Ultrasound-enhanced Thrombolysis Research Articles

Ultrasound-Assisted Thrombolysis for Stroke Therapy

Ultrasound has been shown to increase recombinant tissue plasminogen activator thrombolysis through stable cavitation, or sustained bubble activity, but this mechanism needs further optimization. Use of low-frequency ultrasound in combination with microbubbles stabilized against dissolution, in the form of ultrasound contrast agents, has resulted in greater lytic efficacy in vitro. Summary of Review-This article reviews the motivation for developing ultrasound-enhanced thrombolysis and the existing evidence for its potential as an intervention for ischemic stroke. Stable cavitation is discussed and current in vitro and ex vivo studies of bubble-mediated recombinant tissue plasminogen activator clot lysis are summarized. Ultrasound-driven stable cavitation nucleated by an infusion of an echo contrast agent facilitates recombinant tissue plasminogen activator thrombolysis. Optimization of this gently effervescent phenomenon has the potential to reduce the morbidity and mortality of victims of ischemic stroke.

Safety and Efficacy of Ultrasound-Enhanced Thrombolysis

Ultrasound-enhanced thrombolysis is a promising new approach to facilitate reperfusion therapies for acute ischemic stroke. So far, 3 different ultrasound technologies were used to increase the thrombolytic activity of tissue plasminogen activator (tPA), including transcranial Doppler (TCD), transcranial color-coded duplex (TCCD), and low-frequency ultrasound. We performed a meta-analysis to evaluate the safety and efficacy of ultrasound-enhanced thrombolysis compared to the current standard of care (intravenous tPA). Through Medline, Embase, and Cochrane database search, we identified and abstracted all studies of ultrasound-enhanced thrombolysis in acute cerebral ischemia. Principal investigators were contacted if data not available through peer-reviewed publication were needed. Symptomatic intracerebral hemorrhage (sICH) and recanalization rates were compared between tPA, tPA+TCD+/-microspheres (microS), tPA+TCCD+/-microS, and tPA+low-frequency ultrasound. A total of 6 randomized (n=224) and 3 nonrandomized (n=192) studies were identified. The rates of symptomatic intracerebral hemorrhage in randomized studies were as follows: tPA+TCD, 3.8% (95% CI, 0%-11.2%); tPA+TCCD, 11.1% (95% CI, 0%-28.9%); tPA+low-frequency ultrasound, 35.7% (95% CI, 16.2%- 61.4%); and tPA alone, 2.9% (95% CI, 0%-8.4%). Complete recanalization rates were higher in patients receiving combination of TCD with tPA 37.2% (95% CI, 26.5%- 47.9%) compared with patients treated with tPA alone 17.2% (95% CI, 9.5%-24.9%). In 8 trials of high-frequency (TCD/TCCD) ultrasound-enhanced thrombolysis, tPA+TCD/TCCD+/-microS was associated with a higher likelihood of complete recanalization (pooled OR, 2.99; 95% CI, 1.70-5.25; P=0.0001) when compared to tPA alone. High-frequency ultrasound-enhanced thrombolysis was not associated with an increased risk of symptomatic intracerebral hemorrhage (pooled OR, 1.26; 95% CI, 0.44-3.60; P=0.67). The present safety and signal-of-efficacy data of high-frequency ultrasound-enhanced thrombolysis should be taken into account in the design of future randomized controlled trials.

Ultrasound-Triggered Release of Recombinant Tissue-Type Plasminogen Activator from Echogenic Liposomes

