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Objective To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry.Design Phase II randomised, single blinded, parallel clinical trial.Setting Eight tertiary neonatal intensive care units in eight European countries. Participants 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support.Interventions Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control). Main outcome measuresThe primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography.Randomisation Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (<26 weeks or ≥26 weeks).Blinding Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation. 17.4-171.3) %hours in the control group (P=0.0012). The median burden of hyperoxia was similar between the groups: 1.2 (interquartile range 0.3-9.6) %hours in the experimental group compared with 1.1 (0.1-23.4) %hours in the control group (P=0.98). We found no statistically significant differences between the two groups at term corrected age. No severe adverse reactions were associated with the device.Conclusions Cerebral oxygenation was stabilised in extremely preterm infants using a dedicated treatment guideline in combination with cerebral NIRS monitoring.Trial registration ClinicalTrial.gov NCT01590316.

This review focuses on the clinical use of near infrared spectroscopy (NIRS) to assess brain oxygenation by the tissue oxygenation index (TOI), and monitoring regional cerebral oxygen saturation (rScO₂), cerebral fractional tissue oxygen extraction (cFTOE), which is derived from rScO₂, and systemic oxygen saturation. Its precision and pitfalls are discussed. At this stage, it is clear that NIRS-monitored oxygenation of the brain by rScO₂ or TOI lacks the precision required to be used as a robust quantitative variable to monitor cerebral oxygenation. Intra- and especially interpatient variability are too large for this aim. On the other hand, when used merely as a trend monitor in the individual patient, substantial changes in rScO₂ or TOI and consequently of cFTOE, larger than the limits of agreement, can yield important clinical information that suggest an intervention. Since neonatal intensive care is for a substantial part ‘brain orientated’ this approach seems conceivable. This gives rise to the conclusion that NIRS-monitored TOI, rScO₂ and cFTOE increasingly will have a role in clinical practice as semiquantitative indicators of changes in cerebral oxygenation and oxygen extraction. Combination with other (cerebral) parameters such as amplitude-integrated EEG and blood pressure seems promising for further optimization of monitoring the immature brain.

rSo2 and FTOE seem to reflect secondary energy failure. aEEG showed the closest relationship with outcome after severe birth asphyxia.

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Mesenchymal stem cell (MSC) administration via the intranasal route could become an effective therapy to treat neonatal hypoxic-ischemic (HI) brain damage. We analyzed long-term effects of intranasal MSC treatment on lesion size, sensorimotor and cognitive behavior, and determined the therapeutic window and dose response relationships. Furthermore, the appearance of MSCs at the lesion site in relation to the therapeutic window was examined. Nine-day-old mice were subjected to unilateral carotid artery occlusion and hypoxia. MSCs were administered intranasally at 3, 10 or 17 days after hypoxia-ischemia (HI). Motor, cognitive and histological outcome was investigated. PKH-26 labeled cells were used to localize MSCs in the brain. We identified 0.5×106 MSCs as the minimal effective dose with a therapeutic window of at least 10 days but less than 17 days post-HI. A single dose was sufficient for a marked beneficial effect. MSCs reach the lesion site within 24 h when given 3 or 10 days after injury. However, no MSCs were detected in the lesion when administered 17 days following HI. We also show for the first time that intranasal MSC treatment after HI improves cognitive function. Improvement of sensorimotor function and histological outcome was maintained until at least 9 weeks post-HI. The capacity of MSCs to reach the lesion site within 24 h after intranasal administration at 10 days but not at 17 days post-HI indicates a therapeutic window of at least 10 days. Our data strongly indicate that intranasal MSC treatment may become a promising non-invasive therapeutic tool to effectively reduce neonatal encephalopathy.

The impact of nutrition on brain development in preterm infants has been increasingly appreciated. Early postnatal growth and nutrient intake have been demonstrated to influence brain growth and maturation with subsequent effects on neurodevelopment that persist into childhood and adolescence. Nutrition could also potentially protect against injury. Inflammation and perinatal infection play a crucial role in the pathogenesis of white matter injury, the most common pattern of brain injury in preterm infants. Therefore, nutritional components with immunomodulatory and/or anti-inflammatory effects may serve as neuroprotective agents. Moreover, growing evidence supports the existence of a microbiome-gut-brain axis. The microbiome is thought to interact with the brain through immunological, endocrine, and neural pathways. Consequently, nutritional components that may influence gut microbiota may also exert beneficial effects on the developing brain. Based on these properties, probiotics, prebiotic oligosaccharides, and certain amino acids are potential candidates for neuroprotection. In addition, the amino acid glutamine has been associated with a decrease in infectious morbidity in preterm infants. In conclusion, early postnatal nutrition is of major importance for brain growth and maturation. Additionally, certain nutritional components might play a neuroprotective role against white matter injury, through modulation of inflammation and infection, and may influence the microbiome-gut-brain axis.