The Effects of Product Liability Litigation on the Value of Firms 1 Correspondence:Paul H. RubinDepartment of EconomicsEmory UniversityAtlanta, GA 30322-2240Voice: 404-727-6365Fax: 630-604-9609Email: prubin@Emory.eduhttp://www.Emory.edu/COLLEGE/ECON/Rubi.htmApril 15, 2000 1 We would like to thank Owen Beelders, John Calfee, James Cooper, Chris Curran, Sherry L. Jarrell, and JohnYun, for helpful
10164_honos.qxdCopyright Pulsus Group Inc – Do not copy SPECIAL ARTICLE
Contrast echocardiography in Canada:
Canadian Cardiovascular Society/
Canadian Society of Echocardiography position paper
George Honos (chair) MD FRCPC FACC1, Robert Amyot MD FRCPC2, Jonathan Choy MD FRCPC3, Howard Leong-Poi MD FRCPC4, Greg Schnell MD FRCPC5, Eric Yu MD FRCPC6 G Honos, R Amyot, J Choy, H Leong-Poi, G Schnell, E Yu.
Échocardiographie de contraste au Canada :
Contrast echocardiography in Canada: Canadian Cardiovascular
Énoncé de position de la Société canadienne de
Society/Canadian Society of Echocardiography position paper.
Can J Cardiol 2007;23(5):351-356.
cardiologie / Société canadienne
As an adjunct to transthoracic, transesophageal and stress echocardio-graphy, contrast echocardiography (CE) improves the diagnostic accu- À titre de mesure d’appoint aux échocardiographies transthoraciques, racy of technically suboptimal studies when used in conjunction with trans-œsophagiennes et de stress, l’échocardiographie de contraste (ÉC) améliore la précision diagnostique des examens suboptimaux sur le plan Intravenous ultrasound contrast agents are indicated for left ventricu- technique lorsqu’elle est utilisée en conjonction avec une imagerie lar (LV) opacification and improvement of LV endocardial border delineation in patients with suboptimal acoustic windows.
Les agents de contraste intraveineux sont indiqués avec l’ÉC pour opacifier Demonstrated benefits of CE include improvement in the accuracy of le ventricule gauche et améliorer la visibilité du rebord endocardique VG LV measurements, regional wall motion assessment, evaluation of chez les patients qui présentent des fenêtres acoustiques suboptimales. Les noncompaction cardiomyopathy, thrombus detection, Doppler signal avantages avérés de l’ÉC sont notamment qu’elle améliore la précision desmesures VG, l’évaluation du mouvement pariétal régional, l’évaluation de enhancement and conjunctive use with stress echocardiography.
la cardiomyopathie sans compaction, le dépistage des thrombi, Studies have shown the value of CE in the assessment and quantifica- l’amplification du signal Doppler et l’utilisation concomitante de tion of myocardial perfusion, and recent clinical trials have suggested l’échocardiographie de stress. Les études ont montré l’utilité de l’ÉC dans a role for contrast perfusion imaging in the stratification of patients l’évaluation et la quantification de la perfusion myocardique et selon de with suspected coronary artery disease.
récents essais cliniques, l’imagerie de perfusion avec agent de contraste While it adds some time and cost to the echocardiographic study, CE pourrait faciliter la stratification des patients chez qui on soupçonne une frequently obviates the need for additional specialized, expensive and less accessible cardiac investigations, and allows for prompt and opti- Si elle prend plus de temps et coûte plus cher, l’échocardiographie de mal subsequent patient management. Despite its proven advantages, contraste permet par contre souvent d’éviter le recours à d’autres épreuves CE is presently underused in Canada, and this situation will, unfortu- cardiaques spécialisées qui se révèlent coûteuses et moins accessibles, d’où nately, not improve until several barriers to its use are overcome.
un traitement plus rapide et optimum des patients. Malgré ses avantages Resolving these important hurdles is vital to the future of CE and to éprouvés, l’ÉC est actuellement sous-utilisée au Canada et cette situation its eventual implementation into clinical practice of promising risque fort malheureusement de ne pas s’améliorer tant que certains contrast-based diagnostic and therapeutic applications, including the obstacles à son utilisation ne seront pas surmontés. Et il faudra aplanir ces assessment of perfusion by myocardial CE.
importantes difficultés si l’on veut assurer l’avenir de l’ÉC comme outild’évaluation de la perfusion myocardique et assister éventuellement à son Key Words: Contrast; Echocardiography; Imaging; Perfusion
utilisation à grande échelle dans la pratique clinique, comme n’importequelle autre technique diagnostique et thérapeutique prometteuse à based’agents de contraste.
