Efficacy Of Sonothrombolysis Research Articles

Sonothrombolysis Using Microfluidically Produced Microbubbles in a Murine Model of Deep Vein Thrombosis.

The need for safe and effective methods to manage deep vein thrombosis (DVT), given the risks associated with anticoagulants and thrombolytic agents, motivated research into innovative approaches to resolve blood clots. In response to this challenge, sonothrombolysis is being explored as a technique that combines microbubbles, ultrasound, and thrombolytic agents to facilitate the aggressive dissolution of thrombi. Prior studies have indicated that relatively large microbubbles accelerate the dissolution process, either in an in vitro or an arterial model. However, sonothrombolysis using large microbubbles must be evaluated in venous thromboembolism diseases, where blood flow velocity is not comparable. In this study, the efficacy of sonothrombolysis was validated in a murine model of pre-existing DVT. During therapy, microfluidically produced microbubbles of 18 μm diameter and recombinant tissue plasminogen activator (rt-PA) were administered through a tail vein catheter for 30min, while ultrasound was applied to the abdominal region of the mice. Three-dimensional ultrasound scans were performed before and after therapy for quantification. The residual volume of the thrombi was 20% in animals post sonothrombolysis versus 52% without therapy ( ), indicating a significant reduction in DVT volume. Histological analysis of tissue sections confirmed a reduction in DVT volume post-therapy. Therefore, large microbubbles generated from a microfluidic device show promise in ultrasound-assisted therapy to address concerns related to venous thromboembolism.

Safety, feasibility and efficacy of sonothrombolysis with micro boluses of perfluoropropane as a point of care therapy for patients with acute ST-elevation myocardial infarction.

Despite advances in timely revascularisation of ST elevation myocardial infarction (STEMI) patients, there are several practical and unavoidable delays. Sonothrombolysis (administered during micro boluses of Perfluoropropane) initiated bedside as a point-of-care therapy during the initial evaluation of the patient may potentially mitigate this by producing early culprit vessel revascularisation. This was a prospective, single-centre study on hemodynamically stable patients presenting within 12 hours of a first STEMI who consented for study participation. Fifteen patients were recruited over a 1-month period. Eleven were male. Nine patients had anterior wall STEMI and left anterior descending as culprit vessel. There were no significant changes in safety outcomes. Median First Medical Contact (FMC)-Sono time was 12 min (10-15). Median duration of sonothrombolysis was 14 min (12-16). FMC-device time was 97 min (79-128). Six patients had culprit vessel recanalisation before primary percutaneous coronary intervention (PPCI) which was consistent with the reference rates of therapy-associated recanalisation (p = 0.535). Micro bolus sonothrombolysis maybe safely initiated as a point of care therapy adjunctive to PPCI in hemodynamically stable STEMI patients with reasonable efficacy. Further randomised trials are needed to ascertain its applicability in various geographical and clinical settings.

Sonothrombolysis with microbolus administration of perfluoropropane as point of care therapy for STEMI patients

