Ultrasound-enhanced Thrombolysis Research Articles

Sonothrombolysis in Patients With Acute Ischemic Stroke With Large Vessel Occlusion: An Individual Patient Data Meta-Analysis

Evidence about the utility of ultrasound-enhanced thrombolysis (sonothrombolysis) in patients with acute ischemic stroke (AIS) is conflicting. We aimed to evaluate the safety and efficacy of sonothrombolysis in patients with AIS with large vessel occlusion, by analyzing individual patient data of available randomized-controlled clinical trials. We included all available randomized-controlled clinical trials comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in patients with AIS with large vessel occlusion. The primary outcome measure was the rate of complete recanalization at 1 to 36 hours following intravenous thrombolysis initiation. We present crude odds ratios (ORs) and ORs adjusted for the predefined variables of age, sex, baseline stroke severity, systolic blood pressure, and onset-to-treatment time. We included 7 randomized controlled clinical trials that enrolled 1102 patients with AIS. A total of 138 and 134 confirmed large vessel occlusion patients were randomized to treatment and control groups respectively. Patients randomized to sonothrombolysis had increased odds of complete recanalization compared with patients receiving intravenous thrombolysis alone (40.3% versus 22.4%; OR, 2.17 [95% CI, 1.03-4.54]; adjusted OR, 2.33 [95% CI, 1.02-5.34]). The likelihood of symptomatic intracranial hemorrhage was not significantly different between the 2 groups (7.3% versus 3.7%; OR, 2.03 [95% CI, 0.68-6.11]; adjusted OR, 2.55 [95% CI, 0.76-8.52]). No differences in the likelihood of asymptomatic intracranial hemorrhage, 3-month favorable functional and 3-month functional independence were documented. Sonothrombolysis was associated with a nearly 2-fold increase in the odds of complete recanalization compared with intravenous thrombolysis alone in patients with AIS with large vessel occlusions. Further study of the safety and efficacy of sonothrombolysis is warranted.

Efficacy Estimation of Microbubble-Assisted Local Sonothrombolysis Using a Catheter with a Series of Miniature Transducers.

Intravascular ultrasound has good prospects for clinical applications in sonothrombolysis. The catheter-based side-looking intravascular ultrasound thrombolysis (e.g., Ekosonic catheters) used in clinical studies has a high frequency (2 MHz). The lower-frequency ultrasound requires a larger-diameter transducer. In our study, we designed and manufactured a small ultrasound-based prototype catheter that can emit a lower frequency ultrasound (1.1 MHz). In order to evaluate the safety and efficacy of local low-frequency ultrasound-enhanced thrombolysis, a microbubble (MB) was introduced to augment thrombolysis effect of locally delivered low-intensity ultrasound. The results demonstrated that combination of ultrasound and MB realized higher clot lysis than urokinase-only treatment (17.0% ± 1.2% vs. 14.9% ± 2.7%) under optimal ultrasound settings of 1.1 MHz, 0.414 MPa, 4.89 W/cm2, 5% duty cycle and MB concentration of 60 μg/mL. When urokinase was added, the fibrinolysis accelerated by MB and ultrasound resulted in a further increased thrombolysis rate that was more than two times than that of urokinase alone (36.7% ± 5.5% vs. 14.9% ± 2.7%). However, a great quantity of ultrasound energy was required to achieve substantial clot lysis without MB, leading to the situation that temperature accumulated inside the clot became harmful. We suggest that MB-assisted local sonothrombolysis be considered as adjuvant therapy of thrombolytic agents.

Design of Intravascular Ultrasound-enhanced Thrombolysis Excitation System Based on FPGA

An intravascular ultrasound-enhanced thrombolysis excitation system with adjustable frequency, amplitude and duty cycle was designed based on FPGA (ZYNQ-7Z020). Firstly, the FPGA generated waveform amplitude binary data based on direct digital frequency synthesis (DDS) technology, and then the data was converted into burst signal through an external daughter card, which included D/A conversion circuit, active low-pass filter, power amplifier circuit and impedance matching circuit. The test results demonstrated that the output waveform reached the target with advantages of simple implementation and flexible control, the peak negative pressure generated from ultrasound transducer was doubled by means of an electrical impedance matching network. In vitro thrombus models were applied to verify the excitation system, it turned out that ultrasound cavitation effect generated could accelerate the penetration of urokinase and increase the thrombolysis rate by about 20%.

