Amit J. Thosani, MDAmit J. Thosani, MD

Clinical Fellow, Division of CardiologyClinical Fellow, Division of Cardiology

23 January 200823 January 2008

Contrast Contrast EchocardiographyEchocardiography

Applications of Contrast Applications of Contrast EchocardiographyEchocardiography

Detection of intracardiac shunts:Detection of intracardiac shunts:Patent foramen ovale Patent foramen ovale Atrial septal defectAtrial septal defect

Intrapulmonary shuntIntrapulmonary shunt

Left ventricular opacification/endocardial Left ventricular opacification/endocardial border definitionborder definition

Assessment of myocardial perfusionAssessment of myocardial perfusion

Right vs. Left Heart Right vs. Left Heart ContrastContrast

Agitated salineAgitated saline

Bubble diameter is Bubble diameter is greater than diameter greater than diameter of pulmonary capillariesof pulmonary capillaries

No transpulmonary No transpulmonary passage (in absence of passage (in absence of intrapulmonary shunt)intrapulmonary shunt)

PFO/ASD/Persistent PFO/ASD/Persistent Left Superior Vena Left Superior Vena CavaCava

Microbubble diameter Microbubble diameter of 1-5 µmof 1-5 µm

Able to traverse Able to traverse pulmonary capillary pulmonary capillary bedbed

Resonate at frequency Resonate at frequency of 1.5-7 MHz, of 1.5-7 MHz, corresponding to corresponding to clinical transducer clinical transducer frequenciesfrequencies

Physical PrinciplesPhysical Principles Blood appears black on conventional 2D Blood appears black on conventional 2D

echocardiography because of weak echocardiography because of weak ultrasound scatter by RBCs at ultrasound scatter by RBCs at conventional imaging frequenciesconventional imaging frequencies

Contrast ultrasound is based on scattering Contrast ultrasound is based on scattering of incident ultrasound at gas/liquid of incident ultrasound at gas/liquid interfaceinterface

Results in increased strength of return Results in increased strength of return signalsignal

Physical PrinciplesPhysical Principles Ultrasound generates positive and negative (sinusoidal) Ultrasound generates positive and negative (sinusoidal)

pressurespressures

Microbubbles undergo compression at peak of ultrasound Microbubbles undergo compression at peak of ultrasound wave and expansion at nadirwave and expansion at nadir

Bubble radius may change by a factor of 20 or moreBubble radius may change by a factor of 20 or more

Sound is generated with this movement, and amplified in Sound is generated with this movement, and amplified in combination of movement of thousands of microbubblescombination of movement of thousands of microbubbles

Contrast bubbles oscillating in an ultrasound field are vastly Contrast bubbles oscillating in an ultrasound field are vastly more effective than RBCs at scattering sounds, resulting in more effective than RBCs at scattering sounds, resulting in improved blood pool signalimproved blood pool signal

This generated signal can be distinguished from that of other This generated signal can be distinguished from that of other tissue, resulting in improved imaging capabilitiestissue, resulting in improved imaging capabilities

Resonance and Resonance and HarmonicsHarmonics

ResonanceResonance: a physical property of gas bubbles; an : a physical property of gas bubbles; an optimal frequency of oscillation at which ultrasound optimal frequency of oscillation at which ultrasound absorption and scatter is most efficientabsorption and scatter is most efficient

Insonation of gas bubbles at their resonant frequency Insonation of gas bubbles at their resonant frequency (f(frr) results in non-linear oscillation) results in non-linear oscillation

Alternate expansion and contraction of the bubble Alternate expansion and contraction of the bubble are unequalare unequal

Results in generation of Results in generation of harmonicsharmonics: ultrasound is : ultrasound is produced at a frequency equal to an integer multiple produced at a frequency equal to an integer multiple of the isonating (fundamental) frequencyof the isonating (fundamental) frequency

HarmonicsHarmonics f=velocity/wavelengthf=velocity/wavelength

Wavelength (Wavelength (λλ)=2L/n, )=2L/n, n=# of harmonicn=# of harmonic

Fundamental Fundamental

ff11=v/2L=v/2L

Second harmonic Second harmonic ff22=2v/2L=2f=2v/2L=2f11

Third harmonic Third harmonic ff33=3v/2L=3f=3v/2L=3f11

Harmonic ImagingHarmonic Imaging Microbubbles isonated with ultrasound frequency Microbubbles isonated with ultrasound frequency

ff11 return signals of the second harmonic frequency return signals of the second harmonic frequency (f(f22=2f=2f11) and the fundamental frequency f) and the fundamental frequency f11

