Effect of Microsphere Size Distribution on the Ultrasonographic Contrast Efficacy of Air-Filled Albumin Microspheres in the Left Ventricle of Dog Hearts

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Abstract
The in vitro ultrasonographic contrast efficacy of air-filled albumin microspheres has been found to depend on the size distribution of microspheres. The objective of the current study was to empirically describe the relationship between the size distribution of injected air-filled albumin microspheres and the in vivo contrast efficacy after lung capillary filtration in a dog model. Twenty different air-filled microspheres with large and well-defined differences in size distribution were prepared from nine different batches of Albunex® (Molecular Biosystems Inc.) and subsequently characterized by Coulter counting. The in vivo ultrasonographic contrast enhancement of these preparations was investigated with a VingMed CFM750 in closed chest model in six mongrel dogs. The observed contrast efficacy, measured as gray-level enhancement in the left ventricle (LV), was correlated to the microsphere size distribution, using both univariate and multivariate approaches. The results demonstrated a significant contribution to LV contrast efficacy from microspheres larger than approximately 7 µm, and a lack of contribution from microspheres smaller than approximately 7 µm. Linear relationships were found between LV contrast efficacy, and both the number concentration of microspheres between 8 to 12µm and the total microsphere volume concentration. No significant covariance between in vivo contrast efficacy and the number concentration between 1 to 38 µm or 4 to 10 µm was observed. The multivariate model showed a significant contribution to the in vivo gray-level enhancement from microspheres in the size range 7 to 15 µm, with optimal efficacy per microsphere at approximately 13 µm. Large microspheres (> 7 µm), which had been expected to be trapped in the lung capillary bed, contribute most of the observed ultrasound contrast in the LV of the heart.