Recombinant Tissue Plasminogen Activator Thrombolysis Research Articles

Histotripsy and Catheter-Directed Lytic: Efficacy in Highly Retracted Porcine Clots In Vitro

ObjectiveStandard treatment for deep vein thrombosis (DVT) involves catheter-directed anticoagulants or thrombolytics, but the chronic thrombi present in many DVT cases are often resistant to this therapy. Histotripsy has been found to be a promising adjuvant treatment, using the mechanical action of cavitating bubble clouds to enhance thrombolytic activity. The objective of this study was to determine if histotripsy enhanced recombinant tissue plasminogen activator (rt-PA) thrombolysis in highly retracted porcine clots in vitro in a flow model of occlusive DVT. MethodsHighly retracted porcine whole blood clots were treated for 1 h with either catheter-directed saline (negative control), rt-PA (lytic control), histotripsy, DEFINITY and histotripsy or the combination of rt-PA and histotripsy with or without DEFINITY. Five-cycle, 1.5 MHz histotripsy pulses with a peak negative pressure of 33.2 MPa and pulse repetition frequency of 40 Hz were applied along the clot. B-Mode and passive cavitation images were acquired during histotripsy insonation to monitor bubble activity. ResultsClots subjected to histotripsy with and without rt-PA exhibited greater thrombolytic efficacy than controls (7.0% flow recovery or lower), and histotripsy with rt-PA was more efficacious than histotripsy with saline (86.1 ± 10.2% compared with 61.7 ± 19.8% flow recovery). The addition of DEFINITY to histotripsy with or without rt-PA did not enhance either thrombolytic efficacy or cavitation dose. Cavitation dose generally did not correlate with thrombolytic efficacy. ConclusionEnhancement of thrombolytic efficacy was achieved using histotripsy, with and without catheter-directed rt-PA, in the presence of physiologic flow. This suggests these treatments may be effective as therapy for DVT.

Left ventricular systolic dysfunction predicts clinical prognosis in patients with acute ischemic stroke after intravenous thrombolysis.

Although intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis is the most effective early treatment for acute ischemic stroke (AIS), outcomes vary greatly among patients. Left ventricular systolic dysfunction (LVSD) is prone to distant organ ischemia and may be a predictor for poor prognosis in AIS patients undergoing intravenous thrombolysis (IVT). Our aim was to investigate the predictivity of LVSD diagnosis (as measured by left ventricular ejection fraction (LVEF)) on 90-day clinical outcomes in AIS patients undergoing thrombolysis. The current prospective cohort study continuously enrolled 273 AIS patients from the National Stroke Prevention and Treatment Engineering Management Special Database who underwent IVT and completed echocardiography within 24 h of admission between 2021 and 2023. LVSD was examined by evaluation of the echocardiographic LVEF values using Simpson's biplane method of discs in line with international guidelines, and defined as a LVEF value < 50%. Multivariable ordinal logistic regression model was performed to analyze the association between LVEF and functional outcome at 3 months. Restricted cubic spline (RCS) was used to examine the shape of the dose-response association between reduced LVEF and poor functional outcomes. Subgroup analysis was also employed to further verify the reliability and practicability of the results. Baseline data analysis showed LVSD patients had more comorbidities including on multivariate analyses, LVSD (OR 2.78, 95% CI 1.23 to 6.24, P=0.014), pre-existing diabetes mellitus (OR 2.08, 95% CI 1.11 to 3.90, P=0.023) and NIHSS on arrival (OR 1.31, 95% CI 1.21 to 1.49, P<0.001) were independent predictors of poor functional outcomes (mRS ≥ 3) at 3 months. Multivariable-adjusted spline regression indicated a linear dose-response association between LVEF after IVT and poor functional outcomes (p for linearity < 0.001), with the optimal cutoff values of LVEF being 0.48. Our finding indicated that AIS patients with LVSD after IVT had poorer outcomes, suggesting the need to monitor and optimize LVEF in stroke management.

Mediation of long-pulsed ultrasound enhanced microbubble recombinant tissue plasminogen activator thrombolysis in a rat model of platelet-rich thrombus.

