Presentation on theme: "Contrast Echocardiography"— Presentation transcript:
1 Contrast Echocardiography Amit J. Thosani, MDClinical Fellow, Division of Cardiology23 January 2008
2 Applications of Contrast Echocardiography Detection of intracardiac shunts:Patent foramen ovaleAtrial septal defectIntrapulmonary shuntLeft ventricular opacification/endocardial border definitionAssessment of myocardial perfusion
3 Right vs. Left Heart Contrast Agitated salineBubble diameter is greater than diameter of pulmonary capillariesNo transpulmonary passage (in absence of intrapulmonary shunt)PFO/ASD/Persistent Left Superior Vena CavaMicrobubble diameter of 1-5 µmAble to traverse pulmonary capillary bedResonate at frequency of MHz, corresponding to clinical transducer frequencies
4 Physical PrinciplesBlood appears black on conventional 2D echocardiography because of weak ultrasound scatter by RBCs at conventional imaging frequenciesContrast ultrasound is based on scattering of incident ultrasound at gas/liquid interfaceResults in increased strength of return signal
5 Physical PrinciplesUltrasound generates positive and negative (sinusoidal) pressuresMicrobubbles undergo compression at peak of ultrasound wave and expansion at nadirBubble radius may change by a factor of 20 or moreSound is generated with this movement, and amplified in combination of movement of thousands of microbubblesContrast bubbles oscillating in an ultrasound field are vastly more effective than RBCs at scattering sounds, resulting in improved blood pool signalThis generated signal can be distinguished from that of other tissue, resulting in improved imaging capabilities
6 Resonance and Harmonics Resonance: a physical property of gas bubbles; an optimal frequency of oscillation at which ultrasound absorption and scatter is most efficientInsonation of gas bubbles at their resonant frequency (fr) results in non-linear oscillationAlternate expansion and contraction of the bubble are unequalResults in generation of harmonics: ultrasound is produced at a frequency equal to an integer multiple of the isonating (fundamental) frequency
8 Harmonic ImagingMicrobubbles isonated with ultrasound frequency f1 return signals of the second harmonic frequency (f2=2f1) and the fundamental frequency f1Harmonic imaging: receiver is tuned to receive double the transmitted frequencyHarmonic imaging results in greatly improved signal-to-noise ratio; improves sensitivity to contrastEnables excellent LV cavity opacificationImproved myocardial tissue imaging
9 Acoustic Properties of Microbubbles Lindner JR. Microbubles in medical imaging: current applications and future directions. Nat Rev Drug Discov Jun;3(6):
10 Mechanical IndexSecond harmonic imaging signals increase with increasing ultrasound powerMicrobubbles are deformed by higher ultrasound power to point of destructionMechanical Index (MI)=Acoustic Power/√f0Low mechanical index (0.4 to 0.5) harmonic imaging is used to enhance LV endocardial border definitionMI>0.7 is associated with bubble destruction
15 AlbunexAir-filled sonicated albumin microbubbles (MBI, San Diego, California)1994: First ultrasound contrast agent approved for use in USAlbumin shell designed to prevent outward diffusion of air from microbubblesSubstantial loss of gas volume occurred during transit to systemic circulation following intravenous injectionMarkedly decreased contrast enhancement and short duration of clinically useful contrast
16 Innovations in Microbubble Agents Newer agents designed to improve intravascular stabilityModifications in shell and gas content“Air-tight” polymer shells or lipid-galactose stabilized shells designed to minimize outward diffusion of gasUse of gases less prone to outward diffusion than airInert high-molecular-mass gases with low diffusion coefficients and low solubility in water (low Ostwald coefficient); result in prolonged lifespan of microbubbles
17 OptisonTM Perflutren Protein-Type A Injectable Microspheres GE Healthcare, Buckinhamshire, United KingdomOctafluoropropaneManufacturer has voluntarily suspended marketing since 2005Structural FormulaOptison with red blood cells
18 Definity FDA approval in 2001 Bristol-Myers Squibb Medical Imaging, Billerica, MA$65 million in sales in 2006More than 2 million patients dosed
