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

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1464-1469
Number of pages6
JournalStroke
Volume39
Issue number5
DOIs
StatePublished - May 1 2008

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perflutren
Tissue Plasminogen Activator
Microspheres
Stroke
Intracranial Hemorrhages
Lipids
Safety
Feasibility Studies
Random Allocation
Brain Ischemia
Perfusion
Erythrocytes
Clinical Studies

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke. / Alexandrov, Andrei; Mikulik, Robert; Ribo, Marc; Sharma, Vijay K.; Lao, Annabelle Y.; Tsivgoulis, Georgios; Sugg, Rebecca M.; Barreto, Andrew; Sierzenski, Paul; Malkoff, Marc; Grotta, James C.

In: Stroke, Vol. 39, No. 5, 01.05.2008, p. 1464-1469.

Research output: Contribution to journalArticle

Alexandrov, Andrei ; Mikulik, Robert ; Ribo, Marc ; Sharma, Vijay K. ; Lao, Annabelle Y. ; Tsivgoulis, Georgios ; Sugg, Rebecca M. ; Barreto, Andrew ; Sierzenski, Paul ; Malkoff, Marc ; Grotta, James C. / A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke. In: Stroke. 2008 ; Vol. 39, No. 5. pp. 1464-1469.
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abstract = "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.",
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AU - Alexandrov, Andrei

AU - Mikulik, Robert

AU - Ribo, Marc

AU - Sharma, Vijay K.

AU - Lao, Annabelle Y.

AU - Tsivgoulis, Georgios

AU - Sugg, Rebecca M.

AU - Barreto, Andrew

AU - Sierzenski, Paul

AU - Malkoff, Marc

AU - Grotta, James C.

PY - 2008/5/1

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N2 - 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.

AB - 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.

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