Alan Kricsfeld

Thrombolytic enhancement with perfluorocarbon-exposed sonicated dextrose albumin microbubbles.

Whereas low-intensity, high-frequency ultrasound (US) alone appears to cause minimal thrombolysis, US combined with air-filled microbubbles does increase the amount of urokinase (UK)-mediated clot lysis (CL). Because this phenomenon may be mediated by cavitation-induced streaming, we hypothesized that perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles, which are more stable than air-filled microbubbles, may also enhance US-induced thrombolysis. We measured the percentage CL of equally sized thrombi (1.0 +/- 0.1 mg) made from freshly drawn blood incubated for 2 hours and then exposed to 20 kHz US (0.846 MPa peak negative pressure). The thrombi were bathed in 4 ml of saline solution, UK alone (20,000 U), PESDA alone, or a combination of PESDA with UK. The percentage CL achieved with PESDA and therapeutic US was also compared with the percentage CL achieved with room air-filled sonicated dextrose albumin (RASDA) microbubbles. When compared with US alone (24% +/- 13% CL) or UK alone (17% +/- 3% CL), PESDA plus US produced significantly better CL (43% +/- 17%; p< 0.05). PESDA combined with US also produced significantly greater CL than RASDA combined with US (28% +/- 9%; p < 0.05). The optimal CL was achieved with a combination of PESDA with UK with US (60% +/- 14% CL). We conclude that PESDA microbubbles alone may be capable of inducing thrombolysis when insonified with a low-frequency transducer.

Improved endocardial border resolution during dobutamine stress echocardiography with intravenous sonicated dextrose albumin.

OBJECTIVES The purpose of this study was to determine whether intravenous sonicated dextrose albumin could improve endocardial border resolution during dobutamine stress echocardiography. BACKGROUND Sonicated albumin improves endocardial border resolution in patients undergoing exercise stress echocardiography. Because a sonicated mixture of albumin with dextrose results in better transpulmonary passage than sonicated albumin alone, this agent could be utilized to further improve endocardial border resolution during dobutamine stress echocardiography. METHODS We gave intravenous injections of sonicated dextrose and albumin to 50 patients undergoing dobutamine stress echocardiography. Left ventricular video intensity, contrast agent persistence (in seconds), number of contrast agent-enhanced cardiac cycles and improvement in endocardial border resolution were assessed from the apical four-chamber view at baseline, low dose (10 micrograms/kg body weight per min) and peak dobutamine infusion. RESULTS There was significantly better left ventricular peak video intensity at peak dobutamine infusion than after the same injection at baseline (p < 0.005, analysis of variance). The number of contrast agent-enhanced cardiac cycles in the left ventricular cavity was also significantly longer at peak infusion. Endocardial border resolution was improved (mainly in lateral segments) in 93% of patients at low dose and 95% of patients at peak infusion. CONCLUSIONS Intravenous sonicated dextrose albumin improves endocardial border resolution during dobutamine stress echocardiography.

Noninvasive identification of acute myocardial ischemia and reperfusion with contrast ultrasound using intravenous perfluoropropane-exposed sonicated dextrose albumin

OBJECTIVES The purpose of this study was to determine whether intravenous dextrose albumin sonicated with a commonly used gas of low blood solubility and diffusivity (perfluoropropane) could identify acute myocardial ischemia and reperfusion. BACKGROUND Recently, it has been demonstrated that dextrose albumin sonicated with gases that have low blood solubility and diffusivity results in microbubbles capable of consistently producing myocardial ultrasound contrast after intravenous injection. It remains to be determined, however, whether this contrast agent can visually detect the myocardial blood flow abnormalities seen with acute ischemia or stunned myocardium after reperfusion. METHODS We gave intravenous injections (0.06 ml/kg body weight) of perfluoropropane-exposed sonicated dextrose albumin to 10 open chest dogs. The measured degree of myocardial contrast (0+ to 2+) and background-subtracted peak anterior myocardial videointensity produced from each injection were measured at three stages: 1) under baseline conditions, 2) during acute ischemia produced by a proximal left anterior descending coronary artery ligation lasting 10 to 120 min, and 3) after reflow was established. Coronary blood flow was monitored during all injections by using an ultrasound flow probe placed around the left anterior descending artery. RESULTS Coronary blood flow ranged from 0 to 137 ml/min, and peak myocardial videointensity after intravenous administration of perfluoropropane-exposed sonicated dextrose albumin ranged from 0 to 70 gray scale U. There was consistent visual myocardial opacification in all dogs during baseline conditions and a visually evident decrease in myocardial contrast in the left anterior descending artery distribution after ligation. A relative increase in contrast in this same distribution after intravenous contrast agent administration occurred in 7 of the 10 dogs during reflow. Quantitatively, there was an excellent correlation in individual dogs between peak myocardial videointensity and coronary flow at all stages (mean correlation coefficient 0.95 +/- 0.04, range 0.87 to 0.99). CONCLUSIONS Perfluoropropane-exposed sonicated dextrose albumin is an ultrasound contrast agent that can visually identify myocardial perfusion abnormalities from a peripheral venous injection.

