The Experts below are selected from a list of 564 Experts worldwide ranked by ideXlab platform

Andrei V. Alexandrov - One of the best experts on this subject based on the ideXlab platform.

  • Ultrasound- and Microspheres-Enhanced Thrombolysis for Stroke Treatment: State of the Art
    Current Cardiology Reports, 2010
    Co-Authors: Clotilde Balucani, Andrei V. Alexandrov
    Abstract:

    Intravenous administration of recombinant tissue-plasminogen activator (rt-PA) remains the fastest and widely feasible strategy to initiate treatment in acute ischemic stroke. Because it works by inducing recanalization of an occluded vessel, augmentation of this process is desirable and diagnostic transcranial Doppler (TCD) ultrasound can accomplish this safely. A 2-MHz pulsed-wave monitoring can at least double the chance of early complete arterial recanalization at no increase in the risk of symptomatic intracerebral hemorrhage. Gaseous microspheres, initially developed as ultrasound contrast agents, can further increase the effectiveness of rt-PA. A recent microsphere dose-escalation study called TUCSON showed sustained complete recanalization rates of 67% in patients receiving TCD monitoring with a 1.4-mL Perflutren-lipid microsphere dose compared with controls receiving rt-PA alone with no increase in hemorrhage rate. In this article, we review the current and emerging applications of ultrasound and microspheres in stroke management including augmentation of systemic thrombolysis and implications for future reperfusion strategies.

  • Safety and dose‐escalation study design of Transcranial Ultrasound in Clinical SONolysis for acute ischemic stroke: the TUCSON Trial
    International journal of stroke : official journal of the International Stroke Society, 2009
    Co-Authors: Andrew D Barreto, Andrei V. Alexandrov, Vijay K. Sharma, Annabelle Y. Lao, Paul Sierzenski, Peter D. Schellinger, Pierre Amarenco, Carlos A. Molina
    Abstract:

    Rationale Transcranial Doppler (TCD) monitoring during intravenous tissue plasminogen activator (i.v.-tPA) infusion increases recanalization rates in acute ischemic stroke. Addition of Perflutren-lipid microspheres MRX-801 (microS) may further enhance the process of recanalization. This article describes the design of the Transcranial Ultrasound in Clinical SONolysis (TUCSON) trial. Aims and Design TUCSON is a phase I-II, randomized, placebo-controlled, open-label, safety, dose-escalation clinical trial of microS+TCD ultrasound (sonolysis). Patients with acute ischemic stroke and arterial intracranial occlusions are enrolled within 3 h of symptom onset. All patients receive standard i.v.-tPA and will be randomized to 90 min of continuous 2-MHz TCD+microS or 90 min of saline+brief TCD vessel assessments. The safety profile of four escalating dose tiers will be assessed. Arterial occlusions and recanalization are defined with the Thrombolysis in Brain Ischemia flow grades. Study Outcomes Safety is determined by the rates of symptomatic intracerebral hemorrhage within 36 h. Neurological deficits and outcomes are measured with the National Institute of Health Stroke Scale and modified Rankin Scale (mRS). The signal-of-efficacy is determined by rates of recanalization, dramatic or early clinical recovery within 2 h, clinical recovery at 24-36 h and independent outcome (mRS 0-2) at 90 days.

  • quantification of microspheres appearance in brain vessels implications for residual flow velocity measurements dose calculations and potential drug delivery
    Stroke, 2008
    Co-Authors: Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Marc D. Malkoff, Anne W Alexandrov, Andrei V. Alexandrov
    Abstract:

    Background and Purpose— Characteristics of ultrasound-activated gaseous microspheres (μS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials. Methods— A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler μS traces included large (>8μ) μS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small (<5μ) μS from acute patients without shunts receiving thrombolysis and Perflutren-lipid μS. Results— In 101 μS traces from 50 RLS-positive and 10 thrombolysis+μS treated patients, a large μS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0ms), multi-gate travel time (MGTT) 58.6±19.3 ms versus small μS: duration 8.3ms (IQR 4.3ms), MGTT 43.2±13.9ms, P<0.001. Small μS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P<0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embo...

