James H. Wible

Performance of Delayed-Enhancement Magnetic Resonance Imaging With Gadoversetamide Contrast for the Detection and Assessment of Myocardial Infarction An International, Multicenter, Double-Blinded, Randomized Trial

Background— The identification and assessment of myocardial infarction (MI) are important for therapeutic and prognostic purposes, yet current recommended diagnostic strategies have significant limitations. We prospectively tested the performance of delayed-enhancement magnetic resonance imaging (MRI) with gadolinium-based contrast for the detection of MI in an international, multicenter trial. Methods and Results— Patients with their first MI were enrolled in an acute (≤16 days after MI; n=282) or chronic (17 days to 6 months; n=284) arm and then randomized to 1 of 4 doses of gadoversetamide: 0.05, 0.1, 0.2, or 0.3 mmol/kg. Standard delayed-enhancement MRI was performed before contrast (control) and 10 and 30 minutes after gadoversetamide. For blinded analysis, precontrast and postcontrast MRIs were randomized and then scored for enhanced regions by 3 independent readers not associated with the study. The infarct-related artery perfusion territory was scored from x-ray angiograms separately. In total, 566 scans were performed in 26 centers using commercially available scanners from all major US/European vendors. All scans were included in the analysis. The sensitivity of MRI for detecting MI increased with rising dose of gadoversetamide (P<0.0001), reaching 99% (acute) and 94% (chronic) after contrast compared with 11% before contrast. Likewise, the accuracy of MRI for identifying MI location (compared with infarct-related artery perfusion territory) increased with rising dose of gadoversetamide (P<0.0001), reaching 99% (acute) and 91% (chronic) after contrast compared with 9% before contrast. For gadoversetamide doses ≥0.2 mmol/kg, 10- and 30-minute images provided equal performance, and peak creatine kinase-MB levels correlated with MRI infarct size (P<0.0001). Conclusions— Gadoversetamide-enhanced MRI using doses of ≥0.2 mmol/kg is effective in the detection and assessment of both acute and chronic MI. This study represents the first multicenter trial designed to evaluate an imaging approach for detecting MI.

Bioeffects Considerations for Diagnostic Ultrasound Contrast Agents

Diagnostic ultrasound contrast agents have been developed for enhancing the echogenicity of blood and for delineating other structures of the body. Approved agents are suspensions of gas bodies (stabilized microbubbles), which have been designed for persistence in the circulation and strong echo return for imaging. The interaction of ultrasound pulses with these gas bodies is a form of acoustic cavitation, and they also may act as inertial cavitation nuclei. This interaction produces mechanical perturbation and a potential for bioeffects on nearby cells or tissues. In vitro, sonoporation and cell death occur at mechanical index (MI) values less than the inertial cavitation threshold. In vivo, bioeffects reported for MI values greater than 0.4 include microvascular leakage, petechiae, cardiomyocyte death, inflammatory cell infiltration, and premature ventricular contractions and are accompanied by gas body destruction within the capillary bed. Bioeffects for MIs of 1.9 or less have been reported in skeletal muscle, fat, myocardium, kidney, liver, and intestine. Therapeutic applications that rely on these bioeffects include targeted drug delivery to the interstitium and DNA transfer into cells for gene therapy. Bioeffects of contrast‐aided diagnostic ultrasound happen on a microscopic scale, and their importance in the clinical setting remains uncertain.

Detection of individual microbubbles of ultrasound contrast agents: imaging of free-floating and targeted bubbles.

Rationale and Objectives:During echo examinations with microbubble contrast, individual “dots” of ultrasound reflection can be visualized. To address the question whether these signals represent individual microbubbles, very dilute suspensions of ultrasound contrast agents or individual microbubbles attached to Petri dishes were prepared and studied by ultrasound imaging. Methods:Microbubble suspensions were diluted in saline and evaluated by a clinical ultrasound imaging system. Microbubble concentration was verified by Coulter counter. Single microbubble preparation on a Petri dish was established by streptavidin–biotin interaction under microscopy control and subjected to ultrasound imaging. Results:Ultrasound of dilute microbubble dispersions demonstrated distinct white foci; concentration of these sites was consistent with signals from individual microbubbles as determined by Coulter. Individual microbubbles immobilized on polystyrene were also visualized by ultrasound. Conclusion:Ultrasound medical systems can resolve backscatter signals from individual microbubbles of ultrasound contrast, both in solution and in the targeted immobilized state, implying picogram sensitivity.