Abstract 106: Safety and Efficacy of Sonothrombolysis in Acute Ischemic Stroke Patients With Large Vessel Occlusion: International Collaborative Individual Patient Data Meta-Analysis

Introduction: Conflicting evidence has been published regarding the safety and efficacy of ultrasound-enhanced thrombolysis (sonothrombolysis) in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO). Methods: We conducted an individual participant data meta-analysis of available randomized controlled trials (RCTs) comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in AIS patients with LVO. Results: We included 6 in total RCTs that enrolled 1077 AIS patients. A total of 138 and 134 confirmed LVO patients were randomized to treatment and control groups respectively (median age 68 years, 58% men, median baseline NIHSS score 16). Patients randomized to sonothrombolysis had increased odds of complete recanalization compared to patients receiving intravenous thrombolysis alone (40.3% vs. 22.4%; OR=2.30, 95%CI: 1.05-5.02; adjusted OR=2.33, 95%CI: 1.02-5.34). They also tended to have increased odds of any (complete or partial recanalization (66.4% vs. 53.0%; OR=1.78, 95%CI: 0.95-3.33; adjusted OR=1.85, 95%CI: 0.97-3.53). The likelihood of symptomatic intracranial hemorrhage did not differ between the two groups (7.3% vs. 3.7%, OR=2.52, 95%CI: 0.77-8.29; adjusted OR=2.55, 95%CI: 0.76-8.52). No differences in the likelihood of asymptomatic intracranial hemorrhage (adjusted OR: 1.30, 95%CI: 0.38-4.39), three-month mortality (adjusted OR: 1.23, 95%CI: 0.25-6.05), three-month favorable functional outcome (mRS-scores of 0-1; adjusted OR: 1.43, 95%CI: 0.64-3.19) and three-month functional independence (mRS-scores of 0-2; adjusted OR: 1.43, 95%CI: 0.77-2.64) were documented. Conclusion: Sonothrombolysis was associated with a two-fold increase in the odds of complete recanalization compared to intravenous thrombolysis alone in AIS patients with LVOs. Further study of the safety and efficacy of sonothrombolysis is warranted.

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke.

Background:Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers.Methods:We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials.Results:From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04).Conclusion:Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.

Dual frequency ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro human clot model

Introduction: Stroke causes death and disability in patients throughout the world. At present, the only FDA- approved drug for ischemic stroke is recombinant tissue plasminogen activator (rt- PA). Unfortunately, rtPA can cause intracerebral hemorrhage and must use within limited time window (within 3-4.5 hour after onset of stroke). Ultrasound with rtPA loaded liposomes (rtPA_L) was suggested as adjuvant therapy that reduce the dose of rt-PA and increase its efficiency. Different frequency protocols such as kHz and MHz were used for sonothrombolysis. In this study, we suggested a protocol including both kHz and MHz with rtPA_L The kHz wave could fragment rtPA_Ls and release rtPA, the MHz enhances lytic efficiency of released rt-PA by stable cavitation and its microstreaming. This protocol may reduce bioeffect of ultrasound wave and simultaneously at least maintain rt-PA lytic effect. Materials and Methods: The rt-PA loaded liposomes were prepared by hydrating lipid film with rt-PA and freezing liposomes under air pressure (4 atm). Cylindrical human whole blood clots (1 mm diameter) formed in and around micropipette at 37 ˚C. In combination with rtPA_L ([rtPA]=50 μg/ml) and human plasma, three protocol were used: 1 MHz (1.5 W/cm2_ 30 minutes), 130 kHz ( 0.01 W/cm2_10 s) + 1 MHz (0.5 W/cm2_ 30 minutes) and control. Clots were imaged under microscope and clot lysis were quantified by measuring clot diameters before and after sonication. Results: Statistical analysis of clot diameter varation between two sonication groups (1 MHz (1.5 W/cm2_ 30 minutes), 130 kHz ( 0.01 W/cm2_10 s) + 1 MHz (0.5 W/cm2_ 30 minutes)) do not show significant difference. Conclusion: Not significant difference between two sonication groups indicates that the dual frequency protocol by using less energy and consequently lower bioeffects may have similar effect as single frequency protocol.