Echogenic liposomes (ELIP) were developed as ultrasound-triggered targeted drug or gene delivery vehicles ( Lanza et al. 1997; Huang et al. 2001). Recombinant tissue-type plasminogen activator (rt-PA), a thrombolytic, has been loaded into ELIP ( Tiukinhoy-Laing et al. 2007). These vesicles have the potential to be used for ultrasound-enhanced thrombolysis in the treatment of acute ischemic stroke, myocardial infarction, deep vein thrombosis or pulmonary embolus. A clinical diagnostic ultrasound scanner (Philips HDI 5000; Philips Medical Systems, Bothell, WA, USA) equipped with a linear array transducer (L12-5) was employed for in vitro studies using rt-PA-loaded ELIP (T-ELIP). The goal of this study was to quantify ultrasound-triggered drug release from rt-PA-loaded echogenic liposomes. T-ELIP samples were exposed to 6.9-MHz B-mode pulses at a low pressure amplitude (600 kPa) to track the echogenicity over time under four experimental conditions: (1) flow alone to monitor gas diffusion from the T-ELIP, (2) pulsed 6.0-MHz color Doppler exposure above the acoustically driven threshold (0.8 MPa) to force gas out of the liposome gently, (3) pulsed 6.0-MHz color Doppler above the rapid fragmentation threshold (2.6 MPa) or (4) Triton X-100 to rupture the T-ELIP chemically as a positive control. Release of rt-PA for each ultrasound exposure protocol was assayed spectrophotometrically. T-ELIP were echogenic in the flow model (5 mL/min) for 30 min. The thrombolytic drug remained associated with the liposome when exposed to low-amplitude B-mode pulses over 60 min and was released when exposed to color Doppler pulses or Triton X-100. The rt-PA released from the liposomes had similar enzymatic activity as the free drug. These T-ELIP are robust and echogenic during continuous fundamental 6.9-MHz B-mode imaging at a low exposure output level (600 kPa). Furthermore, a therapeutic concentration of rt-PA can be released by fragmenting the T-ELIP with pulsed 6.0-MHz color Doppler ultrasound above the rapid fragmentation threshold (1.59 MPa). (E-mail: denise.smith@uc.edu)

Ultrasound-enhanced thrombolysis with tPA-loaded echogenic liposomes

Background and Purpose Currently, the only FDA-approved therapy for acute ischemic stroke is the administration of recombinant tissue plasminogen activator (tPA). Echogenic liposomes (ELIP), phospholipid vesicles filled with gas and fluid, can be manufactured to incorporate tPA. Also, transcranial ultrasound-enhanced thrombolysis can increase the recanalization rate in stroke patients. However, there is little data on lytic efficacy of combining ultrasound, echogenic liposomes, and tPA treatment. In this study, we measure the effects of pulsed 120-kHz ultrasound on the lytic efficacy of tPA and tPA-incorporating ELIP (t-ELIP) in an in-vitro human clot model. It is hypothesized that t-ELIP exhibits similar lytic efficacy to that of rt-PA. Methods Blood was drawn from 22 subjects after IRB approval. Clots were made in 20-µL pipettes, and placed in a water tank for microscopic visualization during ultrasound and drug treatment. Clots were exposed to combinations of [tPA] = 3.15 µg/ml, [t-ELIP] = 3.15 µg/ml, and 120-kHz ultrasound for 30 minutes at 37 °C in human plasma. At least 12 clots were used for each treatment. Clot lysis over time was imaged and clot diameter was measured over time, using previously developed imaging analysis algorithms. The fractional clot loss (FCL), which is the decrease in mean clot width at the end of lytic treatment, was used as a measure of lytic efficacy for the various treatment regimens. Results The fractional clot loss FCL was 31% (95% CI: 26-37%) and 71% (56-86%) for clots exposed to tPA alone or tPA with 120 kHz ultrasound. Similarly, FCL was 48% (31-64%) and 89% (76-100%) for clots exposed to t-ELIP without or with ultrasound. Conclusions The lytic efficacy of tPA containing echogenic liposomes is comparable to that of tPA alone. The addition of 120 kHz ultrasound significantly enhanced lytic treatment efficacy for both tPA and t-ELIP. Liposomes loaded with tPA may be a useful adjunct in lytic treatment with tPA.

