Dissertations / Theses on the topic 'Perinatal asphyxia'

Background: Neonatal encephalopathy is a common clinical condition affecting 2-3 per 1,000 neonates in the developed world. 10-15% of cases will die in the neonatal period. Therapeutic hypothermia has become the standard of care in the developed world for infants with moderate to severe neonatal encephalopathy only recently, after 2 decades of experimental and clinical studies. Approximately half the infants who receive therapeutic hypothermia still have an abnormal outcome. Research is now being focused on pre-clinical and Phase II clinical studies of drugs, which act synergistically or additively with therapeutic hypothermia. Magnetic resonance spectroscopy (MRS) techniques provide translational biomarkers, which may be used to speed up the development of safe and effective neuroprotective interventions. The precise relation between MRS and brain histology is unknown and it is unclear whether cooling itself alters the prognostic efficacy of MRS. Aim: (i) To explore the relation between MRS biomarkers and the degree of brain pathology observed in our pre-clinical piglet model of perinatal asphyxia; (ii) To assess the predictive value of MRS biomarkers in infants with neonatal encephalopathy Methods: In our piglet study, data from 2 large piglet asphyxia studies investigating neuroprotective agents were analysed. 1. The first was a study of Xenon-augmented hypothermia. Following transient hypoxia-ischemia, 36 piglets were randomised into 4 groups (each n=9), with intervention from 2-26 h: Group (i) normothermia (38.5oC); Group (ii) normothermia (38.5oC) + 24 h 50% inhaled xenon; Group (iii) 24 h therapeutic hypothermia (rectal temperature (Trectal) 33.5oC) or Group (iv) 24 h 50% inhaled xenon +24 h therapeutic hypothermia (Trectal 33.5oC). 2. The second was a study investigating Amiloride as a neuroprotective agent. Following transient hypoxia-ischemia, 18 male piglets (<24 h of age) were randomized to 2 groups (each n=9) (1) normothermia; or (2) 2.5mg/kg of methyl isobutyl amiloride (MIA) at 10 minutes after resuscitation and 8 hourly thereafter. Both studies were performed on a Bruker 4.7 Tesla MR system. Following resuscitation after hypoxia-ischemia, proton (1H) magnetic resonance (MR) spectra were acquired with repetition time (TR) 5 sec, 128 summed transients, and echo times (TE) 25 ms, 144 ms, and 288 ms. (we measured the following peak area ratios: Lactate/N acetyl aspartate (Lac/NAA) and Lactate/Creatine (Lac/Cr) in both white matter and thalamus). Phosphorus (31P) MR spectra were acquired from whole brain using single-pulse acquire with TR 10 s (we measured inorganic phosphate (Pi)/exchangeable phosphate pool (EPP = Pi + PCr + (2γ +β)-NTP), NTP/EPP). Immunohistochemistry was performed on brain sections for activated Caspase 3, TUNEL positive cells and Iba I (activated microglia) to quantify cell death and microglial activation. For the clinical study, we assessed 45 infants (median gestational age – 40 weeks) with moderate to severe neonatal encephalopathy admitted over a 3 year period to the neonatal unit at UCH. Their neurodevelopmental outcome was assessed at 18 months. Results: (i) Experimental Study - Early Biomarkers Early biomarkers (acquired between 2 and 4 hours after hypoxia-ischemia) in particular thalamic Lac/NAA, predicted the 1H MRS area under the curve values from 0-48h and quantitative immunohistochemistry at 48 hours. Late Biomarkers: WM Lac/Cr at 40-48h after HI demonstrated the highest positive correlation with Tunel positive cell death (R20.98, p = 0.01) and NTP/EPP with microglial ramification (R20.68, p = 0.006); this correlation was present in both treated and untreated piglets. (ii) In the clinical study, deep gray matter Lac/NAA was the most accurate predictor of long term adverse neurological outcome following NE; importantly the predictive accuracy of Lac/NAA was unaltered by preceding therapeutic hypothermia. Conclusions: (i) Early thalamic Lac/NAA predicted the subsequent trajectory of energy disruption; this has importance in understanding the relevance of very early MRS studies in babies. White matter lactate/Cr at 40-48h correlated best with quantitative immunohistochemistry (especially TUNEL positive cells) and this relationship was present with and without preceding therapeutic intervention. (ii) In babies with neonatal encephalopathy, the predictive accuracy of Lac/NAA was unaltered by therapeutic hypothermia.

This thesis describes the results of a study to investigate early cerebral changes in a piglet model of perinatal asphyxia using quantitative diffusion-weighted imaging (DWI) and subsequent work to develop a robust DWI technique to enable similar studies to be performed in neonates. 31Phophorus magnetic resonance spectroscopy and quantitative diffusion and T2 imaging of the cerebrum were performed in a piglet model of perinatal asphyxia. A significant decline in the ratio of phosphocreatine to inorganic phosphate concentrations ([PCr]/[Pi]) was observed during the 48 hours following the transient hypoxicischaemic (H-I) insult. The global directionally averaged apparent diffusion coefficient (ADCav) also declined significantly during the same period and a strong correlation between the [PCr]/[Pi] and ADCav was found. Strong regional and temporal variations in the cerebral response were observed following the H-I insult. In the basal ganglia and parasagittal cortex, significant decline in ADCs was seen approximately 8 hours after the H-I insult. In the thalamus, internal capsule, periventricular white matter and medial cortex, significant ADCs decline was not observed until 32 hours following the H-I insult. A significant T2 increase was observed in the internal capsule but not in the other regions of interest. To enable clinical DWI to be performed in neonates a novel `reacquisition' technique that overcomes the problem of motion artefact in DWI is presented. The reacquisition technique involves the automatic detection and reacquisition of motion-corrupted data in real-time. Computer simulations were used to demonstrate that motion-corrupted data may be detected accurately and reacquired in a time efficient manner. The reacquisition technique was implemented on a Bruker AVANCE scanner in combination with a spinecho 2DFT DWI sequence and an interleaved EPI DWI sequence. The effectiveness of the technique was demonstrated with both a computer-controlled motion phantom and neonates from an ongoing study of perinatal asphyxia.

Perinatal asphyxia remains a major cause of morbidity and mortality throughout the world. Despite improvements in obstetric and neonatal care there has been little improvement in rates of death and disability. Therapeutic hypothermia has recently been shown to be the only effective treatment following perinatal asphyxia. Selective Head Cooling (SHe) and Whole Body Cooling (WBe) are methods of applying therapeutic hypothermia. Yet the optimum method of cooling for maximum neuroprotection and minimum adverse effects remains unclear. We retrospectively compared four methods of cooling newborns following perinatal asphyxia. One method of SHC and three methods of WBC, using water-filled gloves, a coolant- filled mattress, and a water- filled body wrap. All methods maintained rectal t emperature within narrow target range. We found that WBC using a servo- controlled system minimised initial over-cooling and reduced subsequent fluctuation in rectal t emperature compared with manually-controlled WBC or SHe. We found similar variation in rectal temperature, heart rate, and mean arterial blood pressure using SHC and manually controlled WBe. We developed a technique of applying SHC with minimal systemic hypothermia as a t reatment for perinatal asphyxia in our established experimental model. We conducted a study to assess the neuroprotective and physiological effects of our technique compared to standard care under normothermic conditions. We did not find any difference in brain injury between treatment groups but increased mortality in the hypothermia group. We have.previously used a neuropathology score in our established model of perinatal asphyxia in order to assess treatment effects. Our neuropathology score incorporates subjective assessments of area injure'd and morphological cellular changes in several brain regions. We conducted quantitative cell counting to assess brain injury following perinatal asphyxia. Cell count correlated with neuropathology score in the putamen and hippocampus CA1 and we were able to validate our neuropathology score to assess outcome.