394. Thrombolysis for intermediate risk pulmonary embolism in pregnancy

Introduction Pulmonary embolism (PE) in pregnancy is a leading cause of maternal death. Due to inherent haemorrhage risk, thrombolysis is reserved as a lifesaving intervention for massive PE. There is current controversy about using thrombolysis in those with intermediate risk (submassive) PE. We present two cases of intermediate risk PE who failed to respond to IV unfractionated heparin (UFH). Case 1 A 34-year-old para 2 without risk factors for venous thromboembolism (VTE), presented at 22 weeks gestation with hypoxia and breathlessness that confined her to bed for over a week. She had multiple bilateral PEs, right ventricular strain on echocardiogram and elevated troponin and BNP. She did not improve with 24hrs IV UFH and so was treated with systemic thrombolysis according to the MOPPETT regime and then converted to low molecular weight heparin (LMWH). She had an uncomplicated vaginal delivery at 36 weeks with no haemorrhage. Case 2 A 28-year-old para 1, low risk for VTE, presented at 31 weeks with dyspnoea worsening over two weeks. She had bilateral main pulmonary artery PEs, echocardiographic right-sided heart strain and increased levels of troponin and BNP. She was admitted for IV UFH, but within 24 h suffered an acute hypotensive episode. She was not delivered; instead she was treated with ultrasound-enhanced catheter-directed thrombolysis (EKOS, BTG Int’l) via catheters placed in the right and left pulmonary arteries. A total dose of 22 mg alteplase was administered over 24hrs. Fibrinogen was monitored and supplemented if Discussion These cases illustrate that thrombolysis for poorly responding intermediate risk and massive PE need not be withheld in pregnancy, delivery need not be expedited, and pregnancy can continue successfully after treatment.

Catheter-directed thrombolysis of deep vein thrombosis: literature review and practice considerations.

Deep vein thrombosis (DVT) is a major health problem worldwide. The risk of pulmonary embolism following DVT is well established, but the long-term vascular sequelae of DVT are often underappreciated, costly to manage, and can have extremely detrimental effects on quality of life. Treatment of DVT classically involves oral anticoagulation, which reduces the risk of pulmonary embolism but does not remove the clot. Anticoagulation therefore does little to prevent the venous damage and scarring that occurs following DVT, leaving the patient at risk for permanent venous insufficiency and development of post-thrombotic syndrome (PTS). Catheter-directed thrombolysis (CDT) is a minimally invasive endovascular treatment that is used as an adjunct to anticoagulation. CDT lowers the risk of PTS by reducing clot burden and protecting against valvular damage. A catheter is advanced directly to the site of thrombosis under fluoroscopy followed by a slow, prolonged infusion of a relatively low dose of thrombolytic agent. CDT restores venous patency faster than anticoagulation, which hastens the relief of acute symptoms. Adjunctive CDT modalities have become increasingly popular among interventional radiologists, allowing for additional mechanical thrombectomy or ultrasound-enhanced thrombolysis at the time of catheter placement. These pharmacomechanical CDT (PCDT) techniques have the potential to reduce treatment time and associated healthcare costs. Numerous observational and retrospective studies have consistently shown a benefit of CDT plus anticoagulation over anticoagulation alone for prevention of PTS. Patients with long life expectancy and acute thrombosis involving the iliac and proximal femoral veins (iliofemoral DVT) have the greatest benefit from CDT, which may decrease the risk of PTS and/or decrease the severity of PTS symptoms if they do occur. Randomized controlled trials remain limited but generally support the observational data. CDT also plays an important role in those with acute limb-threatening venous occlusion or severe symptoms from DVT. Although adverse outcomes are rare, a potential devastating outcome is intracranial bleeding. While the available literature suggests the risk of serious morbidity from bleeding is quite rare, the absolute risk of bleeding is not clear and will require outcomes data from randomized trials. Future studies should also examine the cost-effectiveness of CDT for PTS prevention, particularly with respect to quality-adjusted life years, and compare the effectiveness of available PCDT devices.

