Intravenous Microbubble Infusion Research Articles

The Impact of Sonothrombolysis on Left Ventricular Diastolic Function and Left Atrial Mechanics Preventing Left Atrial Remodeling in Patients With ST Elevation Acute Myocardial Infarction

The diagnostic ultrasound-guided high mechanical index impulses during an intravenous microbubble infusion (sonothrombolysis) improve myocardial perfusion in acute ST segment elevation myocardial infarction, but its effect on left ventricular diastolic dysfunction (DD), left atrial (LA) mechanics and remodeling is unknown. We assessed the effect of sonothrombolysis on DD grade and LA mechanics. One hundred patients (59±10years; 34% women) were randomized to receive either high mechanical index impulses plus percutaneous coronary intervention (PCI) (therapy group) or PCI only (control group) (n=50 in each group). Diastolic dysfunction grade and LA mechanics were assessed immediately before and after PCI and at 48 to 72hours, 1month, and 6months of follow-up. Diastolic dysfunction grades were classified as grades I, II, and III. The LA mechanics was obtained by two-dimensional speckle-tracking echocardiography-derived global longitudinal strain (GLS). As follow-up time progressed, increased DD grade was observed more frequently in the control group than in the therapy group at 1month and 6months of follow-up (all P<.05). The LA-GLS values were incrementally higher in the therapy group when compared with the control group at 48 to 72hours, 24.0%±7.3% in the therapy group versus 19.6%±7.2% in the control group, P=.005; at 1month, 25.3%±6.3% in the therapy group versus 21.5%±8.3% in the control group, P=.020; and at 6months, 26.2%±8.7% in the therapy group versus21.6%±8.5% in the control group, P=.015. The therapy group was less likely to experience LA remodeling (odds ratio, 2.91 [1.10-7.73]; P=.03). LA-GLS was the sole predictor of LA remodeling (odds ratio, 0.79 [0.67-0.94]; P=.006). Sonothrombolysis is associated with better DD grade and LA mechanics, reducing LA remodeling.

Pilot study of repeated blood-brain barrier disruption in patients with mild Alzheimer\u2019s disease with an implantable ultrasound device

BackgroundTemporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive decline in pre-clinical models of Alzheimer’s disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and efficacy of this approach in patients with mild AD using an implantable ultrasound device.MethodsAn implantable, 1-MHz ultrasound device (SonoCloud-1) was implanted under local anesthesia in the skull (extradural) of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB. 18F-florbetapir and 18F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at 4 and 8 months after the initiation of sonications to monitor the brain metabolism and amyloid levels along with cognitive evaluations. The evolution of cognitive and neuroimaging features was compared to that of a matched sample of control participants taken from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).ResultsA total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at 4 months of − 6.6% (SD = 7.2%) on 18F-florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in the longitudinal change in the glucose metabolism were observed compared to the neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison with the ADNI participants as expected due to the small sample size and duration of the trial.ConclusionsThese results demonstrate the safety of ultrasound-based BBB disruption and the potential of this technology to be used as a therapy for AD patients. Research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease-modifying drugs may further enhance the effects observed.Trial registrationClinicalTrials.gov, NCT03119961

Microbubbles and Ultrasound Accelerated Thrombolysis for Peripheral Arterial Occlusions: The Outcomes of a Single Arm Phase II Trial

Acute peripheral arterial occlusions can be treated by catheter directed thrombolysis (CDT). However, CDT is time consuming and accompanied by the risk of bleeding complications. The addition of contrast enhanced ultrasound and microbubbles could improve thrombus susceptibility to thrombolytic agents and potentially shorten treatment time with a lowered risk of bleeding complications. This article reports the outcomes of the safety and feasibility of this novel technique. In this single arm phase II trial, 20 patients with acute lower limb ischaemia received CDT combined with an intravenous infusion of microbubbles and locally applied ultrasound during the first hour of standard intra-arterial thrombolytic therapy. The primary endpoint was safety, i.e., occurrence of serious adverse events (haemorrhagic complications and/or amputation) and death within one year. Secondary endpoints included angiographic and clinical success, thrombolysis duration, additional interventions, conversion, and quality of life. The study included 20 patients (16 men; median age 68.0 years; range, 50.0 - 83.0; and 40% native artery and 60% bypass graft). In all patients, the use of microbubble contrast enhanced sonothrombolysis could be applied successfully. There were no serious adverse events related to the experimental treatment. Duplex examination showed flow distal from the occlusion after 23.1 hours (range 3.1 - 46.5) with a median thrombolysis time of 47.5 hours (range 6.0 - 81.0). The short term ABI and pain scores significantly improved; however, no changes were observed before or after thrombolysis in the microcirculation. Overall mortality and amputation rates were both 2% within one year. The one year patency rate was 55%. Treatment of patients with acute peripheral arterial occlusions with contrast enhanced sonothrombolysis is feasible and safe to perform in patients. Further research is necessary to investigate the superiority of this new treatment over standard treatment.

Contrast-enhanced Sonothrombolysis to Accelerate Treatment of Acute Peripheral Arterial Occlusions: The Preliminary Results of the Must Trial (A Feasibility and Safety Phase-II Trial)

Introduction: Catheter-directed thrombolysis is a well-established less-invasive alternative to surgical thrombo-embolectomy. However, the risk of hemorrhagic events in patients with an acute peripheral arterial occlusion remains high with up to 10% of patients experiencing bleeding complications, 2% of which are intracranial hemorrhages. The addition of microbubbles and ultrasound (i.e. contrast enhanced sonothrombolysis) could make the thrombus more susceptible for thrombolysis. We are the first to investigate the safety and technical feasibility of this therapy in patients with an acute peripheral arterial occlusion. Methods: The MUST (Microbubble-accelerated sonothrombolysis) trial is a single-centre phase-II trial focusing on patients with acute peripheral arterial occlusions. In this study, 20 patients will receive intravenous infusion of microbubbles and ultrasound in the first hour of the thrombolytic therapy. Primary endpoints are mortality and other serious adverse events. Secondary endpoints are technical, angiographic and clinical success, conversion, additional interventions, treatment duration and complications. During hospitalization, treatment efficacy will be monitored by daily angiography, duplex examination every six hours, ankle-branchial index, microcirculation and pain scores. Results: Currently, we have included 7 out of 20 patients. No mortality or serious adverse events related to the experimental treatment occurred. In 6 patients, thrombolysis was successful and revascularisation was established after 52.3 hours (range 8.0-81.0). The total therapy duration was on average 70.8 hours (range 49.5-99.5). Additional endovascular interventions included three percutaneous transluminal angioplasties and one thrombosuction. In one patient, open surgical treatment was required after 24 hours of unsuccessful thrombolysis due to no inflow in an occluded iliaco-crucal prosthetic bypass proximal of the treated lesion. Conclusion: Preliminary results show promising study outcomes without major complications. We report no mortality or treatment-related serious adverse events. Further inclusions are necessary to evaluate the safety and feasibility of contrast-enhanced sonothrombolysis for patients with acute peripheral arterial occlusions. Successive studies would help to determine the success of this treatment and its applicability in clinical practice worldwide.

Cardiovascular Sonothrombolysis.

This review will provide recent pre-clinical and initial clinical trials exploring the efficacy of sonothrombolysis as an adjunct to current emergent therapies in acute coronary syndromes. The initial clinical trials examining the efficacy of short pulse duration diagnostic ultrasound (DUS) high mechanical index impulses in patients with ST segment elevation myocardial infarction (STEMI) have demonstrated that there is improved patency of the infarct vessel, and improved microvascular flow following percutaneous coronary intervention. Subsequent randomized prospective trials have confirmed that in patients with acute STEMI receiving an intravenous microbubble infusion, diagnostic high mechanical index impulses applied in the apical windows pre- and post-percutaneous coronary intervention have reduced myocardial infarction size, as assessed by magnetic resonance imaging at 72h following presentation, and have been associated with better left ventricular systolic function at 6month follow-up. Sonothrombolysis has potential for improving early epicardial coronary artery patency and reduce left ventricular remodeling when added to current interventional strategies in STEMI.

Sonothrombolysis in ST-Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention

BackgroundPreclinical studies have demonstrated that high mechanical index (MI) impulses from a diagnostic ultrasound transducer during an intravenous microbubble infusion (sonothrombolysis) can restore epicardial and microvascular flow in acute ST-segment elevation myocardial infarction (STEMI). ObjectivesThis study tested the clinical effectiveness of sonothrombolysis in patients with STEMI. MethodsPatients with their first STEMI were prospectively randomized to either diagnostic ultrasound–guided high MI impulses during an intravenous Definity (Lantheus Medical Imaging, North Billerica, Massachusetts) infusion before, and following, emergent percutaneous coronary intervention (PCI), or to a control group that received PCI only (n = 50 in each group). A reference first STEMI group (n = 203) who arrived outside the randomization window was also analyzed. Angiographic recanalization before PCI, ST-segment resolution, infarct size by magnetic resonance imaging, and systolic function (LVEF) at 6 months were compared. ResultsST-segment resolution occurred in 16 (32%) high MI PCI versus 2 (4%) PCI-only patients before PCI, and angiographic recanalization was 48% in high MI/PCI versus 20% in PCI only and 21% in the reference group (p < 0.001). Infarct size was reduced (29 ± 22 g high MI/PCI vs. 40 ± 20 g PCI only; p = 0.026). LVEF was not different between groups before treatment (44 ± 11% vs. 43 ± 10%), but increased immediately after PCI in the high MI/PCI group (p = 0.03), and remained higher at 6 months (p = 0.015). Need for implantable defibrillator (LVEF ≤30%) was reduced in the high MI/PCI group (5% vs. 18% PCI only; p = 0.045). ConclusionsSonothrombolysis added to PCI improves recanalization rates and reduces infarct size, resulting in sustained improvements in systolic function after STEMI. (Therapeutic Use of Ultrasound in Acute Coronary Artery Disease; NCT02410330).

The Thrombolytic Effect of Diagnostic Ultrasound-Induced Microbubble Cavitation in Acute Carotid Thromboembolism.

Acute ischemic stroke is often due to thromboembolism forming over ruptured atherosclerotic plaque in the carotid artery (CA). The presence of intraluminal CA thrombus is associated with a high risk of thromboembolic cerebral ischemic events. The cavitation induced by diagnostic ultrasound high mechanical index (MI) impulses applied locally during a commercially available intravenous microbubble infusion has dissolved intravascular thrombi, especially when using longer pulse durations. The beneficial effects of this in acute carotid thromboembolism is not known. An oversized balloon injury was created in the distal extracranial common CA of 38 porcine carotid arteries. After this, a 70% to 80% stenosis was created in the mid common CA proximal to the injury site using partial balloon inflation. Acute thrombotic CA occlusions were created just distal to the balloon catheter by injecting fresh autologous arterial thrombi. After angiographic documentation of occlusion, the common carotid thrombosis was treated with either diagnostic low MI imaging alone (0.2 MI; Philips S5-1) applied through a tissue mimicking phantom (TMP) or intermittent diagnostic high MI stable cavitation (SC)-inducing impulses with a longer pulse duration (0.8 MI; 20 microseconds' pulse duration) or inertial cavitation (IC) impulses (1.2 MI; 20 microseconds' pulse duration). All treatment times were for 30 minutes. Intravenous ultrasound contrast (2% Definity; Lantheus Medical) was infused during the treatment period. Angiographic recanalization in 4 intracranial and extracranial vessels downstream from the CA occlusion (auricular, ascending pharyngeal, buccinator, and maxillary) was assessed with both magnetic resonance 3-dimensional time-of-flight and phase contrast angiography. All magnetic resonance images were interpreted by an independent neuroradiologist using the thrombolysis in cerebral infarction (TICI) scoring system. By phase contrast angiography, at least mild recanalization (TICI 2a or higher) was seen in 64% of downstream vessels treated with SC impulses compared with 33% of IC treated and 29% of low MI alone treated downstream vessels (P = 0.001), whereas moderate or complete recanalization (TICI 2b or higher) was seen in 39% of SC treated vessels compared with 10% IC treated and 21% of low MI alone treated vessels (P = 0.001). High MI 20-microsecond pulse duration impulses during a commercial microbubble infusion can be used to recanalize acutely thrombosed carotid arteries and restore downstream flow without anticoagulants. However, this effect is only seen with SC-inducing impulses and not at higher mechanical indices, when a paradoxical reversal of the thrombolytic effect is observed. Diagnostic ultrasound-induced SC can be a nonsurgical method of dissolving CA thrombi and preventing thromboembolization.

