title: Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator.
abstract: OBJECTIVE
  We sought to evaluate the effects of administration of microbubbles (MBs) on the beginning, speed, and degree of middle cerebral artery (MCA) recanalization during systemic thrombolysis and continuous 2-MHz pulsed-wave transcranial Doppler (TCD) monitoring.
  
  
  METHODS
  We evaluated 111 patients with acute stroke attributable to MCA occlusion treated with intravenous tissue plasminogen activator (tPA). Thirty-eight patients were treated with tPA plus continuous 2-hour TCD monitoring plus 3 doses of 2.5 g (400 mg/mL) of galactose-based MBs given at 2, 20, and 40 minutes after tPA bolus (MB group). These patients were compared with 73 patients who were allocated to receive tPA plus continuous 2-hour TCD ultrasound (US) monitoring (tPA/US group) or tPA plus placebo monitoring (tPA group), most of whom were enrolled in a previous study of US-enhanced thrombolysis. The beginning, degree, and time to maximum completeness of recanalization during the first 2 hours of tPA bolus were recorded.
  
  
  RESULTS
  Median prebolus National Institutes of Health Stroke Scale (NIHSS) score was 18. Eighty patients (72%) had a proximal and 31 (28%) a distal MCA occlusion on TCD. Thirty-seven patients (33%) received tPA/US, 38 (34%) received tPA/US/MB, and 36 (32%) were treated with tPA alone. Stroke severity, time to treatment, location of MCA occlusion, and presence of carotid artery disease were similar among groups. Two-hour recanalization was seen in 14 (39%), 25 (68%), and 27 patients (71%) in the tPA, tPA/US, and tPA/US/MB groups, respectively (P=0.004). Two-hour complete recanalization rate was significantly (P=0.038) higher in the tPA/US/MB group (54.5%) compared with tPA/US (40.8%) and tPA (23.9%) groups. The time to beginning of recanalization after tPA bolus was 26+/-18 minutes in the tPA/US group and 19+/-12 minutes in the tPA/US/MB group (P=0.12). Four patients (3.6%) experienced symptomatic intracranial hemorrhage: 2 (5.5%), 1 (2.7%), and 1 patient (2.6%) who received tPA only, tPA/US, and tPA/US/MB, respectively, experienced symptomatic intracranial hemorrhage. At 24 hours, 31%, 41%, and 55% of tPA, tPA/US, and tPA/US/MB improved >4 points in the NIHSS score.
  
  
  CONCLUSIONS
  Administration of MBs induces further acceleration of US-enhanced thrombolysis in acute stroke, leading to a more complete recanalization and to a trend toward better short- and long-term outcome.
authors.affiliation: Department of Neurology, Universitat Autonoma de Barcelona, Hospital Vall d'Hebrón, Barcelona, Spain. cmolina@vhebron.net
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Molina
authors.forename: Marc
authors.initials: M
authors.lastname: Ribo
authors.forename: Marta
authors.initials: M
authors.lastname: Rubiera
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.forename: Esteban
authors.initials: E
authors.lastname: Santamarina
authors.forename: Raquel
authors.initials: R
authors.lastname: Delgado-Mederos
authors.forename: Juan F
authors.initials: JF
authors.lastname: Arenillas
authors.forename: Rafael
authors.initials: R
authors.lastname: Huertas
authors.forename: Francisco
authors.initials: F
authors.lastname: Purroy
authors.forename: Pilar
authors.initials: P
authors.lastname: Delgado
authors.forename: José
authors.initials: J
authors.lastname: Alvarez-Sabín
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000473:pathology; D016503:Drug Delivery Systems; D005260:Female; D005690:Galactose / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D007262:Infusions, Intravenous; D008297:Male; D045423:Microbubbles; D008875:Middle Aged; D010919:Placebos; D011994:Recombinant Proteins / Q000008:administration & dosage*; D020521:Stroke / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D015912:Thrombolytic Therapy / Q000379:methods*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*; D016896:Treatment Outcome; D014465:Ultrasonics; D017585:Ultrasonography, Doppler, Transcranial / Q000379:methods
chemical_list: D010919:Placebos; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D005690:Galactose