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 Recent recommendations characterize deliveries at 37+0 weeks through 38+6 weeks as early term. We aimed to review the literature systematically on long‐term cognition, school performance and behavior in children born early term (37+0 to 38+6 weeks) compared with full term (39+0 to 40+6 weeks). Material and methods The review was performed according to the PRISMA Statement. The final literature search was performed on 31 January 2019. We located studies in PubMed, Embase, CINAHL and Cochrane Library. Eligible studies were randomized controlled trials, cohort studies and case‐control studies, with outcome assessment performed at 2‐19 years. We collected information using a structured data form and evaluated study quality using the Newcastle‐Ottawa Scale (NOS). Results We included 42 observational studies published between 2006 and 2018. No restriction on year of publication was made. The mean NOS score was 5.8 with a range from 3 to 9. Compared with children born full term, children born early term had a lower intelligence score in early adulthood and up to some 30% increased risk of attention‐deficit/hyperactivity disorder. Furthermore, we found some 10%‐40% increased risk of cognitive problems, some 25% higher risk of language impairments and another 8%‐75% with poorer overall school performance. No meta‐analysis was conducted due to heterogeneity in the outcome measures. Only 10 studies presented subgroup analyses in spontaneous deliveries or adjusted for type of labor onset/induction. Conclusions Children born early term are at increased risk of cognitive deficits, poorer school performance and behavioral problems compared with children born full term.

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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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Decreased heart rate variability (HRV) may be a biomarker of brain injury severity in neonatal hypoxic-ischemic encephalopathy for which therapeutic hypothermia is standard treatment. While therapeutic hypothermia may influence the degree of brain injury; hypothermia may also affect HRV per se and obscure a potential association between HRV and hypoxic-ischemic encephalopathy. Previous results are conflicting. This study aimed to investigate the effect of hypothermia on HRV in healthy, anaesthetised, newborn piglets. Six healthy newborn piglets were anaesthetised. Three piglets were first kept normothermic (38.5–39.0 °C) for 3 h, then exposed to hypothermia (33.5–34.5 °C) for 3 h. Three piglets were first exposed to hypothermia for 3 h, then rewarmed to normothermia for 3 h. Temperature and ECG were recorded continuously. HRV was calculated from the ECG in 5 min epochs and included time domain and frequency domain variables. The HRV variables were compared between hypothermia and normothermia. All assessed HRV variables were higher during hypothermia compared to normothermia. Heart rate was lower during hypothermia compared to normothermia and all HRV variables correlated with heart rate. Hypothermia was associated with an increase in HRV; this could be mediated by bradycardia during hypothermia.

Background: Epinephrine is an integral component of neonatal resuscitation guidelines, despite sparse evidence. The association between advanced cardiopulmonary resuscitation (CPR) and poor neurodevelopment is well known, and epinephrine may improve short-term survival but at the cost of poor neurologic outcome. Our objectives were to investigate the effect of epinephrine vs placebo in a piglet model of neonatal hypoxic cardiac arrest (CA) by: 1) return of spontaneous circulation (ROSC), 2) time-to-ROSC, 3) markers of CNS outcome by magnetic resonance spectroscopy and imaging (MRS/MRI), and 4) composite endpoint of death or severe CNS outcome. Methods: Twenty-five newborn piglets under 12 hours of age underwent hypoxia. Hypoxia was induced by clamping the endotracheal tube until CA (mean arterial blood pressure <20 mmHg and heart rate <60 bpm). CPR was commenced five minutes after CA. The animals were randomized to either CPR + intravenous epinephrine or CPR + placebo (saline). MRS/MRI was performed six hours after resuscitation. Results: ROSC was more frequent in animals subjected to epinephrine than placebo; RR = 2.31 (95 % CI: 1.09 to 5.77). We found no difference between groups in time-to-ROSC. Among survivors, we found no difference between groups in brain lactate/N-acetyl-aspartate ratios (Lac/NAA), N-acetyl-aspartate/creatine ratios (NAA/Cr), diffusion-weighted-signal, or oxygenation-dependent-signal. We found a tendency towards reduced risk of the composite endpoint of death or severe CNS outcome in animals resuscitated with epinephrine compared to placebo, RR = 0.7 (95 % CI: 0.37 to 1.19).Conclusions: Resuscitation with epinephrine compared to placebo improved ROSC frequency after neonatal hypoxic CA. Surviving animals after resuscitation with epinephrine compared to placebo showed no difference in MRS/MRI markers of brain damage. These results support that epinephrine improves short-term survival without increasing brain injury measured by early imaging biomarkers.