No neuroprotective effect of therapeutic hypothermia following lipopolysaccharide-sensitized hypoxia-ischemia: a newborn piglet study

IntroductionTherapeutic hypothermia is the only proven neuroprotective treatment for hypoxic-ischemic encephalopathy. However, studies have questioned whether therapeutic hypothermia may benefit newborns subjected to infection or inflammation before a hypoxic-ischemic insult. We aimed to compare newborn piglets with lipopolysaccharide-sensitized hypoxia-ischemia treated with and without therapeutic hypothermia with regards to measures of neuroprotection.MethodsA total of 32 male and female piglets were included in this randomized experimental study. Lipopolysaccharides from Escherichia coli were infused intravenously before initiation of a standardized global hypoxic-ischemic insult. The piglets were then randomized to either normothermia or therapeutic hypothermia. After 14 h, the piglets were evaluated. Our primary outcome was brain lactate/N-acetylaspartate ratio assessed by magnetic resonance spectroscopy. Secondary outcomes included measures of magnetic resonance imaging, amplitude-integrated electroencephalography, immunohistochemistry, and concentration of blood cells and cytokines.ResultsPiglets treated with and without therapeutic hypothermia were subjected to comparable global hypoxic-ischemic insults. We found no difference between the two groups with regards to measures of magnetic resonance spectroscopy and imaging, amplitude-integrated electroencephalography, immunohistochemistry, and concentration of blood cells and cytokines.ConclusionWe found no indication of neuroprotection by therapeutic hypothermia in newborn piglets following lipopolysaccharide-sensitized hypoxia-ischemia. However, interpretation of the results is limited by the short observation period. Further studies are required to determine the potential clinical implications of these findings

Data_Sheet_1_Remote ischemic postconditioning increased cerebral blood flow and oxygenation assessed by magnetic resonance imaging in newborn piglets after hypoxia-ischemia.docx

BackgroundWe have previously investigated neurological outcomes following remote ischemic postconditioning (RIPC) in a newborn piglet model of hypoxic-ischemic encephalopathy. The aim of this study was to further investigate potential mechanisms of neuroprotection by comparing newborn piglets subjected to global hypoxia-ischemia (HI) treated with and without RIPC with regards to measures of cerebral blood flow and oxygenation assessed by functional magnetic resonance imaging.Materials and methodsA total of 50 piglets were subjected to 45 min global HI and randomized to either no treatment or RIPC treatment. Magnetic resonance imaging was performed 72 h after the HI insult with perfusion-weighted (arterial spin labeling, ASL) and oxygenation-weighted (blood-oxygen-level-dependent, BOLD) sequences in the whole brain, basal ganglia, thalamus, and cortex. Four sham animals received anesthesia and mechanical ventilation only.ResultsPiglets treated with RIPC had higher measures of cerebral blood flow in all regions of interest and the whole brain (mean difference: 2.6 ml/100 g/min, 95% CI: 0.1; 5.2) compared with the untreated controls. They also had higher BOLD values in the basal ganglia and the whole brain (mean difference: 4.2 T2*, 95% CI: 0.4; 7.9). Measures were similar between piglets treated with RIPC and sham animals.ConclusionPiglets treated with RIPC had higher measures of cerebral blood flow and oxygenation assessed by magnetic resonance imaging in the whole brain and several regions of interest compared with untreated controls 72 h after the HI insult. Whether this reflects a potential neuroprotective mechanism of RIPC requires further study.</p