Abstract
Ultrasound contrast agents (USCA) allows the dynamic detection of blood flow of both the macro and microvasculature. An obvious prerequisite for USCAs is the unhindered passage of clinically relevant dose levels through the microcirculation especially of the lungue, where they have to pass capillaries with diameters of around 4 μm. While smaller microbubbles rapidly passed through the microcirculation along with the red blood cells, larger microbubbles, however, were observed to coalesce and interrupt the blood flow. Whether this might influence the tissue oxygen tension is unclear up to now.
To examine this question a bolus of 2.4 ml SonoVue™ was injected into the suprarenal aorta at a flow rate of 10 ml/s (a dosage usually applied in the clinic). The pO2 in the outer medulla of the kidney was continuously measured using a flexible pO2 microcatheter. In addition, the SonoVue™ injection and its passage through the renal vasculature were documented by the CEUS technology to assess whether the microbubbles passed the kidney.
The study revealed that SonoVue™ induced no changes of the mean oxygen partial pressure in the outer medulla which confirms that these microbubbles on their way through the medullar capillaries did not hinder the co-flow of blood through the renal microvessels in a big animal model with a renal morphology and function comparable to human kidneys. These results demonstrate that the CEUS diagnostic itself did not influence the system to be examined which is a most important prerequisite for any diagnostic method.
With the introduction of ultrasound contrast agents (USCA), diagnostic ultrasound has entered a new era that allows the dynamic detection of blood flow of both the macro and microvasculature [1]. USCAs are shell-coated gas-filled microbubbles that are administered to the systemic circulation. As there is a great difference in echogenicity between the gas in the microbubbles and the soft tissue of the body such microbubbles are used to image the vasculature as well as the blood flow in veins, arteries and also microvessels [2]. An obvious prerequisite for USCAs is the free, unhindered passage of clinically relevant dose levels through the microcirculation. So, microbubbles have to be able to pass capillaries with diameters of around 4 μm [3]. The mean diameter of the microbubbles of SonoVue™ (Bracco, Konstanz, Germany) was described to be 2.5 μm, and more than 90% of the bubbles are smaller than 8 μm [4]. Bigger bubbles traversing the capillary bed would have to deform and adapt their shape to the diameter of the capillaries. Feinstein et al. showed that the smaller microbubbles rapidly passed through the microcirculation along with the red blood cells. Larger microbubbles, however, were observed to coalesce and interrupt the blood flow (subsequently they collapse or shrink [5]). Up to now it is unclear, whether such USCA-induced drop of blood flow might impair the oxygen tension (pO2) in kidneys [6, 7]. The decisive question is, whether the rate of flow disturbance induced by the injection of SonoVue™ could become so relevant as to influence and limit the oxygen supply to the surrounding kidney tissue.
To examine whether an injection of SonoVue™ might influence the pO2 in the tissue of the downstream microcirculation, a bolus of 2.4 ml was injected into the suprarenal aorta at a flow rate of 10 ml/s (a dosage usually applied in the clinic [8]. It was immediately followed by 10 ml of isotonic sodium chloride solution. The pO2 in the outer medulla of the kidney was continuously measured using a flexible pO2 microcather [9]. SonoVue™ injection and its passage through the renal vasculature were documented by the CEUS technology to assess whether the microbubbles passed the kidney [9].
The Bavarian Institutional Animal Care and Use Committee approved the study protocol for the experiments performed in this study (AZ.: 54-2532.1-31/13).
A ANOVA for repeated measures was performed to analyze the influence of both contrast media on the tissue oxygen tension. p-values less than 0.05 were considered significant.
Figure 1 demonstrates that the injection of SonoVue™ had no influence on the mean value of the tissue pO2 in the kidney (see red line in Fig. 1).
Renal tissue oxygen partial pressure in [mmHg] in the outer medulla before and after a bolus of 2.4 ml ultrasound contrast medium (SonoVue™) into the suprarenal aorta (n = 12 pigs). (red line shows the mean value of the 12 animals).
In contrast, the injection of a bolus of 4.32 ml of iodinated contrast medium (Iopromide, Bayer Healthcare, Berlin, Germany) into the suprarenal aorta of the same animals induced a decrease of the mean renal pO2 according to tendency (Fig. 2). 110 seconds after the injection of Iopromide into the renal aorta, pO2 in the outer medulla had decreased by 15% compared to baseline values (p < 0.0748).
Mean tissue oxygen partial pressure in [mmHg] in the outer medulla before and after a bolus of an iodinated contrast medium (Iopromide) into the suprarenal aorta (n = 6 pigs). (red line shows the mean value of the 6 animals).
The study revealed that SonoVue™ induced no changes of the mean oxygen partial pressure in the outer medulla, which confirms that these microbubbles on their way through the medullar capillaries did not hinder the co-flow of blood through the renal microvessels in a big animal model wit a renal morphology and function comparable to human kidneys. These results demonstrate that the CEUS diagnostic itself did not influence the system to be examined which is a most important prerequisite for any diagnostic method.
Disclosure
The University Regensburg, where the study was performed, was sponsored by GE Healthcare.