Harmonic imagingHarmonic imaging: receiver is tuned to receive : receiver is tuned to receive double the transmitted frequencydouble the transmitted frequency

Harmonic imaging results in greatly improved Harmonic imaging results in greatly improved signal-to-noise ratio; improves sensitivity to signal-to-noise ratio; improves sensitivity to contrastcontrast

Enables excellent LV cavity opacificationEnables excellent LV cavity opacification

Improved myocardial tissue imagingImproved myocardial tissue imaging

Acoustic Properties of Acoustic Properties of MicrobubblesMicrobubbles

Lindner JR. Microbubles in medical imaging: current applications and future directions. Nat Rev Drug Discov. 2004 Jun;3(6):527-32.

Mechanical IndexMechanical Index Second harmonic imaging signals increase with Second harmonic imaging signals increase with

increasing ultrasound powerincreasing ultrasound power

Microbubbles are deformed by higher ultrasound Microbubbles are deformed by higher ultrasound power to point of destructionpower to point of destruction

Mechanical Index (MI)=Acoustic Power/√fMechanical Index (MI)=Acoustic Power/√f00

Low mechanical index (0.4 to 0.5) harmonic Low mechanical index (0.4 to 0.5) harmonic imaging is used to enhance LV endocardial imaging is used to enhance LV endocardial border definitionborder definition

MI>0.7 is associated with bubble destructionMI>0.7 is associated with bubble destruction

LV Cavity OpacificationLV Cavity Opacification

LV Cavity OpacificationLV Cavity Opacification

Kitzman DW, Goldman ME, Gilliam LD, Cohen JL, Aurigemma GP, Gottdiener JS. Efficacy and safety of the novel 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 ultrasound contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. images. Am J CardiolAm J Cardiol. 2000 Sep 15;86(6):669-74. . 2000 Sep 15;86(6):669-74.

Microbubble Microbubble Contrast AgentsContrast Agents

Microbubble Contrast Microbubble Contrast AgentsAgents

NameName ManufacturerManufacturer ShellShell GasGas Mean Mean Size Size (µm)(µm)

AlbunexAlbunex Molecular Molecular BiosystemsBiosystems

AlbuminAlbumin AirAir 4.34.3

OptisonOptison Mallinckrodt/Mallinckrodt/

AmershamAmershamAlbuminAlbumin OctafluoroproOctafluoropro

panepane2-4.52-4.5

DefinityDefinity Bristol-Myers Bristol-Myers SquibbSquibb

Lipid/Lipid/surfactantsurfactant

OctafluoroproOctafluoropropanepane

1.1-3.31.1-3.3

ImagenImagentt

ImacorImacor Lipid/Lipid/surfactantsurfactant

N2/N2/

perfluorohexaperfluorohexanene

6.06.0

SonovuSonovuee

Bracco DiagnosticsBracco Diagnostics LipidLipid Sulphur Sulphur hexafluoridehexafluoride

2-32-3

LevovisLevovistt

Schering AGSchering AG Lipid/Lipid/galactosegalactose

AirAir 2-42-4

AlbunexAlbunex Air-filled sonicated albumin microbubbles (MBI, San Air-filled sonicated albumin microbubbles (MBI, San

Diego, California)Diego, California)

1994: First ultrasound contrast agent approved for 1994: First ultrasound contrast agent approved for use in USuse in US

Albumin shell designed to prevent outward diffusion Albumin shell designed to prevent outward diffusion of air from microbubblesof air from microbubbles

Substantial loss of gas volume occurred during transit to systemic circulation following intravenous injection

Markedly decreased contrast enhancement and short duration of clinically useful contrast

Innovations in Microbubble Innovations in Microbubble AgentsAgents

Newer agents designed to improve intravascular Newer agents designed to improve intravascular stabilitystability

Modifications in shell and gas contentModifications in shell and gas content

““Air-tight” polymer shells or lipid-galactose stabilized Air-tight” polymer shells or lipid-galactose stabilized shells designed to minimize outward diffusion of gasshells designed to minimize outward diffusion of gas

Use of gases less prone to outward diffusion than airUse of gases less prone to outward diffusion than air

Inert high-molecular-mass gases with low diffusion coefficients and low solubility in water (low Ostwald coefficient); result in prolonged lifespan of microbubbles

