Mecanismos de lesión cerebral en niños prematuros / Mechanisms of brain injury of the premature baby

Los nacimientos prematuros son uno de los principales indicadores de salud de un país. Están asociados a una alta mortalidad e importante morbilidad en niños con parálisis cerebral y otros trastornos del neurodesarrollo, incluyendo problemas cognitivos y del aprendizaje. Los principales tipos de lesión encefálica en los recién nacidos prematuros son: a) las lesiones de la sustancia blanca, generalmente asociadas a alteraciones neuronales y axonales en la corteza cerebral y otras zonas de sustancia gris; b) hemorragias intracraneanas que incluyen las de la matriz germinal, intraventriculares e intraparenquimatosas y c) del cerebelo. Las lesiones de sustancia blanca incluyen la leucomalacia periventricular quística, no quística (con focos de necrosis microscópicos) y lesiones difusas de sustancia blanca, no necróticas. Estas lesiones tienen múltiples factores etiológicos. Las características anatómicas y fisiológicas de las estructuras vasculares periventriculares predisponen a la sustancia blanca a ser muy vulnerable a las situaciones de isquemia cerebral y, en interacción con factores infecciosos/inflamatorios, activan a las microglías generando estrés oxidativo (por liberación de radicales libres del oxígeno y del nitrógeno), liberación de citoquinas proinflamatorias, liberación de glutamato, fallo energético y alteración de la integridad vascular. Todo lo anteriormente mencionado genera una particular vulnerabilidad de los pre-oligodendrocitos que termina alterando la mielinización. La hipoxia-isquemia también puede producir necrosis neuronal selectiva en diferentes regiones encefálicas. La matriz germinal es un área altamente vascularizada en la región subependimaria periventricular con una estructura capilar muy frágil que la predispone a las hemorragias.

Preterm birth is one of the main country health indicators. It is associated with high mortality and significant morbidity in preterm newborns with cerebral palsy and potential long-term neurodevelopmental disabilities like cognitive and learning problems. The main lesions could be: a) white matter injuries, generally associated with cortical and other regions of grey matter neuronal-axonal disturbances; b) intracranial hemorrhage that includes germinal matrix, intraventricular and parenchymal, c) cerebellum injuries. The white matter lesions include cystic and non-cystic (with microscopic focal necrosis) periventricular leukomalacia and non-necrotic diffuse white matter injury. Multiple etiologic factors are associated with these injuries. Anatomical and physiological characteristics of periventricular vascular structures predispose white matter to cerebral ischemia and, interacting with infection/inflammation factors, activate microglia, generating oxidative stress (mediated by free oxygen and nitrogen radicals), pro-inflammatory cytokine and glutamate toxicity, energetic failure and vascular integrity disturbances. All these factors lead to a particular vulnerability of pre-oligodendrocytes that will affect myelination. Hypoxia-ischemia also may produce selective neuronal necrosis in different cerebral regions. Germinal matrix is a highly vascularized zone beneath ependymal or periventricular region that constitutes a capillary bed with a particular structural fragility that predispose it to hemorrhage.

Hipotermia terapêutica após parada cardíaca: preditores de prognóstico / Therapeutic hypothermia after cardiac arrest: outcome predictors

Resumo Objetivo: A determinação do prognóstico de pacientes em coma após parada cardíaca tem implicações clínicas, éticas e sociais. Exame neurológico, marcadores de imagem e bioquímicos são ferramentas úteis e bem aceitas na previsão da recuperação. Com o advento da hipotermia terapêutica, tais informações devem de ser confirmadas. Neste estudo procurou-se determinar a validade de diferentes marcadores que podem ser utilizados na detecção de pacientes com mau prognóstico durante um protocolo de hipotermia. Métodos: Foram coletados prospectivamente os dados de pacientes adultos, internados após parada cardíaca em nossa unidade de terapia intensiva para realização de protocolo de hipotermia. Nosso intuito foi realizar um estudo descritivo e analítico para analisar a relação entre os dados clínicos, parâmetros neurofisiológicos, de imagem e bioquímicos, e o desfecho após 6 meses, conforme definido pela escala Cerebral Performance Categories (bom, se 1-2, e mau, se 3-5). Foi coletada uma amostra para determinação de neuroenolase após 72 horas. Os exames de imagem e neurofisiológicos foram realizados 24 horas após o período de reaquecimento. Resultados: Foram incluídos 67 pacientes, dos quais 12 tiveram evolução neurológica favorável. Fibrilação ventricular e atividade teta no eletroencefalograma se associaram a bom prognóstico. Pacientes submetidos a resfriamento mais rápido (tempo médio de 163 versus 312 minutos), com lesão cerebral causada por hipóxia/isquemia detectada na ressonância nuclear magnética ou níveis de neuroenolase superiores a 58ng/mL se associaram a desfecho neurológico desfavorável (p < 0,05). Conclusão: A presença de lesão cerebral causada por hipóxia/isquemia e de neuroenolase foram fortes preditores de má evolução neurológica. Apesar da crença de que atingir rapidamente a temperatura alvo da hipotermia melhora o prognóstico neurológico, nosso estudo demonstrou que este fator se associou a um aumento da mortalidade e a uma pior evolução neurológica.