Diagnostic Ultrasound Impulses Improve Microvascular Flow in Patients With STEMI Receiving Intravenous Microbubbles

BackgroundPre-clinical trials have demonstrated that, during intravenous microbubble infusion, high mechanical index (HMI) impulses from a diagnostic ultrasound (DUS) transducer might restore epicardial and microvascular flow in acute ST-segment elevation myocardial infarction (STEMI). ObjectivesThe purpose of this study was to test the safety and efficacy of this adjunctive approach in humans. MethodsFrom May 2014 through September 2015, patients arriving with their first STEMI were randomized to either DUS intermittent HMI impulses (n = 20) just prior to emergent percutaneous coronary intervention (PCI) and for an additional 30 min post-PCI (HMI + PCI), or low mechanical index (LMI) imaging only (n = 10) for perfusion assessments before and after PCI (LMI + PCI). All studies were conducted during an intravenous perflutren lipid microsphere infusion. A control reference group (n = 70) arrived outside of the time window of ultrasound availability and received emergent PCI alone (PCI only). Initial epicardial recanalization rates prior to emergent PCI and improvements in microvascular flow were compared between ultrasound-treated groups. ResultsMedian door-to-dilation times were 82 ± 26 min in the LMI + PCI group, 72 ± 15 min in the HMI + PCI group, and 103 ± 42 min in the PCI-only group (p = NS). Angiographic recanalization prior to PCI was seen in 12 of 20 HMI + PCI patients (60%) compared with 10% of LMI + PCI and 23% of PCI-only patients (p = 0.002). There were no differences in microvascular obstructed segments prior to treatment, but there were significantly smaller proportions of obstructed segments in the HMI + PCI group at 1 month (p = 0.001) and significant improvements in left ventricular ejection fraction (p < 0.005). ConclusionsHMI impulses from a diagnostic transducer, combined with a commercial microbubble infusion, can prevent microvascular obstruction and improve functional outcome when added to the contemporary PCI management of acute STEMI. (Therapeutic Use of Ultrasound in Acute Coronary Artery Disease; NCT02410330)

Diagnostic Ultrasound High Mechanical Index Impulses Restore Microvascular Flow in Peripheral Arterial Thromboembolism

We sought to explore mechanistically how intermittent high-mechanical-index (MI) diagnostic ultrasound impulses restore microvascular flow. Thrombotic microvascular obstruction was created in the rat hindlimb muscle of 36 rats. A diagnostic transducer confirmed occlusion with low-MI imaging during an intravenous microbubble infusion. This same transducer was used to intermittently apply ultrasound with an MI that produced stable or inertial cavitation (IC) for 10 min through a tissue-mimicking phantom. A nitric oxide inhibitor, L-Nω-nitroarginine methyl ester (L-NAME), was pre-administered to six rats. Plateau microvascular contrast intensity quantified skeletal microvascular blood volume, and postmortem staining was used to detect perivascular hemorrhage. Intermittent IC impulses produced the greatest recovery of microvascular blood volume (p < 0.0001, analysis of variance). Nitric oxide inhibition did not affect the skeletal microvascular blood volume improvement, but did result in more perivascular hemorrhage. IC inducing pulses from a diagnostic transducer can reverse microvascular obstruction after acute arterial thromboembolism. Nitric oxide may prevent unwanted bio-effects of these IC pulses.

Utilization of modified diagnostic ultrasound and microbubbles to reduce myocardial infarct size

ObjectiveWe sought to determine whether guided high mechanical index (MI) impulses from a diagnostic ultrasound transducer during an intravenous microbubble infusion could augment low-dose fibrinolytic therapy in treating acute myocardial...

Quantification of dynamic changes to blood volume and vascular flow in the primate corpus luteum during the menstrual cycle.

The objective of the current study was to determine changes to vascular parameters of nonhuman primate dominant ovarian structures by dynamic contrast-enhanced ultrasound (DCE-US). Dynamic contrast-enhanced ultrasound with intravenous microbubble infusion was performed on the rhesus macaque ovary bearing the pre-ovulatory follicle and corpus luteum (CL) sequentially during the natural luteal phase (n = 8) and GnRH antagonist (antide)-induced luteal regression (n = 6). Changes in luteal blood volume (BV) and vascular flow (VF) were observed between stages of the luteal phase Luteal BV was highest in early stage CL, before decreasing 2.5-fold in late stage CL (P < 0.06); in contrast, luteal VF peaked at mid luteal stage (P < 0.01). Two females identified with luteal insufficiency trended toward lower peak BV, compared to typical CLs. Another female was identified with a luteal cyst on the contralateral ovary, and a CL that regressed before P levels declined. After 72 hours of antide exposure, BV was reduced 2.3-fold (P = 0.03). DCE-US provides a sensitive, non-invasive measurement of the dynamics of blood volume and flow in dominant ovarian structures.