Ultrasound (US)-enhanced microbubble (MB) therapy has been investigated as a therapeutic technique to facilitate the thrombolysis for the treatment of pericardial and microvascular obstruction. This study sought to assess the therapeutic effects of long-pulsed US-assisted MB-mediated recombinant tissue plasminogen activator (rt-PA) thrombolysis in a rat model of platelet-rich thrombus. Ferric chloride (10%) was used to induce total arterial occlusion before formation of platelet-rich thrombi. Therapeutic long-tone-burst US (1 MHz, 0.6 MPa, 1,000-µs pulse length) was used, and 2.9×109/mL of lipid MBs and 1 mg/mL of rt-PA were infused. Subsequently, 42 Sprague-Dawley (SD) male rats were randomly divided into seven groups: (I) control; (II) rt-PA; (III) high duty cycle US + MB; (IV) low duty cycle US + rt-PA; (V) high duty cycle US + rt-PA; (VI) low duty cycle US + rt-PA + MB; and (VII) high duty cycle US + rt-PA + MB. The recanalization grades were evaluated after 20 minutes' treatment. Compared to the control, there was significant improvement in recanalization in the US + rt-PA groups (P=0.01 vs. control), US (low duty cycle) + rt-PA + MB (P=0.003 vs. control) and US (high duty cycle) + rt-PA + MB (P<0.001 vs. control) groups, in which recanalization was successfully achieved in all rats. Long-pulsed US-enhanced MB-mediated rt-PA thrombolysis offered a powerful approach in the treatment of platelet-rich thrombus.

Impact of blood pressure variability on hemorrhagic transformation post-rt-PA thrombolysis in patients with acute ischemic stroke

Background: The relationship between blood pressure variability and hemorrhagic transformation after recombinant tissue plasminogen activator thrombolysis in patients with acute ischemic stroke is uncertain due to inconsistent methodologies across studies. This study aimed to elucidate the association between 24-h systolic blood pressure extremes post-admission and hemorrhagic transformation while considering the possibility of hemorrhagic transformation occurring beyond the initial monitoring period. Methods: We enrolled patients admitted to The First Affiliated Hospital of Harbin Medical University for ischemic stroke who were treated with intravenous recombinant tissue plasminogen activator within 4.5 h of symptom onset between January 2020 and December 2022. We analyzed the relationships among admission blood pressure, 24-h post-admission recombinant tissue plasminogen activator (mean, maximum, minimum, extreme difference, standard deviation, and coefficient of variation), immediate and 1-h post-thrombolysis blood pressure, and hemorrhagic transformation occurrence within 36 h post-thrombolysis. The potential for delayed hemorrhagic transformation was also considered during the interpretation of the results. Results: Among the 138 patients, 39.1% experienced post-thrombolytic hemorrhagic transformation. Multivariate analysis revealed that hemorrhagic transformation was significantly associated with coronary artery disease, cerebral leukoaraiosis, large cerebral infarction, elevated random glucose levels, and 24-h systolic blood pressure extremes at admission. Specifically, 24-h systolic blood pressure extremes showed a significant positive correlation with hemorrhagic transformation (OR = 1. 042; 95% CI: 1.000–1.086, p &lt; 0.05). Conclusion: These findings underscore the importance of establishing robust protocols for continuous blood pressure monitoring and intervention strategies tailored to individual risk profiles. Given that hemorrhagic transformation can occur beyond the initial 36 h, clinicians should maintain vigilance for delayed hemorrhagic transformation, particularly in patients with high recombinant tissue plasminogen activator. Strict control of blood pressure, especially minimizing extremes in systolic blood pressure, is essential to ensure the safety of patients undergoing thrombolysis.