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As limitações dos métodos diagnósticos da asfixia perinatal levaram-nos a investigar se o monitoramento dos movimentos corporais do sono (MCS) e do ritmo de sono-vigília (S/V) pode ser utilizado como marcador diagnóstico deste processo patológico. Para tanto, os registros eletromiográfico e eletrocardiográfico de 8 ratos recém-nascidos, Wistar, com 6 a 48h de vida, foram obtidos durante 4 períodos experimentais: período controle - com ratos respirando ar atmosférico, por 30min; período de asfixia - com ratos submetidos a dois períodos de asfixia de 30min (T1 e T2), com seus corpos inteiramente envolvidos por filme de polivinil (PVC); e período de recuperação - com ratos respirando ar ambiente novamente, por 30min. A freqüência cardíaca diminuiu significantemente durante a asfixia, em relação à fase controle. Nós concluímos que o monitoramento dos MCS e do ritmo de sono-vigília se mostrou um parâmetro promissor no diagnóstico da asfixia perinatal e de suas complicações. Este fato, todavia, requer novas investigações para se estabelecer a real viabilidade do método para o uso rotineiro na prática clínica.
The limitations of current diagnostic methods of perinatal asphyxia induced to investigate if monitoring of body movements and of the sleep-wake rhythm can be used as diagnostic marker of this pathologic process. So, electromyogram and electrocardiogram records of 8 newborn Wistar rats, 6 to 48 hours postnatal, were obtained throughout 4 experimental periods: control period - with rats breathing room air for 30 min (ARpre); asphyxia periods - with rats submitted to two 30 min asphyxia periods (T1 and T2) with Its entire body covered with a polyvinyl sheet (PVC); and recovering period - with rats breathing room air for 30 min again. Asphyxia Heart rate was significantly decreased all over the asphyxia period compared with the control phase. In conclusion the monitoring of SBM, and of the sleep-wake rhythm seems to be of utmost value to the perinatal asphyxia diagnosis and its complications. This fact, however, requires new investigations to establish the real viability of the method for clinical practice routine.

Orientador: Katsumasa Hoshino
Banca: Lígia Maria Suppo de Souza Sugolo
Banca: Mônica Levy Andersen
Resumo: As limitações dos métodos diagnósticos da asfixia perinatal levaram-nos a investigar se o monitoramento dos movimentos corporais do sono (MCS) e do ritmo de sono-vigília (S/V) pode ser utilizado como marcador diagnóstico deste processo patológico. Para tanto, os registros eletromiográfico e eletrocardiográfico de 8 ratos recém-nascidos, Wistar, com 6 a 48h de vida, foram obtidos durante 4 períodos experimentais: período controle - com ratos respirando ar atmosférico, por 30min; período de asfixia - com ratos submetidos a dois períodos de asfixia de 30min (T1 e T2), com seus corpos inteiramente envolvidos por filme de polivinil (PVC); e período de recuperação - com ratos respirando ar ambiente novamente, por 30min. A freqüência cardíaca diminuiu significantemente durante a asfixia, em relação à fase controle. Nós concluímos que o monitoramento dos MCS e do ritmo de sono-vigília se mostrou um parâmetro promissor no diagnóstico da asfixia perinatal e de suas complicações. Este fato, todavia, requer novas investigações para se estabelecer a real viabilidade do método para o uso rotineiro na prática clínica.
Abstract: The limitations of current diagnostic methods of perinatal asphyxia induced to investigate if monitoring of body movements and of the sleep-wake rhythm can be used as diagnostic marker of this pathologic process. So, electromyogram and electrocardiogram records of 8 newborn Wistar rats, 6 to 48 hours postnatal, were obtained throughout 4 experimental periods: control period - with rats breathing room air for 30 min (ARpre); asphyxia periods - with rats submitted to two 30 min asphyxia periods (T1 and T2) with Its entire body covered with a polyvinyl sheet (PVC); and recovering period - with rats breathing room air for 30 min again. Asphyxia Heart rate was significantly decreased all over the asphyxia period compared with the control phase. In conclusion the monitoring of SBM, and of the sleep-wake rhythm seems to be of utmost value to the perinatal asphyxia diagnosis and its complications. This fact, however, requires new investigations to establish the real viability of the method for clinical practice routine.
Mestre

A asfixia perinatal e sua mais grave complicação, a encefalopatia hipóxicoisquêmica (EHI) são causas de elevada mortalidade e de sequelas neurológicas no recém-nascido (RN). Evidencias de comprometimento cerebral podem ser detectadas logo na primeira semana de vida e o diagnóstico precoce é de grande importância para o tratamento e seguimento. OBJETIVOS: Verificar a prevalência de asfixia perinatal e de EHI; analisar a utilidade de quatro marcadores sanguíneos: transaminase glutâmica oxalacética (TGO), transaminase glutâmica pirúvica (TGP), desidrogenasse láctica (DHL) e Creatina Quinase MB (CK-MB) coletados ao nascimento, com 24 e 72 horas de vida, como sinalizadores de lesões cerebrais nos RN asfixiados; identificar a presença de alterações neurológicas clínicas pelo Escore de Sarnat e Sarnat (1976) com 24 e 72 horas e com 28 dias de vida e identificar e descrever a presença de lesões cerebrais detectadas pela ultrassonografia de crânio com 24 e 72 horas e com 28 dias de vida. MÉTODO: Estudo de coorte prospectivo no qual foram incluídos RN de termo que apresentaram asfixia perinatal pelo critério de Buonocore (presença ao nascimento de pelo menos dois das seguintes condições clínico-laboratoriais: acidose metabólica com níveis de pH 7,20, Boletim de Apgar no quinto minuto de vida < 6, necessidade de fração inspirada de oxigênio 0,40 para manter uma saturação de oxigênio de 86%). Para realização do pH e dos marcadores bioquímicos foi coletado sangue logo ao nascimento, com 24 e 72 horas de vida. O exame clínico segundo critérios de Sarnat e Sarnat foi realizado com 24 e 72 horas e com 28 dias de vida e a ultrassonografia de crânio nos mesmos momentos. RESULTADOS: De 2.989 nascidos vivos durante o período do estudo, 28 recém-nascidos apresentaram asfixia perinatal (1% do total de nascimentos) e a EHI foi evidenciada em 21,42%. A enzima CK-MB se mostrou um bom marcador de asfixia, pois todos os valores foram superiores a 5,10 ng/ml, e se correlacionaram positivamente com as alterações apresentadas no exame clínico de Sarnat e com a ultrassonografia transfontanela. Os valores das outras enzimas como TGO (24h), TGO e TGP (72h) também se correlacionaram positivamente com as alterações ultrassonográficas as quais mostraram alteração em 3,5% dos pacientes com 24 horas de vida, 25% com 72 horas e 28,6% com 28 dias. A ultrassonografia de crânio com 28 dias mostrou aumento estatisticamente significante, no percentual de resultados anormais quando comparado com o observado com 24h (p=0,039), apesar dos estágios de Sarnat terem melhorado, com maior número de pacientes com estágio I no decorrer dos 28 dias. CONCLUSOES: A prevalência de asfixia perinatal e da EHI estão dentro da faixa citada na literatura. O melhor marcador bioquímico nesta casuística foi a isoenzima CK-MB e se correlacionou com as alterações apresentadas no exame clínico de Sarnat e na USG de crânio. A curva ROC mostrou: os valores de CK-MB de 24 horas em relação à USG de crânio de 72 horas Sensibilidade de 85,7%, Especificidade de 85,7% e Acurácia de 85,7%. O escore clínico de Sarnat não se alterou depois de 72 horas e apresentou correlação com as alterações na USG de crânio e este método de imagem foi adequado para detecção de lesões crebrais precoces e com 28 dias de vida
Perinatal asphyxia and its most serious complication, hypoxic-ischemic encephalopathy (HIE) are causes of high mortality and neurological sequelae in the newborn (NB). Evidence of cerebral impairment can be detected in the first week of life and early diagnosis is very important for the treatment and follow-up. OBJECTIVES: To assess the prevalence of perinatal asphyxia and HIE; consider the usefulness of four blood markers: glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB) collected the birth, with 24 and 72 hours of life, as markers of brain damage in asphyxiated infants, to identify the presence of neurological clinical score by Sarnat and Sarnat (1976) with 24 and 72 hours and 28 days of life and describe the presence of brain lesions detected by cranial ultrasound with 24 and 72 hours and 28 days. METHOD: A prospective cohort study which included fullterm infants who had perinatal asphyxia by Buonocore criteria (presence at birth of at least two of the following clinical and laboratory conditions: metabolic acidosis with pH levels of the umbilical vein 7.20, Apgar score in the fifth minute of life <6, need for inspired oxygen fraction (FiO2) 0.40 to maintain an oxygen saturation of 86%). To perform the pH and biochemical markers of blood was collected at birth, 24 and 72 hours of life. Clinical examination according to criteria of Sarnat and Sarnat was performed with 24 and 72 hours and 28 days of life and cranial ultrasound was performed in the same time. RESULTS: Of 2989 live births during the study period, 28 had asphyxia (1% of total births) and HIE was found in 21.42%. The CK-MB showed that all above normal values (<5.10ng/ml) and correlated with the changes presented in the clinical examination of Sarnat and the USG transfontanelle. The values of other enzymes such as GOT (24h), GOT and GPT (72h) also correlated positively with the brain lesins detected by cranial ultrasound in 3.5% of patients with 24 hours of life, 25% at 72 hours and 28 6% after 28 days. Ultrasonography of brain at 28 days showed a statistically significant increase in the percentage of abnormal results when compared with that observed at 24h (p = 0.039), despite the Sarnat stages have improved, with larger numbers of patients with stage I during the 28 days. CONCLUSION: The prevalence of perinatal asphyxia and HIE is within the range cited in literature. The best biochemical marker in this series was the CK-MB and correlated with the changes presented in the clinical examination of Sarnat and ultrasound transfontanelle. The ROC curve showed: values of CK-MB of 24 hours and USG 72 hours sensitivity of 85.7%, specificity of 85.7% and accuracy of 85.7%. The clinical Sarnat score did not change after 72 hours and correlated with changes in ultrasound transfontanelle and this imaging method proved to be an appropiate study to detect brain lesions early and with 28 days of life

