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Science to Practice |
1 Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Rd, Clinical Center West-302B, Boston, MA 02215 jkruskal@bidmc.harvard.edu
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The ability to accurately quantify blood flow in solid organs is essential for a variety of reasons, including confirmation of organ or tissue viability, assessment of tumor ablation procedures, postoperative imaging where rejection or vascular complications may occur, and determination of the response to angiogenesis-modulating drugs. In a report in the current issue of Radiology, Lucidarme et al (1) have further optimized the use of ultrasonography (US) with microbubble contrast agent enhancement to provide assessments of different components of blood flow.
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In recent years, the application of microbubbles has progressed from use for simple documentation of flow in challenging locations (2,3) to use as tracers for measuring blood flow and tissue perfusion (4). In the current study, Lucidarme et al (1) explored the mathematical models used for obtaining blood flow measurements.
Doppler US has traditionally been used in the estimation of blood flow, but this estimation remains subject to serious errors, is operator dependent, and is often difficult to perform (3). With expanded use and development of US microbubble contrast agents, a variety of innovative applications have been developed. These contrast agents increase the acoustic intensity of reflected beams and are, therefore, useful where Doppler studies may be technically challenging, when signals arise from deep tissues or flow is very slow. In addition, with transit-time methods microbubbles can be used as tracers for measuring blood flow, by following a bolus injection as it traverses an organ (4).
Lucidarme et al (1) used a formula to describe the change in microbubble concentration (related to image intensity) with time for any single compartment where the agent (ie, a molecule, tracer, or drug) enters and exits via a single channel. However, the authors have gone a step further. Until now, as Lucidarme et al discuss, authors of published reports have suggested that microbubble replenishment curves in vivo occur according to an exponential function, and components of flow can thus be quantified when fit to such an exponential curve. Lucidarme et al have shown that when vessels that feed an area being measured have previously been depleted of microbubbles, the replenishment curve is no longer exponential but fits that of a sigmoid curve and can be described theoretically by using an indicator-dilution model—a technique routinely applied to determine cardiac output in patients in the intensive care unit. Furthermore, to account for additional factors, such as organs being supplied by more than one vessel, the authors also studied microbubble replenishment at sites downstream from the location of depletion. Again, these curves fit the indicator-dilution model. These observations are especially important since they are more likely to affect flow measurements acquired in humans, but, more so, they raise an element of doubt concerning the numerous published reports of flow measurement in which exponential modeling alone was used.
The Practice
Clinical use.—The ability to accurately measure components of blood flow in a noninvasive and portable manner responds to an emerging clinical demand emphasized most recently by the development of pro- or antiangiogenic therapies. Authors of several studies (5,6) have described the use of ultrasound-enhanced depletion-replenishment technology for estimating myocardial perfusion, but a demand also exists for similar estimations in solid tumors in patients receiving experimental antiangiogenic treatments. The presence of disease may alter flow in solid organs. In the liver, for example, cirrhosis, allograft rejection, and formation of metastases are examples of flow alterations preceding more traditionally visible disease. This flow alteration may be an early indicator of disease. It is highly likely that these flow indices and flow components will allow monitoring of both the effects of therapies and impending changes, such as progressive fibrosis or rejection. Opportunities clearly exist for prospective studies to compare organ flow versus response to drugs or other therapies for predicting the development of disease progression or optimizing treatment choice.
Future opportunities and challenges.—Opportunities include optimization of microbubble size for evaluation of haphazard tumor perfusion, given that heterogeneous tumor neovasculature is smaller than many of the currently available microbubble agents, including those used in this study. While fractional blood volume has been measured in solid organs, additional indices of flow should be explored in tumors where fewer bubbles may enter, flow is slower, and the emitted acoustic intensity may currently be insufficient to provide useful information. Also, radiologists still seek a reliable imaging correlate of histologic microvessel density; it is possible that the technology described by Lucidarme et al will ultimately provide us with this index.
Summary
By combining emerging technologies and in response to the need for noninvasive measurements of tissue blood flow, Lucidarme et al have validated and further optimized a technique for measuring different, yet important, components of blood flow in vivo. Further refinements and study will undoubtedly improve this technique to best optimize it for clinical applications.
FOOTNOTES
See also the article by Lucidarme et al in this issue
REFERENCES
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