Intravenous ultrasound contrast agents are indicated for left contrast perfusion imaging in the stratification of patients ventricular opacification (LVO) and improvement of LV with suspected coronary artery disease (CAD) (9,10).
endocardial border delineation in patients with suboptimal While the injection of a contrast agent often improves acoustic windows. Benefits of contrast echocardiography (CE) study diagnostic quality, the use of CE in Canada is still quite have been demonstrated for accuracy of LV measurements (1), limited. Time constraints, financial concerns, and a lack of regional wall motion assessment (2), evaluation of noncom- equipment and expertise are some of the many challenges that paction cardiomyopathy (3), thrombus detection (4), Doppler have prevented more widespread use of CE in the past, under- signal enhancement (5) and conjunctive use with stress scoring the importance of developing criteria for the appropri- echocardiography (6). Studies have shown the value of CE in ate use of this simple and useful technique. The present the assessment and quantification of myocardial perfusion document reviews the basic principles and clinical applica- (7,8), and recent clinical trials have suggested a role for tions of CE and provides the Canadian cardiology community 1Sir Mortimer B Davis Jewish General Hospital; 2Hôpital du Sacré-Coeur, Montreal, Quebec; 3University of Alberta Hospital, Edmonton, Alberta; 4St Michael’s Hospital, Toronto, Ontario; 5Foothills General Hospital, Calgary, Alberta; 6University Health Network, Toronto, Ontario Correspondence and reprints: Dr George Honos, Sir Mortimer B Davis Jewish General Hospital, 3755 Côte Ste-Catherine, E-206, Montreal, Quebec H3T 1E2. Telephone 514-340-8283, fax 514-340-7534, e-mail firstname.lastname@example.org Received for publication February 12, 2007. Accepted February 27, 2007 2007 Pulsus Group Inc. All rights reserved Copyright Pulsus Group Inc – Do not copy Honos et al
generation, air-filled agents (16). These newer agents also Echocardiographic contrast agents
encapsulate the gas within lipid shells to further enhance Shell composition
microbubble stability in the circulation (Table 1).
Harmonic imaging, which is available on most ultrasound sys- tems currently in clinical use, was first developed specifically for CE (17). The intent of harmonic imaging was to take advan- tage of the unique physical properties of contrast microbubbles exposed to an ultrasound field. When bubbles are insonated, they oscillate within the acoustic field, going through rapid suc- cessions of compression and expansion. The amplitude of the bubble volume change is maximal at a specific frequency, termed resonant frequency. The resulting backscattered signal therefore includes frequencies that are multiples (harmonics) of the incident (fundamental) frequency. In standard harmonic imaging, only the second harmonic echoes are displayed and the remaining frequencies are filtered out (18). It was then observed that cardiac tissues, such as the endocardium-blood pool boundary, also generate harmonic signals, while many arti- facts do not. The use of second harmonic imaging, therefore,results in substantial improvement in two-dimensional image *In clinical use in Canada; †Formerly known as Bracco Diagnostics Inc; quality, even in the absence of any contrast injection.
Undergoing phase III testing; §Undergoing phase II testing. PESDA Perfluorocarbon (PFC)-exposed sonicated dextrose albumin; SF6 Sulphurhexafluoride Mechanical index
The mechanical index (MI) is an estimate of the ultrasound
output power and is defined as the peak negative acoustic pres-
with some guidance for the implementation of CE in local sure at the focus of the ultrasound beam, divided by the square echocardiography laboratories based on the best available sci- root of the incident frequency (19). MI is user-adjustable and its value appears onscreen on most commercially availableultrasound systems. Many echocardiographic platforms offer BASIC PRINCIPLES
different contrast presets with an MI optimized for LVO and Enhancement of the acoustic signal of blood during echocar- diography was first described in 1968 (11), when it was noted At a high MI, microbubbles are susceptible to destruction that saline injected into the aortic root produced strong echoes by insonation. Therefore, a lower MI is desired during contrast within the aortic lumen. This contrast effect was attributed to imaging to prolong the effect of the agent and optimize the the accidental introduction of small air bubbles into the blood- enhancement of the blood-myocardium interface. However, stream with fluid injections. These air bubbles strikingly the ability to generate strong acoustic signals by microbubble increase the backscatter because of their high impedance to destruction has implications for myocardial CE (MCE). Early ultrasound propagation compared with blood. However, air attempts to assess perfusion using high MI harmonic imaging bubbles present in agitated saline administered intravenously failed because microbubbles were continually destroyed while do not cross the pulmonary circulation because the larger bub- entering the myocardial microvasculature on insonation at the bles are trapped by the microcirculation, while microbubbles high frame rates used in continuous imaging. Intermittent small enough to pass through the pulmonary capillary bed imaging was introduced to overcome this problem. Imaging (smaller than 8 µm) collapse within a few seconds before reach- with this modality is performed at very low frame rates, trig- ing the left heart cavities due to surface tension, surrounding gered according to the electrocardiogram. This allows the pressure and gas diffusion from bubbles into the blood (12,13).
replenishment of microbubble contrast agent into the Early applications of CE were therefore limited to using agitated myocardium in between destructive imaging frames, and saline to detect intracardiac and intrapulmonary shunts, con- enables the qualitative and quantitative (investigational) firm needle placement during pericardiocentesis, and enhance assessment of myocardial perfusion. With intermittent imag- right-sided Doppler signals and two-dimensional images.
ing, delayed and incomplete replenishment implies reduced Agitated saline CE is still widely used in these clinical settings in the modern-day echocardiography laboratory.
To overcome the instability of air-filled microbubbles, and Newer imaging techniques
to allow them to cross the pulmonary capillary bed and reach Other than harmonic imaging, specific modalities have been the left heart, two main strategies were initially adopted.
developed to selectively enhance the microbubble signal, and Substances with surfactant-like properties to reduce surface abolish background noise and tissue signal. These techniques tension (14), as well as a protein shell to encapsulate the bub- use low acoustic power to minimize microbubble destruction bles and limit outward gas diffusion, were included in some for- and prolong the contrast effect, and also maximize the mulations (15). More recently, high-molecular-weight gases microbubble signal intensity to noise ratio. Such ultralow MI (mainly fluorocarbons) with low solubility in blood have been (0.1 to 0.2) technologies are referred to as real-time perfusion used to yield microbubbles with greater stability than the first imaging because they allow assessment of tissue perfusion Copyright Pulsus Group Inc – Do not copy CCS/CSE position paper on contrast echocardiography
during real-time continuous imaging. These newer contrast stimulation. This qualitative analysis of segmental contractility imaging techniques specifically take advantage of the nonlin- is limited by inadequate image quality. Therefore, optimal ear response of microbubbles to an ultrasound field. A unique endocardial delineation of all LV segments at rest and during ultrasound signature from the contrast backscattered signal is stress is of utmost importance to maximize diagnostic accuracy generated by the asymmetrical oscillations of microbubbles, and improve interobserver agreement (33). Image acquisition which can expand more than they can be compressed. By send- at peak stress inherently carries additional challenges over ing sequences of ultrasound pulses of alternating phase and/or baseline recording. Image degradation commonly takes place intensity, the system suppresses the linear backscattered echoes from rest to maximal stress because of the limited time to scan from tissue. On the contrary, the successive nonlinear signals in different incidences in the contexts of patient discomfort, received from microbubbles do not cancel out when added, tachycardia, hyperventilation, increased cardiac translation, and are selectively amplified and displayed. These modalities and sometimes significant ischemia, which have to be are very sensitive for detecting contrast signal while virtually eliminating the surrounding tissue echoes. Real-time perfusion Stress echocardiography in conjunction with LVO has been imaging limits microbubble disruption by the use of a low MI studied mostly with dobutamine testing (6,26,34-37). In several and avoids the need for intermittent triggered imaging.
