Ultrasound contrast agents capable of transpulmonary passage following intravenous injection have been commercially available since the 1990s. These agents are microbubbles, which are smaller than red blood cells and persist long enough (due to reduced rate of gas diffusion) to reach the left ventricle (LV).1–3 Ultrasound contrast agent applications included LV cavity opacification, enhancement of spectral Doppler signals and evaluation of myocardial perfusion at rest or post-stress.3 The commercially available second-generation ultrasound agents are approved by the US Food and Drug Administration (FDA) only for the enhancement of LV endocardial delineation in patients with baseline suboptimal examinations.3 There are currently two commercially available ultrasound contrast agents in the US: Optison™ (perflutren protein-type A microspheres, GE Healthcare, Buckinghamshire, UK) and Definity® (perflutren lipid microspheres, Lantheus Medical Imaging, North Bellirica).
Efficacy of Ultrasound Contrast Agents
Although tissue harmonic imaging has significantly enhanced the diagnostic quality of baseline transthoracic echocardiography,4 the increasing prevalence of obesity and lung disease has added an extra layer of challenge; at least 10–15% of echocardiograms are technically difficult or non-diagnostic despite the use of harmonic imaging. The proportion of non-diagnostic studies is significantly increased during stress echocardiography and in echocardiograms performed in the intensive care unit.3
In non-selected patients, contrast-enhanced echocardiography leads to more accurate assessment of LV volumes and ejection fraction compared with magnetic resonance imaging.5,6 Even with the use of harmonic imaging, ultrasound contrast enhances accuracy and reproducibility in calculation of LV systolic function.6 In selected patients with excellent echocardiographic windows and adequate endocardial visualisation of all segments with harmonic imaging, the utilisation of contrast echocardiography reduces inter- and intra-reader variability in the assessment of LVEF.7
In patients with abnormal LV systolic function undergoing evaluation for LV remodeling, the use of ultrasound contrast agents reduces reader variability and increases accuracy compared with harmonic imaging with computed tomography as a reference standard.8 In intensive care patients, the use of ultrasound contrast agents increases the diagnostic yield of both individual myocardial segment evaluation and overall LV function assessment, and should be considered in all patients with non-diagnostic studies.9
- Feinstein SB, Cheirif J, Ten Cate FJ, et al., Safety and efficacy of a new transpulmonary ultrasound contrast agent: initial multicenter clinical results, J Am Coll Cardiol, 1990;16:316–24.
- Geny B, Mettauer B, Muan B, et al. Safety and efficacy of a new transpulmonary echo contrast agent in echocardiographic studies in patients, J Am Coll Cardiol, 1993;22:1193–8.
- Main ML, Grayburn PA, Clinical applications of transpulmonary contrast echocardiography, Am Heart J, 1999;137:144–53.
- Malhotra V, Nwogu J, Bondmass MD, et al., Is the technically limited echocardiographic study an endangered species? endocardial border definition with native tissue harmonic imaging and Optison contrast: a review of 200 cases, J Am Soc Echocardiogr, 2000;13:771–3.
- Hundley WG, Kizilbash AM, Afridi I, et al., 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;32:1426–32.
- Malm S, Frigstad S, Sagberg E, et al., Accurate and reproducible measurement of left ventricular volume and ejection fraction by contrast echocardiography: a comparison with magnetic resonance imaging, J Am Coll Cardiol, 2004;44:1030–35.
- Nayyar S, Magalski A, Khumri TM, et al., Contrast administration reduces interobserver variability in determination of left ventricular ejection fraction in patients with left ventricular dysfunction and good baseline endocardial border delineation, Am J Cardiol, 2006;98:1110–14.
- Thomson HL, Basmadjian AJ, Rainbird AJ, et al., Contrast echocardiography improves the accuracy and reproducibility of left ventricular remodeling measurements: a prospective, randomly assigned, blinded study, J Am Coll Cardiol, 2001;38:867–75.
- Reilly JP, Tunick PA, Timmermans RJ, et al., Contrast echocardiography clarifies uninterpretable wall motion in intensive care unit patients, J Am Coll Cardiol, 2000;35:485–90.
