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Safety of contrast agents

Contrast Echo Box: Key Reference Library

Find out more about Contrast Echocardiography by exploring the Contrast Echo Box

Safety and Efficacy of Commercially Available Ultrasound Contrast Agents for Rest and Stress Echocardiography: A Multicenter Experience.

Dolan MS, Gala SS, Dodla S, Abdelmoneim SS, Xie F, Cloutier D, Bierig M, Mulvagh SL, Porter TR, Labovitz AJ. 
Reference: Journal of the American College of Cardiology 2009;53:32-38.

Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients)

Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M.
A retrospective review of over 4 million patients who received UCA (Definity) between 2002 – 2007. There was no increase in mortality with UCA and, in fact, pts receiving UCA for echo study were 24% LESS likely to die within 1 day of the study. This included severely unwell patients on intensive or high dependency care units.
Reference: Am J Cardiol 2008;102(12):1742-6

Safety of myocardial flash-contrast echocardiography in combination with dobutamine stress testing for the detection of ischaemia in 5250 studies

Aggeli C, Giannopoulos G, Roussakis G, Christoforatou E, Marinos G, Toli C, et al.
A Greek study of 5250 patients undergoing low MI & high MI MCE combined with dobutamine. There was no increase in death / acute MI using contrast and a low incidence of side-effects.
Reference: Heart 2008;94(12):1571-7

The safety of deFinity and Optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses

Wei K, Mulvagh SL, Carson L, Davidoff R, Gabriel R, Grimm RA, et al.
Retrospective study from 13 sites performing echo studies between January 1, 2001-September 30, 2007. In total, 66,164 doses of Definity and 12,219 doses of Optison (5% of transthoracic/28% stress) were administered. Severe adverse events (SAEs) occurred in 8 patients (0.01%), anaphylactoid reactions in 4 patients (0.006%), there were no deaths and no SAE in hospitalized patients. In conclusion, ultrasound contrast was shown to be a very safe agent and as safe as – if not more safe – than other contrast agents used in other imaging modalities.
Reference: J Am Soc Echocardiogr 2008;21(11):1202-6

Product safety compromises patient safety (an unjustified black box warning on ultrasound contrast agents by the Food and Drug Administration).

This viewpoint paper shows the catastrophic sequences of inaccurate assessment of LV function and misdiagnosis of complications such as pseudoaneurysms and thrombi. In summary, warning and educating health care providers about previously unrecognized risks is important but clinical evidence shows that contrast echocardiography is safe in practice.
Even if there would be a moderate risk by the contrast agent, the risk/benefit still would be very favourable for using contrast agents even in acute myocardial infarction.
References:Grayburn PA. Am J Cardiol. 2008 Mar 15;101(6):892-3

FDA. United States Food and Drug Administration Center for Drug Evaluation and Research alert for healthcare providers

Comments :
In April 2008, the US Food and Drug Administration (FDA) performed a safety review of the US-approved perflutren microsphere contrast agents (Definity and Optison) and revised a previous black box warning. The new contraindications are much less restrictive than the previous contraindications and satisfy the needs of clinical echocardiography.

The Safety of Definity and Optison for Ultrasound Image Enhancement: A Retrospective Analysis of 78,383 Administered Contrast Doses.

Wei K, Mulvagh SL, Carson L, Davidoff R, Gabriel R, Grimm RA, Wilson S, Fane L, Herzog CA, Zoghbi WA, Taylor R, Farrar M, Chaudhry FA, Porter TR, Irani W, Lang RM, FESC. 
Reference: Journal of the American Society of Echocardiography 2008;21:1202-1206.

Safety of Contrast Administration for Endocardial Enhancement During Stress Echocardiography Compared With Noncontrast Stress.

Shaikh K, Chang SM, Peterson L, Rosendahl-Garcia K, Quinones MA, Nagueh SF, Kurrelmeyer K, Zoghbi WA.
Reference: The American Journal of Cardiology 2008;102:1444-1450.

Acute Mortality in Hospitalized patients Undergoing Echocardiography With and Without an Ultrasound Contrast Agent: Results in 18,671 Consecutive Studies.

Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML.
Reference: Journal of the American College of Cardiology 2008;51:1704-1706.

Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients).

Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M.
Serial retrospective studies showing the safety of contrast ultrasound agents in various clinical conditions, at rest or during stress, including critically ill patients and using various settings.
Reference: Am J Cardiol 2008;102:1742-6

Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies

Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML.
18,671 patients who underwent echocardiography within 24hrs of hospital admission (Jan 2005 – Oct 2007) were included in this retrospective analysis (12,475 unenhanced scans, 6,196 Definity contrast used). Vital status at 24 hours available for all patients and there was no difference in mortality between the two groups.
Reference: J Am Coll Cardiol 2008; 51(17):1704-6

Safety of contrast-enhanced echocardiography within 24 h after acute myocardial infarction.