American Institute of Ultrasound in Medicine consensus report on potential bioeffects of diagnostic ultrasound: Executive summary

The continued examination of potential biological effects of ultrasound and their relationship to clinical practice is a key element in evaluating the safety of diagnostic ultrasound. Periodically, the American Institute of Ultrasound in Medicine (AIUM) sponsors conferences bringing experts together to examine the literature on ultrasound bioeffects and to develop conclusions and recommendations related to diagnostic ultrasound. The most recent effort included the examination of effects whose origins were thermal or nonthermal, with separate evaluations for potential effects related to fetal ultrasound. In addition, potential effects due to the introduction of ultrasound contrast agents were summarized. This information can be used to assess risks in comparison to the benefits of diagnostic ultrasound. The conclusions and recommendations are organized into 5 broad categories, with a comprehensive background and evaluation of each topic provided in the corresponding articles in this issue. The following summary is not meant as a substitute for the detailed examination of issues presented in each of the articles but rather as a means to facilitate further study of this consensus report and implementation of its recommendations. The conclusions and recommendations are the result of several rounds of deliberations at the consensus conference, subsequent review by the Bioeffects Committee of the AIUM, and approval by the AIUM Board of Governors.

Detection of individual microbubbles of an ultrasound contrast agent: fundamental and pulse inversion imaging.

The use of ultrasound contrast materials in diagnostic imaging has been steadily increasing, with several agents recently approved for clinical application (1). When contrast echo imaging is performed, individual “speckles” of contrast can be often observed in the interrogated tissues. These white foci may represent the images of individual micron-sized bubbles. This implies exceptional detection sensitivity of ultrasound imaging with contrast agents. The capability of echo imaging to detect individual microbubbles is important for the quantification of the amount of bubbles in the tissues, determination of microvascular volume and targeted microbubble imaging. In order to test the ability of ultrasound imaging to detect individual microbubbles, dilute dispersions of microbubbles were prepared and evaluated by ultrasound imaging in vitro.

Targeting and ultrasound imaging of microbubble-based contrast agents.

Preparation and characterization of targeted microbubbles (ultrasound contrast agents) is described. Specific ligands were attached to the microbubble shell, and ligand-coated microbubbles were selectively attached to various targets, using either an avidin-biotin model system or an antigen-antibody system for targeting to live activated endothelial cells. Firm attachment of microbubbles to the target was achieved. Forces necessary to detach microbubbles from the target were estimated to exceed dozens of pN. Microbubbles were bound to the target even in the rapidly moving stream of the aqueous medium. Down to 20 ng of the ultrasound contrast material on the target surface could be detected by the ultrasound imaging with a commercial medical imaging system. At high bubble density on the target surface, strong ultrasound image attenuation was observed.

Sonography with sonicated albumin in the detection of vesicoureteral reflux

AbstractThe primary radiological procedures for diagnosing vesicoureteral reflux are fluoroscopic and radionuclide cystography. Ultrasonography, with no ionizing radiation, would be useful as a screening tool for the diagnosis of reflux due to its absence of radiation exposure. We evaluated the usefulness of ultrasonography with sonicated albumin in the diagnosis of vesicoureteral reflux. Sonicated albumin contains approximately 3 to 5 × 108 microspheres per ml., which are echogenic. Sonicated albumin was tested in vitro, alone, and in human and porcine urine to assess microsphere stability. Urine dilutions, specific gravity, temperature and pH were used as variables. The mode of delivery was also tested in vitro and in vivo. These studies showed that sonicated albumin microspheres were stable over a wide range of chemical variables and urine composition. Sonicated albumin produced an image of uniform echogenicity when it was pre-loaded into a Foley catheter and followed by saline infusion in vitro.Fluoro...

