Safety of ultrasound contrast agents: "Primum non nocere"?

Diagnostic ultrasound contrast agents (UCA) are mainly indicated to enhance endocardial border delineation in patients with technically difficult echocardiographic examinations1. They have proven to increase the accuracy and reproducibility of regional and global left ventricular (LV) function assessment at rest2-4 and during stress5,6. UCA are also used for qualitative or quantitative determination of myocardial blood flow7, to increase the intensity of Doppler signals. New therapeutic and diagnostic applications, such as drug delivery system and molecular imaging, are now emerging8. In Belgium, UCA are refunded when ultrasound echocardiography without a contrast agent is not conclusive in the following applications: (i) At rest, when the quality of images obtained without contrast agent makes the visualization of at least 5 contiguous segments of a total of 17 not conclusive, and, (ii) during stress when the quality of the images obtained without contrast agent makes the visualization of at least 2 contiguous segments of a total of 17 not conclusive. The segmentation of the left ventricle is based on the recommendations of the American Heart Association. The examinations will be conducted by devices with software for harmonic imaging with a low mechanical index less than or equal to 0.3, allowing the mandatory digital archiving of images before and after contrast. Evidence showing that the above conditions are met, must be held available to the insurer by the medical provider. For echocardiography, the documents would be subjected to peer review. Although, UCA still account for a small proportion of diagnostic examinations9, it was estimated that in 2006, 1∞∞million diagnostic examinations with UCA were performed and that by the end of 2007, Definity® (the European name is Luminity®) has been administered to approximately 2∞∞million patients since approval in 20019,10. In cardiac applications, the reporting of some adverse events after UCA has led to some restriction imposed by the European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA). A post-marketing analysis of 157,838∞∞ studies of Sonovue® (Bracco, Milan, Italy) reported 19 cases of severe, non-fatal (0.012%) and three cases of fatal adverse events (0.002%) after the use of this contrast agent11. Based on these data, EMEA recommended not to use Sonovue® in cardiology in May 2004. These recommendations were partly reversed in November 2004 but there are still some restrictions (exclusion of patients with acute coronary syndromes and unstable heart disease) to the infusion of Sonovue®12. In a similar way, post-marketing analysis from the U.S. reported 10 deaths after the administration of Definity® (Bristol-Myers Squibb Medical Imaging, North REVIEW ARTICLE