Impact of systemic and cerebral acidosis on ischemic stroke and spreading depolarization

PROJECT SUMMARY / ABSTRACT I am an MD/PhD-trained neurointensivist and physiologist navigating a critical career development transition towards becoming an independent investigator. My long-term goal is to improve clinical outcomes of patients with severe ischemic strokes admitted to the intensive care unit (ICU). In the ICU, we can change the levels of carbon dioxide (CO2) or hydrogen ion (H+) in the bloodstream of intubated, mechanically ventilated patients. However, we do not know the optimal ranges of H+ or CO2 to target to support brain recovery and limit secondary injury following stroke. Experimentally elevating systemic CO2 and H+ can reduce the size of strokes in rodents, by mechanisms that are incompletely understood. H+ and CO2 influence cerebral blood flow, and may also shift cellular energy phenotypes in neurons or other brain cells. In parallel, H+ and CO2 levels may also inhibit spreading depolarizations (SDs), waves of powerful neuronal activation that propagate through the vulnerable brain territories adjacent to infarcts, exert immense energetic stress on neurons, and kill neurons with insufficient metabolic supply. SDs play a key role in expanding the size of strokes for many days, corresponding to the time period when patients are in the ICU. In this project, my objective is to identify protective and harmful mechanisms of acid-base physiology relevant to stroke. My hypothesis is that augmenting H+ will improve metabolic supply and energy utilization, inhibit SDs, and reduce the size of strokes. I will test this hypothesis with two specific aims: 1) comparing the effects of systemic and cerebral H+ vs CO2 on cerebral blood flow, cellular energy metabolism, and stroke outcomes in mice, and 2) testing whether elevated extracellular H+ decreases the incidence of SD by inhibiting NMDA receptors. The significance of the proposed research is that completing these studies will provide high-quality physiologic evidence to inform clinical guidelines for the management of acid-base status in ICU patients with stroke and other acute brain injuries.