title: Tirilazad pretreatment improves early cerebral metabolic and blood flow recovery from hyperglycemic ischemia.
abstract: Acidosis may augment cerebral ischemic injury by promoting lipid peroxidation. We tested the hypothesis that when acidosis is augmented by hyperglycemia, pretreatment with the 21-aminosteroid tirilazad mesylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400-500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spectroscopy. During ischemia, microsphere-determined CBF decreased to 8 +/- 4 ml min-1 100 g-1 and intracellular pH decreased to 5.6 +/- 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 +/- 21% of baseline, but then declined progressively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the tirilazad group (77 +/- 35 vs. 36 +/- 19%), although postischemic hyperemia was similar. By 45 min, the tirilazad group had a higher intracellular pH (6.5 +/- 0.5 vs. 5.9 +/- 0.6) and a lower intracranial pressure (18 +/- 6 vs. 52 +/- 24 mm Hg). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was > 67% and pH was > 6.7 in six of eight tirilazad-treated dogs. Thus, tirilazad acts during early reperfusion to prevent secondary metabolic decay associated with severe acidotic ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-4961.
authors.forename: Y
authors.initials: Y
authors.lastname: Maruki
authors.forename: R C
authors.initials: RC
authors.lastname: Koehler
authors.forename: J R
authors.initials: JR
authors.lastname: Kirsch
authors.forename: K K
authors.initials: KK
authors.lastname: Blizzard
authors.forename: R J
authors.initials: RJ
authors.lastname: Traystman
mesh_terms: D000138:Acidosis / Q000150:complications; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001783:Blood Flow Velocity; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002560:Cerebrovascular Circulation; D004285:Dogs; D005071:Evoked Potentials; D006863:Hydrogen-Ion Concentration; D006943:Hyperglycemia / Q000150:complications*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008863:Microspheres; D010710:Phosphates / Q000378:metabolism; D011281:Pregnatrienes / Q000627:therapeutic use*
chemical_list: D010710:Phosphates; D011281:Pregnatrienes; D000255:Adenosine Triphosphate; C053355:tirilazad