© Georg Thieme Verlag KG Stuttgart · New York
20 October 2008 (online)
Gail ter Haar
On October 10th 2007, the FDA requested that a "Boxed Warning and other warnings emphasizing the risk for serious cardiopulmonary reactions be added to the labeling for ultrasound micro-bubble contrast agents used in echocardiography and that use of these products be contraindicated in patients with unstable cardiopulmonary status, including patients with unstable angina, acute myocardial infarction, respiratory failure, or recent worsening congestive heart failure" [FDA 2007]. The background for this warning was that the FDA had "received reports of deaths and serious cardiopulmonary reactions following the administration of ultrasound micro-bubble contrast agents used in echocardiography. Four of the 11 reported deaths were caused by cardiac arrest occurring either during infusion or within 30 minutes following the administration of the contrast agent; most of the serious but non-fatal reactions also occurred in this time frame." One patient died during a stress test, two patients were in severe heart failure, and the fourth was a ventilated patient who had severe respiratory failure and pulmonary emboli.
There has, understandably, been considerable discussion in the literature and at conferences, about this action. It has been pointed out ([Grayburn 2008, Main et al 2007]) that the FDA has responsibility for product safety, but that this is not necessarily the same as patient safety. Patient safety remains the responsibility of the clinician.
With more than 2 million ultrasound examinations using microbubble contrast agents (UCAs) having been carried out since their approval by the FDA 6 years ago, even if all these deaths can correctly be attributed to these bubbles, the associated risk is 1:500,000. This compares favourably with the 1:1000 mortality risk associated with diagnostic coronary angiography ([Johnson et al 1989]), and the 1:2500 risk of myocardial infarction or death with treadmill exercise testing ([Stuart et al 1980]). In a recent paper in which over 18,500 cases were studied, Kuznetsky et al (2008) were unable to show an increased mortality risk associated with contrast-enhanced examination, with 0.4% of hospitalised patients dying within 24 hours of echocardiography, but no statistical difference in mortality being seen between the group in which contrast agents were administered and that which received none.
In the light of this, and other information, the FDA's Cardiovascular and Renal Drugs advisory committee met in June 2008 to discuss the situation. The briefing document (which is available at www.fda.gov/ohrms/dockets/AC/08/briefing/2008-4369b1-01.pdf) states that "FDA has finalized the risk management plan with the manufacturer of Definity and has approved labeling changes that remove most of the contraindications cited in the October, 2007 modification, as well as focused monitoring procedures upon patients with underlying pulmonary hypertension or unstable cardiopulmonary conditions. FDA is working with the manufacturer of Optison to effect similar changes to the label and to finalize a risk assessment and management program." This document also states that concern remains about the accumulating safety data for ultrasound contrast agents, and that products should continue to show a boxed warning highlighting "the risk for serious cardiopulmonary reactions". These contrast agents are now contra-indicated only for patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts, and those with hypersensitivity to perflutren. The boxed warning has been modified to include the instruction " In patients with pulmonary hypertension or unstable cardiopulmonary conditions, monitor vital sign measurements, electrocardiography and cutaneous oxygen saturation during and for at least 30 minutes after DEFINITY®/ Optison administration" (www.definityimaging.com/pdf/prescribinginfo.pdf, md.gehealthcare.com/shared/pdfs/pi/optison_pi.pdf).
Echocardiology remains the examination of choice in patients who are sufficiently ill to warrant invasive cardiovascular investigation. This therefore makes it difficult to differentiate between "association" and "cause" of any adverse events. It is useful in this context to examine the existing contrast agent safety literature. This has recently been reviewed by both the World Federation of Societies for Ultrasound in Medicine & Biology (WFUMB) ([Blomley et al 2007], [Dalecki 2007]) and the American Institute of Ultrasound in Medicine (2008, [Miller et al 2008]).