Background: According to the World Health Organization, between four to nine million newborns develop birth asphyxia. It is estimated that 1.2 million fatal outcomes and at least the same number develop disabling neurological sequelae and developmental delay. Early neurological evaluation promotes the improvement of the life expectancy of serious asphyxiated babies and It can be incorporated into the routine of neonatal intensive care units. Glasgow Coma Scale adapted for children can be an assessment tool used in high-risk newborns. Objective: To compare the clinical outcome of term infants with perinatal asphyxia (PA) moderate and severe that underwent a neurological neonatal serial evaluation protocol during hospital stay, with those not undergoing evaluation. Method: This is an epidemiologic, observational and analytical study, using a quantitative approach. The study considered two groups, intervention and control. For the control group, at first, it was made a survey data in charts and then the longitudinal, prospective, observational approach was adopted during the period of outpatient care. For the intervention group, a longitudinal approach, prospective, observational was used during the hospital stay and follow-up clinic. We sought to investigate the neurological clinical course of children, the length of stay in hospital and delay presence in the development of neuromotor skills. Results: The sample consisted of 112 newborns, 86 infants in the control group and 26 infants in the intervention group. The intervention group showed a median of less hospital stay (p<0.001) than the control group. Full-term newborns diagnosed with PA, which remained for a shortest time in hospital length and were subjected to a serial neurological evaluation protocol, incorporated into standard clinical procedures in the NICU for the management of PA, did not show disturbances in neuromotor development. Conclusion: The use of serial neurological evaluation protocol influenced significantly, the prevalence of delayed neuromotor development.
Introdução: Segundo a Organização Mundial da Saúde, cerca de quatro a nove milhões de recém-nascidos (RN) desenvolvem asfixia ao nascer. Estima-se que 1,2 milhão evoluem para óbito e, pelo menos, o mesmo número desenvolve sequelas neurológicas incapacitantes e atraso no desenvolvimento. A avaliação neurológica precoce promove melhora da perspectiva de vida dos anoxiados graves, podendo, esta, ser incorporada à rotina das unidades de terapia intensiva neonatal. A escala de coma de Glasgow adaptada para crianças poderá ser utilizada em RN de alto risco. Objetivo: Comparar a evolução clínica neurológica dos RN a termo com asfixia perinatal (AP) moderada e grave que foram submetidos a um protocolo de avaliação neurológica neonatal seriada durante período de internamento hospitalar, com aqueles não submetidos à avaliação. Métodos: Trata-se de um estudo epidemiológico, observacional, analítico, com abordagem quantitativa. O estudo considerou dois grupos, intervenção e controle. Para o grupo controle foi feito um levantamento de dados em prontuários e, em seguida, adotada a abordagem longitudinal, prospectiva, observacional, durante o período de atendimento ambulatorial. Para o grupo intervenção, foi utilizada uma abordagem longitudinal, prospectiva, observacional, durante o período intra-hospitalar e em ambulatório de seguimento. Buscou-se investigar a evolução clínica neurológica da criança, o tempo de permanência no serviço hospitalar e presença de atraso no desenvolvimento das habilidades neuromotoras. Resultados: A amostra foi constituída de 112 RN, sendo 86 RN do grupo controle e 26 RN do grupo intervenção. O grupo intervenção mostrou uma mediana de tempo de internamento hospitalar menor (p<0,001) que o grupo controle. RN a termo, diagnosticados com AP, que permaneceram por menor tempo em internamento hospitalar e foram submetidos a um protocolo de avaliação neurológica seriada, incorporado às condutas clínicas padronizadas na UTIN para a gestão da AP, não apresentaram distúrbios no desenvolvimento neuromotor. Conclusão: A utilização do protocolo de avaliação neurológica seriada influenciou a prevalência de atraso no desenvolvimento neuromotor.