Ultrasound-Enhanced Thrombolysis: From Bedside to Bench

HomeStrokeVol. 39, No. 12Ultrasound-Enhanced Thrombolysis: From Bedside to Bench Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBUltrasound-Enhanced Thrombolysis: From Bedside to Bench Jürgen Eggers, MD Jürgen EggersJürgen Eggers Stroke Unit, Department of Neurology, Asklepios Hospital North, Hamburg, Germany Search for more papers by this author Originally published23 Oct 2008https://doi.org/10.1161/STROKEAHA.108.531848Stroke. 2008;39:e193Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 23, 2008: Previous Version 1 To the Editor:We highly appreciate Tsivgoulis and Alexandrov’s1 comment regarding our article about sonothrombolysis with transcranial color-coded sonography (TCCS) and recombinant tissue plasminogen activator.2 However, several conclusions made by these colleagues require a response. The assumption that the multibeam configuration of TCCS causes an increased rate of symptomatic intracranial hemorrhage in the target group is not justified. The overwhelming part of insonation was performed by using the pulsed wave Doppler mode as it was also used by Alexandrov and coworkers in the CLOTBUST trial.3 As we described in the Methods section, multibeam color-coded mode was only used for the identification of the vessel occlusion before starting the continuous insonation.2 Additionally, the exact location of the Doppler sample volume at the targeted occlusion site was recurrently proved by intermitted switching from the Doppler mode to the color-coded mode. This interval of switching depends on the examiner’s choice, either using the so called “refreshing-mode” of the device for an ultrashort period (every 7 seconds during continuous insonation for enhancing thrombolysis in our study) or individually when used for diagnostic purpose. This frequent visualization of the Doppler sample volume location allows optimal targeting of the occlusion site by the ultrasound beam. Because the position of transducer at the acoustic window of the temporal bone did not change, the insonation angle did not vary remarkably.This ability of switching from Doppler mode to color-coded mode by using the same device and transducer makes TCCS such an advanced and useful tool for identifying (and treating) acute intracranial vessel occlusion.2,4 As the pulsed wave Doppler mode enables to measure blood flow velocities at a defined location, the color-coded mode displays the flow of the major part of the Circle of Willis at one glance. Also, the modality of brightness-mode is helpful to identify landmarks which allow locating the site of an occluded middle cerebral artery without any residual flow (like in our study) in Doppler or color-coded mode.The statement by Tsivgoulis that there was only a trend toward a better functional outcome after 90 days as determined by both the modified Rankin Scale and the Barthel Index does not reflect the results of our study correctly. The modified Rankin Scale showed only a trend, but the Barthel Index measurement revealed a highly significant improvement of the target group. However, the Barthel Index is no longer accepted as an end point for stroke trials, so we did not regard this result as valid.Both transcranial Doppler ultrasound and TCCS enhance thrombolysis by the same high-frequency low-energy “diagnostic” transcranial pulsed wave ultrasound. However, in our opinion TCCS is the more advanced tool offering many advantages compared to transcranial Doppler ultrasound.DisclosuresNone.1 Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis from bedside to bench. Stroke. 2008; 39: 1404–1405.LinkGoogle Scholar2 Eggers J, König IR, Koch B, Händler G, Seidel G. Sonothrombolysis with transcranial color-coded sonography and recombinant tissue-type plasminogen activator in acute middle cerebral artery main stem occlusion: results from a randomized study. Stroke. 2008; 39: 1470–1475.LinkGoogle Scholar3 Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill MD, Wojner AW; CLOTBUST Investigators. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004; 351: 2170–2178.CrossrefMedlineGoogle Scholar4 Gerriets T, Postert T, Goertler M, Stolz E, Schlachetzki F, Sliwka U, Seidel G, Weber S, Kaps M. DIAS I: duplex-sonographic assessment of the cerebrovascular status in acute stroke: a useful tool for future stroke trials. Stroke. 2000; 31: 2342–2345.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails December 2008Vol 39, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/STROKEAHA.108.531848PMID: 18948600 Originally publishedOctober 23, 2008 PDF download Advertisement

Tissue Plasminogen Activator Concentration Dependence of 120 kHz Ultrasound-Enhanced Thrombolysis

It has been known for some time that the application of ultrasound can enhance the efficacy of thrombolytic medications such as recombinant tissue plasminogen activator (rt-PA). Potential clinical applications of this ultrasound-enhanced thrombolysis (UET) include the treatment of myocardial infarction, acute ischemic stroke, deep venous thrombosis and other thrombotic disorders. It may be possible to reduce the dose of rt-PA while maintaining lytic efficacy; however there is little data on the rt-PA concentration dependence of UET. In this work, the rt-PA concentration dependence of clot lysis resulting from 120 kHz UET exposure was measured in an in vitro human clot model. Clots were exposed to rt-PA for 30 min, with (UET treated) or without 120 kHz ultrasound (rt-PA treated) at 37°C, and the clot width measured as a function of time. The rt-PA concentration ranged from 0–10 μg/mL. The initial lytic rate for the UET-treated group was greater than that of the rt-PA group at almost all rt-PA concentrations, and exhibited a maximum over concentration values of 1–3 μg/mL. (E-mail: shawge@ucmail.uc.edu)

