Ultrasound induced Bioeffects



Contrast agents for diagnostic ultrasound consist of stabilized microbubbles designed to enhance the echogenicity of blood filled regions and reveal tissue perfusion.  The availability of these agents has enabled the study of cavitation biology in diagnostic ultrasound, a topic of non-ionising radiation biology which was previously a matter of conjecture.  Bioeffects are engendered by intermittent imaging at high peak rarefactional pressure amplitudes (PRPA), which nucleates cavitation within tissue capillaries and allows refill of the capillaries with agent between high PRPA images.  The magnitude and extent of the bioeffects depends not only on the agent dosage and PRPA, but also on ultrasound timing parameters and tissue of interest. Cavitational bioeffects, which have been demonstrated using commercial contrast agents and diagnostic ultrasound in animal models, include heart capillary rupture with cardiomyocyte killing and kidney glomerular capillary haemorrhage into the urinary space with consequent acute tubular necrosis.  The medical significance of such randomly scattered bioeffects is uncertain, but cardiac arrhythmia and hematuria are clinically detectable manifestations. The potential for cavitational biological effects, particularly with common patient conditions which might aggravate otherwise minor health impacts, requires careful risk-benefit considerations for diagnostic ultrasound imaging with contrast agents.

Cavitation Biology and the Safety of Contrast-Aided Diagnostic Ultrasound

Douglas L. Miller, Department of Radiology, University of Michigan, Ann Arbor, MI 48109-0553 USA

Figure 1.  A rat heart (left) after MCE at 1.5 MHz with Evans blue leakage in the scan plane: scale bar 2 mm.  Vital staining of cardiomyocytes (right) seen in fluorescent red in a frozen histological section with a small artery (a): scale bar 50 μm.

Figure 2.  A rat kidney
(a) scanned with 1.5 MHz diagnostic ultrasound and with UCA infused via tail vein.  The blood-filled tubules within the scan plane are visible on the surface of the kidney: scale bar 5 mm.  Histology of a kidney (b), scanned as in (a), showing blood-filled tubules near the surface and glomeruli (G) with capillary haemorrhage filling Bowman's capsule.  A thrombus-like fibrinous clot had formed in one Bowman's capsextended into the neck of the proximal convoluted tubule: scale bar 100 μm.
Figure 3. Exposure-response data for vital staining of cardiomyocytes with Evans blue for 1.5 MHz MCE (left) and for glomerular capillary haemorrhage for 1.5 MHz intermittent imaging (right).  Both bioeffects had a strong dependence on PRPA above apparent thresholds, which are indicated by the arrows. 


For diagnostic ultrasound with UCA, microvascular bioeffects can be induced by cavitation nucleation of the contrast agent gas bodies.  In vivo testing has involved doses and equivalent MI values within the clinically relevant range.  In skeletal and heart muscle, microvascular leakage and petechiae have been observed for intermittently triggered imaging modes.  Premature ventricular contractions were induced for rat and canine models of MCE with approved UCAs.  Cardiomyocyte death with development of histologically defined micro-lesions has been demonstrated for triggered diagnostic imaging with gas body destruction within the  myocardium.  This effect is biologically significant because these indispensable cells are not replaced.  Research in liver and kidney has also revealed microvascular bioeffects.  The kidney may be the most sensitive tissue to UCA related bioeffects, because the rupture of a glomerular capillary yields haemorrhage into the urinary space, from which blood is normally excluded.  This effect is biologically significant because the initial capillary injury is amplified to impact the entire nephron (functional unit) with possible acute tubular necrosis.  The bioeffects of diagnostic ultrasound with UCA depend not only on the agent dose and imaging PRPA, but also on other user-controlled parameters such as agent delivery method and image trigger interval.  

Since doses and tissue equivalent MIs in animal research were often within the clinical range, microvascular bioeffects could be induced during clinical diagnostic ultrasound examination using UCAs.  Clinically observable manifestations include PVCs and hematuria.  Although the bioeffects are certainly biologically significant, the medical significance of the experimentally observed bioeffects is presently uncertain.  These microscale bioeffects might have medically significant consequence under some conditions, particularly in patients who are aged, diabetic (or have other disease states) or under drug treatment.  The cavitation biology of contrast-aided diagnostic ultrasound is a complex and challenging new topic of non-ionising radiation biology.

Acknowledgement:  Supported by the US National Institutes of Health via grant EB00338.

Download the proceedings article from the 19th International Congress on Acoustics Madrid, 2nd to 7th of  September 2007 (ICA 2007Miller.pdf).