INTRODUÇÃO: A asfixia perinatal é uma das principais causa de óbito nos recémnascidos (RN) de termo acima de 2500g no Brasil, sendo também a causa mais importante de encefalopatia e lesão cerebral permanente em crianças. Não existindo ainda um consenso acerca de qual seria o melhor critério para seu diagnóstico. OBJETIVOS: Verificar a prevalência de asfixia e de encefalopatia hipóxico-isquêmica segundo dois critérios diagnósticos, avaliar influência do tipo de parto e a evolução neurológica. MÉTODO: Corte transversal prospectivo, onde foram incluídos 30 recém-nascidos que apresentaram asfixia segundo dois critérios diagnósticos: critério 1 foi preconizado pela AAP/ACOG de 1996 (pH de cordão 7,0, disfunção múltipla de órgãos, manifestações neurológicas na primeira semana de vida além do Apgar entre 0-3 no quinto minuto); o critério 2 foi de Buonocore em 2002, modificado (pH de cordão 7,2, Apgar de 4-6 no quinto minuto e necessidade de fração de oxigênio inspirada 0,40 manter saturação de 86%); num período de dois anos (2004/2006) sendo excluídos aqueles que pudessem apresentar encefalopatia por outras causas como malformações, infecções congênitas, erro inato do metabolismo. Para realizar o diagnóstico foram colhida gasometria de cordão dos recémnascidos a termo que apresentaram Apgar de quinto minuto 6 e feitas provas de função cardíaca, hepática, renal e controle hematológico além da avaliação neurológica pelos critérios clínicos de Sarnat e Sarnat de 1976, para verificar o grau de encefalopatia. RESULTADOS: Durante este período a prevalência observada de asfixia foi de 3,2 por 1000 nascimentos a termo (IC a 95% - [2,1 por mil; 4,5 por mil]) e de encefalopatia de 1,7 por 1000 nascimentos a termo (IC a 95% - [0,8 por mil; 2,5 por mil]). A taxa de mortalidade foi de 16,7% e 36,7% evoluíram com encefalopatia grave. Não houve correlação estatística da asfixia e nem da encefalopatia quanto às características maternas, exceto uma tendência maior nas nulíparas e primíparas com parto normal. Quanto à indicação do parto 46,7% apresentava trabalho de parto sem intercorrências, mas pelo critério 1 houve maior número com sofrimento fetal relacionado à maior gravidade da asfixia. O sexo mais freqüente foi o masculino e em ambos os grupos apresentaram acidose metabólica e respiratória e alterações enzimáticas principalmente cardíacas e hepáticas e, função renal com aumento da creatinina. Foi observado que para Sarnat estágios 1 e 2, leve e moderada, houve uma maior proporção de recém-nascidos no critério 2 enquanto que para o Sarnat estágio 3, grave, a maior proporção foi com o critério 1 Resumo (p = 0,016). Enquanto o Apgar de primeiro minuto não mostrou correlação com a gravidade da encefalopatia, 85% dos recém-nascidos com encefalopatia leve/moderada tiveram Apgar de quinto minuto entre 4-6 e a maioria com quadro grave o Apgar foi entre 0-3 (p = 0,018). Houve uma tendência de acordo com o aumento da gravidade da encefalopatia a uma redução do dióxido de carbono sanguíneo, bicarbonato e aumento negativo do excesso de base além do aumento de enzima cardíaca (creatina fosfoquinase), mas não foi estatisticamente significante. CONCLUSÃO: Não houve correlação estatística entre asfixia e a gravidade da encefalopatia com fatores maternos. Todos os recém-nascidos apresentaram acidose respiratória e metabólica e entre as alterações enzimáticas cardíacas foram as mais importante. Em relação ao índice de Apgar, a nota de quinto minuto mostrou melhor correlação com a gravidade evolutiva dos pacientes. Com o critério 1 (Academia Americana de Pediatria) houve melhor correlação com a mortalidade, no entanto por ser muito rigoroso acaba por excluir recém-nascidos que evoluem com quadros de encefalopatia grave
INTRODUCTION: The perinatal asphyxia is one of the main causes of death in newborns and also the most important cause of encephalopathy and permanent cerebral lesion in children. OBJECTIVES: To check the prevalence of asphyxia and of hypoxic-ischemic encephalopathy in term newborns, using two diagnostic criteria; to assess whether the diagnostic criterion used and the type of obstetric assistance are related to the grade of seriousness of the asphyxia and of the encephalopathy. Methods: Prospective transversal cut study carried out in a public hospital in the East Zone of São Paulo, in which 30 term newborns with perinatal asphyxia were included and classified in two groups, according to two diagnostic criteria adopted: criterion 1 recommended by American Academy of Pediatrics (1996), and which considers as bearer of perinatal asphyxia the newborn presenting: cord pH 7.0, multiple organ dysfunction, neurological manifestations in the first week of life and Apgar value in the fifth minute of life between 0-3. Criterion 2 defined by Buonocore in 2002 and which consists in: cord pH 7.2, Apgar value in the fifth minute of life between 4-6 and fraction inspired of oxygen need 0.40 to maintain a saturation of 86%. To confirm the diagnosis, the following laboratorial examinations were carried out: gasometry, hepatic, renal and cardiac function tests, besides the hematological control. To assess the neurological function and verify the grade of hypoxic-ischemic encephalopathy, the clinical criteria of Sarnat and Sarnat were used. RESULTS: The prevalence of perinatal asphyxia observed in this case was of 3.2 per 1,000 term births (IC at 95% - [2.1 per one thousand; 4.5 per one thousand]) and of hypoxic-ischemic encephalopathy was of 1.7 per 1,000 term births (IC at 95% - [0.8 per one thousand; 2.5 per one thousand]). As regards the criteria used, the newborns of criterion 1 statistically presented more fetal suffering when compared to those of criterion 2, and this fact was also related to the grade of seriousness of the asphyxia. The newborns of the two groups presented cardiac changes with elevation of the specific enzyme, hepatic changes with elevation of the glutamic pyruvic and oxaloacetic transaminases and renal changes proven by elevation of creatinine, besides the relevant respiratory and metabolic acidosis. The newborns with serious metabolic acidosis and high levels of creatine phosphokinase had a greater degree of neurological impairment. In 85% of newborns with light/moderate encephalopathy was verified an Apgar value at fifth minute of life between 4-6, and in newborns with serious encephalopathy this value was between 0-3 (p = 0.018). A positive trend for Summary the presence of asphyxia and encephalopathy was found in children of primiparous mothers and born during normal parturition. When assessing the degree of neurological impairment through the criteria of Sarnat and Sarnat, A greater proportion of newborns of criterion 2 were found in the lighter degrees. In degree 3, which is the most serious, a greater proportion of newborns of criterion 1 (p = 0,016) was found. The mortality rate in these cases was of 16.7%, and most of the newborn were of criterion 1. CONCLUSION: The prevalence of perinatal asphyxia and hypoxic -ischemic encephalopathy is as mentioned in the world literature, and smaller than found in Brazil. Criterion 1 was the one that showed a better correlation with the mortality of patients. However, as it is too rigorous, it may exclude the newborn that survive and develop hypoxic-ischemic encephalopathy. As regards the type of obstetric assistance, despite the fact that no statistically significant difference was observed, there was a positive trend to the presence of asphyxia and encephalopathy in children of primiparous mothers born during normal parturition