Multifold Sonicated Dilutions of Albumin With Fifty Percent Dextrose Improve Left Ventricular Contrast Videointensity After Intravenous Injection in Human Beings

An intravenous injection of a onefold dilution of sonicated albumin with 50% dextrose improves echocardiographic left ventricular cavitary opacification in dogs compared with sonicated albumin. The objective of this study was to determine whether sonicated dilutions of albumin with dextrose would improve left ventricular videointensity after intravenous injection in humans and to delineate what ratio of albumin with dextrose results in optimal left ventricular cavitary opacification. We gave intravenous injections (randomized) of sonicated albumin and three different dilutions of albumin with 50% dextrose sonicated at different time intervals (onefold, threefold, and sevenfold dilutions sonicated albumin for 40 seconds and threefold and sevenfold dilutions sonicated albumin for 80 to 100 seconds) to 10 healthy human volunteers. End-diastolic and end-systolic videointensity and mean transit time from the mid-left ventricular cavity were compared after an 8.0 ml intravenous injection of all six samples. The threefold and sevenfold dilutions sonicated for 80 to 100 seconds produced microbubble concentrations similar to those of sonicated albumin but with significantly larger (5.6 microns versus 4.7 microns for sonicated albumin) size. These dilutions produced significantly higher end-diastolic and end-systolic videointensity, area under the time-intensity curve, and mean transit time compared with sonicated albumin or any of the dilutions sonicated for 40 seconds (p < or = 0.005). These data suggest that multifold dilutions of albumin with dextrose produce improved ultrasound contrast.

Reduction in left ventricular cavitary attenuation and improvement in posterior myocardial contrast with higher molecular weight intravenous perfluorocarbon-exposed sonicated dextrose albumin microbubbles.

Although intravenous perfluoropropane-exposed sonicated dextrose albumin (C3SDA) produces myocardial contrast, the posterior myocardium cannot be visualized with epicardial or transthoracic imaging because of excessive left ventricular cavitary contrast. We hypothesized that higher molecular weight, less diffusible gases such as perfluoropentane-exposed sonicated dextrose albumin (C5SDA) would produce equivalent anterior myocardial contrast at lower intravenous doses with less cavitary attenuation. To test this hypothesis, we compared the anterior and posterior peak myocardial videointensity after 0.06 ml/kg intravenous injections of C3SDA and 0.015 to 0.030 ml/kg intravenous injections of C5SDA in seven open-chest dogs. The ability of C5SDA to detect posterior myocardial perfusion abnormalities was also tested. Despite the lower dose, intravenous C5SDA produced equivalent anterior myocardial contrast but significantly higher posterior myocardial contrast (2.6 +/- 1.9 units peak myocardial videointensity C5SDA versus 0.6 +/- 0.9 units C3SDA; p < 0.0001) because of less acoustic shadowing. The visual detection of posterior ischemia with intravenous C5SDA was also significantly improved. We conclude that increasing the molecular weight of the perfluorocarbon gas in sonicated dextrose albumin will significantly improve the detection of posterior perfusion abnormalities.

Detection of regional perfusion abnormalities during adenosine stress echocardiography with intravenous perfluorocarbon-exposed sonicated dextrose albumin

Although perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles produce myocardial contrast after intravenous injection, it is unknown whether their use can accurately identify myocardial blood-flow abnormalities during stress echocardiography. Accordingly, we compared the background-subtracted peak myocardial videointensity (PMVI) after intravenous injections of PESDA before and during adenosine stress (100 to 140 units/kg/min) in 10 open-chest dogs with angiographically significant left circumflex artery disease. The ratios of PMVI in the ischemic region compared with the adjacent normal left anterior descending perfusion bed were measured, as were wall-thickening and coronary-flow ratios. In the dogs with a >50% diameter stenosis, there was a decrease in PMVI ratio during adenosine stress by >0.20 in 9, whereas wall-thickening ratios decreased in only 5. PMVI in the ischemic zone increased by <1.5 units during adenosine infusion in 8 of 10 dogs, whereas it increased by >1.5 units in 8 of 1O adjacent normal zones. We conclude that regional myocardial-perfusion abnormalities can be detected with intravenous PESDA during adenosine stress echocardiography.

