Air or 100% oxygen for asphyxiated babies? Time to decide

Both experimental and clinical studies have demonstrated that room air is as efficient as 100% oxygen for newborn resuscitation and improves short-term recovery. The recent meta-analysis by Davis and colleagues in the Lancet includes five studies from the past 10 years where asphyxiated infants were randomised or pseudo-randomised to be resuscitated in room air or in 100% oxygen. A significant reduction in mortality was seen when infants were resuscitated in room air compared to 100% oxygen. It is astonishing that a brief exposure of only a few minutes to 100% oxygen may be so toxic to the newborn infant; this finding, however, is supported by increasing evidence from experimental work emphasising that resuscitation in 100% oxygen may be associated with an aggravation of cellular injury when compared with resuscitation in air. It is imperative that these findings are reflected in the new newborn resuscitation guidelines and that further research continues in this area of neonatal medicine. Key areas include defining the best resuscitation practice for the preterm infant, designing adequate multicentre, randomised and blinded studies of term newborn resuscitation with adequate outcome data, and pursuing intense experimental research into the mechanisms and prevention of injury from oxygen free radicals

Mesenchymal Stromal Cell therapy for Hypoxic Ischemic Encephalopathy:Future directions for combination therapy with hypothermia and/or melatonin

Hypoxic ischemic encephalopathy (HIE) remains a leading cause of neonatal mortality and lifelong disability across the world. While therapeutic hypothermia (HT) is beneficial, it is only partially protective and adjuvant treatments that further improve outcomes are urgently needed. In high-income countries where HT is standard care, novel treatments are tested in conjunction with HT. Mesenchymal stromal cells (MSC) represent a paradigm shift in brain protection, uniquely adapting to the host cellular microenvironment. MSC have low immunogenicity and potent paracrine effects stimulating the host tissue repair and regeneration and reducing inflammation and apoptosis. Preclinical studies in perinatal brain injury suggest that MSC are beneficial after hypoxia-ischemia (HI) and most preclinical studies of MSC with HT show protection. Preclinical and early phase clinical trials have shown that allogenic administration of MSC to neonates with perinatal stroke and HIE is safe and feasible but further safety and efficacy studies of HT with MSC in these populations are needed. Combination therapies that target all stages of the evolution of injury after HI (eg HT, melatonin and MSC) show promise for improving outcomes in HIE.</p

Neurogenesis Is Reduced at 48 h in the Subventricular Zone Independent of Cell Death in a Piglet Model of Perinatal Hypoxia-Ischemia

Cellular and tissue damage triggered after hypoxia-ischemia (HI) can be generalized and affect the neurogenic niches present in the central nervous system. As neuroregeneration may be critical for optimizing functional recovery in neonatal encephalopathy, the goal of the present work was to investigate the neurogenic response to HI in the neurogenic niche of the subventricular zone (SVZ) in the neonatal piglet. A total of 13 large white male piglets aged <24 h were randomized into two groups: i) HI group (n = 7), animals submitted to transient cerebral HI and resuscitation; and ii) Control group (n = 6), non-HI animals. At 48 h, piglets were euthanized, and the SVZ and its surrounding regions, such as caudate and periventricular white matter, were analyzed for histology using hematoxylin-eosin staining and immunohistochemistry by evaluating the presence of cleaved caspase 3 and TUNEL positive cells, together with the cell proliferation/neurogenesis markers Ki67 (cell proliferation), GFAP (neural stem cells processes), Sox2 (neural stem/progenitor cells), and doublecortin (DCX, a marker of immature migrating neuroblasts). Hypoxic-ischemic piglets showed a decrease in cellularity in the SVZ independent of cell death, together with decreased length of neural stem cells processes, neuroblast chains area, DCX immunoreactivity, and lower number of Ki67 + and Ki67 + Sox2 + cells. These data suggest a reduction in both cell proliferation and neurogenesis in the SVZ of the neonatal piglet, which could in turn compromise the replacement of the lost neurons and the achievement of global repair

Therapeutic hypothermia modulates the neurogenic response of the newborn piglet subventricular zone after hypoxia-ischemia