Abstract Introduction There are still major obstacles to timely revascularisation of STEMI patients even on arrival to PCI capable centers. Delivery of intermittent high mechanical index(MI) pulses during contrast infusion(Sonothrombolysis) has been shown to improve culprit vessel recanalization rates, reduce infarct size and improve myocardial hemodynamics. Purpose Our objective was to see if sonothrombolysis administered with a low dose of echo contrast(2mL) given as successive microboluses resulted in angiographic recanalisation. This is pertinent in our resource limited setup as continuous infusion needs specialised pumps and cost of echo contrast is high. Methods This was a randomised control trial on 100 patients presenting with first STEMI (within a window period of 12 hours, Killips stage I or II) to the Chest Pain Unit(CPU) of our institution. The intervention was sonothrombolysis during successive microboluses of perfluoropropane followed by PPCI. Technique of Sonothombolysis: 1 vial of perfluoropropane(2mL) is agitated and diluted in 20ML normal saline(0.1%w/v). Using a 3 way stop cock, 2mL solution is given while performing echocardiography in standard views. This leads to good chamber opacification for 40-60 beats. Once chamber opacification is adequately achieved (usually within 10 beats), high MI pulses (>1.1 MI) were given repeatedly after low MI imaging shows replenishment of microbubbles in the myocardial segment. Once opacification wanes, then another bolus of 2mL is given and steps repeated. The control group underwent low MI imaging with 0.2mL of perfluoropropane followed by PPCI. Results The trial was halted after recruitment of 57 patients following an interim analysis which showed no significant benefit with sonothrombolysis. Angiographic recanalization of culprit vessel occured in 28% of cases (8vs6, p=0.589). Baseline characteristics were similar across both groups. The time from first medical contact(FMC) to balloon time were similar. The use of Gp IIb/IIIa inhibitors or thrombus aspiration catheters did not differ. Discussion Sonothrombolysis with successive microboluses of perflouropropane is not effective in producing angiographic recanalization in STEMI patients. Our results vary from that of Mathias et al which showed a 48% angiographic recanalization rate. The protocol of giving microboluses as against continuous infusion could have contributed though we looked specifically for microbubble replenishment in myocardial segments before delivering high MI pulses. Secondly the higher prevalence of diabetes, dyslipidemia and multivessel CAD in our population could have contributed to the lack of efficacy. Thirdly the mean window period (time between onset of symptoms to arrival at CPU) was 7±2.31hrs which could have contributed to thrombus organization and resistance to shearing forces produced by microbubble cavitation. Further randomized studies are needed to see the efficacy of sonothrombolysis in other populations.Table 1.Baseline CharacteristicsTable 2.Results

Contrast enhanced sonothrombolysis using streptokinase loaded phase change nano-droplets for potential treatment of deep venous thrombosis.

Current thrombolytic therapies for deep venous thrombosis are limited due to the wide side effect profile. Contrast mediated sonothrombolysis is a promising approach for thrombus treatment. The current study examines the effectiveness of in vitro streptokinase (SK) loaded phase-change nanodroplet (PCND) mediated sonothrombolysis at 7 MHz for the diagnosis of deep venous thrombosis. Lecithin shell and perfluorohexane core nanodroplets were prepared via the thin-film hydration method and morphologically characterized. Sonothrombolysis was performed at 7 MHz at different mechanical indexes of samples i.e., only sonothrombolysis, PCND mediated sonothrombolysis, sonothrombolysis with SK and SK loaded PCND mediated sonothrombolysis. Thrombolysis efficacy was assessed by measuring clot weight changes during 30 min US exposure, recording the mean gray intensity from the US images of the clot by computer software ImageJ, and spectrophotometric quantification of the hemoglobin in the clot lysate. In 15 minutes of sonothrombolysis performed at high mechanical index (0.9 and 1.2), SK loaded PCNDs showed a 48.61% and 74.29% reduction of mean gray intensity. At 0.9 and 1.2 MI, 86% and 92% weight loss was noted for SK-loaded PCNDs in confidence with spectrophotometric results. A significant difference (P < 0.05) was noted for SK-loaded PCND mediated sonothrombolysis compared to other groups. Loading of SK inside the PCNDs enhanced the efficacy of sonothrombolysis. An increase in MI and time also increased the efficacy of sonothrombolysis. This in vitro study showed the potential use of SK-loaded perfluorohexane core PCNDs as sonothrombolytic agents for deep venous thrombosis.

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.

December 2021 Stroke Highlights

December 2021 <i>Stroke</i> Highlights

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.

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.

Does the administration of sonothrombolysis along with tissue plasminogen activator improve outcomes in acute ischemic stroke? A systematic review and meta-analysis.

