Méthode acoustique basée sur l'agrégation érythrocytaire pour le suivi non invasif de l’inflammation

Any patient undergoing major surgery is at risk of developing a systemic inflammatory syndrome. When disproportionate inflammation occurs, the blood becomes very viscous and the transfer of oxygen to the tissues is weakened. This often causes organ failure and ultimately death. Nevertheless, inflammation is less harmful if detected and treated early. Currently, detection of inflammation is based on the monitoring of vital signs, such as body temperature and respiration rate, or on the estimation of blood markers of inflammation. The first method has the disadvantage of lacking specificity. Blood markers, on the other hand, are direct and quantitative measurements of the patient's inflammatory state but involve blood sampling and processing delays that prevent continuous monitoring of the patient. These difficulties the automation of the evaluation of inflammation and can delay the diagnosis and the associated treatment, especially in the cases of perioperative cares. This thesis presents a set of works aimed at the noninvasive detection and monitoring of inflammation by analyzing the ultrasound signal backscattered by blood. The motivation of the proposed methodology is to continuously monitor the patient's inflammatory response and reduce the time before treatment. The general principle used in the method exploits the collective reaction of red blood cells to the presence of acute phase inflammatory proteins, in particular fibrinogen. Indeed, the concentration of these macromolecules correlates positively with the force of intercellular attraction. Thus, under low flow conditions, the level of erythrocyte aggregation serves as a surrogate marker of the patient's inflammatory state. Although the erythrocyte aggregates are not large enough to be observed in an ultrasound image, they leave a spectral signature on the backscattered blood signal. By fitting the blood spectrum to physical or mathematical models of acoustic diffusion, it is possible to obtain quantitative parameters of clinical interest, such as the size or spatial organization of the aggregate. This type of analysis belongs to the field of quantitative ultrasound which seeks the characterization of tissues from its spectral signatures commonly referred to as the backscattering coefficient. The first objective of this thesis is to evaluate from a clinical point of view the interpretation of the parameters obtained from the ultrasound signal of the blood. Five mathematical models of acoustic backscattering, including both classical and recent versions, were evaluated. In ex vivo experiments and in a preclinical study, we observed that when the erythrocyte aggregation increases, in particular by an inflammatory process, certain parameters offer an excellent contrast and allow its classification. It is concluded that the "structure factor and size estimator", "effective medium theory considering a structure factor" and the "Gaussian" models allow the characterization of several levels of erythrocyte aggregation and are good candidates for the evaluation of the inflammatory reaction in clinics. Pioneer works on the measurement of inflammation required that ultrasound acquisition would be done in an invasive fashion. This fact plays against the general interest of the technique and makes its use impossible in the intensive care room. A second objective of this thesis is thus to propose a protocol for the non-invasive measuring of erythrocyte aggregation. The analyzed solutions concentrate on the compensation of the confounding factors intrinsic to the in vivo measurement, in particular the blood flow. It was observed that the cessation of blood flow rendered the technique sensitive to the previous flow conditions and played against its repeatability. Conversely, ex vivo experiments showed that maintaining a low-flow provided repeatable measures and could distinguish between normal and high extents of erythrocyte aggregation. Validations on a cohort of eleven volunteers showed that the low-flow protocol also offers good in vivo repeatability and correlates significantly with ex vivo laboratory tests of erythrocyte aggregation. Finally, by aiming at the transfer of technology to clinics, the third objective of this thesis was to evaluate the reproducibility of results using ultrafast imaging methods and clinical ultrasound machines. Indeed, previous works on the characterization of erythrocyte aggregation were done with single element transducers, typically used in fundamental research. However, the transducers used in the clinics are equipped with more than a hundred of piezoelectric elements. This configuration allows the formation of focused ultrasound beams as well as ultrafast imaging techniques. Our ex vivo validations demonstrated that the use of these new technologies is quite possible for the characterization of erythrocyte aggregation and leads to results comparable to those of previous technologies.

Keyphrases: Systemic inflammation, Acoustic blood scattering, Erythrocyte aggregation, Quantitative ultrasound, Spectral analysis