The two main focuses of this competitive renewal application are 1) to continue our intensive experimental studies on isovolemic hemodilution and 2) to investigate the effects of fluid replacement with crystalloids (Ringer's lactate-RL) and compare them with the effects of colloids (low molecular weight dextran-LMD) in a model of focal cerebral ischemia. Three main projects are proposed for the 3 year period of the application. The first project will compare the effects of isovolemic hemodilution with crystalloid and colloid. 75 dogs ((60 with internal carotid (ICA) and middle cerebral artery (MCA) occlusion for 6 hours, equally divided in 3 groups: hemodiluted with RL, LMD or not hemodiluted; 15 sham operated, equally divided in 3 groups as controls)) will be studied during the first 2 years. Hemodynamic, rheologic and hematologic parameters and neurological grades will be studied sequentially after arterial occlusion. The volume of brain infarct as determined by fluorescein staining and histopathology will then be compared. The second project to be undertaken during the first 2 years is divided in 2 parts. In the first part we will study the changes in regional cerebral blood flow (rCBF) and tissue oxygen availability (O2a) as the Hct is lowered by 5% decrements from 40 to 25% by stepwise hemodilution in rabbits with occlusion of the ICA and MCA. 30 rabbits will have arterial occlusion (20 hemodiluted and 10 controls) and 10 will be sham operated (5 hemodiluted and 5 sham controls). For the second part four groups of 15 rabbits each will be used either as controls (Hct 40%) or as hemodiluted groups (Hct 35%, 30% and 25% respectively). Sequential changes on rCBF and O2a and volume of brain infarction in the four groups will be compared. The last project will compare the effects of hemodilution at 1 hour. 6 hours and 24 hours after permanent occlusion of the ICA and MCA in dogs (15 dogs in each group and 15 non-hemodiluted controls). Since there is no experience with permanent occlusion in this model, we will perform, before commencing this project, a feasibility study with 6 dogs to ascertain the probability of survival and the severity of the resulting infarct.
