Early metabolic disruption and predictive biomarkers of delayed-cerebral ischemia in aneurysmal subarachnoid haemorrhage

BACKGROUND. Delayed cerebral ischaemia (DCI) following aneurysmal subarachnoid haemorrhage (aSAH) is a major cause of complications and death. Here we set out to identify high-performance predictive biomarkers of DCI and its underlying metabolic disruptions using metabolomics and lipidomics approaches. METHODS. This single-centre retrospective observational study enrolled 61 consecutive patients with severe aSAH requiring external ventricular drainage between 2013 and 2016. Of these 61 patients, 22 experienced a DCI and were classified as DCI+ and the other 39 patients were classified as DCI-. A further 9 patients with other neurological features were included as non aSAH controls. Blood and cerebrospinal fluid (CSF) were sampled within the first 24 h after admission. We carried out LC-MS/MS-based plasma and CSF metabolomic profiling together with total lipid fatty acids analysis.RESULTS. We identified a panel of 20 metabolites that together showed high predictive performance for DCI (area under the receiver operating characteristic curve: 0.968, specificity: 0.88, sensitivity: 0.94). This panel of metabolites included lactate, cotinine, salicylate, 6 phosphatidylcholines, and 4 sphingomyelins. Analysis of the whole set of metabolites to highlight early biological disruptions that might explain the subsequent DCI found peripheral hypoxia driven mainly by higher blood lactate, arginine and proline metabolism likely associated to vascular NO, dysregulation of the citric acid cycle in the brain, defective peripheral energy metabolism and disrupted ceramide/sphingolipid metabolism. We also unexpectedly found a potential influence of gut microbiota on the onset of DCI. CONCLUSION. We identified a high-performance predictive metabolomic/lipidomic signature of further DCI in aSAH patients at admission to a NeuroCritical Care Unit. This signature is associated with significant peripheral and cerebral biological dysregulations. We also found evidence, for the first time, pointing to a possible gut microbiota/brain DCI axis, and proposed the putative microorganisms involved.