19 Left Ventricular Cavity Opacification: Utility and Applications
20 Utility of LV Opacification Improved imaging and analysis of:LV volumeRegional wall motionIntracardiac mass/thrombusPseudoaneurysmApical or mid-cavity hypertrophic cardiomyopathy
21 CMR vs. Contrast Echo for LVEF and LV Volume Assessment 40 patients referred for routine echocardiographyMRI performed (1.5 T, Apical 2, 4; Short axis apexbase)Followed immediately by TTE, once without and once with 2% dodecafluoropentane (EchoGen)Blinded interpretation of dataHundley WG, Kizilbash AM, Afridi I, Franco F, Peshock RM, Grayburn PA. Administration of an intravenous perfluorocarbon contrast agent improves echocardiographic determination of left ventricular volumes and ejection fraction: comparison with cine magnetic resonance imaging. J Am Coll Cardiol 1998; 32(5):
22 CMR vs. Contrast Echocardiography for LVEF Assessment Bland–Altman plots showing the mean difference (solid lines) and the limits of agreement (dashed lines) between echocardiographic and MRI measurements of LVEF. Left = baseline echocardiography; right = post contrast echocardiography. The value for each patient is represented by a diamond. The limits of agreement become more narrow after contrast agent administration.Hundley WG, et al. J Am Coll Cardiol 1998; 32(5):
23 Improvement in LVEF Classification Open Bars=Standard EchocardiographySolid Bars=Contrast EchocardiographyIn subjects with complete visualization of the endocardium, contrast agent administration was of no benefit.If ≥2 endocardial segments were not visualized at baseline, contrast enhancement markedly improved classification of EF subsets.Hundley WG, et al. J Am Coll Cardiol 1998; 32(5):
24 Intracardiac Mass vs. Thrombus Contrast echocardiography has been helpful in distinguishing between intracardiac thrombus or massPresence or absence of vascularity within a mass helps determine tumor vs. thrombus16 patients with intracardiac masses referred for echocardiographySlow intravenous push (0.6 to 1.0 ml) of Optison or continuous intravenous infusion (infusion rate adjusted for optimal enhancement) of DefinityMasses imaged using gray-scale power modulation (SONOS 5500, Philips Medical Systems, Andover, Massachusetts) with a low mechanical index (0.1)Whenever a mass demonstrated perfusion with echocardiographic contrast, an ultrasound impulse of high mechanical index (1.0 to 1.6) was transmitted for four up to 10 frames to destroy microbubbles within the massThis prevented the recording of "false-positive perfusion" due to a saturation artifact secondary to high gain settingsPerfusion of the mass was then confirmed by visualizing gradual contrast replenishment of the mass after the high-mechanical index impulse.Contrast enhancement assessed visually and with dedicated software (Qlab, Phillips Medical Systems)Kirkpatrick JN, Wong T, Bednarz JE, et al. Differential diagnosis of cardiac masses using contrast echocardiographic perfusion imaging. J Am Coll Cardiol 2004; 43:
25 Intracardiac Mass vs. Thrombus (A) A mass filling the right atrium (apical five-chamber view). (B) The mass hyper-enhanced with echocardiographic contrast, compared with the adjacent myocardium. (C) There was no enhancement of the mass or the adjacent myocardium after a high-mechanical index impulse destroyed contrast bubbles, ruling out "false-positive perfusion" of the mass. (D) The biopsy specimen diagnosis was follicular thyroid carcinoma. The blood vessels are stained with CD31 antibody. (E) Perfusion curves of video intensity over time demonstrated greater values for A and ß for the mass than for the adjacent myocardium.Kirkpatrick JN, et al. JACC 2004.
26 Intracardiac Mass vs. Thrombus (A) A left ventricular apical mass (apical four-chamber view). (B) The mass showed no enhancement with contrast, whereas the adjacent myocardium demonstrated enhancement. (C) There was no enhancement of the mass or adjacent myocardium after a high-mechanical index impulse destroyed the contrast agent. (D) The surgical specimen demonstrated no staining with CD34 antibody and minimal cellularity, consistent with thrombus. (E) Perfusion curves of video intensity over time demonstrated no increase in video intensity in the mass from baseline, whereas video intensity increased within the myocardium.Kirkpatrick JN, et al. JACC 2004.