[Blomley et al] (2007), in a WFUMB report, concluded that while there is incomplete knowledge about the potential risk from clinical use of UCAs, they are extremely safe, with a low incidence of side effect. There is no evidence that they are nephrotoxic or cardiotoxic, and result in a much lower incidence of hypersensitivity or allergic events than current X-ray or MR contrast agents.
There appears to be a consensus that an MI value of 0.4 represents the threshold above which bio-effects are seen in bio-effects studies in vivo [Miller et al 2008]. Above this level, bio-effects appear to increase rapidly with both increasing acoustic pressure amplitude and UCA concentration. Effects studied include premature ventricular contractions and petechial haemorrhage. The cells that are most susceptible to damage from diagnostic ultrasound exposure to UCAs are phagocytic cells that have engulfed the microbubbles. In many cases, the damage may be reparable, and the clinical implications of such findings are not known. Good practice would, however, suggest caution when using UCAs.
The AIUM recommends that for ultrasound examinations involving MI values greater than 0.4, the minimum UCA dose and ultrasound exposure consistent with acquisition of good diagnostic information should be used ([AIUM 2008], ). This reinforces the need for the practitioner to be aware of the safety indices (MI and TI) being used for any ultrasound examination. An initial (default start up) setting of MI of less than 0.4 for contrast enhanced ultrasound examinations is recommended.
EFSUMB's position is contained in its current safety statement (EFSUMB 2008):
- 01 AIUM Bioeffects of Diagnostic Ultrasound with Gas Body Contrast Agents 2002 www.aium.org/publications/statements/_statementSelected.asp?statement=25 .
- 02 AIUM American Institute of Ultrasound in Medicine consensus report on potential bioeffects of diagnostic ultrasound. J. Ultrasound Med 2008 27: 503-515
- 03 Blomley M . Claudon M . Cosgrove D . WFUMB symposium on ultrasound contrast agents: clinical applications and safety concerns. Ultrasound in Med. & Biol.. 2007; 33 180-186
- 04 Dalecki D . WFUMB symposium on ultrasound contrast agents: Bioeffects of ultrasound contrast agents in vivo. Ultrasound in Med. & Biol.. 2007; 33 205-213
- 05 EFSUMB (2006) Clinical safety statement www.efsumb.org/ecmus/Clinical-SStatement-202006.pdf .
- 06 FDA (2007) Information for Healthcare ProfessionalsMicro-bubble Contrast Agents (marketed as Definity (Perflutren Lipid Microsphere) Injectable Suspension and Optison (Perflutren Protein-Type A Microspheres for Injection) www.fda.gov/CDER/drug/InfoSheets/HCP/microbubbleHCP.htm .
- 07 Grayburn PA . Product Safety" Compromises Patient Safety (an Unjustified Black Box Warning on Ultrasound Contrast Agents by the Food and Drug Administration). The American Journal of Cardiology. 2008; 101 892-893
- 08 Johnson LW . Lozner EC . Johnson S . et al . Coronary arteriography 1984–1987: a report of the registry of the Society for Cardiac Angiography and Interventions. I. Results and complications. Cathet. Cardiovasc, Diagn.. 1989; 17 5-10
- 09 Kusnetzky LL . Khalid A . Khumri TM . Moe TG . Jones PG . Main ML . Acute Mortality in Hospitalized Patients Undergoing Echocardiography With and Without an Ultrasound Contrast Agent. J.Am.Coll.Cardiol.. 2008; 51 1704-1706
- 10 Main ML . Goldman JH . Grayburn PA . Thinking Outside the "Box" - The ultrasound contrast controversy. J. Am. Coll. Cardiol.. 2007; 50 2434-2437
- 11 Miller DL . Averkiou MA . Brayman AA . Everbach EC . Holland CK . Wible JH . Wu J . Bioeffects considerations for diagnostic ultrasound contrast agents. J. Ultrasound Med. 2008; 27 611-632
- 12 Stuart RJ . Ellestad MH . National survey of exercise stress testing facilities. Chest. 1980; 77 94-97