Contrast echocardiography: current and future applications.

Recent updates in the field of echocardiography have resulted in improvements in image quality, especially in those patients whose ultrasonographic (ultrasound) evaluation was previously suboptimal. Intravenous contrast agents are now available in the United States and Europe for the indication of left ventricular opacification and enhanced endocardial border delineation. The use of contrast enables acquisition of ultrasound images of improved quality. The technique is especially useful in obese patients and those with lung disease. Patients in these categories comprise approximately 10% to 20% of routine echocardiographic examinations. Stress echocardiography examinations can be even more challenging, as the image acquisition time factor is critically important for accurate detection of coronary disease. Improvements in image quality with intravenous contrast agents can facilitate image acquisition and enhance delineation of regional wall motion abnormalities at the peak level of exercise. Recent phase III clinical trial data on the use of Optison and several other agents (currently under evaluation) have revealed that for approximately half of patients, image quality substantively improves, which enables the examination to be salvaged and/or increases diagnostic accuracy. For the "difficult-to-image" patient, this added information results in (1) enhanced laboratory efficiency, (2) a reduction in downstream testing, and (3) possible improvements in patient outcome. In addition, substantial research efforts are underway to use ultrasound contrast agents for assessment of myocardial perfusion. The detection of myocardial perfusion during echocardiographic examinations will permit the simultaneous assessment of global and regional myocardial structure, function, and perfusion-all of the indicators necessary to enable the optimal noninvasive assessment of coronary artery disease. Despite the added benefit in improved efficacy of testing, few data exist regarding the long-term effectiveness of these agents. Currently under evaluation are the clinical and economic outcome implications of intravenous contrast agent use for daily clinical decision making in a variety of patient subsets. Until these data are known, this document offers a preliminary synthesis of available evidence on the value of intravenous contrast agents for use in rest and stress echocardiography. At present, it is the position of this guideline committee that intravenous contrast agents demonstrate substantial value in the difficult-to-image patient with comorbid conditions limiting an ultrasound evaluation of the heart. For such patients, the use of intravenous contrast agents should be encouraged as a means to provide added diagnostic information and to streamline early detection and treatment of underlying cardiac pathophysiology. As with all new technology, this document will require updates and revisions as additional data become available.

Contrast echocardiography: review and future directions.

Recent developments and advances in contrast echocardiography have been made to improve the diagnosis and evaluation of cardiac structures and function. By coupling new developments in acoustic instrumentation with new contrast agents, information that was previously difficult or impossible to gather by standard 2-dimensional echocardiography can now be obtained. Numerous studies have been published confirming the advantages of using contrast during echocardiographic studies, particularly with stress testing and myocardial perfusion. This review aims to summarize (1) the various contrast agents that are available or being developed; (2) factors that have been found to affect the strength of enhanced signals; (3) the new developments in instrumentation that improve the ability of scanners to differentiate echo contrast from cardiac tissue; and (4) the documented and possible future uses of contrast echocardiography.

Tissue-type plasminogen activator therapy versus primary coronary angioplasty: impact on myocardial tissue perfusion and regional function 1 month after uncomplicated myocardial infarction.

OBJECTIVES: This study sought to compare the impact of primary coronary angioplasty and thrombolytic therapy for acute myocardial infarction (AMI) on 1-month infarct size and microvascular perfusion. BACKGROUND: The effect of the reperfusion strategies of primary coronary angioplasty and thrombolytic therapy on microvascular integrity still remains to be determined. METHODS: Sixty-two consecutive patients with a first AMI, undergoing intravenous tissue-type plasminogen activator (t-PA) therapy (32 patients, Group I) or primary angioplasty (30 patients, Group II), were studied. Only patients with 1-month Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 were selected for the study. Patients in whom primary angioplasty was unsuccessful or those with clinical evidence of failed reperfusion were excluded. Microvascular perfusion was assessed at 1 month by intracoronary injection of sonicated microbubbles. Contrast score index (CSI) and wall motion score index (WMSI) were derived using qualitative methods. RESULTS: At baseline there were no significant differences between groups for age, risk factors, time to hospital presentation, Killip class on admission, prevalence of multivessel disease or anterior infarct site, infarct area extension before reperfusion, peak creatine kinase levels and postinfarction treatment. Conversely, significant differences between groups were found at follow-up for percent residual infarct related-artery (IRA) stenosis (70 +/- 12 vs 36 +/- 14 [mean +/- SD], p = 0.0001), CSI (1.02 +/- 0.4 vs. 1.49 +/- 0.5, p = 0.0003) and WMSI (1.67 +/- 0.3 vs. 1.45 +/- 0.3, p = 0.015). In particular, in the subset of patients with TIMI grade 3 flow, a perfusion defect occurred in one or more segments subtended by the IRA in 72% of Group I versus 31% of Group II patients (p < 0.00001) and in 27% of Group I versus 8% of Group II segments (p < 0.00001). CONCLUSIONS: The present study shows, in a highly selected cohort with successful IRA recanalization, that primary angioplasty is more effective than thrombolysis in preserving microvascular flow and preventing extension of myocardial damage at 1-month after AMI.