The mechanism and clinical implication of improved left ventricular videointensity following intravenous injection of multi-fold dilutions of albumin with dextrose

The left ventricular ultrasound videointensity of an intravenous injection of sonicated albumin is improved if the agent is diluted with dextrose prior to sonication. The objective of this study was to determine the mechanism for improved left ventricular ultrasound contrast with intravenous sonicated multi-fold dilutions of albumin with dextrose compared to sonicated albumin alone. Epicardial short axis images of the left ventricle were obtained in 11 mongrel dogs and incremental one part sonicated dilutions (up to 10-fold) of albumin with 5 or 50% dextrose were given intravenously to determine which dilution and dextrose concentration produced optimal left ventricular videointensity. Microbubble size and concentration of these dilutions were measured.The one to seven-fold sonicated dilutions resulted in a slight, but significantly larger microbubble size when compared to sonicated albumin alone (SA), but no difference in concentration. All dilutions produced significantly higher end-diastolic peak videointensity (PVI) in the left ventricle than SA (range 160–569% of SA PVI; p<0.001) with the three to five-fold dilution producing maximal PVI. Five percent dextrose dilutions produced the same videointensity as 50% dilutions.End-systolic videointensity of both 5 and 50% dextrose dilutions were also over 250% higher than SA (p<0.001). This resulted in good or excellent end-systolic endocardial border definition in the majority of injections. Therefore, the mechanism for improved left ventricular chamber opacification with multifold sonicated dilutions of albumin with dextrose appears to be due to a small increase in microbubble size and not increased viscosity or microbubble concentration.

Myocardial perfusion abnormalities during low-dose dobutamine after coronary reperfusion can be demonstrated with intravenous perfluorocarbon-exposed sonicated dextrose albumin ultrasound contrast

We measured background-subtracted peak myocardial videointensity (PMVI) in the left anterior descending and left circumflex perfusion zones in open-chest dogs after intravenous injection of perfluorocarbon-exposed sonicated dextrose albumin ultrasound contrast (PESDA) after reperfusion of a coronary occlusion. These measurements were repeated during low-dose dobutamine (LDD). The ratio of PMVI in the reperfused zone (RZ) compared with the adjacent normal zone (NZ) was measured at baseline and during LDD. Dogs with a >50% diameter residual stenosis were group I (n = 10), and those with <50% residual stenosis were group II (n = 13). Wall-thickening (WT) responses to LDD were not different between groups. Although the PMVI ratio (PMVI(RZ)/PMVI(NZ)) was the same in both groups at baseline, it decreased by >0.1 during LDD in 8 of 10 in group I compared with only 3 of 13 in group II dogs (p = 0.01). PMVI in the RZ increased by > or = 1.5 U in 12 of 13 group II dogs during LDD, but only in 3 of 10 group I dogs. Therefore, intravenous PESDA can be combined with WT responses to define both myocardial function and flow after reperfusion.

Improved myocardial contrast from intravenous perfluoropropane-exposed sonicated dextrose albumin during dobutamine stress echocardiography in humans

Myocardial contrast (MC) from an intravenous (IV) injection of microbubbles in humans during stress eehoeurdiography (SE) would permit the non-invasive detection of both regional myocardial flow and function. IV injections of perfluoropropane-exposed sonicated dextrose albumin (PESDA) have been shown to produce MC in animals, but the safety and efficacy of this contrast has not been tested in humans during SE. Accordingly, we measured peak anterior myocardial videointensity (PMVI) using the parastemal short axis view following IV injections of up to 0.02 milliiiter per kilogram of PESDA at baseline, during tow dose (10 u/kg/min) dobutamine (LDD)), and at peak dobutamine stress (PDS) in seven patients undergoing dobutamine SE. Patient symptoms, heart rate, blood pressure, and oxygen saturation were recorded following each injection. ]V injections of PESDA at base, LDD, and PDS were not associated with symptoms, or changes in heart rate, blood pressure, or oxygen saturation. Compared to baseline, anterior PMVI following IV PESDA tended to increase during LDD, but increased significantly at PDS (PMVI-bare 1.6+1.4; PMVI-PDS 2.9+2.1 Units;p=0.01). None of the patients demonstrated anterior wall motion abnormalities at PDS. An example of the visually evident improvement in MC and improved endocardial border detection in the apical four chamber view following IV PESDA in a patient with a normal SE is shown: