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Bioeffects Considerations for Diagnostic Ultrasound Contrast Agents

Department of Radiology, University of Michigan, Ann Arbor, Michigan USA (D.L.M.); Philips Medical Systems, Bothell, Washington USA (M.A.A.); Applied Physics Laboratory, University of Washington, Seattle, Washington USA (A.A.B.); Department of Engineering, Swarthmore College, Swarthmore, Pennsylvania USA (E.C.E.); Department of Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio USA (C.K.H.); Tyco Healthcare/Mallinckrodt Inc, St Louis, Missouri USA (J.H.W.); and Department of Physics, University of Vermont, Burlington, Vermont USA (J.W.).

Address correspondence to Douglas L. Miller, PhD, University of Michigan, 3315 Kresge III, 200 Zina Pitcher Pl, Ann Arbor, MI 48109-0553 USA. E-mail: douglm{at}umich.edu

Abstract

Diagnostic ultrasound contrast agents have been developed for enhancing the echogenicity of blood and for delineating other structures of the body. Approved agents are suspensions of gas bodies (stabilized microbubbles), which have been designed for persistence in the circulation and strong echo return for imaging. The interaction of ultrasound pulses with these gas bodies is a form of acoustic cavitation, and they also may act as inertial cavitation nuclei. This interaction produces mechanical perturbation and a potential for bioeffects on nearby cells or tissues. In vitro, sonoporation and cell death occur at mechanical index (MI) values less than the inertial cavitation threshold. In vivo, bioeffects reported for MI values greater than 0.4 include microvascular leakage, petechiae, cardiomyocyte death, inflammatory cell infiltration, and premature ventricular contractions and are accompanied by gas body destruction within the capillary bed. Bioeffects for MIs of 1.9 or less have been reported in skeletal muscle, fat, myocardium, kidney, liver, and intestine. Therapeutic applications that rely on these bioeffects include targeted drug delivery to the interstitium and DNA transfer into cells for gene therapy. Bioeffects of contrast-aided diagnostic ultrasound happen on a microscopic scale, and their importance in the clinical setting remains uncertain.

Key Words: acoustic cavitation • contrast agent adverse effects • echocardiography • mechanical index

Abbreviations: CAT, chloramphenicol acetyltransferase • CK, creatine kinase • ECG, electrocardiographic • FDA, Food and Drug Administration • MCE, myocardial contrast echocardiography • MI, mechanical index • PESDA, perfluorocarbon-exposed sonicated dextrose albumin • PRPA, peak rarefactional pressure amplitude • PVC, premature ventricular contraction

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