Prognostic analysis of different therapeutic regimens in patients with acute cardiogenic cerebral embolism

BackgroundFew studies focused on the functional outcomes of patients at 3 months after receiving intravenous thrombolysis, anticoagulation, or antiplatelet therapy within 4.5 h of onset of the cardiogenic cerebral embolism (CCE) subtype.MethodsThe purpose of this retrospective study was to analyse the clinical data of patients with acute CCE and compare the 3-month functional prognoses of patients after administration of different antithrombotic therapies within 4.5 h of stroke onset. A total of 335 patients with CCE hospitalized in our institution were included in this study. The patients were stratified according to the hyperacute treatment received, and baseline clinical and laboratory data were analysed. A 3-month modified Rankin scale (mRS) score of 0–2 was defined as an excellent functional outcome.ResultsA total of 335 patients were divided into thrombolytic (n = 78), anticoagulant (n = 88), and antiplatelet therapy groups (n = 169). A total of 164 patients had a good prognosis at 3 months (mRS ≤ 2). After adjustments were made for age and National Institute of Health Stroke Scale (NIHSS) score, each group comprised 38 patients, and there were no significant differences in sex composition, complications, lesion characteristics, or Oxfordshire Community Stroke Project (OSCP) classification among the three groups. The plasma D-dimer level (µg/ml) in the thrombolytic group was significantly higher than those in the anticoagulant and antiplatelet groups [3.07 (1.50,5.62), 1.33 (0.95,1.89), 1.61 (0.76,2.96), P < 0.001]. After one week of treatment, the reduction in NIHSS in the thrombolytic group was significantly greater than those in the other two groups [3.00 (1.00, 8.00), 1.00 (0.00, 5.00), 1.00 (0.00, 2.00), P = 0.025]. A total of 47 patients (41.2 %) had an mRS score of ≤ 2 at 3 months, and 23 patients died (20.2 %). There was no significant difference in the proportion of patients with a good prognosis or the mortality rate among the three groups (P = 0.363, P = 0.683).ConclusionsThrombolytic therapy is effective at improving short-term and 3-month prognoses. Anticoagulant therapy may be a safe and effective treatment option for patients with the cardiac stroke subtype who fail to receive intravenous recombinant tissue plasminogen activator (r-tPA) thrombolysis within 4.5 h in addition to antiplatelet therapy, as recommended by the guidelines.

Application of quantitative electroencephalogram monitoring in evaluating thrombolytic effect of acute cerebral infarction

To investigate the value of quantitative electroencephalography (qEEG) in the evaluation of thrombolytic efficacy in acute cerebral infarction. A prospective cohort study was conducted. Ninety-four patients with acute cerebral infarction who received intravenous thrombolysis admitted to the department of emergency of Qinhuangdao First Hospital from October 2019 to September 2020 were enrolled. The relative energy values of δ, θ, α and β waves in qEEG before and 2 hours, 24 hours and 7 days after intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis were dynamically monitored, and the power ratio index [DTABR, DTABR = (δ+θ)/(α+β)] was calculated. The National Institutes of Health stroke scale (NIHSS) score was also recorded. The reduction of NIHSS score ≥ 3 or the disappearance of neurological symptoms were regarded as effective thrombolytic therapy. The changes of DTABR before and after thrombolysis in patients with effective and ineffective thrombolysis were analyzed, and the correlation between DTABR and NIHSS score was analyzed by Pearson method. A total of 94 patients were enrolled, including 64 males and 30 females. The average age was (61.71±10.11) years from 36 to 89 years old. Thrombolysis was effective in 57 cases and ineffective in 37 cases. Compared with before thrombolysis, DTABR of the effective group was significantly decreased at 2 hours, 24 hours and 7 days after thrombolysis (left cerebral infarction: 1.87±1.45, 1.59±0.88, 1.58±0.90 vs. 3.82±2.60; right cerebral infarction: 1.55±0.57, 1.41±0.50, 1.35±0.44 vs. 3.20±1.63, all P < 0.05). DTABR did not change or increase significantly at 2 hours, 24 hours and 7 days after thrombolysis compared with before thrombolysis (left cerebral infarction: 3.56±2.57, 3.48±2.19, 3.54±2.50 vs. 3.11±1.62; right cerebral infarction: 5.29±3.93, 5.33±3.94, 5.19±4.52 vs. 4.73±2.43, all P > 0.05). Pearson correlation analysis showed a significant positive correlation between DTABR and NIHSS score in patients with acute cerebral infarction (r = 0.691, P < 0.01). The quantitative index of qEEG, DTABR, can accurately and quickly monitor the process of thrombolysis in acute cerebral infarction, and can effectively evaluate the effect of thrombolysis in patients.

