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

Ultrasound contrast agents (UCAs), delivered as peripheral venous injections, have been developed to enhance the ultrasound image quality. The current application, recognized by the FDA and European Medecines Agency (EMEA) is the enhancement of the left ventricular endocardial border or left ventricular opacification (LVO). These microbubbles with a diameter and an intravascular velocity similar to red blood cells travel through the myocardial capillaries and enable us to visualize myocardial perfusion during myocardial contrast echocardiography (MCE). These agents are also used to quantitate myocardial perfusion most of the time, especially for research purposes. Like all other contrast agents used in medicine, adverse events can also occur with UCAs. Allergic reactions though important are inherent to the use of contrast agents. Their existence, although sometimes very serious (anaphylactoid reactions), imply that the use of UCAs in clinical practice can only be supported if the additional diagnostic information is clinically relevant enough for patient management. The UCAs can only be used by experienced hands and in an environment where facilities for emergency care are immediately available. Above all the previously mentioned ‘acceptable’ adverse events for a contrast agent, two major observations have questioned the safety of UCAs. First, the concomitant use of contrast agents and ultrasound leads to bio-effects demonstrated in experimental studies. Secondly, postmarketing analysis of 157 838 studies of Sonovue brought to light 19 cases of severe non-fatal (0.012%) (strong relationship with UCAs) (18 of 19 were anaphylactoid or vasovagal reactions) and three cases of fatal adverse events (0.002%) (causal relationship uncertain). For the first time, Vancraeynest et al. showed that MCE can cause sub-clinical release of bio-markers in humans. This observation could be the missing link between the demonstrated in vitro bio-effects of UCAs and some of the clinically reported adverse events with Sonovue. What are the facts? What has been demonstrated in vitro in animals and in humans? UCAs contain microbubbles with a diameter of ,5 mm, filled with a perfluorocarbon gas, and surrounded by a shell. Because of these characteristics, they can pass through the pulmonary capillary filter. Due to their acoustic properties, they considerably enhance the backscattering capabilities of blood, thereby imaging the cavity of the left ventricle and also the myocardium. Once they travel into the ultrasound field, they oscillate. These oscillations can result in linear backscatter at low acoustic pressure, nonlinear signals with harmonic frequencies at medium acoustic pressure, and microbubble disintegration at high acoustic pressure. Microbubbles are compressible, and at low acoustic pressure, microbubbles grow and shrink symmetrically around their equilibrium size (stable or non-inertial cavitation). At higher acoustic pressure, however, the expansion and contraction of microbubbles usually become unequal and exaggerated, leading to their destruction (inertial cavitation). Microbubble destruction by ultrasound is the basic principle for the quantification of myocardial blood flow by MCE. Bio-effects of UCAs have been demonstrated in numerous in vitro studies. Even linear bubble oscillations are sufficient to achieve rupture of lipid membranes. Sudden violent collapse of microbubbles can produce high-velocity fluid micro-jets that may penetrate into the adjacent membranes leading to pore formation (sonoporation). Inertial cavitation, which depends on microbubble shell composition, ultrasound frequency, pulse duration, and acoustic power, can lead to secondary shock waves, transient local high temperatures, and shear stress. On the one hand, these bio-effects in vitro must draw the clinician’s attention towards potential harmful adverse events in patients; on the other hand, it opens the door towards potential applications of UCAs in gene and drug delivery. The most common finding in animal studies examining the potential tissue damage and the risk of UCAs together with ultrasound was capillary rupture and haemorrhage or dye extravasations. It is, however, very dangerous to The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.