RESUMEN
There is a need for a method of real-time assessment of brain metabolism during neonatal hypoxic-ischaemic encephalopathy (HIE). We have used broadband near-infrared spectroscopy (NIRS) to monitor cerebral oxygenation and metabolic changes in 50 neonates with HIE undergoing therapeutic hypothermia treatment. In 24 neonates, 54 episodes of spontaneous decreases in peripheral oxygen saturation (desaturations) were recorded between 6 and 81 h after birth. We observed differences in the cerebral metabolic responses to these episodes that were related to the predicted outcome of the injury, as determined by subsequent magnetic resonance spectroscopy derived lactate/N-acetyl-aspartate. We demonstrated that a strong relationship between cerebral metabolism (broadband NIRS-measured cytochrome-c-oxidase (CCO)) and cerebral oxygenation was associated with unfavourable outcome; this is likely to be due to a lower cerebral metabolic rate and mitochondrial dysfunction in severe encephalopathy. Specifically, a decrease in the brain tissue oxidation state of CCO greater than 0.06 µM per 1 µM brain haemoglobin oxygenation drop was able to predict the outcome with 64% sensitivity and 79% specificity (receiver operating characteristic area under the curve = 0.73). With further work on the implementation of this methodology, broadband NIRS has the potential to provide an early, cotside, non-invasive, clinically relevant metabolic marker of perinatal hypoxic-ischaemic injury.
Asunto(s)
Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/terapia , Hipotermia Inducida , Mitocondrias/metabolismo , Oxígeno/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Lesiones Encefálicas/complicaciones , Circulación Cerebrovascular , Femenino , Humanos , Hipotermia Inducida/métodos , Hipoxia/complicaciones , Hipoxia/metabolismo , Hipoxia/terapia , Recién Nacido , Masculino , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Hypoxic ischemic encephalopathy (HIE) leads to significant morbidity and mortality. Impaired autoregulation after hypoxia-ischaemia has been suggested to contribute further to injury. Thalamic lactate/N-Acetylasperate (Lac/NAA) peak area ratio of > 0.3 on proton (1H) magnetic resonance spectroscopy (MRS) is associated with poor neurodevelopment outcome following HIE. Cytochrome-c-oxidase (CCO) plays a central role in mitochondrial oxidative metabolism and ATP synthesis. Using a novel broadband NIRS system, we investigated the impact of pressure passivity of cerebral metabolism (CCO), oxygenation (haemoglobin difference (HbD)) and cerebral blood volume (total haemoglobin (HbT)) in 23 term infants following HIE during therapeutic hypothermia (HT). Sixty-minute epochs of data from each infant were studied using wavelet analysis at a mean age of 48 h. Wavelet semblance (a measure of phase difference) was calculated to compare reactivity between mean arterial blood pressure (MABP) with oxCCO, HbD and HbT. OxCCO-MABP semblance correlated with thalamic Lac/NAA ( r = 0.48, p = 0.02). OxCCO-MABP semblance also differed between groups of infants with mild to moderate and severe injury measured using brain MRI score ( p = 0.04), thalamic Lac/NAA ( p = 0.04) and neurodevelopmental outcome at one year ( p = 0.04). Pressure passive changes in cerebral metabolism were associated with injury severity indicated by thalamic Lac/NAA, MRI scores and neurodevelopmental assessment at one year of age.
