Juefei Wu

Improved sonothrombolysis from a modified diagnostic transducer delivering impulses containing a longer pulse duration.

Although guided high-mechanical-index (MI) impulses from a diagnostic ultrasound transducer have been used in preclinical studies to dissolve coronary arterial and microvascular thrombi in the presence of intravenously infused microbubbles, it is possible that pulse durations (PDs) longer than that used for diagnostic imaging may further improve the effectiveness of this approach. By use of an established in vitro model flow system, a total of 90 occlusive porcine arterial thrombi (thrombus age: 3-4 h) within a vascular mimicking system were randomized to 10-min treatments with two different PDs (5 and 20 μs) using a Philips S5-1 transducer (1.6-MHz center frequency) at a range of MIs (from 0.2 to 1.4). All impulses were delivered in an intermittent fashion to permit microbubble replenishment within the thrombosed vessel. Diluted lipid-encapsulated microbubbles (0.5% Definity) were infused during the entire treatment period. A tissue-mimicking phantom 5 cm thick was placed between the transducer and thrombosed vessel to mimic transthoracic attenuation. Two 20-MHz passive cavitation detection systems were placed confocal to the insonified vessel to assess for inertial cavitational activity. Percentage thrombus dissolution was calculated by weighing the thrombi before and after each treatment. Percentage thrombus dissolution was significantly higher with a 20-μs PD already at the 0.2 and 0.4 MI therapeutic impulses (54 ± 12% vs. 33 ± 17% and 54 ± 22% vs. 34 ± 17%, p < 0.05 compared with the 5-μs PD group, respectively), and where passive cavitation detection systems detected only low intensities of inertial cavitation. At higher MI settings and 20-μs PDs, percentage thrombus dissolution decreased most likely from high-intensity cavitation shielding of the thrombus. Slightly prolonging the PD on a diagnostic transducer improves the degree of sonothrombolysis that can be achieved without fibrinolytic agents at a lower mechanical index.

Diagnostic Ultrasound Induced Inertial Cavitation to Non-Invasively Restore Coronary and Microvascular Flow in Acute Myocardial Infarction

Ultrasound induced cavitation has been explored as a method of dissolving intravascular and microvascular thrombi in acute myocardial infarction. The purpose of this study was to determine the type of cavitation required for success, and whether longer pulse duration therapeutic impulses (sustaining the duration of cavitation) could restore both microvascular and epicardial flow with this technique. Accordingly, in 36 hyperlipidemic atherosclerotic pigs, thrombotic occlusions were induced in the mid-left anterior descending artery. Pigs were then randomized to either a) ½ dose tissue plasminogen activator (0.5 mg/kg) alone; or same dose plasminogen activator and an intravenous microbubble infusion with either b) guided high mechanical index short pulse (2.0 MI; 5 usec) therapeutic ultrasound impulses; or c) guided 1.0 mechanical index long pulse (20 usec) impulses. Passive cavitation detectors indicated the high mechanical index impulses (both long and short pulse duration) induced inertial cavitation within the microvasculature. Epicardial recanalization rates following randomized treatments were highest in pigs treated with the long pulse duration therapeutic impulses (83% versus 59% for short pulse, and 49% for tissue plasminogen activator alone; p<0.05). Even without epicardial recanalization, however, early microvascular recovery occurred with both short and long pulse therapeutic impulses (p<0.005 compared to tissue plasminogen activator alone), and wall thickening improved within the risk area only in pigs treated with ultrasound and microbubbles. We conclude that although short pulse duration guided therapeutic impulses from a diagnostic transducer transiently improve microvascular flow, long pulse duration therapeutic impulses produce sustained epicardial and microvascular re-flow in acute myocardial infarction.

Microbubble mediated thrombus dissolution with diagnostic ultrasound for the treatment of chronic venous thrombi.