trials, contrast use consistently improved endocardial depic- Therefore, wall motion can be assessed in real time without tion and confidence of interpretation during stress echocardio- interruption of image acquisition (16). The great potential of graphy. However, the diagnostic accuracy of stress these approaches is their ability to acquire cardiac systolic echocardiography with LVO compared with noncontrast har- function and myocardial perfusion information simultaneously.
monic imaging stress echocardiography has not been well stud-ied. Some investigators have provided indirect evidence LV FUNCTION ASSESSMENT
suggesting superior stress echocardiography performance in the Accurate determination of LV ejection fraction (LVEF) is detection of CAD with contrast. For example, LVO, during important in the clinical management of patients with cardio- dobutamine stress echocardiography in patients with subopti- vascular disease. For example, LVEF predicts the risk of adverse mal acoustic windows, has shown sensitivity and specificity outcomes in patients with congestive heart failure, as well as similar to noncontrast examinations in subjects with adequate those postmyocardial infarction and following revascularization images (34). In the largest trial of stress echocardiography with (20-24). Several techniques have been used for the determina- contrast (6), 300 consecutive outpatients underwent dobuta- tion of LV volumes and LVEF, among them, echocardiography, mine testing using both noncontrast harmonic imaging and cineventriculography, radionuclide-ventriculography and mag- LVO. Although the subjects were not selected on the basis of netic resonance imaging (MRI). Although echocardiography is having a poor acoustic window, contrast use improved image the most frequently used modality in clinical practice, it has quality and confidence of interpretation both at rest and at gained little acceptance in clinical trials, because prior studies peak stress. Moreover, LVO prevented the deterioration in have indicated that conventional noncontrast echocardiogra- image quality and confidence of interpretation from baseline phy may have significant variability compared with accepted to maximal stress that was observed with noncontrast images.
gold standards, with resultant low interobserver agreement, and Nevertheless, the most important benefits were observed in moderate reproducibility and accuracy to define LVEF. The the subset of patients with suboptimal images, and the general main reasons for the compromise in reproducibility and accu- consensus supports the use of LVO during stress echocardiogra- racy, aside from geometric assumptions, lie with the inadequate discrimination of the endocardial border. CE provides betterendocardial border delineation than nonenhanced echocardio- MYOCARDIAL PERFUSION
The advent of newer myocardial contrast agents that safely tra- CE has been demonstrated to significantly improve agree- verse the pulmonary circulation has permitted the intravenous ment in the measurements of LV volumes and LVEF using cur- administration of contrast to assess not only LV wall motion, rent reference standards, including cineventriculography, but also the myocardial microcirculation. These agents remain radionuclide ventriculography, electron beam computed entirely within the vascular space, have similar rheology to red tomography and MRI (1,27-30). The enhanced accuracy of CE blood cells and are hemodynamically inert. During a constant has been demonstrated in several single-centre and multicentre intravenous infusion of microbubbles, a steady state is achieved studies, with significant reductions in intra- and interobserver within the capillary bed. The ultrasound signal returned from variability when contrast is used in the assessment of ventricu- the bubbles within the myocardium at a steady state can be lar function, volumes and EF (1,27,28-30). The interobserver detected using modern ultrasound imaging modalities and is variability for CE has been demonstrated to reach the same proportional to the number of intact capillaries or myocardial level as that for MRI (1). Ultrasound technologies, including blood volume. Destruction of microbubbles using a high-energy the automatic quantification of LV structure and function using pulse of ultrasound and observation of the subsequent replen- a variety of edge detection and blood pool algorithms, have ishment of microbubbles into the microcirculation permits been greatly facilitated and improved with echocardiographic evaluation of myocardial tissue perfusion (38). Using these contrast agents, and have been shown to correlate well with principles, techniques have been developed to quantify current reference standards (31,32).
myocardial perfusion and have been validated experimentallyby radiolabelled microspheres, and clinically against coronary LVO and stress echocardiography
Doppler flow wires and positron emission tomography imaging.