Contrast echocardiography displays increased subendocardial perfusion after nitroglycerin administration.

A mechanism proposed to contribute to the antianginal effect of nitroglycerin is a redistribution of coronary blood flow to the subendocardium. Contrast echocardiography combines ultrasound with echogenic contrast agents to assess regional myocardial perfusion. This study aims to assess the effect of nitroglycerin on myocardial transmural perfusion with contrast echocardiography in humans. Nine patients scheduled for coronary angiography received 300 microg intracoronary nitroglycerin. Contrast echocardiographic studies were performed before and immediately after the administration of intracoronary nitroglycerin. Videodensitometric analysis was performed off-line to measure subendocardial and subepicardial opacification. Subendocardial opacification greater than subepicardial opacification increased from six of 13 patients before nitroglycerin administration to 11 of 13 after nitroglycerin administration (p <0.05). Similarly, these observations increased from nine of 13 patients to 13 of 13 after nitroglycerin administration during diastole (p <0.05). Contrast echocardiography demonstrates increased subendocardial perfusion after the administration of nitroglycerin in these patients.

Reduced forward output states affect the left ventricular opacification of intravenously administered Albunex.

Albunex is an Food and Drug Administration-approved ultrasound contrast agent used for the enhancement of left ventricular endocardial borders. To determine the efficacy of intravenously administered Albunex with regard to left ventricular opacification (LVO), a retrospective analysis of 117 patients who received 202 injections of Albunex for enhancement of endocardial borders was done (dose 0.08 to 0.22 ml /kg). Patients were routinely referred to our echocardiography laboratory for stress echocardiography for standard indications. Optimized settings for contrast enhancement (3.5 MHz transducer frequency and maximum dynamic range) were used. Four observers graded LVO on a scale from 0 to 3 (0 = no Albunex seen in the ventricular cavity; 3 = Albunex densely seen in the ventricular cavity). Overall, LVO was reported in 166 (82%) of 202 injections or in 91 (78%) of 117 patients. A significant reduction in LVO was noted in patients with mitral regurgitation, tricuspid regurgitation, atrial fibrillation, systolic dysfunction, or pulmonary hypertension (increased pulmonary artery systemic pressure). LVO was seen in 88% of the patients without these conditions. However, only 12 (44%) of 27 patients with one or more of the above conditions had LVO (p < 0.05). LVO can be achieved in the majority of patients after intravenously administered Albunex when imaged with optimal transducer settings. A subset of patients with systolic dysfunction, mitral regurgitation, tricuspid regurgitation, atrial fibrillation, or increased pulmonary artery systemic pressure has less effective LVO with Albunex. Heart disease associated with decreased forward flow appears to be associated with diminished LVO.

Optimizing albunex in the left ventricle: an analysis of the technical parameters of four ultrasound systems in canines and humans.

