, other types being clonic, tonic, and myoclonic. Myoclonic seizures carry the worst prognosis in terms of long-term neurodevelopmental outcome. Hypoxic-ischemic encephalopathy is the most common cause of neonatal seizures. Multiple etiologies often co-exist in neonates and hence it is essential to rule out conditions such as hypoglycemia, hypocalcemia, and meningitis before initiating specific therapy. A comprehensive approach for management of neonatal seizures has been described.

Short term Neurodevelopmental outcome of asphyxiated newborns at tertiary care unit

To find out the short term neurodevelopmental outcome of asphyxiated newborns. Cross-sectional study using prospective data. Neonatal unit of Children's Hospital, Lahore from August, 2000 to July, 2001. We included 150 cases of birth asphyxia and survivors were followed till the age of six months and neurodevelopmental status was assessed by Denver developmental screening test II [DDST-II]. Severity of asphyxia was categorized as no encephalopathy, three different stages of HIE. During follow up visits, normal to delayed developmental status was expected. Infants were divided into two groups. Group A included neonates without HIE and group B with encephlopathy. Among group B, newborns developmental delay was found in 9 neonates and 48 neonates died while in group A neonates there was no child who had developmental delay and only six newborns died.[P value<0.05] There were 117 [78%] males, 35 mothers [23%] had antenatal visits to trained medical professionals. Majority of mothers [76%] had their visits to non doctor personnel like midwives, lady health visitors or nurse. Majority [61%] of study population were home delivered, 24% at private clinics and maternity homes while only 14% came from hospitals. Different stages of HIE have strong correlation with the outcome of these neonates. More effort and resources should be directed to this preventable community problem

Risk factor analysis in asphyxiated newborns and their outcome in relation to stage of hypoxic ischemic encephalopathy

Hypoxic ischemic encephalopathy [HIE] is one of the common causes of neonatal mortality and long term sequale. The incidence is reported at 2-9/1000 live births. To find out the frequency of risk factors in asphyxiated newborns and outcome of these newborns in relation to the stage of hypoxic ischemic encephalopathy in hospital setting. Prospective descriptive study. This study was conducted in the Neonatology Unit of the Department of Paediatrics Unit-II, King Edward Medical University/Mayo hospital, Lahore, over a period of six months from April 01, 2006, to September 30, 2006. All the asphyxiated babies admitted during study period were included in study. Babies having congenital anomalies were excluded. The mothers were interviewed by using a pre-tested structured questionnaire. Out of 449 total admissions in study period, 227[51%] babies were asphyxiated. Eighty five [37%] newborns had stage I HIE, 39% had stage II and 24% had stage III HIE. One hundred and sixty four [73%] were full term. Majority of the newborns were male [60%]. One hundred and thirteen [49%] newborns were between 1.5 and 2.5kg. One hundred and thirty four [59%] babies delivered normally while seventy four [33%] were delivered by caesarian section. Hundred and sixty seven [74%] newborns were referred from government hospitals. Most of the deliveries [80%] were conducted by doctors. Majority of the mothers [48%] were below 25 years of age, 34% mothers were primigravida and 33% mothers received general anesthesia during labor. One hundred and sixty five [73%] babies had cephalic presentation. None of the deliveries were attended by a paediatrician in any of the cases. Maternal hypertension was found in 53 [23%] mothers, gestational diabetes in 9 [4%], hypoxia in 6 [3%], anemia in 31 [14%], toxemia in 19 [8%], pelvic abnormality in 30 [13%] and antepartum hemorrhage in 14 [6%]. No mother was found to be smoker. Eight [4%] babies had cord around the neck during delivery. One hundred and ten [48%] newborns were brought to the neonatal unit within one hour of delivery. Majority 21% of HIE I remained admitted in neonatology unit for less than 24 hours while 27[12%] of babies of HIE III died within 24 hour of admission. Among the factors studied, gestational age, weight, mode of delivery, birth attendant, sedation during labor and late arrival in neonatal unit were found to be significant with p value of < 0.05. HIE is caused by the risk factors that may be antepartum, intrapartum or postpartum. Monitoring for the known risk factors of asphyxia, proper training of primary birth attendants and improvement in neonatal resuscitation services can minimize the incidence of HIE

Brain white matter lesions correlated to newborns death and lethality

OBJECTIVES: to describe hospital lethality rates and factors correlated to death in neonates with brain white matter lesions. METHODS: a retrospective study was performed from January 1994 to December 2001. Neonates with white brain matter lesions were divided into survival and death groups and their medical files reviewed through the single blind method to determine evolution. Death certificates provided the cause of death. The groups were compared through correlation coefficients. Hospital lethality rate was calculated. RESULTS: ninety three cases of white brain matter lesions and seven deaths were determined. Hospital lethality rate was of 8.2. percent (95 percentCI: 2.4-14.0) independently from lesion occurrence time, and of 10.3 percent (95 percentCI: 3.3-17.3) for deaths occurred during prenatal and perinatal periods. Death was correlated to: Apgar score, non-cephalic presentation, gestational age, hyperglicemia, hypercalcemia, convulsion, respiratory insufficiency and atelectasy. CONCLUSIONS: hospital lethality was of 10.3 percent generating the following hypothesis: perinatal asphyxia must be the principal direct and indirect etiologic factor (aggravating the expression of prematurity and infection diseases), of prenatal and perinatal mortality among newborns with white brain matter lesions; and <7 Apgar score in the 5th minute associated to brain white matter lesions, are markers for perinatal asphyxia diagnosis.

OBJETIVOS: descrever a taxa de letalidade hospitalar e fatores correlacionados com o óbito em crianças com lesão da substância branca cerebral (LSB). MÉTODOS: estudo retrospectivo realizado de janeiro de 1994 a dezembro de 2001. Os neonatos com LSB foram divididos em sobreviventes ou óbito, e seus prontuários revisados de forma cega para a evolução. Dos atestados de óbito, a causa de morte. Os grupos foram comparados por coeficientes de correlação. Calculada a taxa de letalidade hospitalar. RESULTADOS: foram encontrados 93 casos de LSB e sete óbitos. A taxa de letalidade hospitalar foi de 8,2 por cento, (IC95 por cento: 2,4-14,0), independentemente da época de instalação da lesão, e de 10,3 por cento (IC95 por cento: 3,3-17,3) para aqueles de ocorrência pré/perinatal. O óbito correlacionou-se com: escore de Apgar, apresentação não-cefálica, idade gestacional, hiperglicemia, hipercalcemia, convulsão, insuficiência respiratória e atelectasia. CONCLUSÕES: a letalidade hospitalar foi de 10,3 por cento e as seguintes hipóteses foram geradas: a asfixia perinatal deve ser o principal fator etiológico, direto e indireto (agravando a expressão das doenças da prematuridade e da infecção), da mortalidade pré/perinatal entre neonatos com LSB; e o escore de Apgar do 5o minuto <7, associado à LSB, são marcadores para o diagnóstico de asfixia perinatal.