  • a pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound activated Perflutren lipid microspheres for acute ischemic stroke
    Stroke, 2008
    Co-Authors: Andrei V. Alexandrov, Robert Mikulik, Marc Ribo, Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Rebecca M. Sugg, Andrew D Barreto
    Abstract:

    Background and Purpose— Ultrasound transiently expands Perflutren-lipid microspheres (μS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated μS with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL μS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. μS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P<0.001. In 75% of subjects, μS permeated to area...

  • A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke
    Stroke, 2008
    Co-Authors: Andrei V. Alexandrov, Robert Mikulik, Marc Ribo, Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Rebecca M. Sugg, Andrew D Barreto, Paul Sierzenski, Marc D. Malkoff
    Abstract:

    Background and Purpose— Ultrasound transiently expands Perflutren-lipid microspheres (μS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated μS with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL μS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. μS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P

Georgios Tsivgoulis - One of the best experts on this subject based on the ideXlab platform.

  • Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial.
    Annals of neurology, 2009
    Co-Authors: Carlos A. Molina, Robert Mikulik, Georgios Tsivgoulis, Andrew D Barreto, Paul Sierzenski, Marc D. Malkoff, Marta Rubiera, Nicole R. Gonzales, Greg Pate, James Ostrem
    Abstract:

    OBJECTIVE: Microspheres (microS) reach intracranial occlusions and transmit energy momentum from an ultrasound wave to residual flow to promote recanalization. We report a randomized multicenter phase II trial of microS dose escalation with systemic thrombolysis. METHODS: Stroke patients receiving 0.9mg/kg tissue plasminogen activator (tPA) with pretreatment proximal intracranial occlusions on transcranial Doppler (TCD) were randomized (2:1 ratio) to microS (MRX-801) infusion over 90 minutes (Cohort 1, 1.4ml; Cohort 2, 2.8ml) with continuous TCD insonation, whereas controls received tPA and brief TCD assessments. The primary endpoint was symptomatic intracerebral hemorrhage (sICH) within 36 hours after tPA. RESULTS: Among 35 patients (Cohort 1 = 12, Cohort 2 = 11, controls = 12) no sICH occurred in Cohort 1 and controls, whereas 3 (27%, 2 fatal) sICHs occurred in Cohort 2 (p = 0.028). Sustained complete recanalization/clinical recovery rates (end of TCD monitoring/3 month) were 67%/75% for Cohort 1, 46%/50% for Cohort 2, and 33%/36% for controls (p = 0.255/0.167). The median time to any recanalization tended to be shorter in Cohort 1 (30 min; interquartile range [IQR], 6) and Cohort 2 (30 min; IQR, 69) compared to controls (60 min; IQR, 5; p = 0.054). Although patients with sICH had similar screening and pretreatment systolic blood pressure (SBP) levels in comparison to the rest, higher SBP levels were documented in sICH+ patients at 30 minutes, 60 minutes, 90 minutes, and 24-36 hours following tPA bolus. INTERPRETATION: Perflutren lipid microS can be safely combined with systemic tPA and ultrasound at a dose of 1.4ml. Safety concerns in the second dose tier may necessitate extended enrollment and further experiments to determine the mechanisms by which microspheres interact with tissues. In both dose tiers, sonothrombolysis with microS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy. Ann Neurol 2009;66:28-38.

  • quantification of microspheres appearance in brain vessels implications for residual flow velocity measurements dose calculations and potential drug delivery
    Stroke, 2008
    Co-Authors: Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Marc D. Malkoff, Anne W Alexandrov, Andrei V. Alexandrov
    Abstract:

    Background and Purpose— Characteristics of ultrasound-activated gaseous microspheres (μS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials. Methods— A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler μS traces included large (>8μ) μS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small (<5μ) μS from acute patients without shunts receiving thrombolysis and Perflutren-lipid μS. Results— In 101 μS traces from 50 RLS-positive and 10 thrombolysis+μS treated patients, a large μS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0ms), multi-gate travel time (MGTT) 58.6±19.3 ms versus small μS: duration 8.3ms (IQR 4.3ms), MGTT 43.2±13.9ms, P<0.001. Small μS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P<0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embo...

