The effect of red blood cell orientation on the electrical impedance of pulsatile blood with implications for impedance cardiography

摘要

Impedance cardiography is an application of bioimpedance analysis primarily used in a research setting to determine cardiac output. It is a non invasive technique that measures the change in the impedance of the thorax which is attributed to the ejection of a volume of blood from the heart. The cardiac output is calculated from the measured impedance using the parallel conductor theory and a constant value for the resistivity of blood. However, the resistivity of blood has been shown to be velocity dependent due to changes in the orientation of red blood cells induced by changing shear forces during flow. The overall goal of this thesis was to study the effect that flow deviations have on the electrical impedance of blood, both experimentally and theoretically, and to apply the results to a clinical setting. The resistivity of stationary blood is isotropic as the red blood cells are randomly orientated due to Brownian motion. In the case of blood flowing through rigid tubes, the resistivity is anisotropic due to the biconcave discoidal shape and orientation of the cells. The generation of shear forces across the width of the tube during flow causes the cells to align with the minimal cross sectional area facing the direction of flow. This is in order to minimise the shear stress experienced by the cells. This in turn results in a larger cross sectional area of plasma and a reduction in the resistivity of the blood as the flow increases. Understanding the contribution of this effect on the thoracic impedance change is a vital step in achieving clinical acceptance of impedance cardiography. Published literature investigates the resistivity variations for constant blood flow. In this case, the shear forces are constant and the impedance remains constant during flow at a magnitude which is less than that for stationary blood. The research presented in this thesis, however, investigates the variations in resistivity of blood during pulsataile flow through rigid tubes and the relationship between impedance, velocity and acceleration. Using rigid tubes isolates the impedance change to variations associated with changes in cell orientation only. The implications of red blood cell orientation changes for clinical impedance cardiography were also explored. This was achieved through measurement and analysis of the experimental impedance of pulsatile blood flowing through rigid tubes in a mock circulatory system. A novel theoretical model including cell orientation dynamics was developed for the impedance of pulsatile blood through rigid tubes. The impedance of flowing blood was theoretically calculated using analytical methods for flow through straight tubes and the numerical Lattice Boltzmann method for flow through complex geometries such as aortic valve stenosis. The result of the analytical theoretical model was compared to the experimental impedance measurements through rigid tubes. The impedance calculated for flow through a stenosis using the Lattice Boltzmann method provides results for comparison with impedance cardiography measurements collected as part of a pilot clinical trial to assess the suitability of using bioimpedance techniques to assess the presence of aortic stenosis. The experimental and theoretical impedance of blood was shown to inversely follow the blood velocity during pulsatile flow with a correlation of -0.72 and -0.74 respectively. The results for both the experimental and theoretical investigations demonstrate that the acceleration of the blood is an important factor in determining the impedance, in addition to the velocity. During acceleration, the relationship between impedance and velocity is linear (r2 = 0.98, experimental and r2 = 0.94, theoretical). The relationship between the impedance and velocity during the deceleration phase is characterised by a time decay constant, ô , ranging from 10 to 50 s. The high level of agreement between the experimental and theoretically modelled impedance demonstrates the accuracy of the model developed here. An increase in the haematocrit of the blood resulted in an increase in the magnitude of the impedance change due to changes in the orientation of red blood cells. The time decay constant was shown to decrease linearly with the haematocrit for both experimental and theoretical results, although the slope of this decrease was larger in the experimental case. The radius of the tube influences the experimental and theoretical impedance given the same velocity of flow. However, when the velocity was divided by the radius of the tube (labelled the reduced average velocity) the impedance response was the same for two experimental tubes with equivalent reduced average velocity but with different radii. The temperature of the blood was also shown to affect the impedance with the impedance decreasing as the temperature increased. These results are the first published for the impedance of pulsatile blood. The experimental impedance change measured orthogonal to the direction of flow is in the opposite direction to that measured in the direction of flow. These results indicate that the impedance of blood flowing through rigid cylindrical tubes is axisymmetric along the radius. This has not previously been verified experimentally. Time frequency analysis of the experimental results demonstrated that the measured impedance contains the same frequency components occuring at the same time point in the cycle as the velocity signal contains. This suggests that the impedance contains many of the fluctuations of the velocity signal. Application of a theoretical steady flow model to pulsatile flow presented here has verified that the steady flow model is not adequate in calculating the impedance of pulsatile blood flow. The success of the new theoretical model over the steady flow model demonstrates that the velocity profile is important in determining the impedance of pulsatile blood. The clinical application of the impedance of blood flow through a stenosis was theoretically modelled using the Lattice Boltzman method (LBM) for fluid flow through complex geometeries. The impedance of blood exiting a narrow orifice was calculated for varying degrees of stenosis. Clincial impedance cardiography measurements were also recorded for both aortic valvular stenosis patients (n = 4) and control subjects (n = 4) with structurally normal hearts. This pilot trial was used to corroborate the results of the LBM. Results from both investigations showed that the decay time constant for impedance has potential in the assessment of aortic valve stenosis. In the theoretically modelled case (LBM results), the decay time constant increased with an increase in the degree of stenosis. The clinical results also showed a statistically significant difference in time decay constant between control and test subjects (P = 0.03). The time decay constant calculated for test subjects (ô = 180 - 250 s) is consistently larger than that determined for control subjects (ô = 50 - 130 s). This difference is thought to be due to difference in the orientation response of the cells as blood flows through the stenosis. Such a non-invasive technique using the time decay constant for screening of aortic stenosis provides additional information to that currently given by impedance cardiography techniques and improves the value of the device to practitioners. However, the results still need to be verified in a larger study. While impedance cardiography has not been widely adopted clinically, it is research such as this that will enable future acceptance of the method.