OptisonOptisonTMTM

Perflutren Protein-Perflutren Protein-Type A Injectable Type A Injectable MicrospheresMicrospheres

GE Healthcare, GE Healthcare, Buckinhamshire, Buckinhamshire, United KingdomUnited Kingdom

OctafluoropropaneOctafluoropropane

Manufacturer has Manufacturer has voluntarily suspended voluntarily suspended marketing since 2005marketing since 2005

http://www.amershamhealth-us.com/optison/monograph/om03-02.htmlOptison with red blood cells

Structural Formula

DefinityDefinity

FDA approval in 2001FDA approval in 2001

Bristol-Myers Squibb Medical Imaging, Billerica, Bristol-Myers Squibb Medical Imaging, Billerica, MAMA

$65 million in sales in 2006$65 million in sales in 2006

More than 2 million patients dosedMore than 2 million patients dosed

Left Ventricular Left Ventricular Cavity Cavity

Opacification: Opacification: Utility and Utility and

ApplicationsApplications

Utility of LV Utility of LV OpacificationOpacification

Improved imaging and analysis of:Improved imaging and analysis of:

LV volumeLV volume

Regional wall motionRegional wall motion

Intracardiac mass/thrombusIntracardiac mass/thrombus

PseudoaneurysmPseudoaneurysm

Apical or mid-cavity hypertrophic Apical or mid-cavity hypertrophic cardiomyopathycardiomyopathy

CMR vs. Contrast Echo for CMR vs. Contrast Echo for LVEF and LV Volume LVEF and LV Volume

AssessmentAssessment 40 patients referred for routine 40 patients referred for routine

echocardiographyechocardiography

MRI performed (1.5 T, Apical 2, 4; Short axis MRI performed (1.5 T, Apical 2, 4; Short axis apexapexbase)base)

Followed immediately by TTE, once without and Followed immediately by TTE, once without and once with 2% dodecafluoropentane (EchoGen)once with 2% dodecafluoropentane (EchoGen)

Blinded interpretation of dataBlinded 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): 1426-32.

CMR vs. Contrast CMR vs. Contrast Echocardiography for LVEF Echocardiography for LVEF

AssessmentAssessment

Hundley WG, et al. J Am Coll Cardiol 1998; 32(5): 1426-32.

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.

Improvement in LVEF Improvement in LVEF ClassificationClassification

Hundley WG, et al. J Am Coll Cardiol 1998; 32(5): 1426-32.

•Open Bars=Standard Echocardiography

•Solid Bars=Contrast Echocardiography

•In 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.

Intracardiac Mass vs. Intracardiac Mass vs. ThrombusThrombus

Contrast echocardiography has been helpful in distinguishing between intracardiac thrombus or Contrast echocardiography has been helpful in distinguishing between intracardiac thrombus or massmass

Presence or absence of vascularity within a mass helps determine tumor vs. thrombusPresence or absence of vascularity within a mass helps determine tumor vs. thrombus

16 patients with intracardiac masses referred for echocardiography16 patients with intracardiac masses referred for echocardiography

Slow intravenous push (0.6 to 1.0 ml) of Optison or continuous intravenous infusion (infusion rate Slow intravenous push (0.6 to 1.0 ml) of Optison or continuous intravenous infusion (infusion rate adjusted for optimal enhancement) of Definityadjusted for optimal enhancement) of Definity

Masses imaged using gray-scale power modulation (SONOS 5500, Philips Medical Systems, Masses imaged using gray-scale power modulation (SONOS 5500, Philips Medical Systems, Andover, Massachusetts) with a low mechanical index (0.1)Andover, Massachusetts) with a low mechanical index (0.1)

Whenever a mass demonstrated perfusion with echocardiographic contrast, an ultrasound impulse 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 of high mechanical index (1.0 to 1.6) was transmitted for four up to 10 frames to destroy microbubbles within the massmicrobubbles within the mass

This prevented the recording of "false-positive perfusion" due to a saturation artifact secondary to This prevented the recording of "false-positive perfusion" due to a saturation artifact secondary to high gain settingshigh gain settings

Perfusion of the mass was then confirmed by visualizing gradual contrast replenishment of the Perfusion of the mass was then confirmed by visualizing gradual contrast replenishment of the mass after the high-mechanical index impulse. mass after the high-mechanical index impulse.

Contrast enhancement assessed visually and with dedicated software (Qlab, Phillips Medical Contrast enhancement assessed visually and with dedicated software (Qlab, Phillips Medical Systems)Systems)

Kirkpatrick JN, Wong T, Bednarz JE, et al. Differential diagnosis of cardiac masses using contrast echocardiographic Kirkpatrick JN, Wong T, Bednarz JE, et al. Differential diagnosis of cardiac masses using contrast echocardiographic perfusion imaging. J Am Coll Cardiol 2004; 43: 1412-1419.perfusion imaging. J Am Coll Cardiol 2004; 43: 1412-1419.

Intracardiac Mass vs. Intracardiac Mass vs. ThrombusThrombus

(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.

(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.

Intracardiac Mass vs. Thrombus

Kirkpatrick JN, et al. JACC 2004.

Assessment of Midcavitary Hypertrophic Cardiomyopathy

Apical Hypertrophic Apical Hypertrophic CardiomyopathyCardiomyopathy

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): 311-3.

Myocardial Myocardial Contrast Contrast

EchocardiographyEchocardiography

Myocardial Contrast Myocardial Contrast Echocardiography (MCE)Echocardiography (MCE)

Ultrasound with high mechanical index (>1.5) Ultrasound with high mechanical index (>1.5) destroys microbubblesdestroys microbubbles

Myocardium with normal perfusion is enhanced Myocardium with normal perfusion is enhanced by microbubbles within 5-7 cardiac cyclesby microbubbles within 5-7 cardiac cycles

Normal myocardium appears opacifiedNormal myocardium appears opacified

Areas of decreased perfusion appear dark or Areas of decreased perfusion appear dark or patchypatchy

Contrast echocardiography allows for real time Contrast echocardiography allows for real time imaging of perfusion and contractilityimaging of perfusion and contractility

Lepper W, Belcik T, Wei K, et al. Myocardial contrast echocardiography. Circulation 2004; 109(25): 3132-5.

Myocardial Contrast Echocardiography

MCE vs. SPECT for CAD MCE vs. SPECT for CAD DetectionDetection

Prospective, multicenter study of 123 pts referred for cardiac catheterization for Prospective, multicenter study of 123 pts referred for cardiac catheterization for known or suspected CADknown or suspected CAD

Rest and vasodilator stress SPECT performed on separate daysRest and vasodilator stress SPECT performed on separate days

MCE studies performed concurrently with stress SPECTMCE studies performed concurrently with stress SPECT

Dipyridamole infused at 0.56 mg/kg for four min and, if tolerated, a further 0.28 Dipyridamole infused at 0.56 mg/kg for four min and, if tolerated, a further 0.28 mg/kg was infused for two minmg/kg was infused for two min

After two min, radiotracer injection (600 MBq of 99mTc-sestamibi) was followed After two min, radiotracer injection (600 MBq of 99mTc-sestamibi) was followed by contrast administration (Sonazoid)by contrast administration (Sonazoid)

Stress MCE images were obtained (apical 2, 3, 4; MI 0.5 followed by pulse of MI Stress MCE images were obtained (apical 2, 3, 4; MI 0.5 followed by pulse of MI 1.0)1.0)

Patients underwent coronary arteriography within four weeks of noninvasive Patients underwent coronary arteriography within four weeks of noninvasive imagingimaging

All images analyzed by observers independently of clinical or other imaging All images analyzed by observers independently of clinical or other imaging data. 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. 2006 Jan 3;47(1):141-5.

Image AssessmentImage Assessment 16-segment left ventricular model was used together with a three-point 16-segment left ventricular model was used together with a three-point

semi-quantitative scale for both MCE and SPECTsemi-quantitative scale for both MCE and SPECT

Any myocardial segment with normal contrast replenishment at rest that Any myocardial segment with normal contrast replenishment at rest that did not fill in one to two seconds after dipyridamole was considered to did not fill in one to two seconds after dipyridamole was considered to demonstrate a reversible MCE perfusion defectdemonstrate a reversible MCE perfusion defect

On SPECT, if the degree of tracer uptake was reduced at stress compared On SPECT, if the degree of tracer uptake was reduced at stress compared with that seen at rest, a reversible defect was diagnosedwith that seen at rest, a reversible defect was diagnosed

A perfusion defect at rest that remained unchanged at stress was A perfusion defect at rest that remained unchanged at stress was considered to be a fixed defectconsidered to be a fixed defect

The presence of a defect in 1 myocardial segment(s) was taken to The presence of a defect in 1 myocardial segment(s) was taken to indicate the presence of CADindicate the presence of CAD

Myocardial contrast echocardiography was analyzed blinded to the wall Myocardial contrast echocardiography was analyzed blinded to the wall thickening data. thickening data.