- Porter TR, Xie F, Kricsfeld A, et al., Improved endocardial border resolution during dobutamine stress echocardiography with intravenous sonicated dextrose albumin, J Am Coll Cardiol, 1994;23:1440–43.
- Kornbluth M, Liang DH, Brown P, et al., Contrast echocardiography is superior to tissue harmonics for assessment of left ventricular function in mechanically ventilated patients, Am Heart J, 2000;140:291–6.
- Shaw LJ, Dittrich HC, Use of intravenous Optison contrast echocardiography reduces downstream resource use and enhances cost savings, Acad Radiol, 1998;(Suppl. 1):S250–51, discussion S252–3.
- Shaw LJ, Gillam L, Feinstein S, et al., Use of an intravenous contrast agent (Optison) to enhance echocardiography: efficacy and cost implications. Optison Multicenter Study Group, Am J Manag Care, 1998;4:SP169–76.
- Shaw LJ, Impact of contrast echocardiography on diagnostic algorithms: pharmacoeconomic implications, Clin Cardiol, 1997;20:I39–48.
- Thanigaraj S, Nease RF Jr, Schechtman KB, et al., Use of contrast for image enhancement during stress echocardiography is cost-effective and reduces additional diagnostic testing, Am J Cardiol, 2001;87:1430–32.
- Labeling for Optison from Drugs@FDA, 2008. Available at: www.fda.gov/cder/foi/label/2008/020899s011lbl.pdf
- Labeling for Definity from Drugs@FDA, 2008. Available at: www.fda.gov/cder/foi/label/2008/021064s009lbl.pdf
- Keen C, Ultrasound contrast advocates take aim at FDA black box warning, 2008. Available at: www.auntminnie.com/index.asp? Sec=sup&Sub=car&Pag=dis&ItemId=79499
- Main ML, Goldman JH, Grayburn PA, Thinking outside the ‘box’—the ultrasound contrast controversy, J Am Coll Cardiol, 2007;50:2434–7.
- Herzog CA, Incidence of adverse events associated with use of perflutren contrast agents for echocardiography, JAMA, 2008;299:2023–5.
- Kusnetzky LL, Khalid A, Khumri TM, et al., Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies, J Am Coll Cardiol, 2008;51:1704–6.
- Wei K, Mulvagh SL, Carson L, et al., The Safety of Definity and Optison for Ultrasound Image Enhancement: A Retrospective Analysis of 78,383 Administered Contrast Doses, J Am Soc Echocardiogr, 2008 (Epub ahead of print).
- PREMIER Research Services, 2008. Available at: www.premierinc.com/quality-safety/tools-services/prs/index.jsp
- Main ML, Ryan AC, Davis TE, et al., Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent; multicenter results in 4,300,966 consecutive patients, Am J Cardiol, 2008; in press.
- Dolan MS, Gala S, Dodla S, et al., Safety and efficacy of commercially available ultrasound contrast agents for rest and stress echocardiography: a multicenter experience, J Am Coll Cardiol, 2008; in press.
- Shaikh K, Chang SM, Peterson L, et al., Safety of Contrast Administration for Endocardial Enhancement during Stress Echocardiography Compared With Non-contrast Stress, Am J Cardiol, 2008; in press.
- Gabriel RS, Smyth YM, Menon V, et al., Safety of Ultrasound Contrast Agents in Stress Echocardiography, Am J Cardiol, 2008; in press.
- Summary minutes of the Cardiovascular and Renal Drugs Advisory Committee 2008. Available at: www.fda.gov/ohrms/dockets/ac/08/minutes/2008-4369m1-final
- United States Food and Drug Administration Center for Drug Evaluation and Research alert for healthcare providers, 2008. Available at: www.fda.gov/cder/drug/infopage/microbubble/ default.htm
- FDA Advisory Committee Briefing Document for the Cardiovascular and Renal Drugs Advisory Committee, 2008. Safety Considerations in the Development of Ultrasound Contrast Agents, 2008. Available at: www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4369b1-01.pdf