Background Central venous catheter (CVC) thrombi result in significant morbidity in children, and currently available treatments are associated with significant risk. We sought to investigate the therapeutic efficacy of microbubble (MB) enhanced sonothrombolysis for aged CVC associated thrombi in vivo. Methods and Results A model of chronic indwelling CVC in the low superior vena cava with thrombus in situ was established after feasibility and safety testing in 7 pigs; and subsequently applied for repeated, sonothrombolytic treatments in 9 pigs (total 24 treatments). Baseline intracardiac echocardiography (ICE, 10.5F, Siemens), fluoroscopy and saline flushing confirmed the absence of any pre-existing CVC thrombus. A thrombus was then allowed to form and age over 24 hours. The created thrombus was localized and measured by ICE, and transthoracic image guided high mechanical index (MI) two-dimensional US treatments (1.1–1.7 MI; iE33, Philips) applied intermittently whenever intravenously infused MBs (3% MRX-801; NuVox) were visualized near the thrombus (n = 10; Group A). Control pigs (n = 10; Group B) received US without MB. All treatments were randomized. Post-treatment thrombus area by ICE planimetry was compared with pre-treatment measurements. Thrombus area measurements before and after treatment were 0.22 and 0.10 cm2 respectively in Group A; compared to 0.24 and 0.21 cm2 in Group B (p  = 0.0003). Effectiveness of longer duration US and MB thrombolytic treatments were studied (n = 4), which suggested that near complete thrombus dissolution is possible. No pulmonary emboli, alterations in oxygen saturation, or hemodynamics occurred with either treatment. Conclusions Guided high MI diagnostic US+systemic MB facilitates reduction of aged CVC associated thrombi in vivo. MB enhanced sonothrombolytic therapy may be a non-invasive safe alternative to thrombolytic agents in treating thrombotic CVC occlusions.

Improvements in cerebral blood flow and recanalization rates with transcranial diagnostic ultrasound and intravenous microbubbles after acute cerebral emboli.

ObjectivesIntravenous microbubbles (MBs) and transcutaneous ultrasound have been used to recanalize intra-arterial thrombi without the use of tissue plasminogen activator. In the setting of acute ischemic stroke, it was our objective to determine whether skull attenuation would limit the ability of ultrasound alone to induce the type and level of cavitation required to dissolve thrombi and improve cerebral blood flow (CBF) in acute ischemic stroke. Materials and MethodsIn 40 pigs, bilateral internal carotid artery occlusions were created with 4-hour-old thrombi. Pigs were then randomized to high–mechanical index (MI = 2.4) short-pulse (5 microseconds) transcranial ultrasound (TUS) alone or a systemic MB infusion (3% Definity) with customized cavitation detection and imaging system transmitting either high-MI (2.4) short pulses (5 microseconds) or intermediate-MI (1.7) long pulses (20 microseconds). Angiographic recanalization rates of both internal carotids were compared in 24 of the pigs (8 per group), and quantitative analysis of CBF with perfusion magnetic resonance imaging was measured before, immediately after, and at 24 hours using T2* intensity versus time curves in 16 pigs. ResultsComplete angiographic recanalization was achieved in 100% (8/8) of pigs treated with image-guided high-MI TUS and MBs, but in only 4 of 8 treated with high-MI TUS alone or 3 of 8 pigs treated with image-guided intermediate-MI TUS and MBs (both P < 0.05). Ipsilateral and contralateral CBF improved at 24 hours only after 2.4-MI 5-microsecond pulse treatments in the presence of MB (P < 0.005). There was no evidence of microvascular or macrovascular hemorrhage with any treatment. ConclusionsGuided high-MI impulses from an ultrasound imaging system produce sustained improvements in ipsilateral and contralateral CBF after acute cerebral emboli.

Validation of admittance computed left ventricular volumes against real‐time three‐dimensional echocardiography in the porcine heart

•  What is the central question of this study? How do left ventricular volumes measured in a large animal using admittance catheterization compare with those measured using three‐dimensional echocardiography or traditional conductance? •  What is the main finding and its importance? Admittance computed left ventricular volumes were validated in baseline conditions and during inotropic stimulation with dobutamine. These results serve as a foundation for the use of admittance in large‐animal experimental models of cardiovascular disease.

