A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke.
OBJECTIVE
Ultrasound transiently expands perflutren-lipid microspheres (muS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated muS with systemic tissue plasminogen activator (tPA).


METHODS
Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL microS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by >or=4 NIHSS points within 72 hours.


RESULTS
Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. muS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8+/-11.3 vs 28.8+/-13.8 cm/s, P<0.001. In 75% of subjects, microS permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of microS infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%, P=0.028. At 2 hours, sustained complete recanalization was 42% versus 13%, P=0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%, P=0.456.


CONCLUSIONS
Perflutren microS reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further microS dose-escalation studies and development of drug delivery to tissues with compromised perfusion.
Alexandrov
Andrei V
AV
Comprehensive Stroke Center/Neurology, The University of Alabama at Birmingham, RWUH M226, 619 19th St South, Birmingham, AL 35249-3280, USA. avalexandrov@att.net
Mikulik
Robert
R
Ribo
Marc
M
Sharma
Vijay K
VK
Lao
Annabelle Y
AY
Tsivgoulis
Georgios
G
Sugg
Rebecca M
RM
Barreto
Andrew
A
Sierzenski
Paul
P
Malkoff
Marc D
MD
Grotta
James C
JC
D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000000981:diagnostic imaging* / Q000188:drug therapy; D002536:Cerebral Arteries / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D003287:Contrast Media / Q000627:therapeutic use; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D005466:Fluorocarbons / Q000627:therapeutic use*; D006801:Humans; D008055:Lipids / Q000627:therapeutic use; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D010865:Pilot Projects; D020521:Stroke / Q000000981:diagnostic imaging* / Q000188:drug therapy; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D016896:Treatment Outcome; D017585:Ultrasonography, Doppler, Transcranial / Q000009:adverse effects / Q000379:methods*
D003287:Contrast Media; D005343:Fibrinolytic Agents; D005466:Fluorocarbons; D008055:Lipids; C042852:perflutren; D010959:Tissue Plasminogen Activator