Association Between the Change of Coagulation Parameters and Clinical Prognosis in Acute Ischemic Stroke Patients After Intravenous Thrombolysis With rt-PA

Acute ischemic stroke patients with intravenous (IV) recombinant tissue plasminogen activator (rt-PA) thrombolysis have different outcomes. The degree of thrombolysis depends largely on the delicate balance of coagulation and fibrinolysis. Thus, our study aimed to investigate the prognostic value of routine coagulation parameters in acute stroke patients treated with rt-PA. From December 2016 to October 2018, consecutive patients treated with standard-dose IV rt-PA within 4.5 h of stroke onset were collected in Beijing Tiantan Hospital. Routine coagulation parameters, including platelet count, mean platelet volume, platelet distribution width, prothrombin time (PT), activated partial thromboplastin time, thrombin time, and fibrinogen, were measured at baseline (h0) and 24 h (h24) after thrombolysis. The change of coagulation parameters was defined as the (h24-h0)/h0 ratio. The prognosis included short-term outcome at 24 h and functional outcome at 3 months. A total of 267 patients were investigated (188 men and 79 women) with a mean age of 60.88 ± 12.31 years. In total, 9 patients had early neurological deterioration within 24 h, and 99 patients had an unfavorable outcome at the 3-month visit. In multivariate logistic regression, the (h24-h0)/h0 of PT was associated with unfavorable functional outcomes at 3 months (odds ratio: 1.42, 95% confidence interval: 1.02-2.28). While the change of other coagulation parameters failed to show any correlation with short-term or long-term prognosis. In conclusion, the prolongation of PT from baseline to 24 h after IV rt-PA increases the risk of 3-month unfavorable outcomes in acute stroke patients.

Association Between Plasma Total Homocysteine Levels and Risk of Early Hemorrhagic Transformation in Patients with Acute Ischemic Stroke: A Hospital-Based Study

ObjectsIn this study, we investigated the association between plasma total homocysteine(tHcy) levels and the risk of early hemorrhagic transformation(HT) in patients with acute ischemic stroke(AIS). MethodsConsecutive hospitalized participants who met the inclusion criteria were enrolled and grouped according to plasma tHcy levels. Participants were divided into a low homocysteine level(L-tHcy) group (<12 µmol/L) and a high homocysteine level group(H-tHcy) (≥ 12 µmol/L). Baseline computed tomography (CT) examination was performed. HT was determined via CT or magnetic resonance imaging within 1 to 3 days after admission. ResultsA total of 1858 patients were screened and 1378 patients completed the this study(797 patients in the H-tHcy group and 581 patients in the L-tHcy group). HT incidence was 5.2% (30/581,) in the L-tHcy group and 11.2% (90/797) in the H-tHcy group(P<0.05). Binary logistic regression analysis showed that initial NIHSS score, tHcy levels, treatment with recombinant tissue plasminogen activator thrombolysis, systolic blood pressure on admission, glucose level on admission, smoking status and estimated glomerular filtration rate were independent risk factors for HT. Receiver operating characteristic analysis showed that tHcy level was a moderately sensitive and specific index to predict the incidence of HT, and the optimal cutoff was 16.56 μmol/L (sensitivity 63.3%, specificity 41.3%). ConclusionOur study findings reveal that high plasma tHcy level is one independent risk factor associated with increased risk of early HT in patients with AIS.

Assessing the Clinical Efficacy of Recombinant Tissue Plasminogen Activator on Acute Cerebral Infarction.