THE RELATIONSHIP BETWEEN TIMING OF RECANALIZATION AND CLINICAL OUTCOME OF ISCHEMIC STROKE DUE TO ACUTE MIDDLE CEREBRAL ARTERY OCCLUSION AFTER ULTRASOUND-ENHANCED THROMBOLYSIS

Purpose: The relationship between arterial recanalization after use of intravenous recombinant tissue plasminogen activator (rtPA) and outcome is still uncertain. The aim of our study was to evaluate the association between the timing and impact of recanalization on functional outcomes in ischemic stroke patients due to acute middle cerebral artery occlusion. Subjects and methods: Nonrandomized 40 stroke patients with proximal middle arterial occlusion on a prebolus TCD receiving intravenously 0.6 mg/kg rtPA within 4.5 hours after stroke onset were monitored with portable diagnostic TCD equipment and a standard headframe. Complete recanalization was defined as thrombolysis in brain ischemia (TIBI) flow grades 4-5. Results: 40 patients (mean age 67±14 years, NIH Stroke Scale [NIHSS] 16.15±8.6 points) were treated at 180±80 minutes from symptom onset. TCD was monitored continously for 120 minutes. Complete recanalization on TCD within 2 hours after bolus was found in 13 patients (32.5%). In this group, NIHSS decreased quickly at 2 hours and 24 hours. Modified Rankins 0-1point was seen in 92.3% of patients with complete recanalization compared to 37.0% of patients with uncomplete recanalization at 90 days. Non-symptomatic intracranial hemorrhage was seen in 1 patient in the group of complete recanalization. Conclusions: Complete recanalization of middle cerebral arteries within 2 hours after IV rtPA treatment plays a role in predicting the good functional and clinical outcomes after ultrasound-enhanced thrombolysis in acute ischemic stroke patients due to acute middle cerebral artery occlusion. Key words: stroke, recombinant tissue plasminogen activator, transcranial Doppler sonography

EFFECT OF CONTINUOUS TRANSCRANIAL DOPPLER ON THROMBOLYSIS IN ISCHEMIC STROKE DUE TO ACUTE MIDDLE CEREBRAL ARTERY OCCLUSION

Purpose: Recombinant tissue plasminogen activator (rtPA) activity may be enhanced with ultrasound, 2 MHz transcranial Doppler (TCD). We performed the trial to determine the efficacy of ultrasound-enhanced thrombolysis compared to the current standard of care (intravenous rtPA). Subjects and methods: We treated 80 patients who had acute ischemic stroke due to occlusion of the middle cerebral artery with intravenous rtPA within 4.5 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 and dramatic clinical recovery at 2 hours. Complete recanalization was defined as thrombolysis in brain ischemia (TIBI) flow grades 4-5. Secondary end points included recovery at 24 hours, a favorable outcome at three months. Results: A total of 80 patients were randomly assigned to receive continuous ultrasonography (40 patients) or placebo (40 patients). Complete recanalization and dramatic clinical recovery within two hours after the administration of a rtPA bolus occurred in 13 patients in the target group (32,5%), as compared with 8 patients in the control group (20%) (P=0.038). At three months, 22 patients in the target group who were eligible for follow-up analysis (55%) and 13 in the control group (32,5%) had favorable outcomes (as indicated by a score of 0 to 1 on the modified Rankin scale) (P=0.012). Intracerebral hemorrhage occurred in five patients in the target group and in four in the control group. Conclusion: In patients with acute ischemic stroke due to occlusion of the middle cerebral artery, continuous transcranial Doppler augments rtPA-induced arterial recanalization, with an increased rate of recovery from stroke, as compared with placebo. Continuous 2-MHz transcranial Doppler ultrasonography for 2 hours is safe. Key words: Stroke, transcranial Doppler, tissue plasminogen activator

Ultrasound-enhanced thrombolysis: Mechanistic observations

Ultrasound and microbubbles have been widely demonstrated to accelerate the breakdown of blood clots, but the mechanisms of treatment require further investigation. In particular, there is a need to clarify the effect on the fibrin matrix—the insoluble polymer mesh that determines a clot’s integrity and mechanical properties. The objective of this in vitro study was to observe in real-time the mechanisms of microbubble-enhanced sonothrombolysis at the microscale. Fluorescently labeled porcine plasma clots were prepared on a glass coverslip and exposed to different types of microbubbles with or without the fibrinolytic agent recombinant tissue plasminogen activator. A 1 mm thick piezoelectric element was coupled with the glass substrate and driven at the resonant frequency of the system (1.9 MHz), with a duty cycle of 5% and a 0.1 Hz pulse repetition frequency. The acoustic field within the clot was characterized using a fiber optic hydrophone. Changes in the fiber network were monitored for 30 min by confocal microscopy.

Shaken and Stirred: Mechanisms of Ultrasound-Enhanced Thrombolysis

The use of ultrasound and microbubbles as an effective adjuvant to thrombolytics has been reported in vitro, ex vivo and in vivo. However, the specific mechanisms underlying ultrasound-enhanced thrombolysis have yet to be elucidated. We present visual observations illustrating two mechanisms of ultrasound-enhanced thrombolysis: acoustic cavitation and radiation force. An in vitro flow model was developed to observe human whole blood clots exposed to human fresh-frozen plasma, recombinant tissue-type plasminogen activator (0, 0.32, 1.58 or 3.15 μg/mL) and the ultrasound contrast agent Definity (2 μL/mL). Intermittent, continuous-wave ultrasound (120 kHz, 0.44 MPa peak-to-peak pressure) was used to insonify the perfusate. Ultraharmonic emissions indicative of stable cavitation were monitored with a passive cavitation detector. The clot was observed with an inverted microscope, and images were recorded with a charge-coupled device camera. The images were post-processed to determine the time-dependent clot diameter and root-mean-square velocity of the clot position. Clot lysis occurred preferentially surrounding large, resonant-sized bubbles undergoing stable oscillations. Ultraharmonic emissions from stable cavitation were found to correlate with the lytic rate. Clots were observed to translate synchronously with the initiation and cessation of the ultrasound exposure. The root-mean-square velocity of the clot correlated with the lytic rate. These data provide visual documentation of stable cavitation activity and radiation force during sub-megahertz sonothrombolysis. The observations of this study suggest that the process of clot lysis is complex, and both stable cavitation and radiation force are mechanistically responsible for this beneficial bio-effect in this in vitro model.

Clot Retraction Affects the Extent of Ultrasound-Enhanced Thrombolysis in an Ex Vivo Porcine Thrombosis Model

We investigated ultrasound-enhanced thrombolysis in two whole-blood clot models using a Food and Drug Administration-approved contrast agent (Definity, Lantheus Medical Imaging; Billerica, MA USA) and thrombolytic drug (recombinant tissue-type plasminogen activator [rt-PA]) (Genentech; South San Francisco, CA USA). Porcine venous blood was collected from donor hogs and coagulated in vials made of two different materials. This method produced clots with differing compositional properties, as determined by routine scanning electron microscopy and histology. Clots were deployed in an ex vivo porcine thrombosis model, and exposed to an intermittent ultrasound scheme previously developed to maximize stable cavitation while acoustic emissions were detected. Exposure to 3.15 μg/mL rt-PA promoted lysis in both clot models, compared with exposure to plasma alone. However, only unretracted clots experienced significant enhancement of thrombolysis in the presence of rt-PA, Definity, and ultrasound, compared with treatment with rt-PA. In these clots, microscopy revealed loose erythrocyte aggregates, a significantly less extensive fibrin network and a higher porosity, which may facilitate increased penetration of thrombolytics by cavitation.

