Mark W. Keller

The behavior of sonicated albumin microbubbles within the microcirculation: A basis for their use during myocardial contrast echocardiography

The purpose of this study was to determine whether the behavior of sonicated albumin microbubbles accurately mimics red blood cell flow in the microcirculation and is thus consistent with their use as in vivo tracers of red blood cell flow during myocardial contrast echocardiography. Accordingly, microbubbles prepared from fluorescein-conjugated albumin and fluorescently labeled red blood cells were injected intravascularly in eight golden hamsters. Their intravascular distribution, velocities, arteriolar-to-venular transit and flux ratios at branch points were determined in the microcirculation of the cheek pouch. Albumin microbubbles (mean diameter, 4.9 +/- 3.6 microns) and red blood cells displayed a similar frequency of distribution across the arteriolar lumen (33% in the central 20% of the arterioles), and their arteriolar velocities were also similar (2.5 +/- 0.7 mm/sec and 2.3 +/- 0.7 mm/sec,p = NS). The mean velocities of microbubbles correlated well with those of red blood cells at baseline and after adenosine application (r = 0.97 and r = 0.89, respectively), as did the calculated maximum velocity (r = 0.98 and r = 0.80, baseline and adenosine, respectively). The velocity profiles across the lumen of the vessels for albumin microbubbles and red blood cells were similar at baseline and after adenosine-induced velocity changes. The flux ratios at branch points also correlated well (r = 0.92, p less than 0.001). Arteriolar-to-venular transit times of albumin microbubbles were similar to those of red blood cells in vessels ranging in size from 22 microns to 45 microns. We conclude that the behavior of albumin microbubbles in the microcirculation mimics that of red blood cells and supports their use as intravascular tracers of red blood cell flow during myocardial contrast echocardiography.

Assessment of regional myocardial blood flow with myocardial contrast two-dimensional echocardiography

It was hypothesized that regional myocardial blood flow could be measured using myocardial contrast echocardiography. Accordingly, arterial blood was perfused into the coronary circulation in 16 dogs. In Group 1 dogs (n = 8), blood flow to the cannulated left circumflex artery was controlled with use of a roller pump, whereas in Group 2 dogs (n = 8) blood flow to the left anterior descending coronary artery was controlled by a hydraulic occluder placed around it. Sonicated microbubbles (mean size 4 microns) were used as the contrast agent. In Group 1 dogs the microbubbles were injected subselectively into the left circumflex artery, whereas in Group 2 dogs they were injected selectively into the left main coronary artery and two-dimensional echocardiographic images were recorded. Computer-generated time-intensity curves were derived from these images and variables of these curves correlated with transmural blood flow measured with radiolabeled microspheres. A gamma-variate function (y = Ate-alpha t) best described the curves, and alpha (a variable of curve width) correlated well with transmural blood flow at different flow rates in all Group 1 and Group 2 dogs (mean r = 0.81 and 0.97, respectively). Other variables of the curve width also correlated well with myocardial blood flow, but peak intensity had a poor correlation with myocardial blood flow in both groups of dogs (r = 0.39 and r = 0.63, respectively). When data from all dogs were pooled, Group 1 dogs still showed good correlation between variables of curve width and myocardial blood flow (r = 0.81); Group 2 dogs did not (r = 0.45). The difference between the two sets of dogs was related to the site of contrast agent injection. It is concluded that measurement of the transit time of microbubbles through the myocardium with two-dimensional echocardiography accurately reflects regional myocardial blood flow. Although injection of contrast agent selectively into the left main coronary artery only allows measurement of relative flow, it may be feasible to measure absolute flow by injecting contrast agent subselectively into a coronary artery. Myocardial contrast echocardiography may, therefore, offer the unique opportunity of simultaneously assessing regional myocardial perfusion and function in vivo.

Importance of two-dimensional echocardiographic assessment of left ventricular systolic function in patients presenting to the emergency room with cardiac-related symptoms.

