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• Winnipeg Acute TBI Biobank

Winnipeg Acute TBI Biobank, Canada

Objective: Over the last 25 years of critical care management of the traumatic brain injury (TBI) patient we have made dramatic improvements. The cornerstone of current physiologic targets focuses on maintaining adequate intra-cranial pressure (ICP) and cerebral perfusion pressure (CPP). However, recent longitudinal data suggests that despite improved ICP control and meeting guideline suggested CPP targets, mortality has remained relatively unchanged. This likely stems from various factors, including untreated impaired cerebrovascular reactivity/autoregulation, which has been demonstrated to remain unchanged overall on longitudinal analysis despite changes in our ICP and CPP therapies over the last 2 to 3 decades. Impaired cerebrovascular reactivity/autoregulation has been linked to worse global outcome in adult traumatic brain injury (TBI). Numerous retrospective single and multi-center studies have confirmed this. Furthermore, recent multi-center prospective data from European TBI outcome study, CENTER-TBI, has provided validation for this strong link with patient outcome, providing additional outcome prediction capabilities with monitoring cerebrovascular reactivity over existing standard prognostic models, such as the IMPACT model. However, our understanding of what drives impaired cerebrovascular reactivity is limited. Our preliminary work suggests diffuse intra-cranial injury patterns, markers of systemic host response to injury and advanced age are associated with worse cerebrovascular reactivity. Aside from this, the exact molecular mechanisms involved in regulation of cerebrovascular reactivity remain theoretical. It is suspected that various mechanistic pathways are involved in controlling cerebral vascular tone, including: myogenic, endothelial, neurotransmitter and metabolic pathways.8 Furthermore, recent literature supports an association between post-injury inflammatory response, autonomic response and spreading cortical depression with altered cerebrovascular responsiveness. In order to understand these mechanisms in more detail, one needs to assess for individual patient genotype, probing the genes responsible for the host response to injury, and also assess the associated protein biomarkers in vitro. With regards to patient genotype, recent work done by our group suggests that a group of targeted single nucleotide polymorphisms (SNP) related to vascular biology are associated with impaired vascular reactivity in moderate/severe TBI. Furthermore, some literature supports various serum and cerebrospinal fluid (CSF)/extracellular fluid based protein biomarkers associated with neuronal injury and host response, and both patient outcome and cerebrovascular response. However, to date, the literature is conducted on relatively small groups of patients with retrospectively assessed data sets, and only individual or limited gene/biomarker assessments. With this study we propose a prospectively maintained biobank for moderate/severe TBI patients admitted to HSC, Winnipeg, with the goal to shedding further light on the molecular mechanisms associated with impaired cerebrovascular reactivity. This prospective biobank will be one of the only in the world, linking blood/serum/CSF with high resolution physiologic and demographic data already collected as part of an ongoing database project at HSC, Winnipeg. It will include collecting blood on admission for genome wide association studies (GWAS), and sequential serum and CSF sampling through the intensive care unit (ICU) phase of the patients stay for protein biomarker studies. The hope is that the results from the future analysis of these samples will lead the development of therapeutic targets to prevent and treat autoregulatory failure in TBI, preventing secondary brain injury and reducing morbidity and mortality both for residents of Manitoba, and those around the world.