Statement on Biological Effects in Tissues with Ultrasound Contrast Agents

Presently commercially available ultrasound contrast agents consist of suspensions of gas bodies (stabilized gaseous microbubbles). The gas bodies have appropriate size and composition for strong, sustained 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 manufacturer’s provided information. In the United States, ultrasound contrast agents have been approved for 1) opacification of the left ventricle and delineation of the left ventricular endocardial borders in patients with suboptimal echocardiograms, 2) characterization of focal liver lesions, 3) evaluation of suspected or known vesicoureteral reflux in pediatric patients, and 4) assessment of fallopian tube patency in women with known or suspected infertility. 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.

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 publications describe adverse bioeffects in mammalian tissue in vivo resulting from exposure to diagnostic ultrasound with gas body contrast agents in the circulation. Disruption of blood brain barrier by therapeutic transcranial ultrasound and induction of premature ventricular contractions by triggered contrast echocardiography have been reported in humans and in laboratory animals. Microvascular leakage, killing of cardiomyocytes, and glomerular capillary hemorrhage, among other bioeffects, have been reported in animal studies.  Based on a review of literature and statements from the World Federation of Ultrasound in Medicine and Biology, the British Medical Ultrasound Society, the American Institute of Ultrasound in Medicine and others^1-7, the AIUM issues the following statement:

Statement on Biological Effects in Tissues with Ultrasound 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 0.4 concurrent with the administration of a gas body contrast agent.

Although the medical significance of such microscale bioeffects is uncertain, minimizing the potential for such effects represents prudent use of diagnostic ultrasound. For imaging with contrast agents at an MI above 0.4, practitioners should use the recommended agent dose and the minimal MI and examination time required to obtain the necessary diagnostic information. The echocardiogram should be monitored for possible adverse events during cardiac-gated perfusion echocardiography with high-MI with gas body contrast agents present, particularly in patients with a history of myocardial infarction or unstable cardiovascular disease.

Furthermore, physicians and sonographers should follow all guidance in the manufacturer's provided information for contrast agents, including precautions, warnings, and contraindications.  Some ultrasound contrast agents contain polyethylene glycol (PEG), which in rare cases can lead to allergic reactions.  Risks of and harm from potential allergic reactions should be considered alongside the benefits of contrast enhanced ultrasound.

References

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; 27:611–632.

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.

4. Dietrich CF et al., Guidelines and good clinical practice recommendations for contrast-enhanced ultrasound (CEUS) in the liver—update 2020 WFUMB in cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound in Med. & Biol 2020; 46:2579-2640.

5. Frinking P. Three decades of ultrasound contrast agents: a review of the past, present and future improvements. Ultrasound in Med. & Biol. 2020; 46:892-908.

6. Muskula PR and Main ML. Safety with Echocardiographic contrast agents. Circ Cardiovasc Imag. 2017; 10:e005459. DOI: 10.1161/CIRCIMAGING.116.005459.

7. ter Haar, G. Safety of Contrast-Enhanced Ultrasound.  In Contrast-enhanced Ultrasound in Pediatric Imaging, P. S. Sidhu et al. (eds.) Springer Nature Switzerland AG 2021. 13-17.