Asunto(s)
Encéfalo/metabolismo , Hipoxia-Isquemia Encefálica/metabolismo , Mitocondrias/metabolismo , Adenosina Trifosfato/biosíntesis , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Presión Sanguínea , Circulación Cerebrovascular , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/etiología , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Homeostasis , Humanos , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/diagnóstico por imagen , Recién Nacido , Ácido Láctico/metabolismo , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Tálamo/metabolismoRESUMEN
OBJECTIVE: Brain proton (1H) magnetic resonance spectroscopy (MRS) lactate/N-acetylaspartate (Lac/NAA) peak area ratio is used for prognostication in neonatal encephalopathy (NE). At 3 Tesla in NE babies, the objectives were to assess: (1) sensitivity and specificity of basal ganglia and thalamus (BGT) 1H MRS Lac/NAA for the prediction of Bayley III outcomes at 2 years using optimised metabolite fitting (Tarquin) with threonine and total NAA; (2) prediction of motor outcome with diffusion-weighted MRI; (3) BGT Lac/NAA correlation with the National Institute of Child Health and Human Development (NICHD) MRI score. SUBJECTS AND METHODS: 55 (16 inborn, 39 outborn) infants at 39w+5 d (35w+5d-42w+0d) with NE admitted between February 2012 and August 2014 to University College London Hospitals for therapeutic hypothermia underwent MRI and 1H MRS at 3T on day 2-14 (median day 5). MRIs were scored. Bayley III was assessed at 24 (22-26) months. RESULTS: 16 babies died (1 inborn, 15 outborn); 20, 19 and 21 babies had poor motor, cognitive and language outcomes. Using a threshold of 0.39, sensitivity and specificity of BGT Lac/NAA for 2-year motor outcome was 100% and 97%, cognition 90% and 97% and language 81% and 97%, respectively. Sensitivity and specificity for motor outcome of mean diffusivity (threshold 0.001 mm2/s) up to day 9 was 72% and 100% and fractional anisotropy (threshold 0.198) was 39% and 94%, respectively. Lac/NAA correlated with BGT injury on NICHD scores (2A, 2B, 3). CONCLUSION: BGT Lac/NAA on 1H MRS at 3T within 14 days accurately predicts 2-year motor, cognitive and language outcome and may be a marker directing decisions for therapies after cooling.
Asunto(s)
Ácido Aspártico/análogos & derivados , Disfunción Cognitiva/etiología , Hipotermia Inducida/métodos , Hipoxia-Isquemia Encefálica/diagnóstico por imagen , Hipoxia-Isquemia Encefálica/terapia , Trastornos del Desarrollo del Lenguaje/etiología , Ácido Aspártico/metabolismo , Humanos , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/metabolismo , Lactante , Recién Nacido , Masculino , Pronóstico , Espectroscopía de Protones por Resonancia MagnéticaRESUMEN
Seizures are common following hypoxic-ischemic brain injury in newborn infants. Prolonged or recurrent seizures have been shown to exacerbate neuronal damage in the developing brain; however, the precise mechanism is not fully understood. Cytochrome-c-oxidase is responsible for more than 90% of ATP production inside mitochondria. Using a novel broadband near-infrared spectroscopy system, we measured the concentration changes in the oxidation state of cerebral cytochrome-c-oxidase (Δ[oxCCO]) and hemodynamics during recurrent neonatal seizures following hypoxic-ischemic encephalopathy in a newborn infant. A rapid increase in Δ[oxCCO] was noted at the onset of seizures along with a rise in the baseline of amplitude-integrated electroencephalogram. Cerebral oxygenation and cerebral blood volume fell just prior to the seizure onset but recovered rapidly during seizures. Δ[oxCCO] during seizures correlated with changes in mean electroencephalogram voltage indicating an increase in neuronal activation and energy demand. The progressive decline in the Δ[oxCCO] baseline during seizures suggests a progressive decrease of mitochondrial oxidative metabolism.
RESUMEN
Therapeutic hypothermia (TH) has become a standard of care following hypoxic ischemic encephalopathy (HIE). After TH, body temperature is brought back to 37 °C over 14 h. Lactate/N-acetylasperatate (Lac/NAA) peak area ratio on proton magnetic resonance spectroscopy ((1)H MRS) is the best available outcome biomarker following HIE. We hypothesized that broadband near infrared spectroscopy (NIRS) measured changes in the oxidation state of cytochrome-c-oxidase concentration (Δ[oxCCO]) and cerebral hemodynamics during rewarming would relate to Lac/NAA. Broadband NIRS and systemic data were collected during rewarming from 14 infants following HIE over a mean period of 12.5 h. (1)H MRS was performed on day 5-9. Heart rate increased by 20/min during rewarming while blood pressure and peripheral oxygen saturation (SpO2) remained stable. The relationship between mitochondrial metabolism and oxygenation (measured as Δ[oxCCO] and Δ[HbD], respectively) was calculated by linear regression analysis. This was reviewed in three groups: Lac/NAA values <0.5, 0.5-1, >1. Mean regression coefficient (r (2)) values in these groups were 0.41 (±0.27), 0.22 (±0.21) and 0.01, respectively. The relationship between mitochondrial metabolism and oxygenation became impaired with rising Lac/NAA. Cardiovascular parameters remained stable during rewarming.