Nucifora G, Marsan NA, Siebelink HM, van Werkhoven JM, Schuijf JD, Schalij MJ, Poldermans Dm FESC, Holman ER, Bax JJm FESC
Although performed in low risk patients, the present study provides further reassurance about the safety of LUMINITY in the acute phase of myocardial infarction. Administration of echo contrast did not induce any significant change in vital signs, physical examination, and ECG. There were no serious adverse events.
Reference: Eur J Echocardiogr 2008;9:816-8

Microbubbles in ultrasound-triggered drug and gene delivery.

Hernot S, Klibanov AL. 
When bio-effects of ultrasound contrast agents in combination with ultrasound exposure are used for ultrasound-triggered drug and gene delivery. An extensive review of the potential role of contrast echo for therapy. 
Reference: Advanced Drug Delivery Reviews 2008;60:1153-1166

Release of cardiac bio-markers during high mechanical index contrast-enhanced echocardiography in humans

Vancraeynest D, Kefer J, Hanet C, FESC, Fillee C, Beauloye C, Pasquet A, Gerber BL, FESC, Philippe M, Vanoverschelde JL, FESC.
This study showed that Myocardial Contrast Echocardiography can cause sub-clinical release of bio-markers in humans.
Reference: Eur Heart J. 2007 May;28(10):1236-41

Bio-effects of ultrasound contrast agents in daily clinical practice: fact or fiction?

Van Camp G, FESC, Droogmans S, Cosyns B.
In extreme situations, rarely seen in clinical practice, the concomitant use of ultrasound and contrast agents can lead to bio-effects in vitro, ex vivo, in animal studies, and in humans. Techniques using low volumes of contrast agents with low-MI imaging should be preferentially used. Each echolaboratory using contrast should have experience with the use of ultrasound enhanced contrast and should be able to treat serious allergic reactions.
Reference: Eur Heart J. 2007 May;28(10):1236-41.

Food and drug administration prescribing information for Definity approved October 2007

Black box warning from the FDA for perfluten-containing ultrasound contrast agents, quoting post-marketing reports of four deaths occurring within 30 minutes of administration of Definity.

Thinking outside the "box" the ultrasound contrast controversy

Main ML, Goldman JH, FESC, Grayburn PA.
Regarding the Black box warning from the FDA for perfluten-containing ultrasound contrast agents. These warnings ignore the proven efficacy of ultrasound contrast agents, the previously established safety of these compounds, the potential risks of alternative procedures, and the likely confounding effect of pseudocomplication. The authors suggest that the FDA Medical Imaging Division convene a panel of cardiologists experienced in a variety of imaging modalities to fully assess the adverse events that have been attributed to these agents.
Reference: J Am Coll Cardiol. 2007 Dec 18;50(25):2434-7

Microvascular permeabilization and cardiomyocyte injury provoked by myocardial contrast echocardiography in a canine model

Miller DL, Driscoll EM, Dou C, Armstrong WF, Lucchesi BR.
This study advances our knowledge of the toxicity area by carefully examining the effects of destruction of a commercially available contrast agent (Definity, Bristol Myers-Squibb, Billerica, Massachusetts) using a clinical ultrasound machine (Vingmed System V, General Electric, Cincinnati, Ohio) and standard ultrasonic acoustic power settings in a dog model. There was an increased vascular permeability present mainly in a transmural pattern across the anterior wall. There was an increased propidium iodide staining was present in all six open-chest dogs that received bubbles and cardiac ultrasound. Finally, the authors showed no evidence of ventricular ectopy in sham treatment or the lower power setting (?1.2 MPA) but a substantial increase in premature ventricular contractions with higher acoustic power (?2.2 MPA) in the open chest model.
Reference: J Am Coll Cardiol. 2006 Apr 4;47(7):1464-8

Safety of dobutamine stress real-time myocardial contrast echocardiography

Tsutsui JM, Elhendy A, FESC, Xie F, O’Leary EL, McGrain AC, Porter TR.
The hemodynamic and adverse effects of real-time contrast echocardiography (RTCE) using Definity® and Optison® in 1.486 patients who underwent dobutamine stress echocardiography over a four-year period were compared with 1,012 patients who underwent conventional dobutamine stress echocardiography (DSE) without contrast. Dobutamine stress RTCE appeared to be a safe and feasible technique for evaluating patients with known or suspected CAD. There was no difference in the incidence of nonsustained ventricular tachycardia, sustained ventricular tachycardia, or supraventricular tachycardia during dobutamine infusion between RTCE and DSE. Myocardial perfusion imaging with RTCE had a higher accuracy for detecting patients with angiographically significant CAD than the analysis of wall motion (84% vs. 66%, respectively; p < 0.001).
Reference : J Am Coll Cardiol 2005; 45.1235-42.