O Magnésio é o segundo cátion intracelular mais comum e desempenha importante papel na modulação de funções de transporte e receptores, atividades enzimáticas, metabolismo energético, síntese de proteínas e ácidos nucleicos e proteção de membranas biológicas. Apesar de sua importância, o conhecimento de sua homeostase não é completo, principalmente por dificuldade de acesso a seus estoques intracelulares e da ausência de métodos laboratoriais confiáveis para medida da fração iônica. O desenvolvimento recente de um eletrodo íon-seletivo permitiu a determinação das concentrações de Mg iônico(Mgi), em pequenas amostras de sangue, o que possibilitou a realização de estudos para determinação desta fração no período neonatal. A presença de alguns distúrbios, como o Crescimento Intra-uterino Restrito(CIUR) e a Asfixia Perinatal, poderiam potencialmente levar a desvios da homeostase do Mg, ainda não totalmente esclarecidos. O objetivo deste estudo foi descrever, em Recém-nascidos de termo(RNT) sem CIUR, os níveis de Mgi e total (MgT) em sangue de cordão umbilical, 3o e 7o dias de vida e comparar os valores obtidos entre os RNT, com e sem CIUR e asfixia perinatal. Realizou-se um estudo prospectivo, no qual foram incluídos 95 RNT, divididos em dois grupos de estudo: Grupo I - sem CIUR(50 RN - 52,6%) e Grupo II - com CIUR(45 RN - 47,4%). A presença de CIUR foi determinada por um peso de nascimento abaixo do percentil 10 para a curva de Ramos(1983), associado a uma relação P/P50 < 0,85. Cada um desses grupos foi subdividido em 2 subgrupos : Grupo Ia - 30 RN (31,6%), sem CIUR e sem asfixia perinatal; Grupo Ib - 20 RN(21,0%), sem CIUR e com asfixia perinatal; Grupo IIa - 40 RN(42,1%), com CIUR e sem asfixia perinatal; Grupo IIb - 5 RN(5,3%), com CIUR e asfixia perinatal. A presença de asfixia perinatal foi indicada por um Apgar de 5o minuto < 6 associada a presença de um dos seguintes critérios: pH de sangue de cordão umbilical < 7,2 , disfunção de um ou mais órgãos, sequelas neurológicas no período neonatal imediato. Foram realizadas determinações de Mgi, Cálcio iônico(Cai), Uréia(U), pH, MgT, Fósforo(P) e Creatinina(Cr), em sangue de cordão umbilical, no 3o e no 7o dias de vida. Verificou-se que nos RNT sem CIUR(Grupo Ia), as concentrações médias de MgT, ao nascimento, foram menores do que as de RN com CIUR e elevaram-se, de forma significante, até o 7o dia de vida, enquanto as de Mgi mantiveram-se. As concentrações de Mgi neste grupo, foram significativamente menores do que as de RN com CIUR(Grupo IIa) durante a 1a semana de vida e do que as de RN com asfixia perinatal(Grupo Ib) no 3o e 7o dias de vida. Concluiu-se que, em RNT sem CIUR, há um aumento dos níveis de MgT durante a 1a semana de vida, sem alteração das concentrações de Mgi. A presença de CIUR, bem como a asfixia perinatal, podem influenciar as concentrações neonatais de Mg, através de seus efeitos de modulação da homeostase deste íon, durante os períodos fetal e neonatal
Magnesium is the second most abundant intracellular cation and plays an important role in regulation of transporting and receptors functions, enzymatic activities, energy metabolism, protein and nucleic acid synthesis and biologic membranes protection. In spite of this, the knowledge of its homeostasis is still limited, mainly due to inacessibility of its intracellular stores and the absence of a reliable methodology to measuring the ionized fraction. The recent development of an ion-selective electrode has allowed not only the determination of ionized magnesium(iMg) concentrations in a small blood sample volume, but also an increasing number of researches as to this fraction in neonatal period. The presence of some disorders,i.e. like Intrauterine Growth Restriction (IUGR) and Perinatal Asphyxia, could lead to an unclear imbalance of magnesium homeostasis, in a way not yet clear. The aim of this study was to describe, in term newborns without IUGR, iMg and Total Mg (TMg) concentrations in umbilical cord blood, third and seventh days of life and to compare the results among term newborns with and without IUGR and perinatal asphyxia. Ninety-five term newborn infants were enrolled in a prospective study and were divided into two study groups: Group I : without IUGR(50RN - 52.6%) and Group II - with IUGR(45RN - 47.4%). Intrauterine growth restriction was defined as a birth weight below the 10th percentil for Ramos Curve(1983) besides to a birth weight ratio <0,85. Each one of these groups were divided in two subgroups: Group Ia :30 RN (31,6%), without IUGR or perinatal asphyxia; Group Ib : 20 RN (21,0%), without IUGR, with perinatal asphyxia ; Group IIa : 40 RN (42,1%), with IUGR, without perinatal asphyxia; Group IIb: 5 RN(5,3%), with perinatal asphyxia and IUGR. Perinatal asphyxia was defined as a 5 minutes Apgar score < 6 besides to one of the following: umbilical cord blood pH < 7,2, disfunction of one or more organs, neonatal neurologic manifestations. iMg, TMg, ionized calcium, urea, pH, phosphorus and creatinine concentrations were determined in umbilical cord blood, third and seventh days of life. We observed that in term newborns without IUGR (Group Ia), TMg concentrations increased significantly during the first week of life, while iMg concentrations remained unchanged. iMg levels in this group, were significantly lower than in the group with IUGR (Group IIa) from birth to 7th day of life and than in the group without IUGR, with perinatal asphyxia (Group Ib) in the third and seventh days of life. We concluded that in term newborns without IUGR, TMg levels increased during the first week of life, while iMg levels remained unchanged. The presence of IUGR, as well as, perinatal asphyxia, may influence neonatal levels of magnesium, through their effect on the modulation of this ion homeostasis, during fetal and neonatal periods

Der Transkriptionsfaktor hypoxia inducible factor-1 (HIF-1) trägt zur Expression von adaptiven Genen unter hypoxischen Bedingungen bei. Zusätzlich wurde vermutet, dass HIF-1 eine Rolle in der Regulation des späten neuronalen Zelltodes spielt. Suspensionszellen und adhärenten PC12-Zellen mit Nervenwachstumsfaktor (NGF) behandelt, wurden als ein experimentelles Modell für die Untersuchung der Beziehung zwischen Hypoxie induziertem Zelltod und Aktivität von HIF-1 herangezogen. Zelltod wurde durchflusszytometrisch mit einer Doppelfärbung (Annexin V und Propidium-Jodid) der Zellen und durch eine Analyse der allgemeinen Zelltodparameter wie LDH und die mitochondriale Dehydrogenase bestimmt. Parallel wurden Zellen mit einem Kontrollvektor und einem hypoxiesensitiven Vektor mit drei Hypoxie-bindenden-Elementen (HBE) transfiziert und die durch HIF-1 aktivierte Luciferase gemessen. Hypoxieexposition der NGF-behandelten PC12-Zellen resultierte in einer höheren Zelltodrate verglichen mit den unbehandelten Kontrollzellen. PC12 Zellen, zwei Tage mit NGF behandelt, zeigten eine bis zu 10-fach verminderte HIF-1-Aktivität. Diese Verminderung könnte zu dem erhöhten hypoxie-induzierten Zelltod durch verminderte Expression von HIF-1alpha-regulierten Genen, welche für die Anpassung an Hypoxie verantwortlich sind, beitragen. Die Verminderung der HIF-1 Aktivität und der Anstieg der Hypoxiesensitivität könnte darauf hinweisen, dass NGF als eine Art hierarchisch organisiertes Signalmolekül fungiert.
The transcription factor hypoxia-inducible factor-1 (HIF-1) strongly contributes to the expression of adaptive genes under hypoxic conditions. In addition, HIF-1 has been implicated in the regulation of delayed neuronal cell death. Suspension-grown and adherent PC12 cells treated with NGF were used as an experimental model for studying the relationship between hypoxia-induced cell death and activation of HIF-1. Cell damage was assessed by flow cytometry of double-stained (annexin V and propidiumiodide) cells, and by analysis of the overall death parameters LDH and mitochondrial dehydrogenase. In parallel, cells were transfected with a control and a three-hypoxia-responsive-elements (HRE)-containing vector and HIF-1-driven luciferase activity was determined. Exposure of NGF-treated PC12 cells to hypoxia resulted in a higher cell death rate when compared to untreated controls. PC12 cells exposed for 2 days to NGF exhibited a decrease of HIF-1 activity up to a factor of ten. This decrease may contribute to the enhanced hypoxia-induced cell death via reduced expression of HIF-1alpha-regulated genes resposible for adaptation to hypoxia, like those for glucose transport proteins and enzymes of the glycolytic chain. The decrease in HIF-1 activity and the increase in hypoxia sensitivity may suggest that NGF act as an hierachically organized signaling molecule.

Dissertação(mestrado) - Universidade Federal do Rio Grande, Programa de Pós-Graduação em Enfermagem, Escola de Enfermagem, 2008.
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A questão norteadora desse estudo surgiu a partir da vivência pessoal e profissional da pesquisadora. Ao pesquisar o tema cuidado à criança portadora de paralisia cerebral, buscou-se respostas para a questão norteadora: Como a família cuida da criança portadora de paralisia cerebral nos três primeiros anos de vida? Para encontrar respostas a essa questão, o estudo teve por objetivo conhecer como a família cuida da criança portadora de paralisia cerebral nos três primeiros anos de vida. Em relação aos objetivos, foram traçados os seguintes pressupostos: a anunciação da situação de saúde da criança não foi realizada conforme as necessidades da família; a incompreensão da situação de saúde da criança dificulta o cuidado prestado a ela pela família; as famílias carecem de apoio por parte da equipe de saúde; as crianças portadoras de necessidades especiais, decorrentes da paralisia cerebral, não recebem os cuidados da família conforme as suas necessidades, porque a mesma não foi orientada, de maneira sistemática e contextualizada, durante a hospitalização; as famílias desconhecem os direitos das crianças; a criança portadora de necessidades especiais, decorrentes da paralisia cerebral, não dispõe de ações e serviços de saúde específicos, para assegurar o suporte necessário as suas fragilidades. O referencial teórico que sustentou a pesquisa englobou: Família - primeiro universo de relações sociais da criança; compreendendo a família no período gestacional; nascimento e fatores de risco para a paralisia cerebral; o processo de adaptação vivenciado pela família: quando o recém-nascido não condiz com o bebê idealizado; o processo de educar /cuidar da família a fim de capacitála para prestar o cuidado à criança portadora de paralisia cerebral. O referencial teórico construído mostrou-se coerente e consistente em relação à análise e interpretação dos dados. Na trajetória metodológica, utilizou-se uma abordagem qualitativa exploratório-descritiva com as seis famílias das crianças portadoras de paralisia cerebral, que nasceram, no período de 2005 a 2007, com APGAR menor ou igual a três no quinto minuto, na cidade de Rio Grande. Para a coleta de dados, utilizou-se o método da entrevista semi-estruturada com esses atores sociais. Com a análise dos dados emergiram três categorias: refletindo sobre a formação do vínculo; o processo de adaptação do ser família; o exercício da cidadania - a saúde como um direito. Dentre os resultados observou-se que o processo de cuidar da criança inicia-se anteriormente ao período gestacional, sendo influenciado pela cultura dos ancestrais da criança. Essa cultura mostrou influenciar na determinação dos mecanismos de defesa que cada integrante da família utilizou no seu processo de adaptação. A principal rede de apoio, ressaltada pelos sujeitos do estudo foi a família ampliada. Evidenciaram-se as dificuldades encontradas pelas famílias em relação aos princípios da integralidade e acessibilidade aos serviços e ações de saúde além de perceber uma lacuna no que concerne ao ideal da assistência prestada pela atenção básica e a realidade a que essas crianças e suas famílias são expostas. Concluiu-se que o desconhecimento dos direitos da criança, bem como do exercício da cidadania dessa população, também, pôde ser constatado, fatos que interferiram no poder dessa população de decidir e mediar a sua própria existência, o que tornou essas famílias objetos passivos, os quais vivem conforme normas impostas por uma sociedade normativa e opressora.
La cuestión norteadora de este estudio surgió a partir de la vivencia personal y profesional de la investigadora. Al investigar el tema cuidado al niño portador de parálisis cerebral, se buscó respuestas a la cuestión norteadora: ¿cómo la familia cuida del niño portador de parálisis cerebral en los tres primeros años de vida? Para encontrar respuestas a esa cuestión, el estudio tuvo como objetivo conocer cómo la familia cuida del niño portador de parálisis cerebral en los primeros años de vida. Con relación a los objetivos, fueron trazados los siguientes presupuestos: la anunciación de la situación de salud del niño no fue realizada conforme las necesidades de la familia; la incomprensión de la situación de salud del niño dificulta el cuidado que le es prestado por la familia.; las familias carecen de apoyo por parte del equipo de salud; los niños portadores de necesidades especiales, resultantes de parálisis cerebral, no reciben los cuidados de la familia conforme sus necesidades, porque esta no fue orientada, de manera sistemática y contextualizada, durante la hospitalización; las familias desconocen los derechos de los niños; el niño portador de necesidades especiales, resultantes de la parálisis cerebral, no dispone de acciones y servicios de salud específicos, para garantizar el suporte necesario a sus fragilidades. El referencial teórico que sostuvo la investigación reunió: Familia – primero universo de relaciones sociales del niño; comprendiendo en el periodo gestacional; nacimiento y factores de riesgo para la parálisis cerebral; el proceso de adaptación vivenciado por la familia: cuando el recién nacido no condice con el bebé idealizado: el proceso de educar/cuidar de la familia a fin de capacitarla para prestar el cuidado al niño portador de parálisis cerebral. El referencial teórico construido se mostró coherente y consistente con relación al análisis e interpretación de los datos. En la trayectoria metodológica, se utilizó un abordaje cualitativo exploratorio-descriptivo con las seis familias de los niños portadores de parálisis cerebral, que nacieron, en el periodo de 2005 a 2007, con APGAR menor o igual a tres en el quinto minuto, en la ciudad de Rio Grande. Para la colecta de datos, se utilizó el método de la entrevista semiestructurada con esos actores sociales. Con el análisis de los datos emergieron tres categorías: reflexionando sobre la formación del vínculo; el proceso de adaptación del ser familia; el ejercicio de la ciudadanía – la salud como un derecho. De estos resultados se observó que el proceso de cuidar de los niños empieza anteriormente al periodo gestacional, siendo influido por la cultura de los ancestrales del niño. Esa cultura mostró influir en la determinación de los mecanismos de defensa que cada integrante de la familia utilizó en su proceso de adaptación. La principal red de apoyo, resaltada por los sujetos del estudio, fue la familia ampliada. Se evidenciaron las dificultades encontradas por las familias con relación a los principios de la integralidad y accesibilidad a los servicios y acciones de salud, además de percibir un hueco con relación al ideal de asistencia prestada por la atención básica y la realidad a que esos niños y sus familias son expuestos. Se concluye que el desconocimiento de los derechos de los niños, así como del ejercicio de la ciudadanía de esa población, también pueden ser constatados, hechos que interfirieron en el poder de esa población de decidir y mediar su propia existencia, lo que les tornó objetos pasivos, los cuales viven conforme normas impuestas por una sociedad normativa y opresora.
The central question of the present study appeared due to the personal and professional experience of the researcher herself. While researching the topic of care to child bearer of brain paralysis, answers were sought for the central question: How does the family take care of a child bearer of brain paralysis in the first three years of age of the child? In order to find answers for this question, the study aimed at knowing how the family takes care of the child bearer of brain paralysis in the first three years of age. Concerning the goals, the following plans were outlined: the announcement of the health situation of the child was not made according to the family necessities; the lack of understanding of the health situation of the child makes the care provided by the family more difficult; the families lack support from the health teams; the children bearers of special necessities, due to brain paralysis, do not receive the proper care by the family according to their necessities, because the family was not informed on how to proceed, in a systematic and contextualized way, during the stay at the hospital; the families do not know the rights of the child; the child bearer of special necessities, due to brain paralysis, does not have specific actions of health services available, in order to assure the necessary support to his / her weaknesses. The theoretical referential which supported the research involved: Family – first universe of social relations of the child; involving the family in the pregnancy period; birth and risk factors for the brain paralysis; the process of adaptation faced by the family: when the newborn does not fulfill the expected baby; the process of educating /taking care of the family in order to enable it to provide the care for the child bearer of brain paralysis. The theoretical referential built came up to coherent and consistent concerning the data analysis and interpretation. In the methodological terms, an exploratory-descriptive qualitative approach was used with the six families of children bearers of brain paralysis, who were born between 2005 and 2007, with APGAR lower or equal to three in the fifth minute, in the city of Rio Grande. For the data collection, a method of semi-structured interview was used with these social subjects. With the data analysis, three categories emerged: reflecting on the development of connection; the process of adaptation of being family; the exercise of citizenship – the health as a right. Among the results it was observed that the process of taking care of the child begins previous to the pregnancy period, being influenced by the culture of the child’s ancestors. This culture was seen as an influence to determine the defense mechanisms that each member of the family used during their adaptation process. The main support network, highlighted by the study subjects was the family as a whole. The difficulties found by the families were highlighted concerning the principles of integrality and accessibility to the health services and actions besides noticing a gap concerning the ideal assistance provided by the basic attention and the reality to which these children and families are exposed to. It was concluded that the fact of now knowing the child’s rights, as well as exercise of citizenship of this population could also be noticed and such facts interfered in the power of this population to decide and measure their own existence, which made these families passive subjects, who live according to the rules imposed by a normative and oppressive society.

A Research Report submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Medicine in Paediatrics. 8 May 2014
Background: Perinatal asphyxia is a significant cause of death and disability. Aim: To determine the outcomes (survival to discharge and morbidity post discharge) of neonates with perinatal asphyxia at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). Methods: This was a descriptive retrospective study. Patient information was obtained from the computerised neonatal database of neonates admitted to CMJAH within 24 hours of birth between 1 January 2006 and 31 December 2011 with a birth weight of >1800 grams and a 5 minute Apgar score <6. Results: 450 babies were included in the study; 185 females (41.1%). Mean birth weight was 3034.80 grams (SD 484.936) and mean gestational age was 39.11 weeks (SD 2.2). Most babies were inborn 391/450 (86.9%) and most were delivered by normal vaginal delivery 270/450 (60%). The overall survival was 390/450 (86.6%). There were 42 babies admitted to ICU. The ICU survival was 37/42 (88.1%). Significant predictors of survival were place of birth (p value 0.006), mode of delivery (p value 0.007) and bag mask ventilation at birth (p value 0.040). The duration of stay (p value 0.000) was significantly longer in survivors (6.49 days SD 6.6). The remaining factors were not significantly different between the two groups. The rate of perinatal asphyxia (Apgar score <6) was 4.68 per 1000 live births; while 3.61 per 1000 live births had evidence of hypoxic ischaemic encephalopathy (HIE). Of the 390 babies discharged from CMJAH, 113 had follow up records (28.97%) to a mean corrected age of 5.88 months (SD 5.03). The majority (90/113 – 79.64%) had normal development. Conclusion: i) The high overall survival and survival after ICU admission provides a benchmark for further care. ii) Obtaining adequate data for long term follow up was not possible with the existing resources and surrogate early markers of outcome and / or more resources to ensure accurate follow-up are needed and iii) the high incidence of HIE suggest that a therapeutic hypothermia service including long-term follow-up component would be beneficial.

A research report is submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Sciences in Child Health Johannesburg, 2016
Background: Leratong Hospital is a regional hospital in the West Rand of Johannesburg, South Africa. Statistics from maternity in 2008 showed high utilisation rates for delivery services at Leratong but a study on neonatal mortality was not yet done. It was therefore essential to measure and analyse the causes of new-born deaths so as to have policies to advance neonatal care. Objectives: To determine the neonatal mortality rate (NMR), the major neonatal causes of death and the occurrence of avoidable health factors. Methods: This was a prospective review of the clinical records of the 46 neonates who died within the 3 month period (15th April 2013 to the 15th July 2013). Data was obtained from neonatal admission and death registers. Information on the number oflive births was obtained from labour ward registers. Delegation books for nurses were checked to determine the number of nursing staff per shift as well as their allocation in different rooms. Neonate's age, birth weight, gender, race, place of origin, reason for admission and cause of death, were analysed. Health factors examined were access to high care services and to the neonatal ICU, number of staff on duty and the use of treatment guidelines. Questionnaires were used to collect information, and the consent to use clinical records was obtained from the mothers. Descriptive statistics were used to describe the frequencies and percentages of variables. Logistic regression of variables was applied to predict mortality. Results: The overall neonatal mortality rate at Leratong Hospital was lower than the rates found in South Africa and other studies in sub-Saharan Africa. Almost 37% of neonates died within 24 hours of admission. The three most common causes of death were: prematurity (39%), perinatal asphyxia (26%) and infection (20%). More than sixty per cent of deaths occurred in the admission room. Three-quarters of neonates who died (74%) were low birth weight neonates. A critical staff shortage (nurse: neonate rati02.: 1:10) was the most common modifiable factor (63% of deaths). Thirty seven per cent of neonates were denied access to ICU. The significant predictors of neonatal death were being born preterm (OR: 3.1, 95% CI 1.7-6.0), extremely low birth weight (OR: 27.5,95% CI 8.2-92.6), very low birth weight (OR: 5.0, 95% CI 2.1-12.3) and birth by caesarean section (OR: 3.2, 95% CI 1.6-6.2). Conclusions: The study found the neonatal mortality rate at Leratong Hospital in 2013 to be lower than rates recorded in South Africa. Our results showed that the most common causes of neonatal mortality were similar to those in other hospitals in sub-Saharan Africa and in South Africa. A high number of neonatal deaths were avoidable by providing high care services (including NCP AP and surfactant) and adequate number of nurses trained in newborn care in the admission room, improving access to neonatal ICU, early detection of perinatal asphyxia and improved neonatal resuscitation, and the supervision of medical doctors.
AC2016