Prevention of Arteriovenous Shunt Occlusion Using Microbubble and Ultrasound Mediated Thromboprophylaxis

Background Palliative shunts in congenital heart disease patients are vulnerable to thrombotic occlusion. High mechanical index (MI) impulses from a modified diagnostic ultrasound (US) transducer during a systemic microbubble (MB) infusion have been used to dissolve intravascular thrombi without anticoagulation, and we sought to determine whether this technique could be used prophylactically to reduce thrombus burden and prevent occlusion of surgically placed extracardiac shunts. Methods and Results Heparin‐bonded ePTFE tubular vascular shunts of 4 mm×2.5 cm (Propaten; W.L Gore) were surgically placed in 18 pigs: a right‐sided side‐to‐side arteriovenous (AV, carotid‐jugular) shunt, and a left‐sided arterio‐arterial (AA, carotid‐carotid) interposition shunt in each animal. After shunt implantation, animals were randomly assigned to one of 3 groups. Transcutaneous, weekly 30‐minute treatments (total of 4 treatments) of either guided high MI US+MB (Group 1; n=6) using a 3% MRX‐801 MB infusion, or US alone (Group 2; n=6) were given separately to each shunt. The third group of 6 pigs received no treatments. The shunts were explanted after 4 weeks and analyzed by histopathology to quantify luminal thrombus area (mm2) for the length of each shunt. No pigs received antiplatelet agents or anticoagulants during the treatment period. The median overall thrombus burden in the 3 groups for AV shunts was 5.10 mm2 compared with 4.05 mm2 in AA (P=0.199). Group 1 pigs had significantly less thrombus burden in the AV shunts (median 2.5 mm2) compared with Group 2 (median 5.6 mm2) and Group 3 (median 7.5 mm2) pigs (P=0.006). No difference in thrombus burden was seen between groups for AA shunts. Conclusion Transcutaneous US with intravenous MB is capable of preventing thrombus accumulation in arteriovenous shunts without the need for antiplatelet agents, and may be a method of preventing progressive occlusion of palliative shunts.

Ultrasound-Induced Microbubble Cavitation for the Treatment of Catheterization-Induced Vasospasm

Visual Abstract

HIGH MECHANICAL INDEX IMPULSES FROM A DIAGNOSTIC TRANSDUCER DURING AN INTRAVENOUS MICROBUBBLE INFUSION CAN REDUCE ULTIMATE INFARCT SIZE WHEN COMPARED TO FULL DOSE TISSUE PLASMINOGEN ACTIVATOR IN ACUTE ST SEGMENT ELEVATION MYOCARDIAL INFARCTION

Guided high mechanical index (MI) impulses from a modified diagnostic ultrasound transducer may be able to reduce the residual microvascular obstruction (MO) that exists following epicardial recanalization in acute ST segment elevation myocardial infarction (STEMI). We sought to determine how much

RELATIONSHIP BETWEEN QUANTITATIVE SEVERITY OF CORONARY STENOSIS, FRACTIONAL FLOW RESERVE FINDINGS, AND DEMAND STRESS MYOCARDIAL PERFUSION FINDINGS IN PATIENT WITH SYMPTOMATIC CORONARY ARTERY DISEASE

Fractional flow reserve (FFR) has been utilized to assess the functional significance of intermediate (50% – 80%) coronary lesions. However, during hyperemic stress, regulation of coronary blood flow is more often controlled by capillary resistance and not stenosis resistance. Real time myocardial

Image-guided sonothrombolysis in a stroke model with a cavitation delivery and monitoring system

Microbubbles (MB) and ultrasound (US) can dissolve intra-arterial thrombi. In order to reproducibly deliver the correct cavitation dose and ensure treatment efficacy and safety, we designed a therapeutic US mode with cavitation monitoring. Therapy delivery and recording of the MB signal are achieved with a sector imaging probe. Monitoring is achieved by spectrally analyzing the MB signal: ultraharmonics are a marker of stable cavitation (SC) and broadband noise characterizes inertial cavitation (IC). We used the system in a pig model. Thrombotic occlusions were created by injecting 4-hour old clots bilaterally into the internal carotids. Forty pigs were randomized to either 2.4 MI, 5 μs pulses with MBs; 1.7 MI, 20 μs pulses with MBs; and 2.4 MI, 5 μs pulses without MBs. Angiographic recanalization rates were compared. Cavitation as a function of MI was estimated in vivo. Dominant SC started at an applied MI of 0.6 (0.3MI in situ after derating by skull attenuation). Dominant IC was estimated to start at a...