BackgroundThis prospective study was designed to test the hypothesis that the assessment of left ventricular systolic function at the time of emergency room (ER) presentation provides valuable diagnostic and prognostic information in patients with cardiac-related symptoms. Methods and ResultsThe study is based on a 2-year follow-up of 171 consecutive patients evaluated in the ER for such symptoms. In the course of follow-up, one third of the patients (55 of 171) suffered a major cardiac event. For those with left ventricular systolic dysfunction (LVSD), the age-adjusted rate of early events (occurring within 48 hours of presentation) was more than eight times higher than for those without LVSD (26.9% versus 3.3%, p < 0.01). For events occurring after 48 hours of ER presentation, LVSD was associated with a nearly fourfold excess of cardiac events (23.9% versus 6.4%, p < 0.01). Other than advanced age, the most important confounder for early events included an abnormal electrocardiogram diagnostic for acute myocardial infarction. Confounders for late events included advanced age and a history of hypertension. LVSD on two-dimensional echocardiography (2DE) was the only finding associated with early and late events after controlling for other risk factors. In addition, the prediction of these events derived from the combination of historical, clinical, electrocardiographic, and 2DE findings was significantly improved when accounting for the presence or absence of LVSD (p < 0.01). ConclusionsWe conclude that the 2DE assessment of left ventricular systolic function provides valuable diagnostic and prognostic information in subjects presenting to the ER with cardiac-related symptoms.

Myocardial contrast echocardiography in humans. II. Assessment of coronary blood flow reserve

The hypothesis that myocardial contrast echocardiography could be used to simultaneously assess coronary blood flow reserve and the size of the perfusion bed supplied by a coronary artery was examined in nine patients and six dogs. All patients were undergoing cardiac catheterization and had single vessel coronary artery disease (greater than or equal to 85% stenosis of either the proximal left anterior descending or the left circumflex coronary artery); the six dogs had a critical stenosis of the left circumflex coronary artery. Three milliliters of sonicated Renografin-76 (mean microbubble size 6 micron) was injected into the left main coronary artery before and after intracoronary administration of papavarine, 6 to 9 mg. The beds supplied by the normal and stenotic vessels could not be differentiated during contrast echocardiography before injection of papavarine. However, after papavarine, the normal vascular bed showed significantly more contrast enhancement than did the bed supplied by the stenotic artery. This disparity in contrast enhancement made it possible to delineate the size of the bed perfused by the stenotic vessels. When quantitative analysis of the time-intensity curves obtained from the echocardiograms was performed in the dogs, the absolute values for the area under the curve, peak contrast intensity and curve width did not correlate with absolute blood flows measured with radiolabeled microspheres. However, the ratios of the areas under the curves derived from the two vascular beds before and after papavarine correlated well with the ratios of blood flows between the two beds during the same stages (r2 = 0.73 by linear regression and r2 = 0.85 by an exponential function). In comparison, the ratios of peak amplitudes and curve widths before and after papavarine had poor correlations with ratios of flows from the two beds (r2 = 0.18 and 0.02, respectively). In conclusion, myocardial contrast echocardiography can be used to simultaneously assess coronary blood flow reserve and the size of the perfusion bed supplied by a stenotic vessel.

Albunex: A Safe and Effective Commercially Produced Agent for Myocardial Contrast Echocardiography

Microbubble solutions of sonicated human serum albumin have been shown to be effective echocardiographic contrast agents free from adverse effects on coronary blood flow, left ventricular function, and systemic hemodynamics. Albunex is a commercially prepared solution of air-filled albumin microspheres prepared from sonicated 5% human serum albumin. The effects of Albunex on coronary blood flow, left ventricular function, and systemic hemodynamics, as well as contrast enhancement were evaluated in 10 open chest, anesthetized dogs. After an intracoronary injection, Albunex did not alter left atrial, left ventricular systolic or end-diastolic, or mean aortic pressures. It did not cause a coronary hyperemic response, alter left ventricular systolic thickening, or lower the peak positive left ventricular dp/dt. It did not alter these measurements even in the presence of a critical coronary stenosis. The contrast opacification produced by Albunex microbubbles was dose dependent (optimal dose range of 0.033 to 0.5 ml/kg), with attenuation occurring at higher doses. In conclusion, although Albunex provides adequate contrast enhancement, intracoronary injection of Albunex does not significantly alter coronary blood flow, left ventricular function, or systemic hemodynamics. Because of the standardized size and concentration of the microspheres, Albunex may be an ideal agent for myocardial contrast echocardiography.