Asunto(s)
Regulación de la Temperatura Corporal , Complejo IV de Transporte de Electrones/metabolismo , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/terapia , Consumo de Oxígeno , Oxígeno/sangre , Recalentamiento , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Biomarcadores/sangre , Circulación Cerebrovascular , Femenino , Hemoglobinas/metabolismo , Humanos , Hipoxia-Isquemia Encefálica/sangre , Hipoxia-Isquemia Encefálica/fisiopatología , Recién Nacido , Ácido Láctico/metabolismo , Modelos Lineales , Masculino , Mitocondrias/metabolismo , Oxidación-Reducción , Oximetría/métodos , Valor Predictivo de las Pruebas , Espectroscopía de Protones por Resonancia Magnética , Espectroscopía Infrarroja Corta , Factores de Tiempo , Resultado del TratamientoRESUMEN
Encephalopathy consequent on perinatal hypoxia-ischemia occurs in 1-3 per 1,000 term births in the UK and frequently leads to serious and tragic consequences that devastate lives and families, with huge financial burdens for society. Although the recent introduction of cooling represents a significant advance, only 40% survive with normal neurodevelopmental function. There is thus a significant unmet need for novel, safe, and effective therapies to optimize brain protection following brain injury around birth. The Naâº/H⺠exchanger (NHE) is a membrane protein present in many mammalian cell types. It is involved in regulating intracellular pH and cell volume. NHE1 is the most abundant isoform in the central nervous system and plays a role in cerebral damage after hypoxia-ischemia. Excessive NHE activation during hypoxia-ischemia leads to intracellular Na⺠overload, which subsequently promotes Ca²âº entry via reversal of the Naâº/Ca²âº exchanger. Increased cytosolic Ca²âº then triggers the neurotoxic cascade. Activation of NHE also leads to rapid normalization of pHi and an alkaline shift in pHi. This rapid recovery of brain intracellular pH has been termed pH paradox as, rather than causing cells to recover, this rapid return to normal and overshoot to alkaline values is deleterious to cell survival. Brain pHi changes are closely involved in the control of cell death after injury: an alkalosis enhances excitability while a mild acidosis has the opposite effect. We have observed a brain alkalosis in 78 babies with neonatal encephalopathy serially studied using phosphorus-31 magnetic resonance spectroscopy during the first year after birth (151 studies throughout the year including 56 studies of 50 infants during the first 2 weeks after birth). An alkaline brain pHi was associated with severely impaired outcome; the degree of brain alkalosis was related to the severity of brain injury on MRI and brain lactate concentration; and a persistence of an alkaline brain pHi was associated with cerebral atrophy on MRI. Experimental animal models of hypoxia-ischemia show that NHE inhibitors are neuroprotective. Here, we review the published data on brain pHi in neonatal encephalopathy and the experimental studies of NHE inhibition and neuroprotection following hypoxia-ischemia.
