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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.

Background Neonatal encephalopathy (NE) contributes substantially to child mortality and disability globally. We compared cytokine profiles in term Ugandan neonates with and without NE, with and without perinatal infection or inflammation and identified biomarkers predicting neonatal and early childhood outcomes. Methods In this exploratory biomarker study, serum IL-1α, IL-6, IL-8, IL-10, TNFα, and VEGF ( Results Cytokine assays on 159 NE and 157 non-NE infants were performed; data on early childhood outcomes were available for 150 and 129, respectively. NE infants had higher IL-10 (p p p p p = 0.013). Among NE infants, IL-10 predicted neonatal mortality (p = 0.01) and adverse early childhood outcome (adjusted OR 2.28, 95% CI 1.35–3.86, p = 0.002). Conclusions Our findings support a potential role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy. Impact Neonatal encephalopathy is a common cause of child death and disability globally. Inflammatory cytokines are potential biomarkers of encephalopathy severity and outcome. In this Ugandan health facility-based cohort, neonatal encephalopathy was associated with elevated serum IL-10 and IL-6, and reduced VEGF at birth. Elevated serum IL-10 within 12 h after birth predicted severity of neonatal encephalopathy, neonatal mortality, and adverse early childhood developmental outcomes, independent of perinatal infection or inflammation, and provides evidence to the contribution of the inflammatory processes. Our findings support a role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy in a sub-Saharan African cohort.

As therapeutic hypothermia is only partially protective for neonatal encephalopathy, safe and effective adjunct therapies are urgently needed. Melatonin and erythropoietin show promise as safe and effective neuroprotective therapies. We hypothesized that melatonin and erythropoietin individually augment 12-h hypothermia (double therapies) and hypothermia + melatonin + erythropoietin (triple therapy) leads to optimal brain protection. Following carotid artery occlusion and hypoxia, 49 male piglets (, As therapeutic hypothermia is partially protective in neonatal encephalopathy, adjunct therapies are required. In a piglet model of perinatal asphyxia, Pang et al. report that melatonin and erythropoietin are safe and individually augment cooling through different mechanisms. Staggered rather than concomitant dosing may be optimal for brain protection., Graphical Abstract Graphical Abstract

Hemodynamic impairment occurs in up to 80% of infants with neonatal encephalopathy (NE). Not all infants benefit from therapeutic hypothermia (HT); there are some indications that the trajectory of brain injury might be modified by neurologic monitoring and early management over the first 72-h period. It is also possible that optimizing hemodynamic management may further improve outomes. The coupling between cerebral blood flow and cerebral metabolism is disrupted in NE, increasing the vulnerability of the newborn brain to secondary injury. Hemodynamic monitoring is usually limited to blood pressure and functional echocardiographic measurements, which may not accurately reflect brain perfusion. This review explores the evidence base for hemodynamic assessment and management of infants with NE while undergoing HT. We discuss the literature behind a systematic approach to a baby with NE with the aim to define best therapies to optimize brain perfusion and reduce secondary injury.

Despite therapeutic hypothermia, survivors of neonatal encephalopathy have high rates of adverse outcome. Early surrogate outcome measures are needed to speed up the translation of neuroprotection trials. Thalamic lactate (Lac)/N-acetylaspartate (NAA) peak area ratio acquired with proton (1H) magnetic resonance spectroscopy (MRS) accurately predicts 2-year neurodevelopmental outcome. We assessed the relationship between MR biomarkers acquired at 24–48 h following injury with cell death and neuroinflammation in a piglet model following various neuroprotective interventions. Sixty-seven piglets with hypoxia–ischemia, hypoxia alone, or lipopolysaccharide (LPS) sensitization were included, and neuroprotective interventions were therapeutic hypothermia, melatonin, and magnesium. MRS and diffusion-weighted imaging (DWI) were acquired at 24 and 48 h. At 48 h, experiments were terminated, and immunohistochemistry was assessed. There was a correlation between Lac/NAA and overall cell death [terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)] [mean Lac/NAA basal ganglia and thalamus (BGT) voxel r = 0.722, white matter (WM) voxel r = 0.784, p < 0.01] and microglial activation [ionized calcium-binding adapter molecule 1 (Iba1)] (BGT r = −0.786, WM r = −0.632, p < 0.01). Correlation with marker of caspase-dependent apoptosis [cleaved caspase 3 (CC3)] was lower (BGT r = −0.636, WM r = −0.495, p < 0.01). Relation between DWI and TUNEL was less robust (mean diffusivity BGT r = −0.615, fractional anisotropy BGT r = 0.523). Overall, Lac/NAA correlated best with cell death and microglial activation. These data align with clinical studies demonstrating Lac/NAA superiority as an outcome predictor in neonatal encephalopathy (NE) and support its use in preclinical and clinical neuroprotection studies.

Background and Purpose— Cerebral microemboli signals (MES) are associated with increased risk of acute stroke syndromes. We compared the effects on cerebral microemboli after carotid endarterectomy of tirofiban with dextran-40. Methods— We used transcranial Doppler ultrasound to study transient MES acutely after carotid endarterectomy between August 2000 and December 2010 in 128 subjects refractory to preoperative antiplatelet treatment. Antithrombotic treatment was given for MES ≥50 hour −1 (tirofiban: 40 patients [age 74 ± 1 {SEM}, males 27, and white 38]; dextran-40: 34 patients [age 69 ± 2, males 22, white 30]). In 54 patients with MES −1 (age 71 ± 1, male 36, white 52), MES were monitored during their spontaneous resolution (controls). Data are median (interquartile range). Results— The time to 50% reduction in MES (tirofiban 23 minutes [15–28]; dextran-56 [43–83]; controls 30 [22–38]; P P Conclusions— These findings suggest that transcranial Doppler-directed tirofiban therapy is more effective than dextran-40 in suppression of cerebral microemboli after carotid endarterectomy.