Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke.

BACKGROUND Transcranial Doppler ultrasonography that is aimed at residual obstructive intracranial blood flow may help expose thrombi to tissue plasminogen activator (t-PA). Our objective was to determine whether ultrasonography can safely enhance the thrombolytic activity of t-PA. METHODS We treated all patients who had acute ischemic stroke due to occlusion of the middle cerebral artery with intravenous t-PA within three hours after the onset of symptoms. The patients were randomly assigned to receive continuous 2-MHz transcranial Doppler ultrasonography (the target group) or placebo (the control group). The primary combined end point was complete recanalization as assessed by transcranial Doppler ultrasonography or dramatic clinical recovery. Secondary end points included recovery at 24 hours, a favorable outcome at three months, and death at three months. RESULTS A total of 126 patients were randomly assigned to receive continuous ultrasonography (63 patients) or placebo (63 patients). Symptomatic intracerebral hemorrhage occurred in three patients in the target group and in three in the control group. Complete recanalization or dramatic clinical recovery within two hours after the administration of a t-PA bolus occurred in 31 patients in the target group (49 percent), as compared with 19 patients in the control group (30 percent; P=0.03). Twenty-four hours after treatment of the patients eligible for follow-up, 24 in the target group (44 percent) and 21 in the control group (40 percent) had dramatic clinical recovery (P=0.7). At three months, 22 of 53 patients in the target group who were eligible for follow-up analysis (42 percent) and 14 of 49 in the control group (29 percent) had favorable outcomes (as indicated by a score of 0 to 1 on the modified Rankin scale) (P=0.20). CONCLUSIONS In patients with acute ischemic stroke, continuous transcranial Doppler augments t-PA-induced arterial recanalization, with a nonsignificant trend toward an increased rate of recovery from stroke, as compared with placebo.

[1]  R. Aaslid,et al.  Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. , 1982, Journal of neurosurgery.

[2]  H. S. Mueller,et al.  The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. , 1985, The New England journal of medicine.

[3]  Peter Grolimund.  Transmission of Ultrasound Through the Temporal Bone , 1986 .

[4]  C G Lauer,et al.  Effect of Ultrasound on Tissue‐Type Plasminogen Activator‐Induced Thrombolysis , 1992, Circulation.

[5]  W. Hacke,et al.  Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke , 1992, Annals of neurology.

[6]  C. Francis,et al.  Characterization of ultrasound-potentiated fibrinolysis in vitro , 1993 .

[7]  H. Furuhata,et al.  Evaluation of the thrombolytic effect of tissue-type plasminogen activator with ultrasonic irradiation: in vitro experiment involving assay of the fibrin degradation products from the clot. , 1994, Biological & pharmaceutical bulletin.

[8]  C. Francis,et al.  Flow through clots determines the rate and pattern of fibrinolysis. , 1994, Thrombosis and haemostasis.

[9]  C. Francis,et al.  Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. , 1995, Ultrasound in medicine & biology.

[10]  Joseph P. Broderick,et al.  Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. , 1995 .

[11]  J. Grotta.  Should thrombolytic therapy be the first-line treatment for acute ischemic stroke? t-PA--the best current option for most patients. , 1997, The New England journal of medicine.

[12]  C. Francis,et al.  Enhancement of fibrinolysis with 40-kHz ultrasound. , 1998, Circulation.

[13]  H. Furuhata,et al.  Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. , 1998, Neurosurgery.

[14]  A. Alexandrov,et al.  Transcranial doppler ultrasound criteria for recanalization after thrombolysis for middle cerebral artery stroke. , 2000, Stroke.

[15]  A. Alexandrov,et al.  Accuracy and Criteria for Localizing Arterial Occlusion With Transcranial Doppler , 2000, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[16]  G. Albers,et al.  Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. , 2000, JAMA.

[17]  D. Blacker.  High Rate of Complete Recanalization and Dramatic Clinical Recovery During tPA Infusion When Continuously Monitored With 2-MHz Transcranial Doppler Monitoring , 2000 .

[18]  M. Hennerici,et al.  Transcranial ultrasound-improved thrombolysis: diagnostic vs. therapeutic ultrasound. , 2001, Ultrasound in medicine & biology.

[19]  C. Francis.  Ultrasound‐Enhanced Thrombolysis , 2001, Echocardiography.

[20]  A. Alexandrov,et al.  Thrombolysis in Brain Ischemia (TIBI) Transcranial Doppler Flow Grades Predict Clinical Severity, Early Recovery, and Mortality in Patients Treated With Intravenous Tissue Plasminogen Activator , 2001, Stroke.

[21]  A. Alexandrov,et al.  Speed of Intracranial Clot Lysis With Intravenous Tissue Plasminogen Activator Therapy: Sonographic Classification and Short-Term Improvement , 2001, Circulation.

[22]  V. Larrue,et al.  High Rate of Recanalization of Middle Cerebral Artery Occlusion During 2-MHz Transcranial Color-Coded Doppler Continuous Monitoring Without Thrombolytic Drug , 2002, Stroke.

[23]  M. Moehring,et al.  Power M-mode Doppler (PMD) for observing cerebral blood flow and tracking emboli. , 2002, Ultrasound in medicine & biology.

[24]  S. Dimauro,et al.  Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig-Hoffmann disease. , 2002, Archives of neurology.

[25]  C. Francis,et al.  Ultrasound Improves Tissue Perfusion in Ischemic Tissue through a Nitric Oxide Dependent Mechanism , 2002, Thrombosis and Haemostasis.

[26]  M. Hennerici,et al.  Ultrasound in the treatment of ischaemic stroke , 2003, The Lancet Neurology.

[27]  I. König,et al.  Effect of ultrasound on thrombolysis of middle cerebral artery occlusion , 2003, Annals of neurology.

[28]  A. Alexandrov,et al.  CLOTBUST: Design of a Randomized Trial of Ultrasound‐Enhanced Thrombolysis for Acute Ischemic Stroke , 2004, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[29]  A. Alexandrov,et al.  Assessment: Transcranial Doppler ultrasonography: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology* , 2004, Neurology.