Therapeutic efficacy of tirilazad in experimental multiple cerebral emboli: a randomized, controlled trial.
OBJECTIVE
A significant proportion of patients who undergo cardiac surgery or carotid endarterectomy appear to develop subtle cognitive deficits, with the occurrence of multiple cerebral microemboli documented by Doppler ultrasound during these procedures. We used an experimental multiple cerebral embolism model to test whether treatment with tirilazad (U74006F), a putative inhibitor of lipid peroxidation, would improve functional outcome after multiple brain emboli.


METHODS
Randomized, controlled trial.


METHODS
Animal care facility procedure room.


METHODS
A total of 44 New Zealand White rabbits weighing 2 to 3.0 kg.


METHODS
Variable quantities of 125I-labeled 50-microns microspheres were injected via a carotid catheter to produce multifocal brain ischemia. Rabbits randomly received either: tirilazad (3 mg/kg i.v.) 5 mins before embolization (pretreatment), or 30 mins after embolization (posttreatment) followed by 1.5 mg/kg every 5 hrs x 3 doses. A third group received vehicle only (control) 5 mins before, followed by three doses every 5 hrs.


RESULTS
The animals were rated by a blinded observer at 18 hrs after ischemia and scored as either grossly abnormal/dead or normal. The animals were killed and the amount of microspheres in the brain that were required to produce abnormal function at 18 hrs was calculated for each group. To determine if tirilazad also modified leukocyte function during ischemia, neutrophil adhesion to laminin was determined at baseline and 18 hrs after ischemia using a myeloperoxidase assay. In this study, pretreatment, but not posttreatment with tirilazad produced a significant reduction in neurologic deficits. Tirilazad also attenuated postischemic increases in neutrophil adhesion.


CONCLUSIONS
Tirilazad pretreatment reduces neurologic deficits from multiple cerebral emboli. This significant protective effect suggests that pretreatment with tirilazad may play a role in clinical situations where the risk of cerebral emboli is high, with changes in leukocyte adherence as a potential mechanism.
Clark
W M
WM
Department of Neurology L226, Oregon Health Sciences University, Portland 97201.
Hotan
T
T
Lauten
J D
JD
Coull
B M
BM
D000818:Animals; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers; D002542:Intracranial Embolism and Thrombosis / Q000097:blood / Q000188:drug therapy*; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008297:Male; D008863:Microspheres; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D011281:Pregnatrienes / Q000627:therapeutic use*; D011817:Rabbits; D011897:Random Allocation
D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D011281:Pregnatrienes; C053355:tirilazad