Direct video-microscopic observation of the dynamic effects of medical ultrasound on ultrasound contrast microspheres.

RATIONALE AND OBJECTIVES Ultrasound can cause destruction of microbubble contrast agents used to enhance medical ultrasound imaging. This study sought to characterize the dynamics of this interaction by direct visual observation of microbubbles during insonification in vitro by a medical ultrasound imaging system. METHODS Video microscopy was used to observe air-filled sonicated albumin microspheres adsorbed to a solid support during insonation. RESULTS Deflation was not observed at lowest transmit power settings. At higher intensities, gas left the microparticle gradually, apparently dissolving into the surrounding medium. Deflation was slower for higher microsphere surface densities. Intermittent ultrasound imaging (0.5 Hz refresh rate) caused slower deflation than continuous imaging (33 Hz). CONCLUSIONS Higher concentrations of microbubbles, lower ultrasound transmit power settings, and intermittent imaging each can reduce the rate of destruction of microspheres resulting from medical ultrasound insonation.

Pharmacokinetics and safety of the MRI contrast agent gadoversetamide injection (optimark) in healthy pediatric subjects

Rational and Objective:This clinical trial examined the pharmacokinetics of gadoversetamide, a magnetic resonance imaging contrast agent, in normal pediatric subjects. Materials and Methods:Seventeen healthy pediatric subjects received a single intravenous injection of gadoversetamide (0.1 mmol/kg, 0.2 mL/kg). Sixteen subjects that were evaluable for pharmacokinetic analysis fell into 2 stratified age groups: 2 years to <5 years and 5 years to <18 years of age. Serum samples were analyzed for total gadolinium as a measure of gadoversetamide concentration. Results:Statistical analysis demonstrated significant (P < 0.05) age-related trends in the mean elimination half-life (t½) of gadolinium with the older group having a slightly longer t½ (1.39 hours) than the younger group (1.19 hours). No age-related changes occurred in volume of distribution or total body clearance, when normalized to body weight or body surface area. Conclusions:Based on this preliminary pharmacokinetic assessment, no adjustment from the approved adult gadoversetamide dose of 0.1 mmol/kg should be necessary for children aged 2 or older.

Destruction of contrast agent microbubbles in the ultrasound field: the fate of the microbubble shell and the importance of the bubble gas content.

Disappearance of ultrasound (US) contrast agents (gasfilled microbubbles) after contrast agent administration in the bloodstream occurs by way of several mechanisms. First, microbubbles are filtered and captured by various organs, including uptake by Kupffer cells in the liver (1,2). Second, gas diffuses from the microbubble core and dissolves in the surrounding medium, leaving the nonechogenic shell behind (3). The third process is the most rapid and important for the practice of diagnostic imaging by US. It is the destruction of microbubbles by the acoustic field of the US medical imaging system. It has been shown that the rate of microbubble destruction in the ultrasound field depends on the ultrasound frequency and pressure (4–7). During imaging, the microbubble contrast agent can be destroyed by a single pulse of the ultrasound, if the ultrasound mechanical index (MI) value is high enough (7,8). This phenomenon has been applied successfully for the imaging of tissue perfusion and perfusion defects (8,9). Thus, the mechanisms of microbubble contrast agent disappearance in the ultrasound field are important and need to be investigated in detail. We have previously reported a microbubble destruction/microscopy study performed with an air-filled microbubble agent, sonicated human serum albumin (Albunex; Mallinckrodt, St Louis, Mo) (10). More recent contrast agents filled with insoluble fluorinated gases, such as Optison (Mallinckrodt), demonstrate extended in vivo circulation and stability (11). It is of interest to evaluate the stability of these microbubbles in the field of the US medical imager. The nature of the gas and the gas exchange may play an important role in the bubble destruction. Here, we describe video microscopic studies performed in vitro for immobilized microbubbles during their insonification. Fluorescence microscopy was used to evaluate the behavior of microbubble shells during the destruction of microbubbles.