Relationship Between Cerebral Oxygenation and Metabolism During Rewarming in Newborn Infants After Therapeutic Hypothermia Following Hypoxic-Ischemic Brain Injury.

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.

Pressure passivity of cerebral mitochondrial metabolism is associated with poor outcome following perinatal hypoxic ischemic brain injury.

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.

Oxygen dependency of mitochondrial metabolism indicates outcome of newborn brain injury.

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.

Proton magnetic resonance spectroscopy lactate/N-acetylaspartate within 2 weeks of birth accurately predicts 2-year motor, cognitive and language outcomes in neonatal encephalopathy after therapeutic hypothermia.

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.

Changes in Cerebral Oxidative Metabolism during Neonatal Seizures Following Hypoxic-Ischemic Brain Injury.

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.

Na⁺/H⁺ exchangers and intracellular pH in perinatal brain injury.

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 Na⁺/H⁺ 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⁺ overload, which subsequently promotes Ca²âº entry via reversal of the Na⁺/Ca²âº exchanger. Increased cytosolic Ca²âº 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.

Outcome following neonatal seizures.

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.