  • a pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound activated Perflutren lipid microspheres for acute ischemic stroke
    Stroke, 2008
    Co-Authors: Andrei V. Alexandrov, Robert Mikulik, Marc Ribo, Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Rebecca M. Sugg, Andrew D Barreto
    Abstract:

    Background and Purpose— Ultrasound transiently expands Perflutren-lipid microspheres (μS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated μS with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL μS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. μS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P<0.001. In 75% of subjects, μS permeated to area...

  • A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke
    Stroke, 2008
    Co-Authors: Andrei V. Alexandrov, Robert Mikulik, Marc Ribo, Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Rebecca M. Sugg, Andrew D Barreto, Paul Sierzenski, Marc D. Malkoff
    Abstract:

    Background and Purpose— Ultrasound transiently expands Perflutren-lipid microspheres (μS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated μS with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL μS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. μS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P

  • Quantification of Microspheres Appearance in Brain Vessels: Implications for Residual Flow Velocity Measurements, Dose Calculations, and Potential Drug Delivery
    Stroke, 2008
    Co-Authors: Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Marc D. Malkoff, Anne W Alexandrov, Andrei V. Alexandrov
    Abstract:

    Characteristics of ultrasound-activated gaseous microspheres (muS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials. A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler microS traces included large (>8 micro) microS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small (<5 micro) microS from acute patients without shunts receiving thrombolysis and Perflutren-lipid microS. In 101 microS traces from 50 RLS-positive and 10 thrombolysis+microS treated patients, a large microS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0 ms), multi-gate travel time (MGTT) 58.6+/-19.3 ms versus small microS: duration 8.3 ms (IQR 4.3 ms), MGTT 43.2+/-13.9 ms, P<0.001. Small microS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P<0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embolus-to-Blood Ratio) 0.927 (0.871 to 0.982), P<0.001. A 15.1-ms duration discriminated size ranges with 98% to 99% accuracy. On average, 130 sequential large (range 51 to 260) and 500 (265-588) small microS can produce continuous flow enhancement for 4 seconds. Small microS velocities on m-mode in obstructed vessels (39.8+/-11.3 cm/s) were similar to large microS in patent vessels (40.8+/-11.5 cm/s; P=0.719) and higher than surrounding red blood cell velocities (28.8+/-13.8 cm/s, P<0.001). With normal or reduced flow, activated muS passage duration through a small power motion Doppler gate can quantify the dose of delivered microS. Ultrasound can determine a minimum number of microS needed to achieve constant flow enhancement and targeted drug delivery. Propagation speed of microS smaller than red blood cells may reflect plasma flow velocities around acute occlusions.

Michael L. Main - One of the best experts on this subject based on the ideXlab platform.

  • Acute Mortality in Critically Ill Patients Undergoing Echocardiography With or Without an Ultrasound Contrast Agent
    JACC. Cardiovascular imaging, 2013
    Co-Authors: Michael L. Main, Amy Ryan, Mark G. Hibberd, Timothy J. Lowe, Paula E. Miller, Gajanan Bhat
    Abstract:

