The aim of this proposal is to characterize the cerebral vascular and metabolic effects of a variety of anesthetic-related drugs and/or interventions. This process is intended to identify possible beneficial or deleterious cerebral actions, specifically as they relate to neurosurgical or neurologically impaired patients. Initial studies will evaluate in dogs the cerebral effects of a new volatile anesthetic, desflurane (I-653). This anesthetic will likely be introduced clinically in the near future, and has the advantage of a rapid onset and offset of action. We will evaluate its effect on cerebral blood flow (CBF), cerebral metabolism (CMRO2), cerebral metabolites, autoregulation of CBF, CO2 reactivity of CBF, cerebrospinal fluid (CSF) production, and anesthetic depth-as determined by the electroencephalogram (EEG) and the minimal alveolar anesthetic concentration (MAC). Should the results suggest a possible cerebral protective effect from ischemic insults, this issue will be tested in appropriate models. Similar studies will determine the cerebral effects of a new alpha-2 adrenergic agonist, dexmedetomidine (MPV-1440), that has anesthetic properties. A new intravenous anesthetic, propofol, possesses promising cerebral protective characteristics similar to thiopental but is extremely short-acting thus avoiding unwanted prolonged brain depression. Cerebral protection studies with propofol will be pursued in a dog model and, if indicated, in a primate model. Other studies will investigate the relationship between CBF and CMRO2 determine whether blood flow is coupled to metabolism or is pathologically attenuated. In other dogs we will determine the state of CO2 reactivity and autoregulation during the post ischemic period. The cerebral arteries from these dogs will subsequently be examined in vitro to determine if the activity of the endothelium- dependent and independent reactivity is altered by global ischemia and reperfusion. Other studies in normal dogs will examine the relationship of CBF, CMRO2, and the EEG during progressive hypothermia to determine if CBF and CMRO2 responses are determined by the direct effects of temperature alone, or by an interaction of temperature and EEG activity. These studies will attempt to explain the unexpected, precipitous decline in CMRO2 which occurs between 28 and 18degreesC. A rabbit model if regional ischemia produced by middle cerebral artery occlusion will be used to further explore the relative cerebral protective effects of thiopental and isoflurane.
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