BACKGROUND: Neuroprotection combined with neuroregeneration may be critical for optimizing functional recovery in neonatal encephalopathy. To investigate the neurogenic response to hypoxia-ischemia (HI) followed by normothermia (38.5 °C) or three different hypothermic temperatures (35, 33.5, or 30 °C) in the subventricular zone (SVZ) of the neonatal piglet. METHODS: Following transient cerebral HI and resuscitation, 28 newborn piglets were randomized to: normothermia or whole-body cooling to 35 °C, 33.5 °C, or 30 °C during 2-26 h (all n = 7). At 48 h, piglets were euthanized and SVZ obtained to evaluate its cellularity, pattern of cell death, radial glia length, doublecortin (DCX, neuroblasts) expression, and Ki67 (cell proliferation) and Ki67/Sox2 (neural stem/progenitor dividing) cell counts. RESULTS: Normothermic piglets showed lower total (Ki67+) and neural stem/progenitor dividing (Ki67+Sox2+) cell counts when compared to hypothermic groups. Cooling to 33.5 °C obtained the highest values of SVZ cellularity, radial glia length processes, neuroblast chains area and DCX immunohistochemistry. Cooling to 30 °C, however, revealed decreased cellularity in the lateral SVZ and shorter radial glia processes when compared with 33.5 °C. CONCLUSIONS: In a neonatal piglet model, hypothermia to 33.5 °C modulates the neurogenic response of the SVZ after HI, highlighting the potential beneficial effect of hypothermia to 33.5 °C on endogenous neurogenesis and the detrimental effect of overcooling beyond this threshold. IMPACT: Neuroprotection combined with neuroregeneration may be critical for optimizing functional recovery in neonatal encephalopathy. Hypothermia may modulate neurogenesis in the subventricular zone (SVZ) of the neonatal hypoxic-ischemic piglet. Cooling to 33.5 °C obtained the highest values of SVZ cellularity, radial glia length processes, neuroblast chains area and doublecortin immunohistochemistry; cooling to 30 °C, however, revealed decreased cellularity and shorter radial glia processes. In a neonatal piglet model, therapeutic hypothermia (33.5 °C) modulates the neurogenic response of the SVZ after hypoxia-ischemia, highlighting also the detrimental effect of overcooling beyond this threshold

Reconstruction of fetal and infant anatomy using rapid prototyping of post-mortem MR images

OBJECTIVES: The recent decline in autopsy rates and lack of human anatomical material donated for research and training has resulted in issues for medical training in the United Kingdom. This study aims to examine the feasibility of making accurate three-dimensional (3D) models of the human body and visceral organs using post-mortem magnetic resonance (MR) imaging and rapid prototyping. METHODS: We performed post-mortem MR imaging using a 3D T2-weighted sequence in 11 fetuses and infants, before autopsy, using either a 1.5-T or 9.4-T MR scanner. Internal organs were reconstructed in silico and 3D models were created by rapid prototyping. RESULTS: The median gestation of fetuses was 20 (range 19-30) weeks and the median age of infants was 12 (range 8-16) weeks. Models created by rapid prototyping accurately depicted structural abnormalities and allowed clear visualisation of 3D relationships. CONCLUSIONS: Accurate 3D modelling of anatomical features from post-mortem imaging in fetuses and infants is feasible. These models could have a large number of medical applications, including improved parental counselling, invaluable teaching resources and significant medico-legal applications to demonstrate disease or injury, without the need to show actual autopsy photographs

Role of Optical Neuromonitoring in Neonatal Encephalopathy—Current State and Recent Advances

Neonatal encephalopathy (NE) in term and near-term infants is a significant global health problem; the worldwide burden of disease remains high despite the introduction of therapeutic hypothermia. Assessment of injury severity and effective management in the neonatal intensive care unit (NICU) relies on multiple monitoring modalities from systemic to brain-specific. Current neuromonitoring tools provide information utilized for seizure management, injury stratification, and prognostication, whilst systemic monitoring ensures multi-organ dysfunction is recognized early and supported wherever needed. The neuromonitoring technologies currently used in NE however, have limitations in either their availability during the active treatment window or their reliability to prognosticate and stratify injury confidently in the early period following insult. There is therefore a real need for a neuromonitoring tool that provides cot side, early and continuous monitoring of brain health which can reliably stratify injury severity, monitor response to current and emerging treatments, and prognosticate outcome. The clinical use of near-infrared spectroscopy (NIRS) technology has increased in recent years. Research studies within this population have also increased, alongside the development of both instrumentation and signal processing techniques. Increasing use of commercially available cerebral oximeters in the NICU, and the introduction of advanced optical measurements using broadband NIRS (BNIRS), frequency domain NIRS (FDNIRS), and diffuse correlation spectroscopy (DCS) have widened the scope by allowing the direct monitoring of oxygen metabolism and cerebral blood flow, both key to understanding pathophysiological changes and predicting outcome in NE. This review discusses the role of optical neuromonitoring in NE and why this modality may provide the next significant piece of the puzzle toward understanding the real time state of the injured newborn brain

Melatonin for Neonatal Encephalopathy: From Bench to Bedside

Neonatal encephalopathy is a leading cause of morbidity and mortality worldwide. Although therapeutic hypothermia (HT) is now standard practice in most neonatal intensive care units in high resource settings, some infants still develop long-term adverse neurological sequelae. In low resource settings, HT may not be safe or efficacious. Therefore, additional neuroprotective interventions are urgently needed. Melatonin’s diverse neuroprotective properties include antioxidant, anti-inflammatory, and anti-apoptotic effects. Its strong safety profile and compelling preclinical data suggests that melatonin is a promising agent to improve the outcomes of infants with NE. Over the past decade, the safety and efficacy of melatonin to augment HT has been studied in the neonatal piglet model of perinatal asphyxia. From this model, we have observed that the neuroprotective effects of melatonin are time-critical and dose dependent. Therapeutic melatonin levels are likely to be 15–30 mg/L and for optimal effect, these need to be achieved within the first 2–3 h after birth. This review summarises the neuroprotective properties of melatonin, the key findings from the piglet and other animal studies to date, and the challenges we face to translate melatonin from bench to bedside

Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients.

Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously