Therapeutic efficacy of tirilazad in experimental multiple cerebral emboli: A randomized, controlled trial

W. M. Clark, T. Hotan, J. D. Lauten, B. M. Coull

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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. Design: Randomized, controlled trial. Setting: Animal care facility procedure room. Subjects: A total of 44 New Zealand White rabbits weighing 2 to 3.0 kg. Interventions: Variable quantities of 125I-labeled 50-μm microspheres were injected via a carotid catheter to produce multifocal brain ischemia. Rabbits randomly received either: tirilazad (3 mg/kg iv) 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. Measurements and Main 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.

Original languageEnglish (US)
Pages (from-to)1161-1166
Number of pages6
JournalCritical care medicine
Volume22
Issue number7
DOIs
StatePublished - 1994

Keywords

  • brain
  • cardiac surgery
  • cardiopulmonary bypass
  • carotid endarterectomy
  • cerebral embolism
  • cerebral ischemia
  • free radicals
  • leukocytes
  • neurologic emergencies
  • neutrophils

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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