Albunex, an intravascular ultrasound contrast agent, has been used clinically to enhance echocardiographic images. The purpose of this study if (1) to determine whether varying the settings on commercially available ultrasound machines has an effect on left ventricular opacification after intravenously administered Albunex and if there is an effect on left ventricular opacification and (2) to determine the ideal settings for each ultrasound scanner. Six canine hearts were imaged with 1 ml injections of intravenously administered Albunex while varying the transducer frequency, preprocessing curves, postprocessing curves, and dynamic range on a variety of ultrasound units. Subsequently 50 human subjects underwent imaging with the various machines while the dynamic range and transducer frequencies were altered. All subjects received two or three intravenous injections of 10 ml Albunex. The opacification of the left ventricular cavitary images in both parts of the study were interpreted visually on a scale of 0 to 4 (0 = none, 1 = trace, 2 = moderate, 3 = dense, and 4 = ideal) by four observers. The maximum compression and transducer frequency of 3.5 MHz showed significant improvement of left ventricular opacification in both canines and humans. These studies have shown that (1) varying the ultrasound unit's parameters affects the quality of left ventricular imaging when Albunex is used to enhance the image, and (2) higher compression and a transducer frequency of 3.5 MHz tend to enhance Albunex images of canine and human hearts.

Safety and feasibility of renal blood flow determination during kidney transplant surgery with perfusion ultrasonography.

Contrast-enhanced perfusion patterns of newly transplanted kidneys were determined in 10 patients. Albumin-stabilized sonicated microspheres were injected into the iliac-renal artery of the transplanted kidney while continuous two-dimensional ultrasound images were recorded. Doppler derived resistance index (RI) of the transplanted kidney's blood flow before injection of contrast (0.68 +/- 0.8) did not differ significantly from RI measured immediately after injection (0.72 +/- 0.13) or RI 24 h after surgery (0.69 +/- 0.11). Heart rate, mean arterial pressure, central venous pressure, and electrocardiogram (ECG) signs for ischemia did not change during contrast injections. Renal scintigraphy and renal biopsy revealed acute tubular necrosis and/or rejection in two patients at 24-48 h. Videodensitometry was used to assess the ratio of inner to outer peak pixel intensity from the recorded tomographic images in six patients. In both patients with acute rejection, the inner to outer cortex peak pixel intensity was greater than 1, whereas it was less than 1 in the remaining four patients with normal postoperative renal function. Visual scores (0-3) of contrast enhancement for three doses of Albunex were evaluated (0.5 mL, 1.0 mL, 2.0 mL). Two milliliters always enabled perfusion assessment. In seven patients the identical dose of Albunex was injected immediately before and 30 s after 2 mg of verapamil was injected directly into the renal artery at the time of surgery. The contrast enhancement score before verapamil (1.4 +/- 0.6) was significantly less than the enhancement score after (2.1 +/- 0.6), implying greater renal blood flow after verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of changes in skeletal muscle blood flow in the dog with contrast ultrasonography.

Intraoperative methods to assess skeletal muscle blood flow or muscle-flap perfusion during vascular reconstructive surgery are limited. At present, techniques enable only anatomic identification of the degree of patency of large vessels. We report here the first use of ultrasonography to assess dynamic changes in skeletal muscle perfusion. Baseline blood flow in the adductor muscle group of the hindlimbs of seven dogs was measured with an electromagnetic flow probe and with contrast ultrasound using the contrast agent Albunex. Blood flow was manipulated in each dog pharmacologically with random administration of intraarterial injections of Neo-Synephrine and papaverine. After each change in blood flow detected by electromagnetic flow probe, flow also was assessed qualitatively by four independent observers who graded video-recorded contrast enhancement in the muscle group on a 0 to 4 scale. Videodensitometry also was used to generate time versus intensity curves in the adductor muscle region of interest. Peak pixel intensity was determined during each flow condition. A total of 21 flow measurements were made with each assessment scheme (electromagnetic flow probe, video enhancement, videodensitometry) for each condition (7 control, 7 papaverine, 7 Neo-Synephrine). Changes in blood flow assessed by video enhancement scores and changes in peak pixel intensity correlated with changes measured by electromagnetic flow probe (r = 0.84 and 0.66, respectively). We conclude that contrast ultrasound may be used to detect changes in skeletal muscle perfusion intraoperatively. Measures of muscle perfused by visual inspection of contrast enhancement and videodensitometric data were in agreement with direct measurements of changes in skeletal muscle blood flow.

The relationship between immediate outcome after cardiac surgery, homogeneous cardioplegia delivery, and ejection fraction.