    The objective of this observational study was to compare 48-h all-cause mortality (as well as hospital stay mortality) among critically ill patients who underwent echocardiography either with or without an ultrasound contrast agent (UCA). The safety of Perflutren-based UCAs has been questioned by the U.S. Food and Drug Administration (particularly when administered to critically ill patients) following rare reports of deaths or life-threatening adverse reactions that occurred in close temporal relationship to UCA administration. This was a retrospective observational outcome study conducted in critically ill patients to compare all-cause 48-h and hospital stay mortality subsequent to echocardiography procedures performed either with or without a UCA. The study utilized discharge data from a database maintained by Premier, Inc. (Charlotte, North Carolina). Premier's database is the largest U.S. hospital-based, service-level comparative database for quality and outcomes research, and provides detailed resource utilization data along with patients' primary and secondary diagnoses and procedure billing codes. A propensity score-matching algorithm between UCA-enhanced echocardiography patients and non-contrast-enhanced echocardiography patients was utilized to reduce the potential for imbalance in covariates of selected patients in the comparison of mortality between groups. Patients undergoing echocardiography with a UCA had lower mortality at 48 h compared with patients undergoing non-contrast-enhanced echocardiography (1.70% vs. 2.50%), with an odds ratio = 0.66 (95% confidence interval [CI]: 0.54 to 0.80). Patients undergoing echocardiography with a UCA had lower hospital stay mortality compared with patients undergoing noncontrast echocardiography (14.85% vs. 15.66%), with an odds ratio = 0.89 (95% CI: 0.84 to 0.96). In critically ill, propensity-matched hospitalized patients undergoing echocardiography, use of a UCA is associated with a 28% lower mortality at 48 h in comparison with patients undergoing non-contrast-enhanced echocardiography. These results are reassuring, given previous reports suggesting an association between UCAs and increased mortality in critically ill patients. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  • CaRES (Contrast Echocardiography Registry for Safety Surveillance): A Prospective Multicenter Study to Evaluate the Safety of the Ultrasound Contrast Agent Definity in Clinical Practice
    Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography, 2012
    Co-Authors: Robert J. Weiss, Mark G. Hibberd, Masood Ahmad, Flordeliza S. Villanueva, Stephen Schmitz, Gajanan Bhat, Michael L. Main
    Abstract:

    Definity (Perflutren lipid microsphere) is an ultrasound contrast agent approved for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. This prospective, open-label, nonrandomized, multicenter, phase 4 surveillance registry study was conducted at 15 clinical sites in the United States and was designed to assess the risk for adverse cardiopulmonary events occurring during or within the initial 30 min after Definity administration in routine clinical practice. Patients with suboptimal baseline images were consecutively approached regarding study participation. Safety monitoring including vital sign measurements, continuous electrocardiographic monitoring, and continuous oxygen saturation was initiated at baseline before Definity administration and then at regular intervals for 30 min after Definity injection. Patients were assessed for adverse events at 30 min after Definity administration and then contacted by telephone at 24 ± 4 hours to record any subsequent adverse events. A total of 1,060 patients were enrolled at 15 clinical sites. Of these, 1,053 (99.3%) received at least one dose of Definity and completed the study. No deaths, serious adverse events, or other significant adverse events occurred during this study. The overall adverse event rate was 10.8% (4.5% in patients undergoing rest echocardiography, 13% in patients undergoing rest and exercise stress echocardiography, and 27.7% in patients undergoing rest and pharmacologic stress echocardiography). The overall drug-related adverse event rate (patients with at least one adverse event reported by the principal investigator as related to Definity) was only 3.5%, and most of these (110 of 114 [96.5%]) were reported by the investigator as mild or moderate in intensity. Definity is well tolerated in routine clinical practice in patients with a high prevalence of cardiopulmonary disease. Copyright © 2012 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

  • The History of Product Label Changes for DEFINITY® in the US
    Spring, 2012
    Co-Authors: Harshal Patil, Michael L. Main
    Abstract:

    DEFINITY® (Perflutren Lipid Microsphere Injectable Suspension, Lantheus Medical Imaging, North Billerica, MA) was approved by the US Food and Drug Administration in 2001 for “opacification of the left ventricular border in patients with technically difficult echocardiograms”. Since then, product labeling has been substantially revised on three occasions, initially due to safety concerns, and more recently to reflect a large body of literature which supports the excellent risk–benefit profile of this agent. This article describes in detail the substantive modifications of the product labeling for DEFINITY since 2001, and the associated supportive scientific data and public regulatory meetings.

  • A retrospective comparison of mortality in critically ill hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent.
    JACC. Cardiovascular imaging, 2010
    Co-Authors: A. Exuzides, Michael L. Main, Chris Colby, Paul A. Grayburn, Steven B. Feinstein, Jonathan H. Goldman
    Abstract:

