Potentiating intra-arterial sonothrombolysis for acute ischemic stroke by the addition of the ultrasound contrast agents (Optison™ & SonoVue®)

Abstract

Transcranial ultrasound in combination with intravenously administered ultrasound contrast agents (UCA) in the presence or absence of recombinant tissue plasminogen activator (rt-PA) has been widely evaluated as a new modality for treatment of ischemic stroke. Despite the successful demonstration of accelerated clot lysis there are inherent limitations associated with this modality such as inconsistency in temporal window thickness and/or potential serious cardiopulmonary reactions to intravenous administration of UCA that prevent broad application to ischemic stroke populations. As a complementary modality, we evaluated potential lysis enhancement by intraarterial ultrasound with concurrent intra-clot delivery of UCA and rt-PA. To this end, clots were formed with average pore diameter similar to clinically retracted clots by adjusting the thrombin concentration. Physical characteristic and retention of UCA after delivery through the catheter as a function of clinically relevant flow rates of 6, 12, 18 ml/h were determined using a microscopic method. The ability of the UCA employed in this study, Optison and SonoVue, to penetrate into the clot was verified using ultrasound B-mode imaging. Clot lysis as a function of rt-PA concentration, 0.009 through 0.5 mg/ml, in the presence and absence of UCA diluted to 1:10, 1:100, and 1:200 v/v at two Peak rarefaction acoustic pressures of 1.3 and 2.1 MPa were evaluated using a weighing method. The study results suggest the addition of only 0.02 ml of 1:100 diluted UCA to rt-PA of 0.009, 0.05, 0.3, and 0.5 mg/ml can enhance the lysis rate by 3.9, 2.6, 1.9 and 1.8 fold in the presence of peak rarefaction acoustic pressure of 1.3 MPa and by 5.1,

Sonothrombolysis for acute ischemic stroke: a systematic review of randomized controlled trials

“…Future studies should focus on the development of the following: 1) microspheres associated with ultrasound for augmenting brain perfusion and drug delivery within the penumbra area; 18 2) an operator-independent ultrasound device that can be used by medical personnel irrespective of experience with TCD or TCCD ultrasonography examinations; 27,28 3) intraarterial ultrasound devices for thrombolysis; 26 and 4) ultrasound catheters for minimally invasive evacuation of intracranial hematomas as a complication of thrombolytic therapy or other causes. 21,24 In the near future, it is possible that high-intensity focused ultrasound neurosurgery for brain tumors, Parkinson disease, epilepsy, and other conditions may become a reality.…”

Application of cavitation promoting surfaces in management of acute ischemic stroke

“…This test system, rt-PA preparation, clot formation, and thrombolysis procedure have been described in detail in a previous publication [24]. Briefly, human pooled citrated blood (Innovative Research, Southfield, MI) was formed into a clot by adding 0.2 ml of 0.25 M calcium chloride and 0.2 ml of 12.5 U/ml bovine thrombin to 2.0mL of blood.…”

“…In vitro studies have demonstrated that low intensity acoustic output of this catheter increases enzyme mediated thrombolysis in the absence of cavitation [8]. Additional studies demonstrated that addition of extraneous US contrast agents to the treatment modality with Microsonic catheter generated acoustic emissions indicative of cavitation and augmented the thrombolysis rate even further [8, 9]. …”

Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery

“…Nonetheless, in patients with an unstable cardiopulmonary status or an acute myocardial infarction, application is contraindicated ( Dolan et al, 2009 ). Soltani et al (2011) tested a mixture of tPA and the CA Optison ® and the soft-shell MB SonoVue ® (now Lumason ® , Bracco, Milano, Italy) in a different setup. Using a catheter as a model of human vessels, they treated in vitro an acute ischemic stroke via intra-arterial sonothrombolysis, suggesting an effective treatment for some stroke patients ( Soltani et al, 2011 ).…”