Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial.
OBJECTIVE
Microspheres (microS) reach intracranial occlusions and transmit energy momentum from an ultrasound wave to residual flow to promote recanalization. We report a randomized multicenter phase II trial of microS dose escalation with systemic thrombolysis.


METHODS
Stroke patients receiving 0.9mg/kg tissue plasminogen activator (tPA) with pretreatment proximal intracranial occlusions on transcranial Doppler (TCD) were randomized (2:1 ratio) to microS (MRX-801) infusion over 90 minutes (Cohort 1, 1.4ml; Cohort 2, 2.8ml) with continuous TCD insonation, whereas controls received tPA and brief TCD assessments. The primary endpoint was symptomatic intracerebral hemorrhage (sICH) within 36 hours after tPA.


RESULTS
Among 35 patients (Cohort 1 = 12, Cohort 2 = 11, controls = 12) no sICH occurred in Cohort 1 and controls, whereas 3 (27%, 2 fatal) sICHs occurred in Cohort 2 (p = 0.028). Sustained complete recanalization/clinical recovery rates (end of TCD monitoring/3 month) were 67%/75% for Cohort 1, 46%/50% for Cohort 2, and 33%/36% for controls (p = 0.255/0.167). The median time to any recanalization tended to be shorter in Cohort 1 (30 min; interquartile range [IQR], 6) and Cohort 2 (30 min; IQR, 69) compared to controls (60 min; IQR, 5; p = 0.054). Although patients with sICH had similar screening and pretreatment systolic blood pressure (SBP) levels in comparison to the rest, higher SBP levels were documented in sICH+ patients at 30 minutes, 60 minutes, 90 minutes, and 24-36 hours following tPA bolus.


CONCLUSIONS
Perflutren lipid microS can be safely combined with systemic tPA and ultrasound at a dose of 1.4ml. Safety concerns in the second dose tier may necessitate extended enrollment and further experiments to determine the mechanisms by which microspheres interact with tissues. In both dose tiers, sonothrombolysis with microS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy. Ann Neurol 2009;66:28-38.
Molina
Carlos A
CA
Neurovascular Unit, Department of Neurology, Hospital Vall d'Hebron, Barcelona, Spain.
Barreto
Andrew D
AD
Tsivgoulis
Georgios
G
Sierzenski
Paul
P
Malkoff
Marc D
MD
Rubiera
Marta
M
Gonzales
Nicole
N
Mikulik
Robert
R
Pate
Greg
G
Ostrem
James
J
Singleton
Walter
W
Manvelian
Garen
G
Unger
Evan C
EC
Grotta
James C
JC
Schellinger
Peter D
PD
Alexandrov
Andrei V
AV
D000368:Aged; D001783:Blood Flow Velocity / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015331:Cohort Studies; D046690:Deep Brain Stimulation / Q000379:methods; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D012720:Severity of Illness Index; D020521:Stroke / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome; D017585:Ultrasonography, Doppler, Transcranial / Q000379:methods*
D010959:Tissue Plasminogen Activator