Published online before print June 9, 2005, doi: 10.1161/01.STR.0000170707.86793.1a
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(Stroke. 2005;36:1441.)
© 2005 American Heart Association, Inc.
Original Contributions |
Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia
Increased Risk of Hemorrhage With Combined Ultrasound and Tissue Plasminogen Activator: Results of a Phase II Clinical Trial
From the Department of Neurology (M.D., O.S., M.G.H.), Universitätsklinikum Mannheim, Germany; the Department of Neurology (A.G.), University Hospital Basel, Switzerland; the Department of Neurology (P.R.), Universitätsklinikum Heidelberg, Germany; the Department of Neurology (M.S.), University of Frankfurt, Germany; the Department of Neurology (U.S.), University of Hamburg, Germany; the Department of Neurology (T.E.), University of Freiburg, Germany; and the Department of Neurology (W.J.K.), Massachusetts General Hospital, Boston.
Correspondence to Michael Daffertshofer, MD, Department of Neurology, University of Heidelberg, Universitätsklinikum Mannheim, Theodor-Kutzer-Ufer 1-3, D-69135 Mannheim, Germany. E-mail daffertshofer{at}neuro.ma.uni-heidelberg.de
Background— Clinical studies using ultrasound at diagnostic frequencies in transcranial Doppler devices provided encouraging results in enhancing thrombolysis with tissue plasminogen activator (tPA) in acute stroke. Low-frequency ultrasound does not require complex positioning procedures, penetrates through the skull better, and has been demonstrated to accelerate thrombolysis with tPA in animal experiments in wide cerebrovascular territories without hemorrhagic side effects. We therefore conducted the first multicenter clinical trial to investigate safety of tPA plus low-frequency ultrasound (300 kHz).
Methods— Acute stroke patients within a 6-hour time window were included (National Institutes of Health Stroke Scale scores >4). Magnetic resonance imaging (MRI) was used to document vascular occlusion and to rule out cerebral hemorrhage. Patients were allocated to combination therapy alternately; the first patient received tPA only, the second patient received tPA plus ultrasound, etc. Follow-up included serial MRI directly thereafter and 24 hours later to confirm recanalization and tissue imaging. Clinical recovery was measured after treatment and 3 months later.
Results— 26 patients (70.4±9.7 years) entered the trial (12 tPA, 14 tPA plus ultrasound). The study was prematurely stopped because 5 of 12 patients from the tPA only group but 13 of 14 patients treated with the tPA plus ultrasound showed signs of bleeding in MRI (P<0.01). Within 3 days of treatment, 5 symptomatic hemorrhages occurred within the tPA plus ultrasound group. At 3 months, neither morbidity nor treatment-related mortality or recanalization rates differed between both groups.
Conclusions— This study demonstrated bioeffects from low-frequency ultrasound that caused an increased rate of cerebral hemorrhages in patients concomitantly treated with intravenous tPA.
Key Words: stroke, acute • thrombolysis • ultrasonography
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