A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke

Abstract

Background and purpose: 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.

Figure 1

Power motion Doppler flow tracks of acute MCA occlusion, µS arrival at thrombus location and early residual flow augmentation with partial recanalization. Upper images (left to right), Depth scale (mm) relative to pretreatment CTA showing areas of no detectable flow on PMD relative to thrombus location, and flow signals in opened parts of the MCA and the anterior cerebral artery (left). Posttreatment CTA inset shows partial recanalization (right). Bottom images (left to right), PMD and spectral Doppler recordings showing sluggish residual flow in the affected MCA (7 cm/s) at the time of tPA bolus (left); initial µS arrival at the thrombus and permeation beyond occlusion to areas with no detectable flow at 20 to 30 seconds from start of µS infusion (middle); and partial recanalization with velocity improvement 24 cm/s at 7 minutes after combined treatment initiation (right). Flow toward the probe is coded as red, whereas flow away from the probe is coded as blue. The blue band at a depth of 40 to 50 mm corresponds to MCA collateral retrograde flow. NIHSS score was 12 points pretreatment, 5 points at 2 hours, and 1 point at 24 hours.

Figure 2

Calculation of µS propagation velocity on time-distance PMD flow tracks (upper image), and corresponding red blood cell velocities of the residual flow at the time of µS appearance on spectral Doppler (lower image). Vertical axis (upper image), depth of insonation (mm). Vertical axis (lower image), blood flow velocity (cm/s). Horizontal axis (both images), total recording time of 4 seconds. Dotted lines show measurements of distance, velocity, and time.

Figure 3

PMD flow tracks show individual and multiple perflutren-lipid µS permeation to areas with no detectable residual flow pretreatment (dotted circles). Upper images demonstrate µS appearance at shallow depths (25 to 40 mm) corresponding to the distal MCA areas that are distal to the residual flow signals on spectral Doppler (lower images). Spectral waveforms were obtained at 50 mm depth (horizontal yellow line). Vertical axis, depth in mm (upper images) and velocity in cm/s (lower images). Horizontal axis, time in seconds.