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Aim: To review the evidence of the effects of neonatal magnesium sulphate for neuroprotection in perinatal asphyxia and hypoxic‐ischaemic encephalopathy (HIE). Method: This was a systematic review of randomized controlled trials (RCTs) (with meta‐analysis) and non‐RCTs assessing magnesium sulphate for treating perinatal asphyxia and HIE at 35 weeks or more gestation (primary outcomes: neonatal death and death or long‐term major neurodevelopmental disability). Results: Twenty‐five RCTs (2099 infants) and four non‐RCTs (871 infants) were included, 23 in low‐ and middle‐income countries (LMICs). In RCTs, reductions in neonatal death with magnesium sulphate versus placebo or no treatment (risk ratio [RR] = 0.68; 95% confidence interval [CI] = 0.53–0.86; 13 RCTs), and magnesium sulphate with melatonin versus melatonin alone (RR = 0.74; 95% CI = 0.58–0.95; one RCT) were observed. No difference in neonatal death was seen for magnesium sulphate with therapeutic hypothermia versus therapeutic hypothermia alone (RR = 0.66, 95% CI = 0.34–1.26; three RCTs), or magnesium sulphate versus phenobarbital (RR = 3.00; 95% CI = 0.86–10.46; one RCT). No reduction in death or long‐term neurodevelopmental disability (RR = 0.52; 95% CI = 0.14–1.89; one RCT) but reductions in several short‐term adverse outcomes were observed with magnesium sulphate. Evidence was low‐ to very‐low certainty because of risk of bias and imprecision. Interpretation: Given the uncertainty of the current evidence, further robust neonatal magnesium sulphate research is justified. This may include high‐quality studies to determine stand‐alone effects in LMICs and effects with and after therapeutic hypothermia in high‐income countries. [ABSTRACT FROM AUTHOR]

Background: Intrauterine inflammation and the requirement for mechanical ventilation independently increase the risk of perinatal brain injury and adverse neurodevelopmental outcomes. We aimed to investigate the effects of mechanical ventilation for 24h, with and without prior exposure to intrauterine inflammation, on markers of brain inflammation and injury in the preterm sheep brain. Methods: Chronically instrumented fetal sheep at ~115 days of gestation were randomly allocated to receive a single intratracheal dose of 1 mg lipopolysaccharide (LPS) or isovolumetric saline, then further randomly allocated 1 h after to receive mechanical ventilation with room air or no mechanical ventilation (unventilated control + saline [UVC, n = 7]; in utero mechanical ventilation + saline [VENT, n = 8], unventilated control + intratracheal LPS [UVC + LPS, n = 7]; in utero ventilation + intratracheal LPS [VENT + LPS, n = 7]). Serial fetal blood and plasma samples were collected throughout the experimental protocol for assessment of blood biochemistry and plasma interleukin (IL)-6 levels. After 24 h of mechanical ventilation, fetal brains were collected for RT-qPCR and immunohistochemical analyses. Results: LPS exposure increased numbers of microglia and upregulated pro-inflammatory related genes within the cortical gray matter (GM) and subcortical white matter (SCWM) (pLPS < 0.05). Mechanical ventilation alone increased astrocytic cell density in the periventricular white matter (PVWM) (pVENT = 0.03) but had no effect on pro-inflammatory gene expression. The combination of ventilation and LPS increased plasma IL-6 levels (p < 0.02 vs. UVC and VENT groups), and exacerbated expression of pro-inflammatory-related genes (IL1β, TLR4, PTGS2, CXCL10) and microglial density (p < 0.05 vs. VENT). Conclusion: This study demonstrates that 24 h of mechanical ventilation after exposure to intrauterine inflammation increased markers of systemic and brain inflammation and led to the upregulation of pro-inflammatory genes in the white matter. We conclude that 24 h of mechanical ventilation following intrauterine inflammation may precondition the preterm brain toward being more susceptible to inflammation-induced injury. [ABSTRACT FROM AUTHOR]

Asphyxiated neonates must have oxygenation rapidly restored to limit ongoing hypoxic-ischemic injury. However, the effects of transient hyperoxia after return of spontaneous circulation (ROSC) are poorly understood. We randomly allocated acutely asphyxiated, near-term lambs to cardiopulmonary resuscitation in 100% oxygen (“standard oxygen”, n = 8) or air (n = 7) until 5 minutes after ROSC, or to resuscitation in 100% oxygen immediately weaned to air upon ROSC (“rapid-wean”, n = 7). From 5 minutes post-ROSC, oxygen was titrated to target preductal oxygen saturation between 90–95%. Cerebral tissue oxygenation was transiently but markedly elevated following ROSC in the standard oxygen group compared to the air and rapid-wean groups. The air group had a delayed rise in cerebral tissue oxygenation from 5 minutes after ROSC coincident with up-titration of oxygen. These alterations in oxygen kinetics corresponded with similar overshoots in cerebral perfusion (pressure and flow), indicating a physiological mechanism. Transient cerebral tissue hyperoxia in the standard oxygen and air groups resulted in significant alterations in mitochondrial respiration and dynamics, relative to the rapid-wean group. Overall, rapid-wean of oxygen following ROSC preserved striatal mitochondrial respiratory function and reduced the expression of genes involved in free radical generation and apoptosis, suggesting a potential therapeutic strategy to limit cerebral reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: The feasibility and benefits of continuous sustained inflations (SIs) during chest compressions (CCs) during delayed cord clamping (physiological-based cord clamping; PBCC) are not known. We aimed to determine whether continuous SIs during CCs would reduce the time to return of spontaneous circulation (ROSC) and improve post-asphyxial blood pressures and flows in asystolic newborn lambs.Methods: Fetal sheep were surgically instrumented immediately prior to delivery at ~139 days' gestation and asphyxia induced until lambs reached asystole. Lambs were randomised to either immediate cord clamping (ICC) or PBCC. Lambs then received a single SI (SIsing; 30 s at 30 cmH2O) followed by intermittent positive pressure ventilation, or continuous SIs (SIcont: 30 s duration with 1 s break). We thus examined 4 groups: ICC +SIsing, ICC +SIcont, PBCC +SIsing, and PBCC +SIcont. Chest compressions and epinephrine administration followed international guidelines. PBCC lambs underwent cord clamping 10 min after ROSC. Physiological and oxygenation variables were measured throughout.Results: The time taken to achieve ROSC was not different between groups (mean (SD) 4.3±2.9 min). Mean and diastolic blood pressure was higher during chest compressions in PBCC lambs compared with ICC lambs, but no effect of SIs was observed. SIcont significantly reduced pulmonary blood flow, diastolic blood pressure and oxygenation after ROSC compared with SIsing.Conclusion: We found no significant benefit of SIcont over SIsing during CPR on the time to ROSC or on post-ROSC haemodynamics, but did demonstrate the feasibility of continuous SIs during advanced CPR on an intact umbilical cord. Longer-term studies are recommended before this technique is used routinely in clinical practice. [ABSTRACT FROM AUTHOR]