Ultrasound-Enhanced Thrombolysis Using Definity ® as a Cavitation Nucleation Agent

Ultrasound has been shown previously to act synergistically with a thrombolytic agent, such as recombinant tissue plasminogen activator (rt-PA) to accelerate thrombolysis. In this in vitro study, a commercial contrast agent, Definity ®, was used to promote and sustain the nucleation of cavitation during pulsed ultrasound exposure at 120 kHz. Ultraharmonic signals, broadband emissions and harmonics of the fundamental were measured acoustically by using a focused hydrophone as a passive cavitation detector and used to quantify the level of cavitation activity. Human whole blood clots suspended in human plasma were exposed to a combination of rt-PA, Definity ® and ultrasound at a range of ultrasound peak-to-peak pressure amplitudes, which were selected to expose clots to various degrees of cavitation activity. Thrombolytic efficacy was determined by measuring clot mass loss before and after the treatment and correlated with the degree of cavitation activity. The penetration depth of rt-PA and plasminogen was also evaluated in the presence of cavitating microbubbles using a dual-antibody fluorescence imaging technique. The largest mass loss (26.2%) was observed for clots treated with 120-kHz ultrasound (0.32-MPa peak-to-peak pressure amplitude), rt-PA and stable cavitation nucleated by Definity ®. A significant correlation was observed between mass loss and ultraharmonic signals (r = 0.85, p < 0.0001, n = 24). The largest mean penetration depth of rt-PA (222 μm) and plasminogen (241 μm) was observed in the presence of stable cavitation activity. Stable cavitation activity plays an important role in enhancement of thrombolysis and can be monitored to evaluate the efficacy of thrombolytic treatment. (E-mail: Christy.Holland@uc.edu)

Inadequate Acoustical Temporal Bone Window in Patients with a Transient Ischemic Attack or Minor Stroke: Role of Skull Thickness and Bone Density

Transcranial Doppler (TCD) ultrasonography may provide important diagnostic and prognostic information in patients with ischemic stroke or transient ischemic attack. TCD also enhances the effect of thrombolytic treatment in patients with acute stroke. In some patients, especially elderly women, TCD cannot be performed because of temporal bone window failure (WF). We investigated whether skull thickness or bone density on computed tomography scans predicts WF. In 182 patients with a transient ischemic attack or minor ischemic stroke, skull thickness and bone density measurements were made at the level of the temporal bone window. Multiple logistic regression analysis was used to relate independent variables to WF and to adjust the estimates for possible confounding factors. TCD signals were absent on the symptomatic side in 22 female and 11 male patients (18%). Both skull thickness and radiodensity at the level of the temporal bone window were strongly related to WF as well as age and female gender. After adjustment according to age and gender, skull thickness at the temporal bone window was an independent prognostic factor of WF (odds ratio [OR]: 2.3 per mm increase in skull thickness, 95% confidence interval [CI]: 1.4 to 3.8). Radiodensity of the temporal bone decreased with age in women (−52 HU per 10 y over 50 y of age, 95% CI: −73 to −30) but in men (−10 HU per 10 y over 50 y of age, 95% CI: −33 to 13), no statistically significant association was observed. We computed probabilities of WF for each patient individually. With a probability cut point of 50%, 33% of the patients with WF and 97% of the patient without WF were correctly identified. The area under the receiver operating characteristic (ROC) curve of this simple prediction model including age, gender and skull thickness was 0.88; the area under the ROC curve of a gender-stratified model including age, skull thickness and radiodensity was 0.90. This difference was not statistically or clinically significant p = 0.13). WF is more common in women because density of the temporal bone in elderly women is low. Absence of WF can be predicted by a combination of three simple parameters: skull thickness, age and gender. This may help to select patients with ischemic stroke for diagnostic TCD screening and to facilitate targeted delivery of ultrasound-enhanced thrombolysis. (E-mail: a.wijnhoud@erasmusmc.nl)

Treatment of Critical Limb Ischemia Using Ultrasound-Enhanced Thrombolysis (PARES Trial): Final Results

To evaluate the safety and performance of ultrasound-enhanced thrombolysis in the treatment of acute thrombotic or embolic occlusion of the lower limb arteries. From April 2005 to July 2006, 25 patients (15 men; mean age 64.1 years, range 37-82) presenting with acute (<14 days old) occlusions of the lower limb arteries were treated with local thrombolysis [recombinant tissue plasminogen activator (rtPA)] in a dosage of 1.0 mg/h using the EKOS Lysus Peripheral Catheter System with an ultrasound core. No bolus injection of rtPA was given. The mean occlusion length was 25.1 cm (range 2-70). The technical success rate was 100%. Total clot removal was achieved in 22 (88%) patients after 16.9 hours (range 5-24) using a mean 17 mg (range 5-25) of rtPA. In 8 cases, total clot removal of the main lesion was achieved after 6 hours (6 mg of rtPA). In 1 patient, lysis was stopped after 2.5 hours because of bleeding due a dislocation of the introducer sheath. In 2 cases, total clot removal could not be achieved; these patients were successfully treated with thromboaspiration. At the 1-month follow-up, the treated vessel was still patent in 20 patients. Two reocclusions occurred; 1 was treated with a bypass graft and the other with conservative therapy. There were no cases of amputation or death during follow-up. There were no side effects related to rtPA or the catheter system. This study demonstrates that local lysis of acute arterial occlusions using the Lysus Peripheral Catheter System is safe and effective. Blood flow is restored quickly.

Ultrasound-Enhanced Thrombolysis in Acute Ischemic Stroke: Potential, Failures, and Safety

Experimental and pilot clinical evidence shows that thrombolysis with intravenous tissue plasminogen activator (TPA) can be enhanced with ultrasound. Ultrasound delivers mechanical pressure waves to the clot, thus exposing more thrombus surface to circulating drug. The international multicenter phase II CLOTBUST trial showed that, in patients with acute ischemic stroke, transcranial Doppler (TCD) monitoring augments TPA-induced arterial recanalization, with a nonsignificant trend toward an increased rate of recovery from stroke, compared with placebo. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 hours after TPA bolus occurred in 25% of patients treated with TPA + TCD (n = 63), compared with 8% of those who received TPA alone (n = 63, P = 0.02). Different results were achieved in smaller studies that used transcranial color-coded duplex sonography (TCCD) and a nonimaging therapeutic ultrasound system. The findings of the TRUMBI trial (26 patients) underscored the adverse bioeffects of mid-kilohertz (300 kHz) ultrasound, such as promotion of bleeding in brain areas both affected and unaffected by ischemia. Exposure to multifrequency, multielement duplex ultrasound resulted in a trend toward a higher risk of hemorrhagic transformation. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of a single-beam, 2-MHz TCD with perflutren lipid microspheres. Enhancement of intra-arterial TPA delivery is being clinically tested with 1.7-2.1 MHz pulsed-wave ultrasound (EKOS catheter). Multinational dose escalation studies of microspheres and the development of an operator-independent ultrasound device are underway.

Ultrasound-Induced Thermal Elevation in Clotted Blood and Cranial Bone

Ultrasound thermal effects have been hypothesized to contribute to ultrasound-assisted thrombolysis. To explore the thermal mechanism of ultrasound-enhanced thrombolysis with recombinant tissue plasminogen activator (rt-PA) for the treatment of ischemic stroke, a detailed investigation is needed of the heating produced in skull, brain and blood clots. A theoretical model is developed to provide an estimate for the worst-case scenario of the temperature increase in blood clots and on the surface of cranial bone exposed to 0.12- to 3.5-MHz ultrasound. Thermal elevation was also assessed experimentally in human temporal bone, human clots and porcine clots exposed to 0.12 to 3.5-MHz pulsed ultrasound in vitro with a peak-to-peak pressure of 0.25 MPa and 80% duty cycle. Blood clots exposed to 0.12-MHz pulsed ultrasound exhibited a small temperature increase (0.25° C) and bone exposed to 1.0-MHz pulsed ultrasound exhibited the highest temperature increase (1.0° C). These experimental results were compared with the predicted temperature elevations. (E-mail: nahirnvm@email.uc.edu)

Ultrasound-Enhanced Thrombolysis

To report a single-center clinical experience with ultrasound-enhanced thrombolysis in the treatment of both arterial and venous thromboses. From January 2005 to June 2006, 33 patients (23 men; age range 39-90 years) with 36 occlusions were treated using ultrasound-enhanced thrombolytic therapy for acute and chronic arterial and venous occlusions. After diagnostic angiography, the occlusions were crossed with an appropriately sized Lysus infusion catheter for infusion of urokinase (80,000-120,000 IU/h). Technical success and complete lysis was achieved in 96% of the arterial and 83% of the venous occlusions. Two patients with chronic occlusions (one superficial femoral artery and one iliac vein) were refractory to lytic therapy. Average time for complete lysis was 16.4 hours (range 3-25) for arterial occlusions and 21.2 hours (range 6-43) in patients with deep vein thrombosis. Successful clot lysis can be achieved with a high rate of success in a shorter time than conventional thrombolysis using ultrasound-enhanced thrombolysis in both acute and chronic arterial and venous thromboses.

Duty Cycle Dependence of Ultrasound Enhanced Thrombolysis in a Human Clot Model

Combined ultrasound and tissue plasminogen activator (rt-PA) therapy, or ultrasound enhanced thrombolysis (UET), has been shown to improve recanalization in patients with acute ischemic stroke. We measured the effect of ultrasound duty cycle on the lytic efficacy of 120 kHz UET in an in vitro human clot model. The hypothesis was that an increase in duty cycle increases rt-PA lytic efficacy. Human whole blood clots were exposed to 120-kHz ultrasound and rt-PA for 30 min in human plasma. The duty cycle ranged from 0% to 80%, where 0% represents sham exposure. Clot lytic rate was measured by recording the clot width over time. The clot width after 30 min exposure to rt-PA and ultrasound decreases with increasing duty cycle. The initial lytic rate increased linearly with duty cycle. (E-mail: meuniejn@uc.edu)

Monitoring and simulating stable cavitation during ultrasound-enhanced thrombolysis

The presence of stable cavitation has been shown to be highly correlated with thrombolytic efficacy for recombinant tissue plasminogen activator (rt‐PA) mediated thrombolysis. A commercial contrast agent, Definity, was used with 120 kHz pulsed ultrasound to nucleate, promote, and sustain stable cavitation. The effect of stable cavitation on increased penetration of rt‐PA into the clots is discussed. Also, the possibility of lowering the rt‐PA dose using sustained stable cavitation adjuvant to thrombolytics is presented. To understand the bubble dynamics involved, the bubble response was studied using the Keller‐Miksis model and stable and inertial cavitation thresholds were studied as a function of bubble radius. The largest mass loss (26.2%) was observed for clots treated with 120 kHz ultrasound (0.32 MPa peak‐to‐peak pressure amplitude, 80% duty cycle), rt‐PA (96 μg/ml) and stable cavitation nucleated by Definity. A comparable mass loss of 22% was observed at a much lower concentration of 11 μg/ml in the presence of stable cavitation. In addition, the simulation results provide insight into the nuclei sizes relevant for this therapeutic application and possible mechanisms involved.

Ultrasound Enhanced Thrombolysis: Applications in Acute Cerebral Ischemia

Intravenous tissue plasminogen activator (TPA) improves patient chances to recover from stroke by inducing mostly partial recanalization of large intracranial thrombi. TPA activity can be enhanced with ultrasound including 2 MHz transcranial Doppler (TCD). TCD identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. The international multi-center CLOTBUST trial showed that ultrasound enhances thrombolytic activity of a drug in humans thereby confirming multi-disciplinary experimental research conducted worldwide for the past 30 years.In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 hours after TPA bolus occurred in 25% of patients treated with TPA+TCD compared to 8% who received TPA alone (p=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the Target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months, subject for a pivotal trial. However, different results were achieved in a small TRUMBI trial and another study that used Transcranial Color-Coded Duplex Sonography (TCCD). Adverse bio-effects of mid-KHz (300) ultrasound promote bleeding, including brain areas not-affected by ischemia while exposure to multi-frequency / multi-element duplex ultrasound resulted in a trend towards higher risk of hemorrhagic transformations.To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of a single beam 2 MHz TCD with perflutren-lipid microspheres. Enhancement of intra-arterial TPA delivery is being clinically tested with 1.7-2.1 MHz pulsed wave ultrasound (EKOS catheter). Multi-national dose escalation studies of microspheres and the development of an operator independent ultrasound device are underway.