Myocardial contrast echocardiography without significant hemodynamic effects or reactive hyperemia: A major advantage in the imaging of regional myocardial perfusion☆☆☆

All agents used for myocardial contrast echocardiography to date produce adverse hemodynamic effects and alter coronary blood flow. It was hypothesized that because 5% human albumin, when sonicated for use as a contrast agent, is neither hyperosmolar nor a calcium chelator, it would not have significant effects on coronary blood flow, left ventricular function or systemic hemodynamics. Albumin microbubbles of two distinct sizes (mean size 2.9 and 5.8 micron) were produced and compared with nonsonicated albumin, nonsonicated Renografin, sonicated Renografin and hand-agitated Renografin for their effects on hemodynamics, coronary blood flow and regional left ventricular systolic thickening in 15 open chest anesthetized dogs. None of the albumin solutions significantly altered left atrial, left ventricular systolic and end-diastolic and mean aortic pressures. These agents did not cause a coronary hyperemic response or alter left ventricular systolic thickening, but slightly lowered the peak positive left ventricular maximal rate of rise in pressure (dP/dt) (-4.1 +/- 5.4%, p less than 0.01). In contrast, all the Renografin solutions caused significant changes in all these variables (p less than 0.02). In six dogs. albumin solutions did not alter these variables even in the presence of critical coronary stenosis. The contrast opacification produced by 5.8 micron albumin microbubbles was equivalent to that produced by sonicated Renografin. Compared with an equivalent amount of saline and nonsonicated albumin solutions, 10 ml of sonicated albumin did not produce any evidence of infarction, embolization or hemorrhage in the myocardium, brain or kidneys of rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraoperative assessment of regional myocardial perfusion using quantitative myocardial contrast echocardiography: An experimental evaluation☆☆☆

To test the hypothesis that myocardial contrast echocardiography can be used to quantitate regional myocardial flow in the arrested heart at the time of delivery of cardioplegic solution, data were acquired in 13 dogs on cardiopulmonary bypass. Different degrees of stenosis were placed in random order on the left anterior descending coronary artery. For each stenosis, myocardial contrast echocardiography was performed by injecting sonicated albumin microbubbles into the cross-clamped aortic root at the time of delivery of cardioplegic solution. The resultant echocardiographic images were analyzed on an off-line computer. Background-subtracted time-intensity plots were generated, and an exponential function, f(t) = Ce-alpha t + De- beta t, was applied to each plot. Variables that reflected the total number of microbubbles entering the coronary artery bed, such as the area under the curve and the peak height of the curve, correlated best with radiolabeled microsphere-measured myocardial flow (r = 0.92 and r = 0.91, respectively). Variables that reflected the appearance of contrast microbubbles in the myocardium, such as the initial slope and the slope at 1 s, also had a good correlation with myocardial flow (r = 0.84 and r = 0.89, respectively). Variables that reflected the washout of contrast medium from the myocardium, such as the slope of the descending portion of the curve, had only a fair correlation with myocardial flow (r = 0.65). In six dogs, the technique of injecting contrast medium into the cross-clamped aortic root was also examined. Although continuous infusion of contrast medium produced smaller perturbations in mean aortic and distal left anterior descending artery pressures compared with a bolus injection (p less than 0.01), the correlation between the variables of the time-intensity curves and flow was equally close with both techniques. It is concluded that it is possible to quantitate myocardial flow by using myocardial contrast echocardiography at the time of delivery of cardioplegic solution in dogs on cardiopulmonary bypass. The implementation of this technique in humans might be useful in guiding the sequence of graft placement and thereby improving myocardial preservation during coronary artery bypass operations.