ABSTRACT Objective: The determination of coma patient prognosis after cardiac arrest has clinical, ethical and social implications. Neurological examination, imaging and biochemical markers are helpful tools accepted as reliable in predicting recovery. With the advent of therapeutic hypothermia, these data need to be reconfirmed. In this study, we attempted to determine the validity of different markers, which can be used in the detection of patients with poor prognosis under hypothermia. Methods: Data from adult patients admitted to our intensive care unit for a hypothermia protocol after cardiac arrest were recorded prospectively to generate a descriptive and analytical study analyzing the relationship between clinical, neurophysiological, imaging and biochemical parameters with 6-month outcomes defined according to the Cerebral Performance Categories scale (good 1-2, poor 3-5). Neuron-specific enolase was collected at 72 hours. Imaging and neurophysiologic exams were carried out in the 24 hours after the rewarming period. Results: Sixty-seven patients were included in the study, of which 12 had good neurological outcomes. Ventricular fibrillation and electroencephalographic theta activity were associated with increased likelihood of survival and improved neurological outcomes. Patients who had more rapid cooling (mean time of 163 versus 312 minutes), hypoxic-ischemic brain injury on magnetic resonance imaging or neuron-specific enolase > 58ng/mL had poor neurological outcomes (p < 0.05). Conclusion: Hypoxic-ischemic brain injury on magnetic resonance imaging and neuron-specific enolase were strong predictors of poor neurological outcomes. Although there is the belief that early achievement of target temperature improves neurological prognoses, in our study, there were increased mortality and worse neurological outcomes with earlier target-temperature achievement.

Learning and survival memory undergoing a permanent bilateral carotid ligation in rats

PURPOSE: To evaluate the effect of cerebral hypoxia-ischemia on memory and learning survival of rats submitted to permanent bilateral carotid ligation (PBCL). METHODS: Twenty-four survivors of PBCL were evaluated after 30 days with regard to memory and learning using a water survival maze. Twenty-three healthy rats were used as control group. The results were expressed by their means and standard error of the mean (SEM). p<0.05 was used for rejecting the null hypothesis. The study was approved by the Ethics Committee for animal investigation. RESULTS: The mortality rate for the surgery was 44.4%. The latency time to find the survival platform was higher in rats that underwent PBCL (Normal: 10.24 ± 1.85s - Study: 25.30 ± 4.69s - Mann - Whitney p=0.0388). Additionally, the type of swimming and the spatial stability of the studied rats on the survival platform were compromised in these animals. CONCLUSION: The permanent bilateral carotid ligation induces change in the learning and survival memory.

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

Coma anóxico-isquémico en 46 pacientes: Evolución a treinta días y su relación con los reflejos de tronco / The absence of brainstem reflexes does not predict short term mortality in anoxic ischemic coma

Background: Anoxic-ischemic coma has a poor outcome with a high rate of mortality and morbidity. Therefore, clinical predictors of prognosis are needed for therapeutic decision-making. Patients and methods: Prospective analysis of 46 patients, 31 male, age range 19-85 years, with anoxic-ischemic coma following cardiac arrest. All the patients included in our study remained comatose with a Glasgow Coma Scale (GCS) score of six or less points, after their stabilization in the Intensive Care Unit. They were evaluated clinically using the pupillary light reflex, corneal reflex and vestibulo-ocular reflex testing, induced by caloric stimulation with cold water. Survival was evaluated using life tables. All patients were followed until the thirtieth day after the anoxic-ischemic event. Results: Thirty five patients (76%) died within the next twenty-nine days, 8 patients (18%) reached the vegetative state, 2 patients (4%) achieved a recovery with disability, and only 1 patient (2%) was discharged without sequelae. One day, five and 30 days survival rates were 89, 53 and 29%, respectively. The abolition of all brainstem reflexes was not a predictor of mortality. Conclusion: Thirty day survival in this group of patients was 29% and the absence of brainstem reflexes was not a predictor of mortality.

The neonatal intensive care unit at the University Hospital of the West Indies: The first few years' experience / La Unidad de Cuidados Intensivos Neonatales del Hospital Universitario de West Indies Primeros años de experiencia

A retrospective analysis of neonates admitted for ventilatory support to the neonatal intensive care unit at the University Hospital of the West Indies between August 2001 and December 2004 was conducted. One hundred and thirty-eight neonates fulfilled criteria for admission into the study. Ninety-eight (71) were inborn, 88 (64) survived and 50 (36) died. The median age at death was 72 hours and 72of non-survivors died within one week of life. The main reasons for admission into the unit were respiratory distress syndrome 87(63), followed by hypoxic ischaemic encephalopathy 15 (11), surgical indications 13 (9) and meconium aspiration syndrome 11 (8). Babies with meconium aspiration syndrome and surgical problems had the best survival 82and 85respectively. Survival rates increased with increasing birthweight and gestational age. The most common complication seen was air leaks. The judicious use of neonatal intensive care measures in a developing country can result in a reduction of morbidity and mortality. However to maximize on benefits versus cost in an atmosphere of budgetary constraint evidence based management policies and protocols must be developed and implemented.