Therapeutic application of contrast-enhanced ultrasound and low-dose urokinase for thrombolysis in a porcine model of acute peripheral arterial occlusion

The addition of local ultrasound (US) with a contrast agent to standard intra-arterial thrombolysis can accelerate the thrombolytic treatment of stroke and myocardial infarction. The contrast agent consists of microsized gas-filled bubbles that collapse when exposed to US, causing destabilization of the clot and making the clot surface more susceptible to fibrinolytics. In this study, we investigated the effect of additional US and microbubbles on standard low-dose intra-arterial thrombolysis in a porcine model of extensive peripheral arterial occlusion. Extensive arterial thrombosis was induced in 10 pigs in the 4-cm external iliac artery by clamping and injection of 100 IU of bovine thrombin. A transcutaneous laser Doppler flow probe and an ultrasonic perivascular flow probe assessed microcirculation and arterial flow respectively. The urokinase-only (UK) group (n = 4) received standard thrombolytic therapy: intra-arterial bolus injection of 500,000 IU, followed by a continuous low-dose urokinase (50,000 IU/h) infusion through an intra-arterial catheter and local intermittent application of US, 1 second on, 5 seconds off, to visualize vascular patency during the first hour of therapy and to ensure microbubbles replenished the proximal portion of the occluded artery. The urokinase plus microbubbles (UK+) group (n = 6) received the same urokinase therapy with a concomitant intravenous infusion of microbubbles and local intermittent application of US. The contrast infusion protocol consisted of a bolus of two vials of 5 mL in the first 15 minutes and then three times 5 mL slowly hand-injected continuously during the next 45 min. After 3 hours of therapy, the animals were euthanized, and thrombi were harvested and weighed. All organs were cut in thin slices and macroscopically inspected for potential (hemorrhagic) adverse events, and tissue samples were taken. Median thrombus weights were 1.1 g (range, 0.8-1.3 g) in the UK+ group vs 1.6 g (range, 1.3-1.9 g) in the UK group (P = .01). Arterial blood flow increased in four of six pigs in the UK+ group by a mean 61% vs in one of four in the UK group, with 1%. Microcirculation and lower limb arterial pressure levels improved after the start of therapy in the UK+ group, contrary to a trend of decline in the UK group. No signs of bleeding complications were observed in either group. In this experimental pilot study, the addition of contrast-enhanced US accelerated the thrombolytic effect of low-dose intra-arterial thrombolysis in peripheral arterial occlusions. Further clinical studies are warranted.

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.

Destruction of Walker-256 tumor vasculature by a novel ultrasound cavitation technique

To explore the feasibility of disrupting tumor microcirculation by the cavitation of microbubbles enhanced ultrasound (US) and analyze its pathological mechanism. Twenty-four SD male rats with subcutaneously transplanted Walker-256 tumor were divided into 3 groups, i.e. ultrasound plus microbubbles group (US + MB), US group and sham group. Pulsed US was delivered to tumor for 3 minutes during an intravenous infusion of microbubbles at 0.2 ml/kg in the US + MB group. The control groups received only the US exposure or the MB injection. Tumor perfusion was visualized with contrast enhanced ultrasound before and 0 min after treatment. Finally the pathological examination was performed. The contrast perfusion of Walker-256 tumors vanished immediately after treatment in the US + MB group and the gray scale value (GSV) decreased from 121 ± 12 (pre-treatment) to 81 ± 9 (post-treatment, P < 0.01). There was no significant difference of GSV before and after treatment in two control groups (P > 0.05). The GSV values were 112 ± 14 and 111 ± 12 pre-treatment and 113 ± 14 and 103 ± 13 post-treatment in the sham and US groups. The pathological examination showed remarkable hemorrhage, endothelial injuries, increased intercellular edema and in situ thrombosis. Microbubble-enhanced ultrasound can significantly disrupt tumor vasculature and block its circulation. And it may become a novel physical anti-angiogenetic therapy for tumor.