    To compare acute mortality in critically ill hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (UCA). Because of serious cardiopulmonary reactions reported immediately after administration of Perflutren-containing UCAs, the FDA required a black box safety warning for this class of agents, including Perflutren protein-type A microspheres injectable suspension. This study used the largest hospital service-level database in the U.S. All adult patients undergoing in-patient echocardiography between January 2003 and October 2005 were identified (n = 2,588,722, of which 22,499 received Perflutren protein-type A microspheres injectable suspension). Of the 22,499 contrast echocardiography patients, 2,900 had diagnoses meeting criteria for critical illness (heart failure, acute myocardial infarction, arrhythmia, respiratory failure, pulmonary embolism, emphysema, and pulmonary hypertension). To control for the differences between the contrast and noncontrast patients, we used propensity score matching. Variables used in the construction of the propensity score included comorbidities, demographic factors, hospital-specific factors, level of care, and mechanical ventilation status. Patients receiving contrast echocardiography were matched to 4 control patients who received noncontrast echocardiography. Conditional logistic regression was used to estimate mortality effects. There were 167 deaths in the study among critically ill patients, 38 of 2,900 from the contrast group and 129 of 11,600 from the control group. The contrast agent was not associated with an increase in same-day mortality (odds ratio: 1.18; 95% confidence interval: 0.82 to 1.71; p = 0.37). Before matching, contrast patients showed greater morbidity than noncontrast patients (Deyo-Charlson comorbidity score 2.45 vs. 2.25, p < 0.0001). After propensity score matching, these differences were significantly reduced, showing that both groups were well balanced. There is no increase in mortality in critically ill patients undergoing echocardiography with the UCA compared with case-matched control patients. Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  • Ultrasound contrast agents: balancing safety versus efficacy.
    Expert opinion on drug safety, 2009
    Co-Authors: Michael L. Main, Jonathan H. Goldman, Paul A. Grayburn
    Abstract:

    In October, 2007, the FDA issued a new 'black box' warning, several new disease state contraindications and a mandated 30-min post-procedure monitoring period for the ultrasound contrast agents Definity (Perflutren lipid microsphere injectable suspension, Lantheus Medical Imaging, North Billerica, MA, USA) and Optison (Perflutren protein type A microspheres for injectable suspension, GE Healthcare, Buckinghamshire, UK). These labeling changes were largely secondary to reports of 4 patient deaths, and approximately 190 other 'serious cardiopulmonary reactions' that were temporally related but not clearly causally attributable to Definity administration. Contrast agent use in the US plummeted in the immediate aftermath of this FDA action, with many hospitals, physician offices and outpatient imaging centers suspending contrast echocardiography altogether. This review will focus on the immediate response from the international physician community, new contrast agent safety data published within the past year, results of a special meeting of the FDA Cardio-Renal panel devoted to contrast agent safety in June 2008, recently issued revised product labeling for both agents and future prospects for contrast echocardiography.

Marc D. Malkoff - One of the best experts on this subject based on the ideXlab platform.

  • Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial.
    Annals of neurology, 2009
    Co-Authors: Carlos A. Molina, Robert Mikulik, Georgios Tsivgoulis, Andrew D Barreto, Paul Sierzenski, Marc D. Malkoff, Marta Rubiera, Nicole R. Gonzales, Greg Pate, James Ostrem
    Abstract:

    OBJECTIVE: Microspheres (microS) reach intracranial occlusions and transmit energy momentum from an ultrasound wave to residual flow to promote recanalization. We report a randomized multicenter phase II trial of microS dose escalation with systemic thrombolysis. METHODS: Stroke patients receiving 0.9mg/kg tissue plasminogen activator (tPA) with pretreatment proximal intracranial occlusions on transcranial Doppler (TCD) were randomized (2:1 ratio) to microS (MRX-801) infusion over 90 minutes (Cohort 1, 1.4ml; Cohort 2, 2.8ml) with continuous TCD insonation, whereas controls received tPA and brief TCD assessments. The primary endpoint was symptomatic intracerebral hemorrhage (sICH) within 36 hours after tPA. RESULTS: Among 35 patients (Cohort 1 = 12, Cohort 2 = 11, controls = 12) no sICH occurred in Cohort 1 and controls, whereas 3 (27%, 2 fatal) sICHs occurred in Cohort 2 (p = 0.028). Sustained complete recanalization/clinical recovery rates (end of TCD monitoring/3 month) were 67%/75% for Cohort 1, 46%/50% for Cohort 2, and 33%/36% for controls (p = 0.255/0.167). The median time to any recanalization tended to be shorter in Cohort 1 (30 min; interquartile range [IQR], 6) and Cohort 2 (30 min; IQR, 69) compared to controls (60 min; IQR, 5; p = 0.054). Although patients with sICH had similar screening and pretreatment systolic blood pressure (SBP) levels in comparison to the rest, higher SBP levels were documented in sICH+ patients at 30 minutes, 60 minutes, 90 minutes, and 24-36 hours following tPA bolus. INTERPRETATION: Perflutren lipid microS can be safely combined with systemic tPA and ultrasound at a dose of 1.4ml. Safety concerns in the second dose tier may necessitate extended enrollment and further experiments to determine the mechanisms by which microspheres interact with tissues. In both dose tiers, sonothrombolysis with microS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy. Ann Neurol 2009;66:28-38.