Asunto(s)
Encéfalo/metabolismo , Hipoxia-Isquemia Encefálica/metabolismo , Neuronas/metabolismo , Intercambiadores de Sodio-Hidrógeno/metabolismo , Animales , Modelos Animales de Enfermedad , Metabolismo Energético , Femenino , Humanos , Concentración de Iones de Hidrógeno , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/patología , Hipoxia-Isquemia Encefálica/terapia , Recién NacidoRESUMEN
Neonatal seizures are the most common manifestation of neurological disorders in the newborn period and an important determinant of outcome. Overall, for babies born at full term, mortality following seizures has improved in the last decade, typical current mortality rates being 10% (range: 7-16%), down from 33% in reports from the 1990s. By contrast, the prevalence of adverse neurodevelopmental sequelae remains relatively stable, typically 46% (range: 27-55%). The strongest predictors of outcome are the underlying cause, together with the background electroencephalographic activity. In preterm babies, for whom the outlook tends to be worse as background mortality and disability are high, seizures are frequently associated with serious underlying brain injury and therefore subsequent impairments. When attempting to define the prognosis for a baby with neonatal seizures, we propose a pathway involving history, examination, and careful consideration of all available results (ideally including brain magnetic resonance imaging) and the response to treatment before synthesizing the best estimate of risk to be conveyed to the family.
Asunto(s)
Encéfalo/metabolismo , Desarrollo Infantil , Neurogénesis , Neuronas/metabolismo , Convulsiones/fisiopatología , Animales , Encéfalo/patología , Infarto Cerebral/fisiopatología , Epilepsia/diagnóstico , Epilepsia/etiología , Epilepsia/mortalidad , Epilepsia/fisiopatología , Humanos , Mortalidad Infantil , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Sistema Nervioso/etiología , Neuronas/patología , Nacimiento Prematuro/fisiopatología , Pronóstico , Convulsiones/diagnóstico , Convulsiones/etiología , Convulsiones/mortalidadRESUMEN
Objetivo. Valorar un incremento inesperado de la incidencia en nuestro Hospital de episodios aparentemente letales en recién nacidos en las primeras 2 horas de vida. Esto ha sucedido en los 2 últimos años desde que el contacto piel con piel madre-hijo se estableció como práctica habitual. Métodos. Se ha realizado una valoración completa de los datos de todos los pacientes para detectar posibles factores de riesgo. También se ha analizado la diferente incidencia en cuatro periodos sucesivos a lo largo de los últimos 35 años con 208.220 nacidos vivos. Resultados. En el último periodo el aumento de incidencia de estos sucesos ha sido estadísticamente significativa. Se han detectado varios factores potenciales de riesgo: contacto piel con piel, primiparidad, incidencia aumentada durante la noche y suceder en el segundo periodo de adaptación neonatal (30 a 90 minutos de vida). Dos de nuestros 8 pacientes tienen secuelas neurológicas y otro de ellos murió. Conclusión. Los episodios aparentemente letales en las primeras 2 horas de vida son poco frecuentes, pero sus consecuencias pueden ser graves. El contacto piel con piel entre la madre y el neonato en la sala de partos durante el periodo de adaptación neonatal precoz puede constituir uno de los principales factores de riesgo. En tanto que el contacto piel con piel se ha mostrado beneficioso y sin riesgos aparentes, debemos estimular su práctica. Pero deberíamos garantizar la preparación del equipo y la atención durante su transcurso, especialmente si la madre está sola o concurren otros factores de riesgo(AU)
Objective. To evaluate an unexpected increase in the incidence of apparently life threatening events and sudden deaths in neonates during the first 2hours after birth in our hospital. This increase occurred in the first 2 years after generalized skin-to-skin contact between mother and infant became routine practice. Methods. Full information on all our patients was collected to evaluate possible risk factors. Differences in incidence in four successive periods comprising the previous 35 years, with 208220 live neonates, were also analyzed. Results. In the last period, there was a statistically significant increase in the rate of apparently life threatening events and sudden deaths in neonates. Several potential risk factors were detected: skin-to-skin contact, primiparity, an increased incidence in night hours and the invariable occurrence of these events in the second period of neonatal adaptation (30 to 90minutes of life). Of eight patients with apparently life-threatening events, two had neurological sequelae and another died. Conclusion. Apparently life threatening events in the first 2hours of life are uncommon but may have serious consequences. One of the main risk factors may be skin-to-skin contact between mother and infant in the delivery room during the early adaptation period. As such contact has been proven to be beneficial and without apparent risks, this practice should be promoted. However, maternity staff should be vigilant during skin-to-skin contact, especially if the mother is alone with her neonate or other risk factors are present(AU)