Abstract TP254: Clot Dissolution Is Better With Ultrasound Assisted Thrombolysis For Fresh Clots With Higher Cholesterol Content

Background: Intravenous tissue plasminogen activator (IV-tPA) remains the only drug for arterial recanalization in acute ischemic stroke (AIS). Clot composition differs according to the stroke etiology- clot from heart being fresh and rich in fibrin while the clot from an ulcerated plaque is rich in cholesterol. These characteristics might influence the therapeutic response to tPA as well as ultrasound-enhanced thrombolysis. We evaluated the impact of cholesterol content and age of the clot on its dissolution with tPA and ultrasound in an in-vitro model. Methods: Clot was prepared by mixing horse blood with Calcium-chloride solution. Cholesterin was added to increase cholesterol level up to 100 mg/dL. Periodic serum replacement was used to ‘age’ the clot. The clots were exposed to continuous 2-MHZ diagnostic transcranial Doppler (TCD) ultrasound (acoustic intensity 340mW/cm2) during thromolysis with tPA (355 IU/ml). Efficiency of thrombolysis was calculated as the percentage of clot weight-loss after 60 minutes. Clot characteristics after lysis were evaluated with surface emission microscope (SEM). Results: Significant increase in the weight of clot occurred with its increasing age (from 2 to 10 hours, the clot-weight increased from 37.28±2.87mg to 51.56±5.34mg; p&lt;0.005). Exposure to ultrasound and tPA resulted in significant reduction in the clot-weight at 1 hour (from 35.50±3.23% to 24.71±2.11%; p&lt;0.005). Although, no significant differences were noted between clot-cholesterol levels and lysis with TCD or tPA alone, combination of these modalities induced significant lysis in clots with higher cholesterol levels (clot-weight reduced by 41.68±2.3%) as compared to clots with normal cholesterol (30.60±4.10%; p&lt;0.005). SEM demonstrated thicker and denser fibrin network in aged clots while higher number of activated platelets were noted on the surface of cholesterol-rich clots. Conclusion: Ultrasound-assisted thrombolysis with tPA work better for fresh thrombi with higher cholesterol levels. Our findings provide insights into the differential recanalization rates in acute ischemic stroke of various etiologies

Validation of a finite-difference acoustic propagation model of transcranial ultrasound

Adjuvant ultrasound exposure improves rtPA thrombolysis in stroke patients. Transmission of 120-kHz ultrasound through the temporal bone is efficient but exhibits skull-dependent distortion and reflection. Numerical models of acoustic propagation through human skull based on computed tomography (CT) data have been developed. The objective of our study was to validate a finite-difference model of transcranial ultrasound quantitatively. The acoustic fields from a two-element annular array (120 kHz and 60 kHz) were acquired in four ex-vivo human skulls with a calibrated hydrophone (10 kHz-800 kHz frequency range). The spatial distributions of the acoustomechanical properties of each skull were obtained from CT scans and used for simulations. Predicted acoustic fields and waveform shapes were compared with corresponding hydrophone measurements and were in good agreement. Transmitted wave amplitudes were systematically underestimated (14%) and reflected wave amplitudes were overestimated (30%). The acoustic impedance of each skull was likely underestimated from the CT scans. However, high correlation between predictions and measurements (R&amp;lt;+&amp;gt;2&amp;lt;+&amp;gt;=0.93 and R&amp;lt;+&amp;gt;2&amp;lt;+&amp;gt;=0.88 for transmitted and reflected wave amplitudes, respectively) demonstrates that this model can be used quantitatively for evaluation of 120-kHz ultrasound-enhanced thrombolysis. This work was supported by NIH-RO1-NS047603.

Effect of skull anatomy on intracranial acoustic fields for ultrasound-enhanced thrombolysis

Transcranial ultrasound improves thrombolytic drug efficacy in ischemic stroke therapy. The goal of this study was to determine the ideal ultrasound parameters for obtaining peak rarefactional pressures exceeding the stable cavitation threshold at the left anterior clinoid process (lACP) of the skull. This location is near the origin of the middle cerebral artery, a common site for ischemic stroke. For 0.5, 1.1 and 2.0-MHz ultrasound transducers, pulse repetition frequencies (PRF) ranging from 5.4-8.0 kHz were studied at a 50% duty cycle. Attenuation and ultrasound beam distortion were measured from a cadaveric human skull. Each transducer was placed near the left temporal bone such that the unaberrated maximum acoustic pressure would be located at the lACP. A hydrophone measured the acoustic field around the lACP. Free-field measurements were taken in the same locations to determine attenuation and beam focus distortion. For 5 skulls, the average pressure attenuation at the lACP was 68±19, 91±5.1, and 94±4.7% for 0.5, 1.1, and 2.0 MHz, respectively. The degree of displacement of the beam focus depended on the skull properties, but not the center frequency nor PRF. In conclusion, lower frequencies exhibited lower attenuation and improved penetration at the lACP. This work was supported by NIH-3P50-NS044283-06S1.

Exploratory analysis of estimated acoustic peak rarefaction pressure, recanalization, and outcome in the transcranial ultrasound in clinical sonothrombolysis trial

Acoustic peak rarefaction pressure (APRP) is the main factor that influences ultrasound-enhanced thrombolysis. We sought to determine whether recanalization rate and functional outcomes in the Transcranial Ultrasound in Clinical SONothrombolysis (TUCSON) trial could be predicted by estimated in vivo APRP. We developed an acoustic attenuation model to estimate the in vivo APRP at the arterial occlusion site in each subject of the TUCSON trial with CT scans eligible for measurements. Variables included temporal bone thickness, depth of arterial occlusion site, and average attenuation of skin and brain tissues. Recanalization was defined as partial or complete using the Thrombolysis in Brain Infarction flow grades. Functional independence was assessed at 3 months using the modified Rankin Scale score (mRS, 0-1). APRP was calculated in 20 acute ischemic stroke patients treated with sonothrombolysis (mean age, 64 ± 15 years, 65% men; median NIHSS score, 13; IQR, 6-17). The mean APRP was 30.2 ± 15.5 kPa (range, 8-68 kPa). Patients with persisting occlusion had nonsignificantly lower APRP than patients with partial or complete recanalization (25.2 ± 8.0 versus 32.3 ± 17.7 kPa; p = 0.228). Patients who were functionally independent at 3 months had nonsignificantly higher APRP than patients with worse outcome (35.1 ± 19.5 versus 25.9 ± 11.2 kPa; p = 0.217). Our exploratory analysis suggests a potentially important role of successful energy delivery to augment thrombolysis with 2-MHz ultrasound in acute ischemic stroke patients.