Jeetley P, et al. JACC 2006

Myocardial Contrast Myocardial Contrast Echocardiography (MCE)Echocardiography (MCE)

Jeetley P, et al. JACC 2006

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.

MCE vs. SPECT for CAD MCE vs. SPECT for CAD DetectionDetection

Anterior Circulation

Jeetley P, et al. JACC 2006.

Open Bar=SPECTSolid Bar=MCE

Posterior Circulation

All Coronary Distributions

Recent IssuesRecent Issues

FDA “Black Box” FDA “Black Box” WarningWarning

Issued on October 10, 2007Issued on October 10, 2007

Post-marketing reports of 11 deaths 1-12 hours following Post-marketing reports of 11 deaths 1-12 hours following administration of perflutren-based contrast agentsadministration of perflutren-based contrast agents

10 patient deaths following Definity injection and 1 death 10 patient deaths following Definity injection and 1 death following Optison injectionfollowing Optison injection

4 patient deaths temporally related to contrast injection4 patient deaths temporally related to contrast injection

Perflutren-based compounds contraindicated for use in Perflutren-based compounds contraindicated for use in patients with:patients with:1. Acute coronary syndromes1. Acute coronary syndromes2. Acute myocardial infarction2. Acute myocardial infarction3. Worsening or clinically unstable heart failure3. Worsening or clinically unstable heart failure

http://www.fda.gov/cder/drug/InfoSheets/HCP/microbubbleHCP.htm

Definity Safety DataDefinity Safety Data 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. 2000 Sep 15;86(6):669-74.

Patients referred for echocardiogram with suboptimal views

Definition: endocardial borders not visible in ≥ 2 of 6 segments in either apical 4- or 2-chamber view

211 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 examinations

Information obtained before the perflutren or placebo injections and 24, 48, and 72 hours after administration.

Safety DataSafety DataAdverseAdverse

ExperienceExperiencePlacebo Placebo

(n=42)(n=42)5 ul/kg5 ul/kg

(n=85)(n=85)10ul/kg10ul/kg

(n=85)(n=85)All Perflutren All Perflutren

(n=169)(n=169)

HeadacheHeadache 3 (7%)3 (7%) 4 (5%)4 (5%) 5 (6%)5 (6%) 9 (5%)9 (5%)

DizzinessDizziness 1 (2%)1 (2%) 2 (2%)2 (2%) 1 (1%)1 (1%) 3 (2%)3 (2%)

Back PainBack Pain 00 00 3 (4%)3 (4%) 3 (2%)3 (2%)

NauseaNausea 00 2 (2%)2 (2%) 1 (1%)1 (1%) 3 (2%)3 (2%)

FlushingFlushing 00 00 2 (2%)2 (2%) 2 (1%)2 (1%)

Chest painChest pain 00 00 2 (2%)2 (2%) 2 (1%)2 (1%)

PruritisPruritis 00 1 (1%)1 (1%) 1 (1%)1 (1%) 2 (1%)2 (1%)

RashRash 00 1 (1%)1 (1%) 1 (1%)1 (1%) 2 (1%)2 (1%)

SweatingSweating 00 1 (1%)1 (1%) 1 (1%)1 (1%) 2 (1%)2 (1%)

IV Site PainIV Site Pain 1 (2%)1 (2%) 1 (1%)1 (1%) 00 1 (1%)1 (1%)

FatigueFatigue 1 (2%)1 (2%) 1 (1%)1 (1%) 0 0 1 (1%)1 (1%)

Kitzman DW, Goldman ME, Gilliam LD, Cohen JL, Aurigemma GP, Gottdiener JS. Efficacy and safety of the novel ultrasound 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. contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Am J CardiolCardiol. 2000 Sep 15;86(6):669-74. . 2000 Sep 15;86(6):669-74.

Safety DataSafety Data No clinically significant change in physical examination,

vital signs, electrocardiographic tracings, or chemistry or hematology laboratory values

Adverse event rates similar across treatment groups

30 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 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. contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Am J

CardiolCardiol. 2000 Sep 15;86(6):669-74.. 2000 Sep 15;86(6):669-74.