  • quantification of microspheres appearance in brain vessels implications for residual flow velocity measurements dose calculations and potential drug delivery
    Stroke, 2008
    Co-Authors: Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Marc D. Malkoff, Anne W Alexandrov, Andrei V. Alexandrov
    Abstract:

    Background and Purpose— Characteristics of ultrasound-activated gaseous microspheres (μS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials. Methods— A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler μS traces included large (>8μ) μS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small (<5μ) μS from acute patients without shunts receiving thrombolysis and Perflutren-lipid μS. Results— In 101 μS traces from 50 RLS-positive and 10 thrombolysis+μS treated patients, a large μS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0ms), multi-gate travel time (MGTT) 58.6±19.3 ms versus small μS: duration 8.3ms (IQR 4.3ms), MGTT 43.2±13.9ms, P<0.001. Small μS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P<0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embo...

  • A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke
    Stroke, 2008
    Co-Authors: Andrei V. Alexandrov, Robert Mikulik, Marc Ribo, Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Rebecca M. Sugg, Andrew D Barreto, Paul Sierzenski, Marc D. Malkoff
    Abstract:

    Background and Purpose— Ultrasound transiently expands Perflutren-lipid microspheres (μS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated μS with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL μS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. μS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P

  • Quantification of Microspheres Appearance in Brain Vessels: Implications for Residual Flow Velocity Measurements, Dose Calculations, and Potential Drug Delivery
    Stroke, 2008
    Co-Authors: Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Marc D. Malkoff, Anne W Alexandrov, Andrei V. Alexandrov
    Abstract:

    Characteristics of ultrasound-activated gaseous microspheres (muS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials. A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler microS traces included large (>8 micro) microS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small (<5 micro) microS from acute patients without shunts receiving thrombolysis and Perflutren-lipid microS. In 101 microS traces from 50 RLS-positive and 10 thrombolysis+microS treated patients, a large microS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0 ms), multi-gate travel time (MGTT) 58.6+/-19.3 ms versus small microS: duration 8.3 ms (IQR 4.3 ms), MGTT 43.2+/-13.9 ms, P<0.001. Small microS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P<0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embolus-to-Blood Ratio) 0.927 (0.871 to 0.982), P<0.001. A 15.1-ms duration discriminated size ranges with 98% to 99% accuracy. On average, 130 sequential large (range 51 to 260) and 500 (265-588) small microS can produce continuous flow enhancement for 4 seconds. Small microS velocities on m-mode in obstructed vessels (39.8+/-11.3 cm/s) were similar to large microS in patent vessels (40.8+/-11.5 cm/s; P=0.719) and higher than surrounding red blood cell velocities (28.8+/-13.8 cm/s, P<0.001). With normal or reduced flow, activated muS passage duration through a small power motion Doppler gate can quantify the dose of delivered microS. Ultrasound can determine a minimum number of microS needed to achieve constant flow enhancement and targeted drug delivery. Propagation speed of microS smaller than red blood cells may reflect plasma flow velocities around acute occlusions.