This meta-analysis was conducted to assess the safety and efficacy of sonothrombolysis along with intravenous recombinant tissue plasminogen activator, alteplase (IV rtPA), in the management of acute ischemic stroke. Electronic databases were searched under different meSH terms without the restriction of time and language. 1415 studies were analyzed and seven studies that matched the inclusion criteria were selected. Multiple safety and efficacy outcomes were extracted. Our pooled analysis demonstrated that there is no significant difference between sonothrombolysis group and control group in preventing mortality (RR 1.10 [0.81, 1.50]; p = 0.55; I2 = 0%) and intracranial hemorrhage (RR 1.11 [0.76, 1.63]; p = 0.59; i2 = 0%), however, among the efficacy outcomes; complete recanalization after 60-120min was achieved more effectively in the sonothrombolysis group (RR 2.11 [1.48, 3.03]; p ≤ 0.0001; I2 = 0%). The rest of the efficacy outcomes like neurological improvement at 24h (RR 1.20 [0.92, 1.57]; p = 0.18; I2 = 40%) and excellent functional outcome after 3months (RR 1.19 [0.93, 1.52]; p = 0.17; I2 = 35%) showed no significant differences between the two groups. In subgroup analysis, we found that sonothrombolysis led to a better neurological improvement in patients who were less than 65years of age (RR 1.20 [0.92, 1.57]; p = 0.05; I2 = 40%). Moreover, there were no significant differences in the following of the subgroups assessed: (a) microsphere or microbubble use, (b) Ultrasound frequency (2MHz or < 2MHz), (c) transcranial Doppler (TCD) duration (1h or 2h), (d) age (≤ 65 or > 65).

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial

Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77-1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80-1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53). Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. Cerevast Therapeutics.

Efficacy of Sonothrombolysis Using Microbubbles Produced by a Catheter-Based Microfluidic Device in a Rat Model of Ischemic Stroke.

Limitations of existing thrombolytic therapies for acute ischemic stroke have motivated the development of catheter-based approaches that utilize no or low doses of thrombolytic drugs combined with a mechanical action to either dissolve or extract the thrombus. Sonothrombolysis accelerates thrombus dissolution via the application of ultrasound combined with microbubble contrast agents and low doses of thrombolytics to mechanically disrupt the fibrin mesh. In this work, we studied the efficacy of catheter-directed sonothrombolysis in a rat model of ischemic stroke. Microbubbles of 10-20µm diameter with a nitrogen gas core and a non-crosslinked albumin shell were produced by a flow-focusing microfluidic device in real time. The microbubbles were dispensed from a catheter located in the internal carotid artery for direct delivery to the thrombus-occluded middle cerebral artery, while ultrasound was administered through the skull and recombinant tissue plasminogen activator (rtPA) was infused via a tail vein catheter. The results of this study demonstrate that flow focusing microfluidic devices can be miniaturized to dimensions compatible with human catheterization and that large-diameter microbubbles comprised of high solubility gases can be safely administered intraarterially to deliver a sonothrombolytic therapy. Further, sonothrombolysis using intraarterial delivery of large microbubbles reduced cerebral infarct volumes by approximately 50% vs. no therapy, significantly improved functional neurological outcomes at 24h, and permitted rtPA dose reduction of 3.3 (95% CI 1.8-3.8) fold when compared to therapy with intravenous rtPA alone.

The Role of Sonolysis and Sonothrombolysis in Acute Ischemic Stroke: A Systematic Review and Meta‐analysis of Randomized Controlled Trials and Case‐Control Studies

To assess the evidence on the safety and efficacy of sonothrombolysis in acute stroke. Electronic databases and grey literature were searched under different MeSH terms from 1970 to present. Randomized control trials (RCTs) and case control studies (CCSs) on sonolysis and sonothrombolysis alone or with microsphere in acute stroke patients (>18 old). Outcome measures included complete recanalization (CR) at 1-2 and 24 hours, 3 months modified Rankin Scale (mRS), and symptomatic intracerebral hemorrhage (sICH). Data was extracted to Review Manager software. Fifty-seven studies were retrieved and analyzed. Ten studies (7 RCTs and 3 CCSs) were included in our meta-analysis, which revealed that sonolysis and sonothrombolysis are safe (OR of sICH: 1.14; 95% confidence interval (CI): 0.56- 2.34;P=0.71) and effective (OR of CR at 1-2 hours: 2.95;95% CI: 1.81-4.81;P<0.00001) and have more than two-fold higher likelihood of favourable long-term outcome (3-month mRS 0-2; OR: 2.20; CI:1.52-3.19;P<0.0001). Further subgroup analysis based on the presence of microsphere revealed that it is safe (OR of sICH: 1.18; CI:0.433.24;P=0.75) and effective (OR of CR: 2.61; CI: 1.36-4.99;P=0.004). Subgroup analysis based on sonolysis revealed to be safe and effective. This novel treatment appears safe and effective. The evidence of microsphere as an enhancement of sonothrombolysis is evolving.

