Background Several studies have investigated heart rate variability (HRV) as a biomarker for acute brain injury in hypoxic ischemic encephalopathy (HIE). However, the current evidence is heterogeneous and needs further reviewing to direct future studies. We aimed to systematically review whether HIE severity is associated with HRV. Methods This systematic review was conducted according to the preferred reporting items for systematic review and meta analyses (PRISMA). We included studies comparing neonates with severe or moderate HIE with neonates with mild or no HIE with respect to different HRV measures within 7 days of birth. Article selection and quality assessment was independently performed by two reviewers. Risk of bias and strength of evidence was evaluated by the Newcastle-Ottawa scale (NOS) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results We screened 1187 studies. From these, four observational studies with 248 neonates were included. For all HRV measures, the strength of evidence was very low. Neonates with severe or moderate HIE showed a reduction in most HRV measures compared to neonates with mild or no HIE with a greater reduction in those with severe HIE. Conclusions Moderate and severe HIE was associated with a reduction in most HRV measures. Accordingly, HRV is a potential biomarker for HIE severity during the first week of life. However, the uncertainty calls for more studies. Electronic supplementary material The online version of this article (10.1186/s12887-019-1603-7) contains supplementary material, which is available to authorized users.

Introduction: Hypoxic ischemic encephalopathy (HIE) is a major cause of death and disability in children worldwide. Apart from supportive care, the only established treatment for HIE is therapeutic hypothermia (TH). As TH is only partly neuroprotective, there is a need for additional therapies. Intermittent periods of limb ischemia, called remote ischemic postconditioning (RIPC), have been shown to be neuroprotective after HIE in rats and piglets. However, it is unknown whether RIPC adds to the effect of TH. We tested the neuroprotective effect of RIPC with TH compared to TH alone using magnetic resonance imaging and spectroscopy (MRI/MRS) in a piglet HIE model. Methods: Thirty-two male and female piglets were subjected to 45-min global hypoxia-ischemia (HI). Twenty-six animals were randomized to TH or RIPC plus TH; six animals received supportive care only. TH was induced through whole-body cooling. RIPC was induced 1 h after HI by four cycles of 5 min of ischemia and 5 min of reperfusion in both hind limbs. Primary outcome was Lac/NAA ratio at 24 h measured by MRS. Secondary outcomes were NAA/Cr, diffusion-weighted imaging (DWI), arterial spin labeling, aEGG score, and blood oxygen dependent (BOLD) signal measured by MRI/MRS at 6, 12, and 24 h after the hypoxic-ischemic insult. Results: All groups were subjected to a comparable but mild insult. No difference was found between the two intervention groups in Lac/NAA ratio, NAA/Cr ratio, DWI, arterial spin labeling, or BOLD signal. NAA/Cr ratio at 24 h was higher in the two intervention groups compared to supportive care only. There was no difference in aEEG score between the three groups. Andelius et al. Remote Postconditioning and Neonatal Encephalopathy Conclusion: Treatment with RIPC resulted in no additional neuroprotection when combined with TH. However, insult severity was mild and only evaluated at 24 h after HI with a short MRS echo time. In future studies more subtle neurological effects may be detected with increased MRS echo time and post mortem investigations, such as brain histology. Thus, the possible neuroprotective effect of RIPC needs further evaluation.

There are a variety of devices that quantify biological properties of cerebral tissue. Installing such device will cause a local insertion trauma, which will affect early measurements. Current literature proposes minimum one hour of observation before acquiring first measurements when using microdialysis. It is unknown whether this applies to other intracerebral devices. We therefore aimed to investigate time needed to reach steady state when using microdialysis and two intracerebral probes in a piglet model. Ten newborn piglets less than 24 hours of age were anaesthetized. Two probes (Codman and OxyLite/OxyFlo) and a microdialysis catheter (CMA Microdialysis) were installed 10 mm into the left hemisphere. Probes measured intracranial pressure, cerebral blood flow, and oxygen tension. The microdialysis catheter measured lactate, glucose, glycerol, and pyruvate. Measurements were acquired hourly for 20 hours. Lactate and glycerol peaked immediately after insertion and reached steady state after approximately four hours. Glucose, pyruvate, cerebral blood flow, and intracranial pressure reached steady state immediately. Oxygen tension reached steady state after 12 hours. With time, interindividual variability decreased for the majority of measurements. Consequently, time to stabilization after insertion depends on the choice of device and is crucial to obtain valid baseline values with high degree of precision.

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Bone wax and water-soluble polymer wax had similar long-term effects on bone mechanical properties. Histology confirmed our hypothesis and showed a more extensive foreign body reaction in animals treated with bone wax than in those treated with water-soluble polymer wax.