Catheter-Based Reperfusion Treatment of Pulmonary Embolism

Case Presentation: A 76-year-old man with a history of hemicolectomy for colon cancer 10 days previously was admitted because of syncope and severe shortness of breath. On physical examination, the patient was hemodynamically unstable, with a systolic arterial pressure of 80 mm Hg, a heart rate of 124 beats per minute, and distended jugular veins. He was agitated and unable to speak full sentences. His respiratory rate was 28 breaths per minute, and oxygen saturation was 80% on room air. Contrast-enhanced computed tomography showed a filling defect of the left main pulmonary artery, complete occlusion of the left lower lobe pulmonary artery, nonobstructive filling defects of the right lower lobe pulmonary artery, and right ventricular enlargement (right-to-left ventricular dimension ratio of 1.4) (Figure 1). The hemodynamic situation remained unchanged after initiation of treatment with oxygen, intravenous unfractionated heparin, and normal saline. Figure 1. Contrast-enhanced chest computed tomogram from the first case. Left, Complete occlusion of the left lower lobe pulmonary artery (large arrow) and nonobstructive filling defect in the right lower lobe pulmonary artery (small arrow). Right, The subannular right-to-left ventricular dimension ratio was obtained from the reconstructed 4-chamber view.1 Right (47.3 mm) and left (33.9 mm) ventricular dimensions were measured perpendicular to the interventricular septum and 1 cm above the atrioventricular annulus plane. The right-to-left ventricular dimension ratio was calculated as 1.4. Case Presentation: A 55-year-old woman suddenly developed acute shortness of breath 3 weeks after resection of a meningioma. On physical examination, the patient appeared hemodynamically stable, with a systolic arterial pressure of 100 mm Hg, a heart rate of 96 beats per minute, a respiratory rate of 18 breaths per minute, and an oxygen saturation of 89% while receiving 3 L of oxygen via face mask. A contrast-enhanced computed tomography confirmed subtotal filling defects in both main pulmonary …

Safety and Efficacy of Ultrasound-enhanced Thrombolysis in the Treatment of Acute Middle Cerebral Artery Infarction

Despite appropriate therapy with intravenous (IV) tissue plasminogen activator (tPA), a significant proportion of patients with acute middle cerebral artery (MCA) infarction continue to suffer residual disability or death. The therapeutic use of transcranial Doppler ultrasonography (TCD) concomitantly with IV tPA is speculated to increase recanalization rates and improve clinical outcomes in patients with acute MCA stroke. To critically appraise the evidence concerning the safety and efficacy of the simultaneous delivery of IV tPA and continuous TCD monitoring as an acute therapy in patients with MCA territory infarction. The objective was addressed through the development of a structured, critically appraised topic. This incorporated a clinical scenario, background information, a structured question, literature search strategy, results, critical appraisal, clinical bottom line, and expert commentary from vascular neurology. In a multicenter phase II randomized controlled study, 126 patients with acute MCA stroke were randomized to receive treatment with IV tPA and continuous TCD monitoring or placebo monitoring. Complete recanalization or dramatic clinical recovery within 2 hours after the administration of a tPA bolus occurred in 31 patients in the target group (49%), as compared with 19 patients in the control group (30%); P=0.03. At 3 months, of the patients eligible for follow-up, 22 of 53 (42%) in the target group and 14 of 49 (29%) in the control group had favorable outcomes; P=0.20. Four symptomatic intracerebral hemorrhages were noted in each group. Therapeutic use of continuous TCD monitoring concomitantly with IV tPA increases recanalization rates in patients with acute MCA stroke relative to treatment with IV tPA alone without increasing the complication of intracerebral hemorrhage.

Ultrasound-enhanced thrombolysis in porcine clots in a flow system

Ultrasound and ultrasound contrast agent microbubbles (UCAM) are able to mechanically induce clot reduction. The aim of the study was to demonstrate the efficacy of various ultrasound conditions to enhanced thrombolysis in porcine clots inside a flow system. Clots were formed by infusing 4.1 ml of blood in transfer pipets. The pipets contained Dacron grafts to anchor the clot and initiated its formation. A 14-gage needle was placed at the center of the pipet and removed after clot formation to allow flow inside the clot. The clots were treated for 20 min with ultrasound and homemade UCAM at a concentration of 107 microbubbles/ml (flow rate 0.9 ml/min). Thrombolysis was monitored using an ultrasound scanner in pulse inversion mode. Results show that the radiation force causes the microbubbles to be pushed against the inner clot wall and cavitation induced lysis. The portion of the clot closest to the transducer was not affected by the therapy as the microbubbles were pushed in the direction of propagation. Mechanical clot reduction was observed in real-time in a flow system at various acoustic settings.