Oxygen dependency of mitochondrial metabolism indicates outcome of newborn brain injury

Abstract

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.

A Bayesian framework for the analysis of systems biology models of the brain

“…We apply this method when simulating the physiological Relations 72 3 3 Variables 168 40 128 Parameters 697 139 227 blood pressure, arterial oxygen saturation and/or partial pressure of CO 2 . 45 The models are driven with input signals, such as the blood pressure and/or oxygen 46 saturation, and simulate brain tissue measurments of oxygenation, blood volume and 47 metabolism, as well as the middle cerebral artery velocity (Vmca) and the cerebral 48 metabolic rate of oxygen (CMRO 2 ). The model can be split into roughly 3 49 compartments -blood flow, oxygen transport and metabolism -with boundaries chosen 50 to minimise interdependence.…”

“…A major interest within our research group is to use these models and approaches to 514 understand and investigate further our novel measures of brain tissue physiology and 515 metabolism and how they are linked to brain injury [44,45]. In particular, we are 516 interested in neonatal hypoxic ischaemic injury.…”

Developing a Model to Simulate the Effect of Hypothermia on Cerebral Blood Flow and Metabolism

“…Somewhere between 700,000 deaths amongst neonates can be attributed to HIE alone [1]. Following neonatal HI injury or birth asphyxia, infants are treated with therapeutic hypothermia at a temperature of 33.5 °C, as well as a variety of medications such as morphine and atracurium [2]. However, 45-55% of cases treated with hypothermia end with death or moderate to severe neurodevelopmental disability [1,3].…”

“…However, 45-55% of cases treated with hypothermia end with death or moderate to severe neurodevelopmental disability [1,3]. The brain of neonates undergoing hypothermia treatment is monitored through a variety of methods such as electro-encephalography (EEG) [4] and near-infrared spectroscopy (NIRS) [2,5]. Additionally, in the few hospitals with appropriate facilities, when the infant is stable enough (usually a week after birth) and following treatment they image the brain with magnetic resonance spectroscopy (MRS) [6].…”

“…Our approach to analyse this multimodal data has been multifaceted and includes the development and application of (1) a physiology-informed 'mathematical model' of the cerebral circulation under a systems biology approach, which is specially designed for the interpretation of NIRS signals [7][8][9][10][11][12]; and (2) 'signal processing' methods quantifying the interrelationships between signals both in time-and frequency-domain to quantify indices of cerebral blood flow, oxygenation and metabolic regulation [2,5].…”