The diagnosis and stratification of significant CAD by stress The excellent spatial resolution and the temporal ability of echocardiography depends on the identification of regional MCE to assess the rate of myocardial blood flow make it an wall motion deterioration with exercise or pharmacological ideal tool to evaluate the adequacy of myocardial perfusion.
Copyright Pulsus Group Inc – Do not copy Honos et al
MCE has been clinically shown to reliably identify the pres- and interobserver agreement for the assessment of resting ence or absence of myocardial reperfusion following primary regional wall motion, to reduce interobserver variability and percutaneous coronary intervention (the ‘no-reflow’ phenom- enhance the reproducibility of stress echocardiography studies, enon) (39), predict subsequent LV function post-MI (40), to help define altered cardiac anatomy by improving the determine myocardial viability after ischemic injury (41), and echocardiographic detection rates of myocardial rupture, assess infarct-related artery patency and the degree of collateral pseudoaneurysms, intracardiac thrombi, aortic dissection, LV support to the infarcted territory (42). Multiple studies have noncompaction and apical hypertrophic cardiomyopathy, and also used MCE in conjunction with dobutamine or vasodilator to enhance left-sided Doppler velocity signals in the assess- (adenosine or dipyridamole) stress to detect CAD with a sen- ment of intracardiac pressures and transvalvular gradients.
sitivity and specificity comparable with that of nuclear tech- Ultrasound contrast agents have also been used during trans- niques (43-45). Two studies have demonstrated the esophageal echocardiography in aortic dissection assessment incremental prognostic value of MCE over routine clinical and left atrial appendage thrombus detection.
assessment in risk-stratifying patients who present to the emer- Despite improvements in ultrasound imaging techniques, gency room with chest pain syndromes (46,47). Finally, Basic including the widespread availability of harmonic imaging, an et al (48) recently demonstrated that MCE was able to accu- estimated 10% of resting echocardiograms and 30% of stress rately classify patients at risk for cardiac disease, and provided echocardiograms remain diagnostically suboptimal. In these prognostic information comparable with validated nuclear circumstances, the use of CE improves diagnostic accuracy and may contribute to a cost-effective pattern of care. This is Despite the safety (49) and potential utility of MCE, the achieved through the impact of the reduced downstream repet- initial enthusiasm over the use of MCE for perfusion imaging itive testing in patients with an initially nondiagnostic has not translated into routine clinical use, because several echocardiogram, a reduced rate of false-positive and false- outstanding issues remain. It is important to note that MCE is negative echocardiograms as a result of improved image qual- a technically challenging modality, and requires an experi- ity and increased laboratory efficiency in evaluation of enced operator and optimal acoustic windows to obtain accu- labour-intensive, difficult-to-image patients. In a study involv- rate results. Interpretation of images to reliably differentiate ing multiple Canadian centres, Tardif et al (51) studied the perfusion defects from imaging artifacts is very user-dependent.
impact of contrast stress echocardiography on resource use in An early multicentre study (50) of the use of MCE in routine the management of patients with suspected CAD, comparing practice by novice users demonstrated poor sensitivity com- it with standard stress nuclear perfusion imaging. The authors pared with nuclear techniques for the detection of CAD.
found that contrast stress echocardiography had a similar suc- While phase III trials of a contrast agent proving the accuracy cess rate to nuclear perfusion imaging in diagnosing CAD, but of MCE for the detection of CAD have been performed, most had a 28% lower cost, along with the potential for additional results are still unpublished, and currently, no contrast agent cost savings through the elimination of additional tests due to has been approved for use in perfusion imaging. Other unre- false-positive nuclear perfusion scans. Castello et al (52) solved issues include the optimal method of analysis – online showed that a ‘sonographer-driven’ CE protocol for LV assess- qualitative versus offline quantitative analysis of perfusion ment was feasible, decreased the decision time for contrast studies, optimal imaging techniques for perfusion assessment, injection, and significantly improved LV global and regional real-time versus intermittent imaging modalities and the opti- wall motion visualization in technically difficult patients.
mal mode of contrast administration (constant infusion versus Despite the overwhelming evidence of its benefit, CE remains bolus). These shortcomings have limited the adoption of this highly underused in Canada. Barriers to the greater use of CE technique for the assessment of myocardial perfusion.
include the requirement of insertion of an intravenous access Currently, MCE should be considered an experimental tech- for contrast injection, lack of budget for the cost of the con- nique, with clinical use limited to experienced centres alone.
trast agent, the need for additional scanning time, lack of However, the development of newer contrast agents, contin- physician experience with CE and the absence of physician ued refinements in ultrasound imaging modalities, optimiza- reimbursement in most regions of the country.
tion of online analysis, and successful completion of large, The most promising future clinical application of CE is the multicentre studies of MCE perfusion imaging demonstrating noninvasive assessment of myocardial perfusion. Potential its diagnostic and prognostic use will be important steps in advantages of MCE over other available methods for assess- ment of perfusion, such as nuclear single-photon emissioncomputed tomography and positron emission tomography PRESENT AND FUTURE
techniques include the simultaneous assessment of perfusion CLINICAL APPLICATIONS
and regional wall motion in real-time, with good spatial and Currently, ultrasound contrast agents are approved for use in temporal resolution; the ability to quantify myocardial blood Canada to improve image quality in suboptimal echocardio- flow and flow reserve; portability, allowing the performance of grams by opacifying the LV cavity and improving endocardial studies at the bedside, in the emergency room, coronary or border delineation. These ultrasound contrast agents have intensive care unit and the operating room; and the use of a been proven to be safe and effective in numerous clinical stud- non-nephrotoxic, nonradioactive and safe contrast agent.
ies (1-10), they are easy to use and they can be used with vir- Finally, research continues into future novel and exciting tually all currently available echocardiographic systems.
diagnostic and therapeutic applications for CE. These include During transthoracic echocardiography, these agents have molecular imaging of pathophysiological molecular and cellu- been shown in clinical trials to improve the qualitative assess- lar processes, such as thrombosis, endothelial dysfunction, ment of global LV systolic function, to improve the accuracy inflammation (53) and angiogenesis (54), using contrast LV volumes and LVEF quantification, to improve the accuracy ultrasound and ‘site-targeted’ microbubbles, as well as the use Copyright Pulsus Group Inc – Do not copy CCS/CSE position paper on contrast echocardiography
of ultrasound-mediated destruction of designer ‘carrier’ 14. Schlief R, Staks T, Mahler M, et al. Successful opacification of the microbubble agents for the site-specific delivery of drugs, lig- left heart chambers on echocardiographic examination afterintravenous injection of a new saccharide based contrast agent.
ands and genes for therapeutic applications (55).
15. Feinstein SB, Cheirif J, Ten Cate FJ, et al. Safety and efficacy of a CONCLUSION
new transpulmonary contrast agent: Initial multicenter clinical As an adjunct to transthoracic echocardiography, trans- results. J Am Coll Cardiol 1990;16:316-24.
16. Porter TR, Xie F. Visually discernible myocardial echocardiographic esophageal echocardiography and stress echocardiography, CE, contrast after intravenous injection of sonicated dextrose albumin when used in conjunction with harmonic imaging, improves microbubbles containing high molecular weight, less soluble gases.
the diagnostic accuracy of technically suboptimal studies due to poor acoustic windows. While adding some time and cost to 17. Burns PN, Powers JE, Fritzsch T. Harmonic imaging: A new imaging and Doppler method for contrast enhanced ultrasound.
the echocardiographic study, CE frequently obviates the need for additional specialized, expensive and less accessible cardiac 18. Porter TR, Xie F, Kricsfeld D, Armbruster RW. Improved investigations, and allows for prompt and optimal subsequent myocardial contrast with second harmonic transient ultrasound patient management. Despite its proven advantages, CE is response imaging in humans using intravenous perfluorocarbon- presently underused in Canada, and this situation will, unfor- exposed sonicated dextrose albumin. J Am Coll Cardiol1996;27:1497-501.
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HR & Administrative September 28, 2011 Key Topics in This Issue: Open Enrollment Prescription Drugs Coming Off Patent Voluntary Benefits Open Enrollment Mistakes to Avoid ___________________________ As the season for Open Enrollment and renewal of your employee benefits plans descends, a few timely reminders may help avoid enrollment mistakes that can resul