Se llevó a cabo un análisis retrospectivo de recién nacidos ingresados para recibir soporte respiratorio en la Unidad de Cuidados Intensivos Neonatales (UCIN) del Hospital Universitario de West Indies, entre agosto de 2001 y diciembre de 2004. Ciento treinta y ocho neonatos cumplieron con los criterios de admisión al estudio. Noventa y ocho (71%) fueron pacientes inborn, es decir, nacidos en el mismo hospital, 88 (64%) sobrevivieron y 50 (36%) fallecieron. La edad promedio de muerte fue 72 horas y el 72% de los que no sobrevivieron murió en el transcurso de la primera semana de vida. Las razones principales de ingreso a la unidad fueron el síndrome de insuficiencia respiratoria 87(63%), seguido por la encefalopatía hipóxica isquémica 15 (11%), indicaciones quirúrgicas 13 (9%) y el síndrome de aspiración de meconio 11 (8%). Los bebés con síndrome de aspiración meconial y problemas quirúrgicos, tuvieron los mejores índices de supervivencia – 82% y 85% respectivamente. Las tasas de supervivencia experimentaron un incremento proporcional al aumento del peso al nacer y la edad gestacional. La complicación más comúnmente observable fue el escape de aire. El uso juicioso de medidas en el cuidado intensivo neonatal puede traducirse en una reducción de la morbilidad y la mortalidad. Sin embargo, a fin de maximizar los beneficios frente a los costos en una atmósfera de limitaciones presupuestarias, se hace indispensable implementar y desarrollar políticas y protocolos de administración basados en evidencias.

Urinary 8-isoprostane and S100B protein concentrations as predictors of hypoxic-ischemic brain damage in asphyxiated neonates

Newborn infants with perinatal asphyxia are prone to the development of hypoxic-ischemic encephalopathy [HIE]. To date, there are no reliable methods for proper identification of infants who are at high risk of HIE after asphyxial insult. We sought to evaluate urinary levels of a lipid peroxidation marker, 8-isoprostane, and a brain specific protein, S100B protein, as non-invasive tools that might help early identification of postasphyxial hypoxic-ischemic brain damage and prediction of its outcome. Thirty term neonates with perinatal asphyxia were evaluated in comparison to 15 matched healthy controls. Urinary concentrations of 8-isoprostane [by ELISA] and S100B protein [by immunoluminometric technique] were determined at first urination [time 1] and repeated in a second sample obtained 24-48 hours postnatally [time 2]. Asphyxiated neonates were clinically monitored for their neurological pattern over the first two postnatal weeks and were subsequently classified as mild [grade I, n=8], moderate [grade II, n=12] and severe [grade III, n=10] HIE. Eleven of these neonates [36.7%] died in the NICU. The results obtained were interpreted in relation to the grade of HIE severity and mortality. Urinary concentrations of 8-isoprostane and S100B protein were significantly higher in asphyxiated neonates at both monitored times, as compared to controls. Levels of both markers were related to the grade of HIE severity being significantly higher in neonates who developed grade II as compared to grade I, while highest levels were found in grade III. A significant increase in urinary 8-isoprostane from time 1 to time 2 was only found in grade III [p<0.05] while S100B protein increased over that time period in grades II and III [p<0.01, respectively]. Survivors showed significantly lower mean level of each marker as compared to those with fatal outcome [p<0.001, respectively], at both monitored times. Diagnostic performance tests revealed that S100B protein was superior to 8-isoprostane, at the two monitored times, for prediction of HIE severity and mortality. At first urination, a cut-off value for S100B protein of 0.3 micro g/L could best predict development of grades II and III HIE with a positive predictive value [PPV] of 100% and an efficacy of 95.5%. Meanwhile, an optimum cut-off value of 6.89 microg/mg creatinine for 8-isoprostane, had a PPV of 90.48% and an efficacy of 88.89% for grades II and III prediction. As predictors of mortality at first urination, an optimum cut-off value for S100B protein of 2.12 micro g/L and for 8-isoprostane of 10.4 micro g/mg creatinine had corresponding PPVs of 90.9% and 90%, respectively and efficacies of 93.3% and 90%, respectively. There was no significant difference in the overall diagnostic performance of each of the two markers either for disease severity or mortality prediction between both monitored times [p>0.05, respectively]. 8-isoprostane and S100B protein levels are increased in urine following birth asphyxia. S100B protein is superior to 8-isoprostane for prediction of both HIE severity and mortality. It could be speculated that measurement of urinary concentrations of these markers, soon after birth, could serve as a clinically useful and relatively simple non-invasive tool to predict the risk for developing HIE following birth asphyxia and its short-term outcome