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(Stroke. 2008;39:1464.)
© 2008 American Heart Association, Inc.

Original Contributions

A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke

Andrei V. Alexandrov, MD; Robert Mikulik, MD; Marc Ribo, MD; Vijay K. Sharma, MD; Annabelle Y. Lao, MD; Georgios Tsivgoulis, MD; Rebecca M. Sugg, MD; Andrew Barreto, MD; Paul Sierzenski, MD; Marc D. Malkoff, MD James C. Grotta, MD

From the Comprehensive Stroke Center (A.V.A., G.T., R.M.S.), University of Alabama Medical School, Birmingham; Stroke Program (A.V.A., R.M., M.R., R.M.S., A.B., J.C.G.), The University of Texas-Houston Medical School, Houston; Neurosonology and Stroke Program (A.V.A., V.K.S., A.Y.L., G.T., M.D.M.), Barrow Neurological Institute, Phoenix, Ariz; and Emergency Medicine (P.S.), Christiana Healthcare, Wilmington, Del.

Correspondence to Dr Andrei V. Alexandrov, Comprehensive Stroke Center/Neurology, The University of Alabama at Birmingham, RWUH M226, 619 19th St South, Birmingham, AL 35249-3280. E-mail avalexandrov{at}att.net

Background and Purpose— Ultrasound transiently expands perflutren-lipid microspheres (µS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated µS 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 µS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by 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. µS 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, µS permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of µS 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 µS reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further µS dose-escalation studies and development of drug delivery to tissues with compromised perfusion.

Key Words: microspheres • thrombolysis • stroke • occlusion • transcranial Doppler