BACKGROUND: Optimal myocardial protection during cardiac surgery with ischemic arrest is predicated on among other variables, homogeneous cardioplegia distribution. Contrast echocardiography has been shown to provide information regarding the intramyocardial distribution of cardioplegia solution. To test the hypothesis that information regarding cardioplegia distribution derived from contrast echocardiography may be associated with immediate clinical outcome after cardiac surgery, data from 21 patients were examined retrospectively. METHODS: Contrast-enhanced cardioplegia distribution patterns of the left ventricle short axis view obtained with transesophageal echocardiography were examined off-line by four observers blinded to clinical outcome. Contrast effect was scored for eight equally divided myocardial segments (0 = no contrast, 1 = nonuniform contrast, 2 = uniform contrast, 3 = excessive contrast). The scores were then averaged between segments and between observers to generate an antegrade, a retrograde, and a combined global contrast score for each patient. RESULTS: Seventeen patients were separated from bypass without difficulty (group A) and 4 patients required sustained inotropic therapy or an intra-aortic balloon pump to facilitate separation from bypass (group B). As would be expected, group A patients had a higher average preoperative ejection fraction than did group B patients (60 percent +/- 14 vs 31 percent +/- 7, p < 0.01). In group A, however, for 4 of 17 patients (23 percent), low preoperative ejection fraction was not predictive of postoperative exogenous circulatory support requirements. Group A patients also had significantly higher antegrade (1.6 vs 1.2, p < 0.02), retrograde (1.7 vs 1.1, p < 0.02), and combined global contrast scores (1.7 vs 1.1, p < 0.01) than did group B patients. All patients with low preoperative ejection fraction and low intraoperative contrast scores required exogenous support to separate from cardiopulmonary bypass. CONCLUSION: Contrast echocardiography makes possible an evaluation of the intensity and distribution of contrast-enhanced cardioplegia delivery and we believe the efficacy of intraoperative myocardial protection. Although low preoperative ejection fraction is a known predictor of poor immediate postoperative outcome following cardiac surgery, not all patients with low preoperative ejection fractions require inotropic support postoperatively. Our results suggest that monitoring cardioplegia distribution with contrast echocardiography may offer insight for better patient stratification based on intraoperative myocardial protection in patients with low ejection fraction. We believe a more extensive evaluation of this relationship should be pursued in a prospective manner.

Contrast echocardiography.

Myocardial contrast echocardiography (MCE) is an ultrasound imaging technique which promises to provide a safe, noninvasive means of assessing myocardial perfusion. A contrast agent, consisting of a suspension of air-filled microspheres, serves as an ultrasound tracer. When these microspheres are injected intravascularly, the acoustic interface created between the blood and the microspheres enhances the reflected ultrasound signals. Thus, the flow pattern of the microspheres represent the actual blood flow patterns. This paper will review the field of contrast echocardiography, its background and history, the development of ultrasound contrast agents, and a variety of experimental as well as clinical uses. Contrast echocardiography has been utilized in the cardiac catheterization laboratory for the assessment of "risk area," assessment of collateral blood flow and assessment of coronary blood reserve. In the operating room, contrast echo is utilized for the determination of cardioplegic perfusion, assessment of graft patency and evaluation of valvular regurgitation. In the future, with the technical advancement in ultrasound imaging and the active interest and growth in the field of myocardial perfusion imaging using contrast echocardiography, the ability to provide routine real-time perfusion imaging may become a reality.

Pitfalls in quantitative contrast echocardiography: the steps to quantitation of perfusion.