Value of Two-dimensional Echocardiography for Determining the Basis of Hemodynamic Compromise in Critically Ill Patients: A Prospective Study

We postulated that because the first step in the management of critically ill patients with hypotension, pulmonary edema, or both is to determine whether the cause is cardiac or noncardiac, direct visualization of the heart with two-dimensional echocardiography would be useful for determining the basis of hemodynamic compromise in such patients. Accordingly, 49 consecutive patients (33 men and 16 women; mean age 61 +/- 15 years) underwent two-dimensional echocardiography within 2 hours of placement of a pulmonary artery flotation catheter for determining the reason for hypotension, pulmonary edema, or both. To discriminate between cardiac and noncardiac causes, hemodynamic and two-dimensional echocardiographic data were evaluated independently by two to three blinded interpreters based on predetermined criteria. There was complete agreement between pulmonary artery catheter and two-dimensional echocardiographic data in 36 (86%) of the 42 patients in whom interpretable data were available in terms of cardiac versus noncardiac causes. The two modalities agreed in all patients with hypotension alone and disagreed in 2 of the 20 patients with pulmonary edema alone and 4 of the 14 patients with combined hypotension and pulmonary edema. In cases of discordance, the two tests provided complimentary information, particularly in patients with sepsis in whom the stroke volume may be normal to high but left ventricular systolic function may be depressed. The time taken for pulmonary artery catheter placement was 63 +/- 45 minutes versus 19 +/- 7 minutes for two-dimensional echocardiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraoperative demonstration of coronary collateral flow using myocardial contrast two-dimensional echocardiography

Abstract The extent of coronary collateral vessels and their significance are controversial issues. 1 The controversy regarding collaterals in man is related, to a large extent, to the lack of an appropriate method to assess collateral function in vivo. The most frequently used technique of assessing collateral blood vessels is coronary angiography. This technique, however, can only detect vessels >100 to 200 μ in diameter. 1 It has been shown in animals, particularly dogs, that most of the collateral vessels are 1 Furthermore, the angiographic assessment of collateral vessels is unrelated to the functional capacity of these channels. 1 Myocardial contrast echocardiography is a new technique capable of demonstrating myocardial perfusion in humans. 2 This technique uses the intracoronary or intraaortic injection of microbubbles of air. The size of these microbubbles is similar to that of red blood cells, as is their intravascular rheology. 3 The appearance of these microbubbles within regions of the myocardium remote from the site of injection should, therefore, reflect collateral flow. This technique has been shown to demonstrate collateral flow in dogs. 4

Success of internal mammary bypass grafting can be assessed intraoperatively using myocardial contrast echocardiography.

To determine whether the success of internal mammary artery bypass grafting can be assessed intraoperatively using myocardial contrast echocardiography, sonicated Renografin-76 was injected into the aortic root of 11 dogs during the delivery of cardioplegic solution. Studies were performed with the left anterior descending coronary artery patent and totally occluded, and after internal mammary artery bypass grafting distal to the occluded vessel. Flow rate during cardioplegia was constant for all three stages in each experiment. Myocardial contrast echocardiography clearly demonstrated homogeneous myocardial perfusion with the left anterior descending coronary artery patent, lack of perfusion in the left anterior descending artery bed during its occlusion and excellent perfusion of the occluded bed after internal mammary artery bypass grafting distal to the occlusion in 10 of the 11 dogs. In one dog, the bypass graft was technically inadequate and contrast opacification was not noted in the left anterior descending artery bed after internal mammary artery bypass grafting. The exponential function C(t) = Ae-alpha t + Be-beta t was fitted to computer-derived time-intensity curves from the myocardium, where alpha denotes contrast washout and beta denotes contrast appearance. Respective values for alpha and beta (mean + 1 SD) were similar for the patent left anterior descending coronary artery and after internal mammary artery bypass grafting distal to the occluded artery (0.11 +/- 0.10 versus 0.10 +/- 0.10, and 2.5 +/- 2.4 versus 1.1 +/- 0.56). In conclusion, myocardial contrast echocardiography has potential for intraoperative assessment of the adequacy of coronary artery bypass grafting.