Contrast echocardiography using gas-filled bubbles have been used for 40 years,1 although the clinical use of agents capable of pulmonary transit for left heart opacification started about 15 years ago. Microbubble solutions made by a variety of manufacturers have now been approved for clinical use in North America, Europe, Australia and some Asian countries. Indeed, Definity (a lipid shell filled with perfluorocarbon) has been administered to about two million patients since 2001.2 Why then has there been a cluster of recent papers about the safety of contrast agents?3^–6

Ultrasound waves produce compression and rarefaction of tissue that they traverse, but at normal diagnostic power, this has no or negligible biological effects. However, ultrasound interacts with microbubbles, the consequences of which are determined by mechanical index,7 derived from the inverse of the square root of the frequency and the peak negative pressure. At very low mechanical index, bubbles oscillate linearly (that is, expansion and contraction are similar) and this process becomes non-linear at low-intermediate mechanical index (leading to the generation of harmonic signals). At high mechanical index, the oscillation increases and the bubble shatters, releasing energy that may cause local cavitation, free radical production and heating.8 While in vitro studies are poor analogues of in vivo effects, including non-physiological effects, such as near-boundary shear …