Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial

Carlos A. Molina, Andrew D. Barreto, Georgios Tsivgoulis, Paul Sierzenski, Marc Malkoff, Marta Rubiera, Nicole Gonzales, Robert Mikulik, Greg Pate, James Ostrem, Walter Singleton, Garen Manvelian, Evan C. Unger, James C. Grotta, Peter D. Schellinger, Andrei Alexandrov

Research output: Contribution to journalArticle

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Abstract

Objective: Microspheres (μS) 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 μS 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 μS (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. Interpretation: Perflutren lipid μS 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 μS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy.

Original languageEnglish (US)
Pages (from-to)28-38
Number of pages11
JournalAnnals of Neurology
Volume66
Issue number1
DOIs
StatePublished - Jul 1 2009

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Tissue Plasminogen Activator
Clinical Trials
Cerebral Hemorrhage
perflutren
Blood Pressure
Microspheres
Stroke
Hypertension
Lipids
Safety

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. / Molina, Carlos A.; Barreto, Andrew D.; Tsivgoulis, Georgios; Sierzenski, Paul; Malkoff, Marc; Rubiera, Marta; Gonzales, Nicole; Mikulik, Robert; Pate, Greg; Ostrem, James; Singleton, Walter; Manvelian, Garen; Unger, Evan C.; Grotta, James C.; Schellinger, Peter D.; Alexandrov, Andrei.

In: Annals of Neurology, Vol. 66, No. 1, 01.07.2009, p. 28-38.

Research output: Contribution to journalArticle

Molina, CA, Barreto, AD, Tsivgoulis, G, Sierzenski, P, Malkoff, M, Rubiera, M, Gonzales, N, Mikulik, R, Pate, G, Ostrem, J, Singleton, W, Manvelian, G, Unger, EC, Grotta, JC, Schellinger, PD & Alexandrov, A 2009, 'Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial', Annals of Neurology, vol. 66, no. 1, pp. 28-38. https://doi.org/10.1002/ana.21723
Molina, Carlos A. ; Barreto, Andrew D. ; Tsivgoulis, Georgios ; Sierzenski, Paul ; Malkoff, Marc ; Rubiera, Marta ; Gonzales, Nicole ; Mikulik, Robert ; Pate, Greg ; Ostrem, James ; Singleton, Walter ; Manvelian, Garen ; Unger, Evan C. ; Grotta, James C. ; Schellinger, Peter D. ; Alexandrov, Andrei. / Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. In: Annals of Neurology. 2009 ; Vol. 66, No. 1. pp. 28-38.
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AU - Molina, Carlos A.

AU - Barreto, Andrew D.

AU - Tsivgoulis, Georgios

AU - Sierzenski, Paul

AU - Malkoff, Marc

AU - Rubiera, Marta

AU - Gonzales, Nicole

AU - Mikulik, Robert

AU - Pate, Greg

AU - Ostrem, James

AU - Singleton, Walter

AU - Manvelian, Garen

AU - Unger, Evan C.

AU - Grotta, James C.

AU - Schellinger, Peter D.

AU - Alexandrov, Andrei

PY - 2009/7/1

Y1 - 2009/7/1

N2 - Objective: Microspheres (μS) 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 μS 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 μS (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. Interpretation: Perflutren lipid μS 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 μS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy.

AB - Objective: Microspheres (μS) 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 μS 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 μS (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. Interpretation: Perflutren lipid μS 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 μS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy.

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