Current methods used clinically to assess myocardial perfusion are invasive and expensive. As the technology of ultrasound imaging improves, CE may provide a relatively inexpensive, noninvasive means of quantitating myocardial perfusion. Issues regarding stability of microbubble contrast agents must be studied more closely under physiologic conditions. As such, encapsulated microbubbles may provide more stability under physiologic pressures than free gas microbubbles. Introducing high concentrations of contrast, either by hyperconcentrating the contrast agent or by increasing the injection rate, may provide greater stability under physiologic conditions. Further, before quantitative statement of tissue perfusion can be made, the relationship between tracer concentration and system response must be established. Further, a "linear" postprocessing ultrasound setting does not eliminate this requirement as data must still undergo nonlinear transformation during log compression and time-gain compensation. Additionally, issues regarding "electronic thresholding" must be explored more extensively in vivo. Commercial ultrasound scanners, in their present form, may not offer adequate sensitivity for absolute quantitative studies. Further development of modified ultrasound systems may provide sufficient sensitivity for quantitative perfusion imaging. CE offers a potentially powerful tool in the clinical management of patients with ischemic heart disease. Conventional coronary angiography provides information on the size of a lesion, but accompanying tissue perfusion distal to the lesion cannot be determined. Doppler ultrasonography determines velocity of blood flow in large vessels but does not offer the potential to quantitate tissue perfusion. Clearly, CE has a place in the future of diagnostic imaging. The recent work of Ito et al. demonstrated the qualitative potential of CE in the identification of "areas at risk" in patients who had undergone thrombolysis or percutaneous transluminal coronary angioplasty after an acute myocardial infarction. With further improvement in the ultrasound imaging techniques and microbubble stability, CE may offer an inexpensive, noninvasive means of assessing myocardial perfusion.

Assessment of renal blood flow with contrast ultrasonography.

Sonicated albumin microspheres, a digitalizing ultrasound system, and a mathematical model for flow were used to determine whether blood flow in the canine kidney could be assessed with contrast ultrasound. Albunex ultrasound contrast microspheres were injected into the aorta while ultrasound images of the kidney and aorta were recorded simultaneously. Ultrasound data were obtained during contrast injections at 93 different renal blood flow rates in nine dogs. Contrast dose was calibrated to ultrasound system response for both aortic and renal images. A linear relationship between microbubble concentration used and pixel intensity was established (r = 0.89 for aortic images and r = 0.91 for renal images). Renal blood flow was manipulated from baseline by means of a hydraulic renal artery occluder and by intravenous dopamine or fenoldopam infusion. Blood flow calculated with contrast ultrasonography was compared with direct measurement obtained with an electromagnetic flow probe at each flow rate. Direct measurement correlated with rates calculated with contrast ultrasonography (r = 0.84, 95% confidence limits from 0.75 to 0.90). Overall, calculations tended to overestimate absolute flow measurements, and overestimation of flow tended to be greater during pharmacologically manipulated flow rates. We conclude the changes and trends in renal blood flow can be serially assessed in vivo with contrast ultrasonography, but technical limitations of present commercial ultrasounds systems preclude absolute quantification at this time.

In vitro calculation of flow by use of contrast ultrasonography.

Contrast echocardiography has been used for qualitative assessment of cardiac function, and its potential for quantitative assessment of blood flow is being explored. With the development of an ultrasound contrast agent capable of passage through the microcirculation, a mathematical model based on classic dye dilution theory, and a digital ultrasound acquisition system, absolute quantitation of myocardial perfusion may be feasible. This study validates the mathematical model in a simple in vitro tube system. Flow was delivered at variable rates through an in vitro tube system while a longitudinal section was imaged with a modified commercial ultrasound scanner. Albunex contrast agent was injected, and videointensity data were captured and analyzed off line. Time-intensity curves were generated, and flow was calculated by use of a mathematical model derived from classic dye dilution mathematics. For 39 different flow rates, ranging for 9.2 to 110 ml/seconds, a correlation coefficient of r = 0.928 (p < 0.001) with a slope of 0.97 was calculated. We conclude that (1) contrast ultrasonography is capable of quantitative determination of flow in an in vitro system, and (2) a mathematical model based on dye dilution theory can be used to calculate flow with accuracy and precision.

A comparison of methods for the detection of myocardial ischemia during noncardiac surgery: automated ST-segment analysis systems, electrocardiography, and transesophageal echocardiography.