Ultrasound Enhanced Thrombolysis for Stroke

In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA) therapy, a low rate of early arterial recanalization was suspected because only a few stroke patients may have had early dramatic clinical improvement. Tissue plasminogen activator activity can be enhanced with ultrasound, including 2 MHz transcranial Doppler (TCD). Transcranial Doppler identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. For the first time in clinical medicine, the international multicenter CLOTBUST trial showed that ultrasound enhances the thrombolytic activity of a drug in humans, thereby confirming multidisciplinary experimental research conducted worldwide for the past 30 years. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 h after TPA bolus occurred in 25% of patients treated with TPA+TCD compared with 8% who received TPA alone (P=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of 2 MHz TCD with ultrasound contrast agents or (microbubbles): TCD+TPA+Levovist; TCD+TPA+MRX nano-platform (C(3)F(8)). Intra-arterial TPA delivery can be enhanced with 1 x 7-2 x 1 MHz pulsed wave ultrasound (EKOS catheter, IMS trial). Dose escalation studies of microbubbles, ultrasound exposure, and the development of an operator-independent ultrasound device are underway.

Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke

Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke

Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke

Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke

Future directions for recanalization therapy in acute ischemic stroke

Currently, the only treatment approved by the US Food and Drug Administration for the treatment of acute stroke is the intravenous recombinant tissue plasminogen activator, which must be administered within a 3 h window. The majority of ischemic stroke patients do not receive intravenous thrombolysis, primarily because they enter the healthcare system too late. Alternative treatment strategies being used or investigated include intra-arterial thrombolysis, endovascular clot disruption, and manipulation and angioplasty with or without stenting. The most promising new revascularization technologies beyond conventional thrombolysis for acute ischemic stroke are ultrasound-enhanced thrombolysis, mechanical clot extraction devices and stent angioplasty. Advances in neuroimaging may allow physicians to determine the etiology of a stroke and tailor treatment accordingly for the maximal clinical benefit for affected patients.

Effect of mild hypothermia on the thrombolytic efficacy of 120 kHz ultrasound enhanced thrombolysis in an in-vitro human clot model

Introduction Ischemic stroke causes substantial death and disability. Currently, recombinant tissue plasminogen activator (rt-PA) is the only FDA approved therapy. However, there are dangerous side effects and therapy must start within 3 h of onset. Therefore, there is interest in adjunctive therapies such as ultrasound enhanced thrombolysis (UET) and hypothermia. Recently, transcranial ultrasound during rt-PA therapy was shown to improve vessel recanalization. Also hypothermia (32–34 °C) was shown to be safe and possibly improve outcome. This suggests combining UET and hypothermia to treat ischemic stroke. Little is known about the effects of hypothermia on UET, and in-vitro rt-PA efficacy is reduced for T < 37 °C. Here, the effects of hypothermia on UET in in-vitro human clot are presented. It is hypothesized that UET efficacy at 33 °C is less than at 37 °C. Materials and methods Whole blood was drawn from volunteers. Clots were made, incubated at 37 °C and aged for 2 days for maximal lytic resistance. Clots were exposed to human fresh-frozen plasma (control), hFFP and rt-PA ([rt-PA] = 3.2 μg/ml), hFFP and 120 kHz ultrasound (US), and hFFP, rt-PA and ultrasound (UET) at 33 °C and 37 °C. Clot percent mass loss (Δ m) was measured to determine thrombolytic efficacy. Data were analyzed using mixed-model analysis of variance. Results and conclusions US and rt-PA independently increased Δm (3.5 ± 1.0% and 5.1 ± 0.9% respectively; p < 0.01) over control. UET increased Δm an additional 8.1 ± 1.3% ( p = 0.026) The effect of temperature on Δ m (− 1.6 ± 0.7%) was not significant ( p = 0.09). Hypothermia did not reduce UET efficacy in this in-vitro model.