Microbubble Augmented Ultrasound Sonothrombolysis Decreases Intracranial Hemorrhage in a Rabbit Model of Acute Ischemic Stroke

Objectives—Increasing evidence confirms 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. Materials and Methods—Rabbits (n=158) received a 1.0-mm clot angiographically injected into the internal carotid artery causing infarcts. Rabbits were randomized to six 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). Ultrasound groups received pulsed wave US (1 MHz, 0.8 W/cm 2 ) 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 sacrificed 24 hours later and infarct volume and incidence, location, and severity of ICH were determined by histology and pathological 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 following embolization decreased the incidence of ICH and efficacy was similar to tPA in reducing infarct volume.