Presently available ultrasound contrast agents
consist of suspensions of gas bodies (stabilized gaseous microbubbles). The gas
bodies have the correct size for strong echogenicity with diagnostic ultrasound
and also for passage through the microcirculation. Commercial agents undergo
rigorous clinical testing for safety and efficacy before Food and Drug
Administration approval is granted, and they have been in clinical use in the
United States since 1994. Detailed information on the composition and use of
these agents is included in the package inserts. In the United States, contrast
agents have been approved for opacification of the left ventricular chamber and
delineation of the left ventricular endocardial border. Outside the United
States, additional approved indications include imaging lesions of the breast
and liver, portal vein, and extracranial carotid and peripheral arteries. Many
other diagnostic applications are under development or clinical testing.
Contrast agents carry some potential for nonthermal bioeffects when ultrasound interacts with the gas bodies. The mechanism for such effects is related to the physical phenomenon of acoustic cavitation. Several published reports describe adverse bioeffects in mammalian tissue in vivo resulting from exposure to diagnostic ultrasound with gas body contrast agents in the circulation. Induction of premature ventricular contractions by triggered contrast echocardiography in humans has been reported for a noncommercial agent and in laboratory animals for commercial agents. Microvascular leakage, killing of cardiomyocytes, and glomerular capillary hemorrhage, among other bioeffects, have been reported in animal studies. Two medical ultrasound societies have examined this potential risk of bioeffects in diagnostic ultrasound with contrast agents and provide extensive reviews of the topic: the World Federation for Ultrasound in Medicine and Biology Contrast Agent Safety Symposium1 and the American Institute of Ultrasound in Medicine 2005 Bioeffects Consensus Conference.2 More recently, the British Medical Ultrasound Society issued a detailed assessment of methods for the safe use of diagnostic ultrasound, including use of contrast agents.3 Based on a review of these reports and recent literature, the Bioeffects Committee issues the following statement:
Statement on Mammalian Biological Effects of Diagnostic Ultrasound With Gas Body Contrast Agents
Induction of premature ventricular
contractions, microvascular leakage with petechiae, glomerular capillary
hemorrhage, local cell killing, and other effects in mammalian tissue in vivo
have been reported and independently confirmed for diagnostic ultrasound
exposure with a mechanical index (MI) above about 0.4 and a gas body contrast
agent present in the circulation.
Although the medical significance of such microscale bioeffects is uncertain, minimizing the potential for such effects represents prudent use of diagnostic ultrasound. In general, for imaging with contrast agents at an MI above 0.4, practitioners should use the minimal agent dose, MI, and examination time consistent with efficacious acquisition of diagnostic information. In addition, the echocardiogram should be monitored during high-MI contrast cardiac-gated perfusion echocardiography, particularly in patients with a history of myocardial infarction or unstable cardiovascular disease. Furthermore, physicians and sonographers should follow all guidance provided in the package inserts of these drugs, including precautions, warnings, and contraindications.
1. World Federation of Ultrasound in Medicine and Biology. Symposium on Safety of Ultrasound in Medicine: Ultrasound Contrast Agents. Safety of ultrasound contrast agents. Ultrasound Med Biol 2007; 33:171–234.
2. Miller DL, Averkiou MA, Brayman AA, et al.
Bioeffects considerations for diagnostic ultrasound contrast agents. J Ultrasound Med 2008;
3. Miller DL. The safe use of contrast-enhanced diagnostic ultrasound. In: ter Haar G (ed). The Safe Use of Ultrasound in Medical Diagnosis. London, England: British Institute of Radiology; 2012:105–124.