Abstract 595: Functional, Histologic, and Radiographic Characteristics of Global Ischemia-reperfusion Brain Injury in a Mouse Model Of Cardiac Arrest

Abstract

Cardiac arrest (CA) and subsequent CPR constitute a clinically relevant form of global ischemia-reperfusion injury (IR). Global IR often results in widespread ischemic brain damage and severe neurologic sequelae. In the present study, we sought to describe the functional, histologic, and radiographic brain changes that occur following CA/CPR. 8–10 week old C57BL/6 mice were subjected to 12 minutes of normothermic cardioplegic CA and resuscitated with chest compressions, mechanical ventilation, and epinephrine. Sham mice underwent surgery, but not CA. At 3 and 24 hours, 10-point functional neurological score and rectal temperature were assessed prior to trans-cardiac perfusion with PBS and 10% buffered formalin. Sectioned brains were stained using hematoxylin and eosin (H/E) and the terminal deoxyuridine triphosphate nick end-labeling (TUNEL) technique. An additional cohort of mice underwent quantitative diffusion MRI at 24 and 72 hours, gadolinium (Gd)-enhanced MRI at 24 hours, and quantitative T2 imaging at 72 hours. Compared to shams, mice undergoing CA/CPR displayed significantly lower functional neurological score at 3 hours (3±2 vs. 10±0; P<.001) and 24 hours (8±1 vs. 10±0, P<.05), and significantly higher rectal temperature at 3 hours (35.8±1.5 vs. 34.1±0.8, P<.001) and lower rectal temperature at 24 hours (33.8±2.5 vs. 37.1±0.8, P=.08). TUNEL and H/E staining revealed injury in the cortex, thalamus, hippocampus, and cerebellum, but neither a consistent pattern nor clear temporal progression was observed. Gd-enhanced MRI revealed increased signal intensity, particularly in the cortex, after CA (3.7×105±0.96×105 vs. 0.66×105±0.017×105, P<.05), consistent with breakdown of the blood-brain barrier. Diffusion MRI revealed a strong trend towards globally decreasing diffusion coefficients at 24 and 72 hours (P=0.14), consistent with widespread cell death. In our model of CA, global IR results in poor neurological function and global injury by MRI that is not reflected by early histology. MRI thus appears to be a more sensitive measure of visualizing neurological injury in the early stages after CA and may predict the delayed neuronal death remarked upon by other authors.