Combining radiation force with cavitation for enhanced sonothrombolysis

The use of acoustic radiation force has been suggested for enhancing the delivery of therapeutic substances, whereas sonothrombolysis has been developed for years as treatment by itself, or in combination with thrombolytic agents or ultrasound contrast agents. We have examined the efficacy of using acoustic radiation force to enhance the targeting of microbubbles in cavitation-induced sonothrombolysis in a flow phantom system. A clot was targeted by microbubbles using avidin-biotin binding, and the process was observed using a confocal microscope. We found that the experimental group in which radiation force was combined with cavitation showed an additional 3% to 9% weight reduction of the thrombus relative to the cavitation group. We also found that the fluorescence intensity of the clot increased with the microbubble concentration at each acoustic setting. Microbubbles traveled 10 to 20 μm further than the control group after being exposed to radiation force, cavitation, or both. These observations confirm that radiation force helps microbubbles to distribute into a clot (as does cavitation). Therefore, combining radiation force with cavitation would provide additional thrombolysis effects (based on clot weight measurements) relative to cavitation alone. A local delivery method based on acoustic radiation force has the potential to improve the safety and efficacy of sonothrombolysis.

Safety and efficacy of sonothrombolysis using bilateral TCD monitoring by diagnostic 2 MHz probes - a pilot study

Sonothrombolysis is a new treatment method for patients with acute ischemic stroke (IS). Various ultrasound frequencies and intensities are being tested these days. The aim of this pilot study was to assess the safety and efficacy of sonothrombolysis using 2 diagnostic probes and bilateral monitoring in patients with acute occlusion of the middle cerebral artery (MCA). Twelve consecutive IS patients (7 males; age 47 - 78, average 64.1 ± 9.4 years) with acute MCA occlusion and contraindication of thrombolysis were included in the study. 60-min bilateral 2-MHz pulsed-wave Doppler monitoring of the area of occlusion was performed in all patients (Group 1). The control group consisted of 37 IS patients (20 males; age 32 - 78, average 62.2 ± 12.1 years) treated with standard sonothrombolysis and selected from the Thrombotripsy Study database (Group 2). The differences in number of recanalized arteries after a 1 h treatment, independent patients (modified Rankin scale [mRS] value of 0 - 2) after 90 days and symptomatic intracerebral hemorrhages (SICH) were statistically evaluated. Complete recanalization was found in 4 (30.0%) Group 1 and in 12 (32.4%) Group 2 patients. Seven (58.3%) Group 1 and 22 (59.5%) Group 2 patients were independent after 90 days. SICH was found in none of Group 1 patients and in 1 (2.7%) of the Group 2 patients (P>0.05 in all cases). In this pilot study, sonothrombolysis using 2 probes and bilateral monitoring is safe but not more effective than standard sonothrombolysis in acute IS patients with MCA occlusion.