Sonothrombolysis of Intra-Catheter Aged Venous Thrombi Using Microbubble Enhancement and Guided Three-Dimensional Ultrasound Pulses

Central venous and arterial catheters are a major source of thromboembolic disease in children. The investigators hypothesized that guided high-mechanical index (MI) impulses from diagnostic three-dimensional (3D) ultrasound during an intravenous microbubble infusion could dissolve these thrombi. An in vitro system simulating intracatheter thrombi was created and then treated with guided high-MI impulses from 3D ultrasound, using low-MI microbubble sensitive imaging pulse sequence schemes to detect the microbubbles. Ten aged thrombi >24 hours old were tested using 3D ultrasound coupled with a continuous diluted microbubble infusion (group A) and 10 with 3D ultrasound alone (group B). The mean thrombus age was 28.6 hours (range, 26.6-30.3 hours). Group A exhibited a 55 +/- 19% reduction in venous thrombus size compared with 31 +/- 10% in group B (P = .008). Feasibility testing was performed in four pigs, establishing an in vivo model to investigate further the efficacy of this approach. Sonothrombolysis of aged intracatheter venous thrombi can be achieved with commercially available microbubbles and guided high-MI ultrasound from a diagnostic 3D transducer.

_2 tumor by ultrasound mediated microbubble disruption

：Objective To investigatethe feasibility of VX_2 tumor growth inhibition by using ultrasound mediated microbubbledisruption.Methods Twenty-one New Zealand white rabbits bearing subcutaneous VX_2tumorwere randomly divided into 3 groups for the impact factors including microbubbles(MB)andultrasound(US).Pulsed focused ultrasound was delivered directly to the tumor surface forten minutes following intravenous infusion of microbubbles in theexperimental(US+MB)group.The two control groups were applied with only saline injectionand sham US exposure.The procedure was repeated every 72 hours until the 30th day.Contrastand grey scale ultrasonography were acquired after every treatment to get the tumorperfusion and measurement.Results The diameters were sized every 72h in a course of 30days.The average maxium diameter of the US+MB,US,and SHAM groups increased from(1.1±0.1)cm,(1.2±0.1)cm,(1.2±0.1)cmto(2.1±0.5)cm,(3.0±0.9)cm,(3.4±0.7)cm,respectively.The maximal diameter of the US+MBgroup was significantly smaller than those of the two control groups.Conclusions The VX_2tumor growth can be inhibited by ultrasound mediated microbubbte disruption effects.

Contrast-enhanced Harmonic Compound US of the Spleen to Increase Staging Accuracy in Patients with Hodgkin Lymphoma: A Prospective Study

To prospectively compare contrast material-enhanced harmonic compound ultrasonography (US), computed tomography (CT), and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in detecting nodular infiltration in the spleen of patients with newly diagnosed Hodgkin lymphoma. After institutional review board approval and informed consent, 100 consecutive patients with Hodgkin lymphoma during pretreatment staging were prospectively investigated for possible spleen involvement by comparing harmonic compound US (integrated with intravenous infusion of microbubbles in 33 patients) with CT and FDG PET. Findings indicative of malignant nodules with the imaging procedures were regarded as lymphoma infiltration; in case of discrepancy, response to treatment was regarded as evidence of lymphoma. Malignant nodules were detected with CT in 13 patients, with FDG PET in 13 patients, and with contrast-enhanced harmonic compound US in 30 patients. Coincidental findings of malignancy with all three imaging techniques occurred in 13 patients; 17 patients had only US-detectable malignant nodules, which showed disappearance or relevant decrease after chemotherapy. Overall, the spleen had nodular infiltration in 30 patients (13 for imaging finding concordance; 17 for typical contrast-enhanced harmonic compound US findings and chemotherapy-related nodule size modifications). Thus, both CT and FDG PET provided false-negative results in 17 of 30 patients compared with contrast-enhanced harmonic compound US, the results of which translated into disease upstaging in 13 patients. Harmonic compound US with contrast enhancement for the characterization of possible nodules provides a higher sensitivity than does CT or FDG PET in the detection of splenic involvement by Hodgkin lymphoma.