Clinicians often fail to detect intraoperative ischemic electrocardiographic (ECG) changes when viewing oscilloscopes. Automated ST-segment monitors promise to increase the detection of such ECG changes. We investigated the capacity of two commercially available ST-segment monitors to detect intraoperative myocardial ischemia in patients at high risk for developing intraoperative myocardial ischemia during vascular and other noncardiac procedures. The ST-segment monitors were compared with two reference monitors: (a) printed eight-lead ECGs, as interpreted by a cardiologist, and (b) the presence of segmental wall motion abnormalities and thickening abnormalities detected by transesophageal echocardiography (TEE). We also examined the capacity of the printed ECG to diagnose myocardial ischemia when compared with TEE. We studied 44 patients who underwent TEE, printed multilead ECG, oscilloscope monitoring of leads V5 and II, and measurement of ST-segment deviation from the baseline using an automated Hewlett Packard ST-segment device. The sensitivities for the Hewlett Packard system were 40% for TEE-diagnosed myocardial ischemia and 75% for ECG-diagnosed ischemia. Comparison of the printed ECG with TEE revealed that ST-segment changes in the printed ECG, as analyzed by a cardiologist, were 25% sensitive and 62% specific for the detection of TEE-diagnosed myocardial ischemia. When T-wave inversions were added to ST-segment depression as a criterion for the diagnosis of myocardial ischemia by the printed ECG, the sensitivity of ECG for the detection of intraoperative myocardial ischemia, as determined by TEE, was 40% and specificity was 58%. Twenty-three of the 44 patients were simultaneously monitored in leads I, II, and V5 with an automated Marquette ST-segment monitor.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of intravenous Albunex injections on pulmonary arterial pressure, gas exchange, and left ventricular peak intensity.

Contrast ultrasonography may be used to assess regional tissue perfusion. The purpose of this study was to evaluate the safety and efficacy of a new, commercially prepared ultrasound contrast agent (Albunex) in dogs. The injections were administered from peripheral intravenous (IV), right atrial (RA), and pulmonary artery (PA) sites. Acute pulmonary hemodynamic and gas exchange effects of low-dose (0.5, 1.0, 2.0 ml) Phase I injections, and high-dose (2.0, 5.0, 10, 20 ml) Phase II injections of Albunex were evaluated in nine dogs. Immediately before and after each injection, pulmonary artery pressure (PAP) and oxygen tension (PO2) were determined. In addition, left ventricular cavity opacification was assessed visually and by videodensitometric off-line analysis. Visual assessment was performed by four blinded observers who graded on a scale of 0 to 3 (0 = no contrast enhancement of the left ventricular (LV) cavity; 1 = weak or suboptimal contrast enhancement; 2 = optimal or excellent contrast enhancement; and 3 = attenuation of the ultrasound signal following a contrast injection). Peak pixel intensity was also determined with videodensitometric analysis. Results showed that significant changes in PAP or PO2 were not noted after Albunex injections, regardless of injection site or dose range. The average change in PAP after Albunex injection was 1.0 mm Hg +/- 1.2 mm Hg (NS), and the average change in PO2 after Albunex injections was 6.2 mm Hg +/- 6.7 mm Hg (NS). The left ventricular cavity peak pixel intensity was dependent on both injection site (PA = RA > IV) and dose range (2.0 = 1.0 > 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Advances in contrast echocardiography: intraoperative perfusion assessment.

Contrast ultrasound techniques provide on-line assessments of regional tissue perfusion. Intraoperative clinical studies of cardiac revascularization and renal transplantation have been performed and are currently under active clinical investigation. The potential to diagnose and manage patients through the use of contrast ultrasound techniques is just beginning to be realized. With continued development of the contrast agents and improved computer-aided software analyses programs, the future of the real-time perfusion imaging looks bright.

Myocardial perfusion: contrast echocardiography perspectives.

Contrast echocardiography may become a useful means of quantifying transmural regional myocardial perfusion patterns, experimentally and clinically, in a variety of settings. Contrast echocardiography has already been used in the operating room to study perfusion during coronary artery bypass graft (CABG) surgery. Other recent studies have demonstrated the ability of contrast echocardiography to predict wall motion improvement following acute myocardial infarction and therapeutic intervention. This is significant in the light of the discrepancy that has recently been shown between epicardial coronary vessel diameter and coronary flow. Studies suggest that both tissue and blood flow and volume may be quantitatively evaluated using contrast echocardiography, and these parameters ultimately may be used to assess tissue viability or vascular reserve. Contrast echocardiography techniques have been shown to be safe and reliable, and provide a high degree of spatial and temporal resolution.