To assess the efficacy of intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis on clinical outcomes and risk of death in patients with acute cerebral infarction. Patients (n = 258) with acute cerebral infarction, treated within 4-5 h of the episode, were grouped according to whether intravenous thrombolysis was performed using rt-PA or not. Both groups received routine treatment for cerebral infarction, but the former received rt-PA intravenously at a dosage of 0.9 mg/kg. The National Institutes of Health Stroke Scale (NIHSS) score, clinical efficacy, and risk of bleeding and death were compared between the two groups. The NIHSS score and clinical effects for the rt-PA group were more favorable than those of its counterpart (P < 0.05), though there was no significant difference in risk of an intracranial hemorrhage. The mortality rate for the rt-PA group was lower than that of the control group (P < 0.05). Administration of intravenous rt-PA thrombolysis within 4.5 h of an acute cerebral infarction had a significant impact and did not increase risk of intracranial hemorrhage or death.

Improving timely treatment with a stroke emergency map: The case of northern China.

ObjectiveThe Chinese stroke emergency map (SEM) was implemented in 2017 to reduce prehospital and hospital delays for acute ischemic stroke (AIS) patients suitable for intravenous recombinant tissue plasminogen activator (rt‐PA) thrombolysis. However, data on the time delay following the implementation of an SEM in China are limited.MethodsData for suspected stroke patients from the SEM registry center of Taiyuan, Shanxi Province, from August 2017 to July 2019, patients’ characteristics, thrombolysis rate, and functional outcome at 90 days were analyzed.ResultsOne thousand seven hundred and eighty six patients who arrived at hospitals within 4.5 hr of onset were included; 35.9% arrived by emergency medical services (EMSs), and 1,207 (67.6%) of the population received intravenous rt‐PA. As a result of the SEM, the number of patients treated with rt‐PA increased from 63.9% in phase 1 (August 2017 to July 2018) to 70.5% in phase 2 (August 2018 to July 2019). The median onset‐to‐door and onset‐to‐needle times decreased by five minutes (100 [IQR: 62–135] vs. 105 [IQR: 70–145], p = .005) and nine minutes (158 [IQR: 124–197] vs. 167 [IQR: 132–214], p = .001), respectively. Patients in phase 2 achieved greater independent function outcome at 90 days (79.9% vs. 72.1%; adjusted odds ratio, 2.010; 95% confidence interval, 1.444–2.798). The binary logistic regression models revealed that shorter onset‐to‐needle time (OR: 0.994; 95% CI: 0.992–0.997; p < .001) and lower baseline NIHSS scores (OR: 39.120; 95% CI: 23.477–65.188; p < .001 and OR: 18.324; 95% CI: 11.425–29.388; p < .001 and OR: 3.123; 95% CI: 2.044–4.773; p < .001) were significant predictors for the independent function outcome.ConclusionThe implementation of a stroke emergency map is more likely to reduce prehospital delays and improve function outcomes. Future efforts should attempt to increase EMS usage.

Early prediction of the 3-month outcome for individual acute ischemic stroke patients who received intravenous thrombolysis using the N2H3 nomogram model.

Background:The aim of this study was to establish a nomogram model for individualized early prediction of the 3-month prognosis in patients with acute ischemic stroke (AIS) who were treated with intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis.Methods:A total of 691 patients were included in this study; 564 patients were included in the training cohort, while 127 patients were included in the test cohort. The main outcome measure was a 3-month unfavorable outcome (modified Rankin Scale 3–6). To construct the nomogram model, stepwise logistic regression analysis was applied to select the significant predictors of the outcome. The discriminative performance of the model was assessed by calculating the area under the receiver operating characteristic curve (AUC-ROC). A decision curve analysis was used to evaluate prognostic value of the model.Results:The initial National Institutes of Health Stroke Scale [NIHSS, odds ratio (OR), 1.35; 95% confidence interval (CI), 1.28–1.44; p < 0.001], delta NIHSS (changes in the NIHSS score from baseline to 24 h, OR, 0.75; 95% CI, 0.70–0.79; p < 0.001), hypertension (OR, 2.07; 95% CI, 1.32–3.31; p = 0.002), hyperhomocysteinemia (Hhcy, OR, 2.18; 95% CI, 1.20–4.11; p = 0.013), and the ratio of high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) (HDL-C/LDL-C, OR, 3.29; 95% CI, 1.00–10.89; p = 0.049) (N2H3) were found to be independent predictors of a 3-month unfavorable outcome from multivariate logistic regression analysis and were incorporated in the N2H3 nomogram model. The AUC-ROC of the training cohort was 0.872 (95% CI, 0.841–0.902), and the AUC-ROC of the test cohort was 0.900 (95% CI, 0.848–0.953).Conclusion:The study presented the N2H3 nomogram model, with initial NIHSS score, delta NIHSS, hypertension, Hhcy, and HDL-C/LDL-C as predictors. It therefore provides an individualized early prediction of the 3-month unfavorable outcome in AIS patients treated with intravenous rt-PA thrombolysis.

