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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044486-02
Application #
3303608
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1991-04-01
Project End
1995-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Lanier, W L; Hofer, R E; Gallagher, W J (1996) Metabolism of glucose, glycogen, and high-energy phosphates during transient forebrain ischemia in diabetic rats: effect of insulin treatment. Anesthesiology 84:917-25
Lanier, W L; Albrecht 2nd, R F; Laizzo, P A (1996) Divergence of intracranial and central venous pressures in lightly anesthetized, tracheally intubated dogs that move in response to a noxious stimulus. Anesthesiology 84:605-13
Wass, C T; Lanier, W L; Hofer, R E et al. (1995) Temperature changes of > or = 1 degree C alter functional neurologic outcome and histopathology in a canine model of complete cerebral ischemia. Anesthesiology 83:325-35
Wagner 4th, S R; Lanier, W L (1994) Metabolism of glucose, glycogen, and high-energy phosphates during complete cerebral ischemia. A comparison of normoglycemic, chronically hyperglycemic diabetic, and acutely hyperglycemic nondiabetic rats. Anesthesiology 81:1516-26
Lanier, W L; Iaizzo, P A; Milde, J H et al. (1994) The cerebral and systemic effects of movement in response to a noxious stimulus in lightly anesthetized dogs. Possible modulation of cerebral function by muscle afferents. Anesthesiology 80:392-401
Iaizzo, P A; Wedel, D J (1994) Response to succinylcholine in porcine malignant hyperthermia. Anesth Analg 79:143-51
Wedel, D J; Gammel, S A; Milde, J H et al. (1993) Delayed onset of malignant hyperthermia induced by isoflurane and desflurane compared with halothane in susceptible swine. Anesthesiology 78:1138-44
Katusic, Z S; Milde, J H; Cosentino, F et al. (1993) Subarachnoid hemorrhage and endothelial L-arginine pathway in small brain stem arteries in dogs. Stroke 24:392-9
Christopherson, T J; Milde, J H; Michenfelder, J D (1993) Cerebral vascular autoregulation and CO2 reactivity following onset of the delayed postischemic hypoperfusion state in dogs. J Cereb Blood Flow Metab 13:260-8
Hofer, R E; Lanier, W L (1992) Effect of hydroxyethyl starch solutions on blood glucose concentrations in diabetic and nondiabetic rats. Crit Care Med 20:211-5

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