Experimentelle und klinische Grundlagen der Sonothrombolyse

Die Prognose eines Schlaganfallpatienten hängt entscheidend vom Erfolg und vom Zeitpunkt der Rekanalisation eines intrakraniellen Gefäßverschlusses ab. Verschiedene therapeutische rekanalisierende Verfahren stehen dem behandelnden Arzt zur Verfügung. Einzig zugelassene Therapieform ist jedoch nach wie vor die systemische Thrombolyse mit rt-PA. Die transkranielle Beschallung des verschlossenen Gefäßes während einer systemischen Thrombolyse („Sonothrombolyse”) kann die Zeitdauer bis zur Rekanalisation verkürzen und die Rekanalisationsrate erhöhen. Eine zunehmende Zahl an klinischen und experimentellen Untersuchungen belegen diese synergistischen Effekte. Bei Kontraindikationen gegen die Gabe von rt-PA zeigt Ultraschall möglicherweise auch bei alleiniger Anwendung therapeutische Effekte. In den bisherigen klinischen Studien kamen vor allem transkranielle Doppler- und Farbduplexgeräte zum Einsatz. Darüber hinaus wurden verschiedene Ansätze untersucht, die möglicherweise zu einem verbesserten therapeutischen Wirkungsgrad der Sonothrombolyse führen. Hierzu gehören die Erprobung von Ultraschallgeräten mit geringeren (kHz) Frequenzen oder der zusätzliche Einsatz gashaltiger Mikrobläschen. Insgesamt ergeben sich für die Sonothrombolyse enorme Einsatzmöglichkeiten, da sie bei einer großen Patien­tengruppe eine Therapieoption „in der Hand des Neurologen” darstellt. Eine abschließende Bewertung ist derzeit jedoch noch nicht möglich. Neben dem definitiven klinischen Wirkungsnachweis müssen klinische Multizenterstudien, aber auch präklinische tierexperimentelle Evaluationen den Nachweis einer ausreichenden Behandlungssicherheit erbringen. Diese Arbeit gibt eine Übersicht über die wichtigsten experimentellen und klinischen Entwicklungen der Sonothrombolyse.

Ultrasound Accelerates Thrombolysis of Acutely Induced Platelet-Rich Thrombi Similar to Those in Acute Myocardial Infarction

Although sonothrombolysis has been studied for development of recanalization that is safer and more efficacious than the methods currently used, there have been no studies of the efficacy of sonothrombolysis for the platelet-rich thrombi that typically cause acute myocardial infarction (AMI). The effects of adding ultrasound (US) to pharmacological lysis of platelet-rich thrombi was examined in a rabbit model of femoral artery occlusion. In 35 rabbits, the right femoral artery was balloon-injured repeatedly at 4-week intervals to induce platelet-rich thrombi. Two hours after the induction of occlusive thrombi, 27,500 IU/kg tissue plasminogen activator (tPA) were injected via an ear vein, with or without transcutaneous US (continuous wave, 1 MHz, 0.75 W/cm2), or 13,750 IU/kg tPA was administered with US (n=10). Significantly higher rates of successful thrombolysis (Thrombolysis In Myocardial Infarction grade 3) were observed with US (90.0%) than without it (10.0%), irrespective of the dose of tPA used (p<0.01). The peak flow velocity in affected femoral arteries was significantly higher with US (p<0.01), and histological examination confirmed complete dissolution of thrombi. However, the thrombi were not affected by US alone (n=5). US facilitates thrombolysis of platelet-rich thrombi and could be a useful component of thrombolytic therapy following AMI.

Efficacy of sonothrombolysis in a rat model of embolic ischemic stroke*1

Efficacy of sonothrombolysis in a rat model of embolic ischemic stroke*1

Efficacy of sonothrombolysis in a rat model of embolic ischemic stroke

The key goal in the treatment of acute ischemic stroke is fast vessel recanalization. Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is efficient in humans but mean time for recanalization is within hours. Ultrasound bio-effects has been shown to facilitate rt-PA mediated thrombolysis in peripheral arteries. We used an embolic stroke model in the rat. In all rats we induced an ischemic stroke by a selective occlusion of the middle cerebral artery with whole blood clots. From an entire collective of 54 rats 47 completed the protocol ( n=7 died early). Four different groups (no treatment n=6; full dose rt-PA treatment only [10 mg/kg per body weight] n=14, half dose rt-PA treatment plus ultrasound n=10, and full dose rt-PA treatment plus ultrasound n=17) were investigated. We found a significant reduction of absolute as well as relative infarct volume in the full dose rt-PA plus ultrasound group (81±72 mm 3; P<0.05) in comparison to untreated rats (253±159 mm 3; P<0.05) as well as in comparison to rats treated with full dose rt-PA only (167±91 mm 3; P<0.05). There were five intracranial bleedings giving a bleeding rate of 9.3%. In summary: ultrasound treatment in addition to rt-PA is more effective than single rt-PA treatment in reducing infarct volume and safe with regard to bleeding.