Safety DataSafety 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 unknown

15 patients with COPD: 12 with mild disease

2 with moderate disease1 with severe disease

These patients may be at increased risk of adverse events because of impaired cardiopulmonary reserve

Adverse 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 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. contrast agent perflutren (definity) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Am J CardiolCardiol. 2000 Sep 15;86(6):669-74. . 2000 Sep 15;86(6):669-74.

Additional Safety DataAdditional Safety Data Dose ranging studies showed no changes in systemic or Dose ranging studies showed no changes in systemic or

pulmonary hemodynamics, myocardial contractility, regional pulmonary hemodynamics, myocardial contractility, regional myocardial blood flow, even after 30 injections capable of myocardial blood flow, even after 30 injections capable of myocardial opacification over 10 minutesmyocardial opacification over 10 minutes

No cellular uptake or mitochondrial metabolismNo cellular uptake or mitochondrial metabolism

Fluorocarbon gases are insoluble in blood, biologically inert, Fluorocarbon gases are insoluble in blood, biologically inert, and excreted by the lungs within minutesand excreted by the lungs within minutes

Large scale Phase III studies involving > 1700 patients revealed Large scale Phase III studies involving > 1700 patients revealed no safety concernsno safety concerns

Skyba DM, Camarano G, Goodman NC, Price RJ, Skalack TC, Kaul S. Hemodynamic characteristics, myocardial kinetics, and microvascular rheology Skyba 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 of FS-069, a second generation echocardiographic contrast agent capable of producing myocardial opacification from a venous injection. J Am Coll Cardiol 1996; 28: 1292-300.Coll Cardiol 1996; 28: 1292-300.

Cohen JL, Cheirif J, Segar DS, et al. Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new 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: 746-52.echocardiographic contrast agent. Results of a phase III Multicenter Trial. J Am Coll Cardiol 1998; 32: 746-52.

Definity Related DeathsDefinity Related Deaths Patient 1: Patient 1:

Infarct related cardiomyopathyInfarct related cardiomyopathyCardiac arrest 1 minute into exercise stress Cardiac arrest 1 minute into exercise stress testtestReceived Definity injection 30 min priorReceived Definity injection 30 min prior

Patient 2:Patient 2:Elderly patient in CCUElderly patient in CCURecent MI, Severe LV systolic dysfunctionRecent MI, Severe LV systolic dysfunctionCardiac arrest shortly after contrast Cardiac arrest shortly after contrast echocardiographyechocardiography

Definity Related DeathsDefinity Related Deaths Patient 3:Patient 3:

70 y man, CABG, CHF, DVT70 y man, CABG, CHF, DVT

Contrast echocardiogram in setting of Contrast echocardiogram in setting of worsening heart failureworsening heart failure

Sudden cyanosis, hypotension, and death Sudden cyanosis, hypotension, and death 5 minutes after completion of study5 minutes after completion of study

Massive PE reported as likely cause of Massive PE reported as likely cause of deathdeath

Definity Related DeathsDefinity Related Deaths Patient 4:Patient 4:

35 y old morbidly obese woman with PPCM35 y old morbidly obese woman with PPCM

Admitted to ICU with multilobar pneumoniaAdmitted to ICU with multilobar pneumonia

Mechanical ventilation and multiple pressorsMechanical ventilation and multiple pressors

Cardiac arrest immediately after Definity injectionCardiac arrest immediately after Definity injection

Post mortem: RV thrombus and multiple Post mortem: RV thrombus and multiple pulmonary embolipulmonary emboli

““Pseudocomplication”Pseudocomplication” Main ML, Goldman JH, and Grayburn PA. Thinking outside Main ML, Goldman JH, and Grayburn PA. Thinking outside

the “Box”—the ultrasound contrast controversy. J Am Coll the “Box”—the ultrasound contrast controversy. J Am Coll Cardiol 2007; 50 (25): 2434-2437.Cardiol 2007; 50 (25): 2434-2437.

Complications occurring after a medical procedure may be Complications occurring after a medical procedure may be due to either the procedure itself or due to progression of due to either the procedure itself or due to progression of the underlying disease statethe underlying disease state

Major cardiovascular events are more likely to occur in Major cardiovascular events are more likely to occur in patients who are “ill enough” to require diagnostic testingpatients who are “ill enough” to require diagnostic testing

Echocardiography often the test of choice (or the only test Echocardiography often the test of choice (or the only test available) for critically ill patients (shock, hypotension, available) for critically ill patients (shock, hypotension, tamponade, etc.)tamponade, etc.)

Association of adverse events following contrast Association of adverse events following contrast administration does not establish causalityadministration does not establish causality