In Vitro Thrombolytic Efficacy of Single- and Five-Cycle Histotripsy Pulses and rt-PA

Although primarily known as an ablative modality, histotripsy can increase the efficacy of lytic therapy in a retracted venous clot model. Bubble cloud oscillations are the primary mechanism of action for histotripsy, and the type of bubble activity is dependent on the pulse duration. A retracted human venous clot model was perfused with and without the thrombolytic recombinant tissue plasminogen activator (rt-PA). The clot was exposed to histotripsy pulses of single- or five-cycle duration and peak negative pressures of 0–30 MPa. Bubble activity within the clot was monitored via passive cavitation imaging. The combination of histotripsy and rt-PA was more efficacious than rt-PA alone for single- and five-cycle pulses with peak negative pressures of 25 and 20 MPa, respectively. For both excitation schemes, the detected acoustic emissions correlated with the degree of thrombolytic efficacy. These results indicate that rt-PA and single- or multicycle histotripsy pulses enhance thrombolytic therapy.

Peripheral Monocyte Count Predicts Outcomes in Patients with Acute Ischemic Stroke Treated with rtPA Thrombolysis.

The aim of this study was to investigate the predictive value of the monocyte count as a prognostic biomarker on 90days in patients with acute ischemic stroke (AIS) treated with recombinant tissue plasminogen activator (rtPA) thrombolysis. In total, 206 patients with AIS treated in our institute between 2013 and 2018 were retrospectively enrolled. All patients received rtPA thrombolytic therapy within 4.5h of AIS onset. Using receiver operating characteristic (ROC) curve analysis, patients were divided into two groups according to monocyte count: a low monocyte count (LMC) group (monocytes < 0.53 × 109/L) and a high monocyte count (HMC) group (monocytes ≥ 0.53 × 109/L). Patients' functional outcomes 90days after AIS were assessed using the modified Rankin Scale. More patients had a poor outcome in the HMC group than in the LMC group (49.32% vs.31.58%, p = 0.012). Multivariate logistic regression analysis revealed that infarct volume (odds ratio = 1.03, 95% confidence interval 1.01-1.04, p < 0.001), systolic pressure at admission (odds ratio = 1.02, 95% confidence interval 1.00-1.04, p = 0.016), fasting blood glucose at admission (odds ratio = 1.41, 95% confidence interval 1.18-1.67, p < 0.001), and monocyte count ≥ 0.53 × 109/L (odds ratio = 2.25, 95% confidence interval 1.09-4.62, p = 0.028) were independently associated with a poor outcome in AIS patients treated with rtPA thrombolysis. A peripheral monocyte count ≥ 0.53 × 109/L is an independent prognostic marker on 90-days in patients with AIS treated with rtPA thrombolysis.

The effect of 220 kHz insonation scheme on rt-PA thrombolytic efficacy in vitro

Ultrasound-enhanced recombinant tissue plasminogen activator (rt-PA) thrombolysis is under development as an adjuvant to ischemic stroke therapy. The goal of this study was to design a pulsed ultrasound (US) exposure scheme that reduced intracranial constructive interference and tissue heating, and maintained thrombolytic efficacy relative to continuous wave (CW) insonation. Three 220 kHz US schemes were evaluated, two pulsed insonation schemes (15 cycles, 68 µs pulse duration, 33% or 62.5% duty cycle) and an intermittent CW insonation scheme (50 s active, 30 s quiescent) over a 30-min treatment period. An in silico study using a finite-difference model of transcranial US propagation was performed to estimate the intracranial acoustic field and temperature rise in the skull for each insonation scheme. In vitro measurements with flow were performed to assess thrombolysis using time-lapse microscopy. Intracranial constructive interference was not reduced with pulsed US using a pulse length of 15 cycles compared to intermittent CW US. The 33.3% duty cycle pulsed US scheme reduced heating in the temporal bone as much as 60% relative to the intermittent CW scheme. All insonation schemes promoted sustained stable cavitation in vitro and augmented thrombolysis compared to rt-PA alone (p < 0.05). Ultraharmonic (UH) and harmonic cumulative energy over a 30 min treatment period was significantly higher (p < 0.05) for the intermittent CW US scheme compared to either pulsed US scheme. Despite the difference in cavitation emissions, no difference was observed in the clot lysis between the three US schemes. These findings demonstrate that a 33.3% duty cycle pulsed US scheme with a 15-cycle burst can reduce bone heating and achieve equivalent thrombolytic efficacy as an intermittent CW scheme.

Shenzhen stroke emergency map improves access to rt-PA for patients with acute ischaemic stroke

Prehospital delay is one of the major causes of low rate of intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis for acute ischaemic stroke in China. Regional emergency systems have been...

Histotripsy-enhanced thrombolysis

Deep vein thrombosis (DVT) is a major public health problem, affecting 600,000 Americans annually with a healthcare cost of $10 billion. Standard interventional techniques are not effective for the chronic thrombus components present in 27% to 43% of DVT cases. Histotripsy is a focused ultrasound therapy that employs the mechanical action of bubble clouds to ablate tissue and induce vigorous fluid mixing. We have demonstrated synergy between histotripsy and the thrombolytic recombinant tissue plasminogen activator (rt-PA) for dissolution of retracted venous clots in vitro. Here, the role of histotripsy-induced bubble activity in rt-PA clot dissolution will be discussed. The rt-PA thrombolytic efficacy of histotripsy pulses that nucleate bubble activity either via (1) shock wave scattering or (2) exceeding the intrinsic cavitation threshold of the clot will be presented. The impact of each histotripsy type on the formed elements that comprise the clot will be described, as well as the likelihood of containing mechanical activity within the target zone. Finally, the utility of passive cavitation imaging to quantify the bubble activity necessary for liquefaction of tissue-mimicking phantoms representative of acute and chronic pathologies will be presented.

Intrinsic threshold versus shock scattering histotripsy treatment of clots in vitro

Catheter-directed thrombolytics are the frontline therapy for iliofemoral deep vein thrombosis. We have demonstrated that histotripsy can enhance the efficacy of the thrombolytic recombinant tissue plasminogen activator (rt-PA) through the mechanical activity of bubble clouds. Depending on the histotripsy pulse duration, bubble activity can be initiated via shock wave scattering or exceeding the peak negative pressure of the intrinsic cavitation threshold. In this study, the thrombolytic efficacy and bubble activity of shock scattering and intrinsic threshold histotripsy were compared. The mass loss was assessed of retracted human whole blood clots exposed to rt-PA (0 or 2.68 μg/mL) and histotripsy pulses of 1 (intrinsic threshold) or 5 (shock scattering) cycles duration. During the histotripsy exposure, bubble cloud emissions were captured on a linear array and processed to form passive acoustic images. The combination of rt-PA and histotripsy was more efficacious than rt-PA alone at 25 MPa peak negative pressure for single-cycle pulses, and 20 MPa peak negative pressure for five-cycle pulses. The degree of thrombolytic efficacy correlated with bubble cloud emissions within the clot. Overall, these results indicate that rt-PA and shock scattering or intrinsic threshold histotripsy is a promising combination thrombolytic therapy.

Rt-PA with remote ischemic postconditioning for acute ischemic stroke.

ObjectiveTo investigate the feasibility and safety of remote ischemic postconditioning (RIPC) in acute ischemic stroke patients after intravenous recombinant tissue plasminogen activator (rt‐PA) thrombolysis (IVT).MethodsWe performed a pilot randomized trial involving acute ischemic stroke patients with IVT. The patients were randomized 1:1 to receive RIPC or standard medical therapy. In the RIPC group, the participants underwent instant RIPC within 2 h of IVT, followed by repeated RIPC therapy for 7 days. The feasibility end point was the completion of RIPC and time from the first RIPC to finishing IVT in the RIPC group. The safety end point included tissue and neurovascular injury resulting from RIPC, changes in vital signs, level of plasma myoglobin, any hemorrhagic transformation, and other adverse events.ResultsThirty patients (15 RIPC and 15 Control) were recruited after IVT. The mean age was 65.7 ± 10.2 years, with a National Institutes of Health Stroke Scale (NIHSS) score of 6.5 (4.0–10.0). The completion rate for RIPC was 97.0%. The mean time from first RIPC to completing IVT was 66.0 (25.0–75.0) min in the RIPC group. One case of hemorrhagic transformation was observed in the RIPC group. No significant difference was found in the level of myoglobin between the two groups (P > 0.05).Interpretation RIPC is effective and safe for AIS patients after intravenous rt‐PA thrombolysis.

Sonothrombolysis: Effect of 220kHz insonation scheme

Introduction Ultrasound-enhanced recombinant tissue plasminogen activator (rt-PA) thrombolysis is under development as an adjuvant to ischemic stroke therapy. Methods Thrombolytic efficacy was evaluated for three 220-kHz US schemes, two pulsed insonation schemes (15 cycles, 68 µs pulse duration, 33% or 62.5% duty cycle) and an intermittent continuous wave (CW) insonation scheme (50 s active, 30 s quiescent) over a 30-min treatment period. In vitro measurements with flow were performed to assess thrombolysis using time-lapse microscopy. An in silico study using a finite-difference model of transcranial US propagation was performed to estimate the intracranial acoustic field as well as the temperature rise for each insonation scheme. Results Intracranial constructive interference was not reduced with pulsed US using a pulse length of 15 cycles compared to intermittent CW US. The 33.3% duty cycle pulsed US scheme reduced heating in the temporal bone as much as 60% relative to the intermittent CW scheme. All insonation schemes promoted sustained stable cavitation in vitro and augmented thrombolysis compared to rt-PA alone (p Conclusion These findings demonstrate that a 33.3% duty cycle pulsed US scheme with a 15-cycle burst can reduce bone heating and achieve equivalent thrombolytic efficacy as an intermittent CW scheme.

Preclinical Validation of the Therapeutic Potential of Glasgow Oxygen Level Dependent (GOLD) Technology: a Theranostic for Acute Stroke

In acute stroke patients, penumbral tissue is non-functioning but potentially salvageable within a time window of variable duration and represents target tissue for rescue. Reperfusion by thrombolysis and/or thrombectomy can rescue penumbra and improve stroke outcomes, but these treatments are currently available to a minority of patients. In addition to the utility of Glasgow Oxygen Level Dependent (GOLD) as an MRI contrast capable of detecting penumbra, its constituent perfluorocarbon (PFC) oxygen carrier, combined with normobaric hyperoxia, also represents a potential acute stroke treatment through improved oxygen delivery to penumbra. Preclinical studies were designed to test the efficacy of an intravenous oxygen carrier, the perfluorocarbon emulsion Oxycyte® (O-PFC), combined with normobaric hyperoxia (50% O2) in both in vitro (neuronal cell culture) and in vivo rat models of ischaemic stroke. Outcome was assessed through the quantification of lipid peroxidation and oxidative stress levels, mortality, infarct volume, neurological scoring and sensorimotor tests of functional outcome in two in vivo models of stroke. Additionally, we investigated evidence for any positive or negative interactions with the thrombolytic recombinant tissue plasminogen activator (rt-PA) following embolus-induced stroke in rats. Treatment with intravenous O-PFC + normobaric hyperoxia (50% O2) provided evidence of reduced infarct size and improved functional recovery. It did not exacerbate oxidative stress and showed no adverse interactions with rt-PA. The positive results and lack of adverse effects support human trials of O-PFC + 50% O2 normobaric hyperoxia as a potential therapeutic approach. Combined with the diagnostic data presented in the preceding paper, O-PFC and normobaric hyperoxia is a potential theranostic for acute ischaemic stroke.