Quantitative assessment of coronary stenosis by harmonic power Doppler with a simple pulsing sequence and vasodilator stress in patients

ObjectivesWe examined whether myocardial contrast echocardiography (MCE) with harmonic power Doppler (HPD) employing a simple ultrasound pulsing sequence enables estimation of the severity of coronary artery stenosis in patients. BackgroundContrast intensity (CI) during MCE with intravenous microbubble infusion is dependent on the myocardial blood flow velocity (MBFV) and pulsing interval (PI). MethodsBased on an in vitro experiment, we devised the MBFV index calculated as the reciprocal of the magnitude of CI decay produced by abrupt PI shortening during intermittent imaging. In 68 coronary artery territories from 49 patients, myocardial HPD images were acquired during intravenous infusion of Levovist, while the long PI with 1:10 electrocardiographic gating was shortened to 1:1, both at baseline and during adenosine triphosphate infusion. The MBFV index in each coronary territory and MBFV reserve as the ratio between hyperemia and baseline were compared with the severity of corresponding coronary artery stenosis assessed by quantitative coronary angiography (QCA) or by pressure guide wire as the fractional flow reserve (FFR). ResultsBoth the MCE-derived MBFV index during hyperemia and MBFV reserve exhibited significant negative correlations with the QCA-derived stenosis severity (r = −0.56 and r = −0.64, respectively). The MBFV reserve positively correlated with FFR (r = 0.89). By combining the cutoff values of the MBFV index during hyperemia and MBFV reserve, ≥75% of stenoses defined by QCA were determined, with a sensitivity of 77.3%, specificity of 93.4%, and accuracy of 88.3%. ConclusionsShortening of PI during intravenous MCE with intermittent HPD imaging under vasodilator stress enables assessment of coronary artery stenoses in patients.

Myocardial blood flow measurements in rats with simple pulsing contrast echocardiography

Relationship between contrast intensity and ultrasound (US) pulsing interval has been utilized to quantify myocardial blood flow (MBF) during myocardial contrast echocardiography (MCE). We tested if an MCE method employing a simple pulsing sequence during intravenous contrast infusion has the ability to quantify MBF in rats. We performed MCE in 17 rats using a 5- to 12-MHz broadband transducer during microbubble infusion via the femoral vein. Acoustic density (AD) from the anterior wall of the left ventricle imaged in the short axis plane was plotted against the frame number after shortening the pulsing interval (PI) from 1:20 to 1:1 end-systolic ECG gating. The relation between AD and frame number was fitted to a decay function. The rate of the AD decay was decreased during dipyridamole infusion, but was increased by causing coronary stenosis. The AD during long PI imaging remained unchanged during the interventions. Estimated MBF by MCE after correction by heart rate exhibited a close correlation (r = 0.83) with the present “gold standard” of colored microsphere-derived MBF. Thus, the decay rate of the contrast intensity obtained with the high-frequency transducer after abrupt shortening of PI during intravenous microbubble infusion may provide for noninvasive measurement of MBF in rats. (E-mail: komori@kms.ac.jp)

Noninvasive in vivo clot dissolution without a thrombolytic drug: recanalization of thrombosed iliofemoral arteries by transcutaneous ultrasound combined with intravenous infusion of microbubbles.

Previous in vivo studies have shown that microbubbles not only enhance the effectiveness of thrombolytic agents in the presence of ultrasound but may also augment clot dissolution without thrombolytic drugs. The objective of this study was to examine the efficacy of arterial clot disruption by a noninvasive, nonlytic approach with intravenous administration of perfluorocarbon-exposed sonicated dextrose albumin (PESDA) and transcutaneous delivery of ultrasound alone. Pairs of iliofemoral arteries in 10 rabbits were randomized to receive transcutaneous ultrasound treatment or no ultrasound treatment after an acute artery thrombotic occlusion and intravenous PESDA infusion. Five arteries from 3 additional rabbits served as controls (ultrasound alone). All 10 iliofemoral arteries treated with PESDA + ultrasound were recanalized by angiography after ultrasound treatment. None of the 10 contralateral arteries treated with PESDA alone and none of the 5 arteries treated with ultrasound alone were patent after 1 hour. D-Dimer levels did not change after intravenous PESDA + ultrasound-mediated reperfusion. In vivo arterial clot dissolution can be achieved with intravenous microbubbles and transcutaneous ultrasound delivery alone. This technique has potential for clinical application in patients with acute arterial and venous thrombotic occlusions.