27 Assessment of Midcavitary Hypertrophic Cardiomyopathy
28 Apical Hypertrophic Cardiomyopathy Soman P, Swinburn J, Callister M, Stephens NG, Senior R. Apical hypertrophic cardiomyopathy: bedside diagnosis by intravenous contrast echocardiography. J Am Soc Echocardiogr 2001; 14(4):
30 Myocardial Contrast Echocardiography (MCE) Ultrasound with high mechanical index (>1.5) destroys microbubblesMyocardium with normal perfusion is enhanced by microbubbles within 5-7 cardiac cyclesNormal myocardium appears opacifiedAreas of decreased perfusion appear dark or patchyContrast echocardiography allows for real time imaging of perfusion and contractilityLepper W, Belcik T, Wei K, et al. Myocardial contrast echocardiography. Circulation 2004; 109(25):
32 MCE vs. SPECT for CAD Detection Prospective, multicenter study of 123 pts referred for cardiac catheterization for known or suspected CADRest and vasodilator stress SPECT performed on separate daysMCE studies performed concurrently with stress SPECTDipyridamole infused at 0.56 mg/kg for four min and, if tolerated, a further 0.28 mg/kg was infused for two minAfter two min, radiotracer injection (600 MBq of 99mTc-sestamibi) was followed by contrast administration (Sonazoid)Stress MCE images were obtained (apical 2, 3, 4; MI 0.5 followed by pulse of MI 1.0)Patients underwent coronary arteriography within four weeks of noninvasive imagingAll images analyzed by observers independently of clinical or other imaging data.Jeetley P, Hickman M, Kamp O, et al. Myocardial contrast echocardiography for the detection of coronary artery stenosis: a prospective multicenter study in comparison with single-photon emission computed tomography. J Am Coll Cardiol Jan 3;47(1):141-5.
33 Image Assessment16-segment left ventricular model was used together with a three-point semi-quantitative scale for both MCE and SPECTAny myocardial segment with normal contrast replenishment at rest that did not fill in one to two seconds after dipyridamole was considered to demonstrate a reversible MCE perfusion defectOn SPECT, if the degree of tracer uptake was reduced at stress compared with that seen at rest, a reversible defect was diagnosedA perfusion defect at rest that remained unchanged at stress was considered to be a fixed defectThe presence of a defect in 1 myocardial segment(s) was taken to indicate the presence of CADMyocardial contrast echocardiography was analyzed blinded to the wall thickening data.Jeetley P, et al. JACC 2006
34 Myocardial Contrast Echocardiography (MCE) Reversible perfusion defects (arrows) in the posterior wall, apex, and septum in a patient with multivessel disease (bottom). The top panel shows the corresponding resting study demonstrating normal perfusion.Jeetley P, et al. JACC 2006
35 MCE vs. SPECT for CAD Detection All Coronary DistributionsOpen Bar=SPECTSolid Bar=MCEAnterior CirculationPosterior CirculationJeetley P, et al. JACC 2006.
37 FDA “Black Box” Warning Issued on October 10, 2007Post-marketing reports of 11 deaths 1-12 hours following administration of perflutren-based contrast agents10 patient deaths following Definity injection and 1 death following Optison injection4 patient deaths temporally related to contrast injectionPerflutren-based compounds contraindicated for use in patients with:1. Acute coronary syndromes2. Acute myocardial infarction3. Worsening or clinically unstable heart failure
38 Definity Safety DataKitzman DW, Goldman ME, Gilliam LD, Cohen JL, Aurigemma GP, Gottdiener JS. Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Cardiol Sep 15;86(6):Patients referred for echocardiogram with suboptimal viewsDefinition: endocardial borders not visible in ≥ 2 of 6 segments in either apical 4- or 2-chamber view211 patients randomized in 2:2:1 scheme to 5 uL/kg perflutren dose (85 pts), 10 uL/kg (84 pts), or saline placebo (42 pts)Safety assessed by evaluation of adverse events, clinical laboratory tests (serum chemistry, hematology, and urinalysis, electrocardiograms), vital signs, and physical examinationsInformation obtained before the perflutren or placebo injections and 24, 48, and 72 hours after administration.
39 Safety Data Adverse Experience Placebo (n=42) 5 ul/kg (n=85) 10ul/kg All Perflutren(n=169)Headache3 (7%)4 (5%)5 (6%)9 (5%)Dizziness1 (2%)2 (2%)1 (1%)3 (2%)Back Pain3 (4%)NauseaFlushing2 (1%)Chest painPruritisRashSweatingIV Site PainFatigueKitzman DW, Goldman ME, Gilliam LD, Cohen JL, Aurigemma GP, Gottdiener JS. Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Cardiol Sep 15;86(6):
40 Safety DataNo clinically significant change in physical examination, vital signs, electrocardiographic tracings, or chemistry or hematology laboratory valuesAdverse event rates similar across treatment groups30 of 169 patients (18%) in the combined perflutren-treated group (15% in the 5 ml/kg group and 20% in the 10 ml/kg group)6 of 42 placebo-treated patients (14%)Headache was most frequently reported adverse event (9 of 169 patients who received perflutren (5%) and 3 of 42 patients who received placebo (7%)Kitzman DW, Goldman ME, Gilliam LD, Cohen JL, Aurigemma GP, Gottdiener JS. Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Cardiol Sep 15;86(6):
41 Safety Data 77 of 211 patients had COPD or CHF 62 patients with CHF: 17 NYHA Class I28 NYHA Class II11 NYHA Class III1 NYHA Class IV5 classified as unknown15 patients with COPD:12 with mild disease2 with moderate disease1 with severe diseaseThese patients may be at increased risk of adverse events because of impaired cardiopulmonary reserveAdverse event profiles in these disease subgroups were similar to the overall group, were not clinically significant, and were not different from placebo.Kitzman DW, Goldman ME, Gilliam LD, Cohen JL, Aurigemma GP, Gottdiener JS. Efficacy and safety of the novel ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Cardiol Sep 15;86(6):
42 Additional Safety Data Dose ranging studies showed no changes in systemic or pulmonary hemodynamics, myocardial contractility, regional myocardial blood flow, even after 30 injections capable of myocardial opacification over 10 minutesNo cellular uptake or mitochondrial metabolismFluorocarbon gases are insoluble in blood, biologically inert, and excreted by the lungs within minutesLarge scale Phase III studies involving > 1700 patients revealed no safety concernsSkyba DM, Camarano G, Goodman NC, Price RJ, Skalack TC, Kaul S. Hemodynamic characteristics, myocardial kinetics, and microvascular rheology of FS-069, a second generation echocardiographic contrast agent capable of producing myocardial opacification from a venous injection. J Am Coll Cardiol 1996; 28:Cohen JL, Cheirif J, Segar DS, et al. Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent. Results of a phase III Multicenter Trial. J Am Coll Cardiol 1998; 32:
43 Definity Related Deaths Patient 1:Infarct related cardiomyopathyCardiac arrest 1 minute into exercise stress testReceived Definity injection 30 min priorPatient 2:Elderly patient in CCURecent MI, Severe LV systolic dysfunctionCardiac arrest shortly after contrast echocardiography
44 Definity Related Deaths Patient 3:70 y man, CABG, CHF, DVTContrast echocardiogram in setting of worsening heart failureSudden cyanosis, hypotension, and death 5 minutes after completion of studyMassive PE reported as likely cause of death
45 Definity Related Deaths Patient 4:35 y old morbidly obese woman with PPCMAdmitted to ICU with multilobar pneumoniaMechanical ventilation and multiple pressorsCardiac arrest immediately after Definity injectionPost mortem: RV thrombus and multiple pulmonary emboli
46 “Pseudocomplication” Main ML, Goldman JH, and Grayburn PA. Thinking outside the “Box”—the ultrasound contrast controversy. J Am Coll Cardiol 2007; 50 (25):Complications occurring after a medical procedure may be due to either the procedure itself or due to progression of the underlying disease stateMajor cardiovascular events are more likely to occur in patients who are “ill enough” to require diagnostic testingEchocardiography often the test of choice (or the only test available) for critically ill patients (shock, hypotension, tamponade, etc.)Association of adverse events following contrast administration does not establish causality