Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke

Alexandrov, Andrei V.; Molina, Carlos A.; Grotta, James C.; Garami, Zsolt; Ford, Shiela R.; Alvarez-Sabin, José; Montaner, Joan; Saqqur, Maher; Demchuk, Andrew M.; Moyé, Lemuel A.; Hill, Michael D.; Wojner, Anne W.

doi:10.1056/nejmoa041175

Cited by 975 publications

(536 citation statements)

References 27 publications

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“…In this study, we used the standard ultrasound parameters used for transcranial sonothrombolysis;5, 12 however, even in the absence of skull attenuation, there did not appear to be a large additive benefit over tPA alone. Ultrasound power is attenuated through the skull by as much as 99%,13, 14 yet evidence that higher power increases clot lysis15 indicates that power attenuation likely limits the efficacy of intracranial sonothrombolysis.…”

Section: Discussionmentioning

confidence: 99%

Thrombolytic Recanalization of Carotid Arteries Is Highly Dependent on Degree of Stenosis, Despite Sonothrombolysis

Tomkins

Hood

Pepperall

et al. 2016

JAHA

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BackgroundStroke associated with acute carotid occlusion is associated with poor effectiveness of tissue plasminogen activator (tPA) thrombolysis and poor prognosis. Rupture of atherosclerotic plaques resulting in vascular occlusions may occur on plaques, causing variable stenosis. We hypothesized that degree of stenosis may affect recanalization rates with tPA. Ultrasound+tPA (sonothrombolysis) has been shown to improve recanalization for intracranial occlusions but has not been tested for carotid occlusion. Our primary aim was to determine thrombolytic recanalization rates in a model of occlusion with variable stenosis, with a secondary aim to investigate sonothrombolysis in this model.Methods and ResultsRat carotid arteries were crushed and focal stenosis created (25% baseline Doppler flow) with a silk‐suture tie invoking thrombosis and occlusion. To model mild or severe stenosis, the tie was released pretreatment or left in place. Animals were treated with tPA (10 mg/kg) or tPA+ultrasound (2‐MHz) in each stenosis model (n=7/group). Recanalization was assessed by Doppler flow. Thrombolytic recanalization rates were significantly higher in mild stenosis groups (71% versus 0% with severe stenosis; P<0.0001). Recanalization rates were not significantly higher with additional ultrasound in either model.ConclusionsIn this model, the degree of carotid stenosis had a large effect on thrombolytic recanalization. Sonothrombolysis using standard parameters for intracranial sonothrombolysis did not increase recanalization. Further testing is warranted. The degree of underlying stenosis may be an important predictor of thrombolytic recanalization, and clinical correlation of these findings may provide new approaches to treatment selection for patients with carotid occlusion.

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Section: Discussionmentioning

confidence: 99%

Thrombolytic Recanalization of Carotid Arteries Is Highly Dependent on Degree of Stenosis, Despite Sonothrombolysis

Tomkins

Hood

Pepperall

et al. 2016

JAHA

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“…Like ultrasound, diastolic turbulence inhibits coagulation [432]. Thrombosis is rare in arteries, where turbulence is intense, but thrombophlebitis is common in veins, where turbulence is sluggish [433].…”

Section: The Turbulence Mechanismmentioning

confidence: 99%

“…Insoluble fibrin elevations disrupt red cell aggregates and induce turbulence during systolic acceleration that strains and collapses structurally defective red cells, causing sickle-cell anemia crisis [435][436][437][438][439][440]. Systolic turbulence also retards peak end-systolic blood velocity, which exaggerates diastolic turbulent lateral forces at the expense of turbulent mixing, elevates blood pressure, increases blood coagulability, and accelerates atherosclerosis [118,183,185,196,268,385,396,424,432,[441][442][443][444][445][446][447][448][449][450][451]. Insoluble fibrin binds red cells into a clot after it reduces turbulent mixing below a threshold [161, 432,452].…”

Section: The Turbulence Mechanismmentioning

confidence: 99%

“…Thrombin-activated platelets release thromboxane that induces local vasoconstriction to temporarily reduce flow and turbulence, which increases coagulability. Rising levels of insoluble fibrin increase local blood viscosity to reduce pulsatile turbulent mixing below a threshold (see "turbulence mechanism" on page 10), whereupon insoluble fibrin binds red cells into a durable, viscoelastic, selectively permeable "red clot" that substitutes for the damaged vascular endothelium by isolating damaged tissues from flowing blood [84,161,169,432,452]. The enormous molecular size of Factor VIII prevents it from penetrating the clot and interacting with the other enzymes, so that clot formation is self-limiting.…”

Section: The Tissue Repair Component Inflammation and Apoptosismentioning

confidence: 99%

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Stress repair mechanism activity explains inflammation and apoptosis

Coleman¹

2012

ABB

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“…Ultrasound can induce microstreams within the clot to increase the distribution of rt-PA for improved thrombolysis. Transcranial ultrasound-enhanced intravenous thrombolysis leads to an absolute 20% increase in the rate of middle cerebral artery (MCA) recanalization according to CLOTBUST results (5). Moreover, transcranial ultrasound has been shown to accelerate clot dissolution in some patients with contraindications for rt-PA, although these preliminary data should be confirmed in the setting of a large trial.…”

Section: Pharmacology Of Restoration Of Cerebral Perfusionmentioning

confidence: 99%

Stroke pathophysiology: management challenges and new treatment advances

Jordán

Ikuta

García-García

et al. 2007

J. Physiol. Biochem.

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J. JORDÁN, I. IKUTA, J. GARCÍA-GARCÍA, S. CALLEJA and T. SEGURA. Stroke pathophysiology: Management challenges and new treatment advances (minireview). J. Physiol. Biochem., 63 (3), 261-278, 2007. Stroke is the second leading cause of death and the first cause of lost disabilityadjusted years in developed countries. During the past decade, new developments in thrombolytic therapy have led to the implementation of emergency intervention protocols for the treatment of ischemic stroke, replacing the widespread sense of therapeutic nihilism in the past. Treatment with rtPA has shown to be effective within the first 3 hours following stroke onset and the FDA and the European Medical Agency (EMEA) have approved its use. Acknowledging the urgency and intricacies of stroke, Stroke Units allow the monitoring of physiological parameters in the acute phase of stroke and are considered an important management tool that can significantly improve the quality of care provided to the patient. The concept of neuroprotective therapy for acute ischemic stroke to salvage tissue at risk and improve functional outcome is based on sound scientific principles and extensive preclinical animal studies demonstrating efficacy. However, most neuroprotective drugs in clinical trials have failed, possibly due to inadequate preclinical testing or flawed clinical development programs. Several new treatment strategies are under development and are being tested. This review is directed at understanding the management of acute ischemic stroke pathophysiology. We address the management challenges and new treatment advances by integrating the knowledge of possible pharmacological targets for acute ischemic stroke. We hope to shed new light upon the controversy surrounding the management of acute ischemic stroke in an attempt to elucidate why failed clinical trials continue to occur despite promising neuroprotective preclinical studies.

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Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke

Abstract: 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.

Cited by 975 publications

References 27 publications

Thrombolytic Recanalization of Carotid Arteries Is Highly Dependent on Degree of Stenosis, Despite Sonothrombolysis

Thrombolytic Recanalization of Carotid Arteries Is Highly Dependent on Degree of Stenosis, Despite Sonothrombolysis

Stress repair mechanism activity explains inflammation and apoptosis

Stroke pathophysiology: management challenges and new treatment advances

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