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  • A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke
    2016
    Co-Authors: Annabelle Y. Lao
    Abstract:

    Background and Purpose—Ultrasound transiently expands Perflutren-lipid microspheres (S), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated S with systemic tissue plasminogen activator (tPA). Methods—Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPATCD) or Target (tPATCD2.8 mL S). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by 4 NIHSS points within 72 hours. Results—Fifteen subjects were randomized 3:1 to Target, n12 or Control, n3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. S reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.811.3 vs 28.813.8 cm/s, P0.001. In 75 % of subjects, S permeated to areas with no pretreatment residual flow, and in 83 % residual flow velocity improved at a median of 30 minutes from start of S infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118 % above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50 % versus 18%, partial 33 % versus 33%, none 17 % versus 49%, P0.028. At 2 hours, sustained complete recanalization was 42 % versus 13%, P0.003, and NIHS

  • Safety and dose‐escalation study design of Transcranial Ultrasound in Clinical SONolysis for acute ischemic stroke: the TUCSON Trial
    International journal of stroke : official journal of the International Stroke Society, 2009
    Co-Authors: Andrew D Barreto, Andrei V. Alexandrov, Vijay K. Sharma, Annabelle Y. Lao, Paul Sierzenski, Peter D. Schellinger, Pierre Amarenco, Carlos A. Molina
    Abstract:

    Rationale Transcranial Doppler (TCD) monitoring during intravenous tissue plasminogen activator (i.v.-tPA) infusion increases recanalization rates in acute ischemic stroke. Addition of Perflutren-lipid microspheres MRX-801 (microS) may further enhance the process of recanalization. This article describes the design of the Transcranial Ultrasound in Clinical SONolysis (TUCSON) trial. Aims and Design TUCSON is a phase I-II, randomized, placebo-controlled, open-label, safety, dose-escalation clinical trial of microS+TCD ultrasound (sonolysis). Patients with acute ischemic stroke and arterial intracranial occlusions are enrolled within 3 h of symptom onset. All patients receive standard i.v.-tPA and will be randomized to 90 min of continuous 2-MHz TCD+microS or 90 min of saline+brief TCD vessel assessments. The safety profile of four escalating dose tiers will be assessed. Arterial occlusions and recanalization are defined with the Thrombolysis in Brain Ischemia flow grades. Study Outcomes Safety is determined by the rates of symptomatic intracerebral hemorrhage within 36 h. Neurological deficits and outcomes are measured with the National Institute of Health Stroke Scale and modified Rankin Scale (mRS). The signal-of-efficacy is determined by rates of recanalization, dramatic or early clinical recovery within 2 h, clinical recovery at 24-36 h and independent outcome (mRS 0-2) at 90 days.

  • quantification of microspheres appearance in brain vessels implications for residual flow velocity measurements dose calculations and potential drug delivery
    Stroke, 2008
    Co-Authors: Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Marc D. Malkoff, Anne W Alexandrov, Andrei V. Alexandrov
    Abstract:

    Background and Purpose— Characteristics of ultrasound-activated gaseous microspheres (μS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials. Methods— A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler μS traces included large (>8μ) μS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small (<5μ) μS from acute patients without shunts receiving thrombolysis and Perflutren-lipid μS. Results— In 101 μS traces from 50 RLS-positive and 10 thrombolysis+μS treated patients, a large μS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0ms), multi-gate travel time (MGTT) 58.6±19.3 ms versus small μS: duration 8.3ms (IQR 4.3ms), MGTT 43.2±13.9ms, P<0.001. Small μS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P<0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embo...

  • a pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound activated Perflutren lipid microspheres for acute ischemic stroke
    Stroke, 2008
    Co-Authors: Andrei V. Alexandrov, Robert Mikulik, Marc Ribo, Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Rebecca M. Sugg, Andrew D Barreto
    Abstract:

    Background and Purpose— Ultrasound transiently expands Perflutren-lipid microspheres (μS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated μS with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL μS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. μS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P<0.001. In 75% of subjects, μS permeated to area...

  • A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke
    Stroke, 2008
    Co-Authors: Andrei V. Alexandrov, Robert Mikulik, Marc Ribo, Vijay K. Sharma, Annabelle Y. Lao, Georgios Tsivgoulis, Rebecca M. Sugg, Andrew D Barreto, Paul Sierzenski, Marc D. Malkoff
    Abstract:

    Background and Purpose— Ultrasound transiently expands Perflutren-lipid microspheres (μS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated μS with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL μS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. μS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P