L’encéphalopathie hypoxique-­‐ischémique cause des milliers de victimes à travers le monde chaque année. Les enfants survivants à un épisode hypoxique-­‐ischémique sont à risque de développer des problèmes neurologiques incapacitants comme une paralysie cérébrale, un retard mental, une épilepsie ou des troubles d’ordre comportemental. Les modèles animaux ont amélioré nos connaissances sur les mécanismes sous-­‐jacents aux dommages cérébraux, mais elles sont encore trop incomplètes pour être capables de prévenir les problèmes neurologiques. Ce projet vise à comprendre l’impact d’un épisode asphyxique périnatale associé à des convulsions ainsi que l’activation de l’adenosine monophosphate-­‐activated protein kinase (AMPK) sur les circuits GABAergiques inhibiteurs en développement chez la souris. Dans le but d’investiguer le sort des neurones inhibiteurs, appelés interneurones, suite à un épisode asphyxique périnatal associé à des convulsions avec des animaux transgéniques, nous avons pris avantage d’un nouveau modèle d’hypoxie permettant d’induire des convulsions chez la souris. Deux populations d’interneurones représentant ensemble environ 60% de tous les interneurones corticaux ont été étudiées, soit les cellules exprimant la parvalbumine (PV) et les cellules exprimant la somatostatine (SOM). L’étude stéréologique n’a montré aucune mort neuronale de ces deux populations d’interneurones dans l’hippocampe chez les souris hypoxique d’âge adulte. Par contre, le cortex des souris hypoxiques présentait des zones complètement ou fortement dépourvues de cellules PV alors que les cellules SOM n’étaient pas affectées. L’utilisation d’une lignée de souris transgénique exprimant une protéine verte fluorescente (GFP) dans les cellules PV nous a permis de comprendre que les trous PV sont le reflet de deux choses : 1) une diminution des cellules PV et 2) une immaturité des cellules PV restantes. Puisque les cellules PV sont spécifiquement affectées dans la première partie de notre étude, nous avons voulu étudier les mécanismes moléculaires sous-­‐jacents à cette vulnérabilité. L’AMPK est un senseur d’énergie qui orchestre le rétablissement des i niveaux d’énergie cellulaire dans le cas d’une déplétion énergétique en modulant des voies de signalisation impliquant la synthèse de protéines et l’excitabilité membranaire. Il est possible que l’activation d’AMPK suite à un épisode asphyxique périnatal associé à des convulsions soit néfaste à long-­‐terme pour le circuit GABAergique en développement et modifie l’établissement de l’innervation périsomatique d’une cellule PV sur les cellules pyramidales. Nous avons étudié cette hypothèse dans un modèle de culture organotypique en surexprimant la forme wild-­‐type (WT) de la sous-­‐unité α2 d’AMPK, ainsi qu’une forme mutée dominante négative (DN), dans des cellules PV individuelles. Nous avons montré que pendant la phase de formation synaptique (jours post-­‐natals équivalents EP 10-­‐18), la surexpression de la forme WT désorganise la stabilisation des synapses. De plus, l’abolition de l’activité d’AMPK semble augmenter le nombre de synapses périsomatiques faits par la cellule PV sur les cellules pyramidales pendant la phase de formation et semble avoir l’effet inverse pendant la phase de maturation (EP 16-­‐24). La neurotransmission GABAergique joue plusieurs rôles dans le cerveau, depuis la naissance jusqu’à l’âge adulte des interneurones, et une dysfonction des interneurones a été associée à plusieurs troubles neurologiques, comme la schizophrénie, l’autisme et l’épilepsie. La maturation des circuits GABAergiques se fait majoritairement pendant la période post-­‐natale et est hautement dépendante de l’activité neuronale et de l’expérience sensorielle. Nos résultats révèlent que le lourd fardeau en demande énergétique d’un épisode asphyxique périnatal peut causer une mort neuronale sélective des cellules PV et compromettre l’intégrité de leur maturation. Un des mécanismes sous-­‐ jacents possible à cette immaturité des cellules PV suite à l’épisode hypoxique est l’activation d’AMPK, en désorganisant leur profil d’innervation sur les cellules pyramidales. Nous pensons que ces changements dans le réseau GABAergique pourrait contribuer aux problèmes neurologiques associés à une insulte hypoxique.
Hypoxia-­‐ischemia encephalopathy causes thousands of victims each year around the world. Children surviving such hypoxia-­‐ischemia insults are at risk of developing disabling neurological problems such as cerebral palsy, epilepsy or cognitive problems. Animal models have improved our knowledge about the underlying mechanisms causing cerebral injury, but it is still too incomplete to be able to prevent neurological problems. This project aims to understand the impact of a perinatal asphyxic insult associated with seizures as well as the activation of adenosine monophosphate-­‐activated protein kinase (AMPK) on developing inhibitory GABAergic networks in mouse. With the objective to study the fate of inhibitory cells, called interneurons, following a perinatal asphyxia insult associated with seizures in transgenic animals, we took advantage of a new hypoxia model allowing us to induce seizures in mice. Cells expressing parvalbumin (PV) and cells expressing somatostatin (SOM) were studied as together they represent about 60% of all cortical interneurons. A stereological study showed no cell death within those two interneuron populations in the hippocampus of adult hypoxic mice. However, the cortex of hypoxic mice showed zones with complete or strongly lacking PV cells, whereas SOM cells were not affected. A transgenic mouse line allowed us to show that PV holes are the reflection of two things 1) a decrease in PV cells and 2) immaturity of surviving PV cells. Because PV cells a selectively affected in the first part of our study, we wanted to study the molecular mechanisms underlying this vulnerability. AMPK is a metabolic energy sensor that orchestrates the recovery of energy in cells undergoing energy depletion by modulating cellular pathways involved in protein synthesis and membrane excitability. It is possible that the activation of AMPK following a perinatal asphyxic insult associated with seizures is detrimental for developing GABAergic networks and modifies the establishment of perisomatic innervation of PV cells on excitatory pyramidal cells. We have studied this hypothesis in an organotypic system by overexpressing the wild-­‐type (WT) form and the dominant negative (DN) form of AMPK iv α 2 sub-­‐unit in individual PV cells. We have observed that during the synaptic formation phase (equivalent post-­‐natal day EP 10-­‐18), overexpressing WT AMPK disorganises synapse stabilisation. Moreover, abolishing AMPK activity with the transfection of AMPK DN seems to increase the number of perisomatic synapses made by PV cells onto pyramidal cells, and seems to have the inverse effect during the synaptic maturation phase (EP 18-­‐24). GABAergic neurotransmission plays many roles in the brain, from interneurons birth to adulthood, and a dysfunction in GABAergic neurotransmission has been associated with many neurological diseases such as schizophrenia, autism and epilepsy. GABAergic networks maturation mainly happens postnatally and is highly dependent on neural activity and sensory experience. Our results reveal that the heavy energetic burden caused by an asphyxic insult can cause selective PV cells death and interfere with their maturation. AMPK activation following an asphyxic insult could be one mechanism interfering with PV cells maturity by disorganising their pattern of innervation onto pyramidal cells. We think that these GABAergic networks alterations could contribute to the neurological problems associated to a hypoxic insult.

Orientação : Manuel Pequito ; co-orientação : Cole Sciba, Korin Potenza
A Encefalopatia Neonatal Equina foi a doença escolhida para estudo durante o decorrer de quatro meses de estágio no Weems and Stephens Equine Hospital e dois meses de estágio no San Luis Rey Equine Hospital e Trifecta Equine Athletic Center (ambos localizados nos EUA), para análise no presente estudo. É uma doença comum em neonatos equinos que afeta principalmente o SNC e é observada entre as primeiras 24h a 72h de vida pós-parto, associada a uma vasta terminologia, nomeadamente ‘Hypoxic-Ischemic’, ‘Encephalopathy’ e ‘Neonatal Maladjustment Syndrome’, onde vulgarmente os poldros que sofrem da doença são designados como ‘Dummy foals’. Os dados relativos aos neonatos equinos selecionados foram recolhidos presencialmente no decorrer do estágio com base num protocolo de receção de poldros e com o consentimento dos proprietários. O diagnóstico foi realizado através da história clínica, observação dos sinais demonstrados pelos poldros, bem como realização de exames complementares. Os principais sinais clínicos incluiram estados de alerta depressivos, dificuldade em se colocarem em estação, dificuldade em se alimentarem, assim como perda ou diminuição do reflexo de sucção e dificuldade em encontrar o úbere da égua, perda do tónus lingual e convulsões. O tratamento realizado baseou-se numa terapêutica de suporte, correção de alterações clínicas através da administração de anti-inflamatórios e antibióticos de largo espetro, bem como terapêutica de suporte para alterações noutros sistemas, quando aplicável. Foi ainda realizada a técnica de ‘Madigan Foal Squeeze’ a todos os poldros do estudo. Na generalidade, o prognóstico dos poldros era bom, com exceção de dois poldros onde se observou um prognóstico reservado a mau. Poldros que durante os primeiros cinco dias de vida apresentaram melhorias dos sinais clínicos e sem complicações secundárias associadas a quadros clínicos de septicémia, foi observado uma recuperação da doença. Ao contrário, os poldros que não responderam positivamente aos tratamentos, tiveram uma sobrevida entre cinco a sete dias. Associada ao tratamento, a técnica de ‘Madigan Foal Squeeze’ demonstrou ter um papel importante ao nível da recuperação, tornando-a mais rápida. A ENE revelou ser uma doença bastante complexa e com necessidade de uma melhor investigação, uma vez que afeta o SNC e apresenta etiologias multifatoriais
Equine Neonatal Encephalopathy was the disease chosen during the four-month internship at Weems and Stephens Equine Hospital and a two-month internship at the San Luis Rey Equine Hospital and Trifecta Equine Athletic Center (both located in the USA) for analysis in the present study. It is a common disease in equine neonates that mainly affects the CNS and is observed between the first 24 hours and 72 hours of postpartum life, associated with a wide range of terminology, namely ‘Hypoxic-Ischemic’, ‘Encephalopathy’ and ‘Neonatal Maladjustment Syndrome’ where commonly the foals suffering from the disease are designated as ‘Dummy foals’. Data on the selected equine neonates were collected in person during the externship on the basis of a protocol of receipt of foals and with the consent of the owners. The diagnosis was made through the clinical history, observation of the signs demonstrated by the foals, as well as accomplishment of complementary exams. The main clinical signs observed were depressive states of alertness, difficulty in getting up, difficulty in feeding, as well as loss or decrease of sucking reflex and difficulty in finding the udder of the mare, loss of lingual tonus and seizures. The treatment was based on supportive therapy, correction of clinical changes through the administration of anti-inflammatories and broad-spectrum antimicrobials, as well as supportive therapy for changes in other systems, when applicable. The "Madigan Foal Squeeze" technique was also carried out on all the foals of the study. In general, the prognosis of the foals was good, except for two foals where a reserved to poor prognosis was observed. Foals that during the first five days of life presented with improvement of the clinical signs and without secondary complications associated to clinical pictures of septicemia, a recovery of the disease was observed. On the contrary, the foals that did not respond positively to the treatments, had a survival between five and seven days. Associated with the treatment, the Madigan Foal Squeeze technique has proven to play an important role in the recovery, making it faster. ENE has been shown to be a very complex disease and in need of better investigation, since it affects the CNS and presents multifactorial etiologies.