title: Microbubble-augmented ultrasound sonothrombolysis decreases intracranial hemorrhage in a rabbit model of acute ischemic stroke.
abstract: OBJECTIVE
  Increasing evidence confirms that microbubble (MB)-augmented ultrasound (US) thrombolysis enhances clot lysis with or without tissue plasminogen activator (tPA). Intracranial hemorrhage (ICH) is a major complication militating against tPA use in acute ischemic stroke. We quantified the incidence of ICH associated with tPA thrombolysis and MB + US therapy and compared infarct volumes in a rabbit model of acute ischemic stroke.
  
  
  METHODS
  Rabbits (n = 158) received a 1.0-mm clot, angiographically injected into the internal carotid artery causing infarcts. Rabbits were randomized to 6 test groups including (1) control (n = 50), embolized without therapy, (2) US (n = 18), (3) tPA only (n = 27), (4) tPA + US (n = 22), (5) MB + US (n = 27), and (6) tPA + MB + US (n = 14). US groups received pulsed wave US (1 MHz, 0.8 W/cm) for 1 hour; rabbits with tPA received intravenous tPA (0.9 mg/kg) over 1 hour. Rabbits with MB received intravenous MB (0.16 mg/kg) given over 30 minutes. Rabbits were killed 24 hours later and infarct volume and incidence, location, and severity of ICH were determined by histology and pathologic examination.
  
  
  RESULTS
  Percentage of rabbits having ICH outside the infarct area was significantly decreased (P = 0.004) for MB + US (19%) rabbits compared with tPA + US (73%), US only (56%), tPA (48%), tPA + MB + US (36%), and control (36%) rabbits. Incidence and severity of ICH within the infarct did not differ (P > 0.39). Infarct volume was significantly greater (P = 0.002) for rabbits receiving US (0.97% ± 0.17%) than for MB + US (0.20% ± 0.14%), tPA + US (0.15% ± 0.16%), tPA (0.14% ± 0.14%), and tPA + MB + US (0.10% ± 20%) rabbits; these treatments collectively, excluding US only, differed (P = 0.03) from control (0.45% ± 0.10%).
  
  
  CONCLUSIONS
  Treatment with MB + US after embolization decreased the incidence of ICH and efficacy was similar to tPA in reducing infarct volume.
authors.affiliation: Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Flores
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Hennings
authors.forename: John D
authors.initials: JD
authors.lastname: Lowery
authors.forename: Aliza T
authors.initials: AT
authors.lastname: Brown
authors.forename: William C
authors.initials: WC
authors.lastname: Culp
mesh_terms: D000818:Animals; D002544:Cerebral Infarction / Q000150:complications / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D020300:Intracranial Hemorrhages / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D045423:Microbubbles / Q000627:therapeutic use*; D011817:Rabbits; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014464:Ultrasonic Therapy
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator