The Role of Functional Arterial Properties in Prediction of Clinical Outcomes of Septic Patients. Doctoral Thesis

Abstract

Sepsis is defined as multiple organ damage caused by dysfunctional systemic host response to infection. It is a frequent cause of admission to intensive care unit and carries high mortality. Vascular dysfunction due to reduced nitric oxide bioavailability plays an important role in the pathogenesis of sepsis and multiple organ failure. Conduit arteries, especially the aorta, play a major role in ensuring efficient cardiac function and optimal flow in the periphery due to their viscoelastic properties. Resistance arteries and arterioles adjust peripheral blood flow according to the metabolic needs of the tissues. Laboratory studies on isolated artery models and animal research show that acute systemic inflammation can cause impaired vasoreactivity in peripheral vascular beds and aortic stiffening of conduit arteries which affects hemodynamic efficiency. This thesis aims to characterize parameters describing functional properties of arteries in intensive care patients with severe sepsis and septic shock and clarify their association with the development of multiple organ dysfunction syndrome and mortality. This thesis consists of three parts. In part 1, systematic review and meta-analysis of published literature were performed to evaluate the measurement of endothelial function using vasoreactivity tests as a risk stratification tool in intensive care patients with sepsis. From the studies included in this review, there is evidence of moderate strength that vascular reactivity is impaired in septic patients, but not enough evidence has been provided to suggest that it is a consequence of endothelial dysfunction or is convincingly related to clinical outcomes. In part 2, the author undertook a prospective observational cohort study examining aortic stiffness in patients with sepsis using carotid-femoral pulse wave velocity measurement. Forty-five adult intensive care patients were recruited to the study within 24 hours of admission to intensive care. Carotid-femoral pulse wave velocity was measured once initial resuscitation was completed. Patients were followed up to hospital discharge or death. This study found that patients with severe sepsis and septic shock have higher aortic stiffness than the general population. No convincing association was found between admission pulse wave velocity and progression of multiple organ failure or mortality, although the group with pulse wave velocity > 24.7 m/s had shorter survival time. Part 3 extends the previous study and examines stiffness of both elastic and muscular arteries at two time points, at admission and after 48 hours of treatment. It also examines confounders associated with changes in carotid-femoral and carotid-radial pulse wave velocity. It found increased aortic and even higher upper limb artery stiffness among the septic population. Higher carotid-femoral pulse wave velocity was associated with higher mean arterial blood pressure and lower C reactive protein concentration. Pulse wave velocity in elastic and muscular arteries decreased after a 48-hour treatment period in survivors. In non-survivors, carotid-radial pulse wave velocity stayed consistently high. Overall, this study has shown that altered static and dynamic parameters of artery function are highly prevalent in patients with sepsis and associated with unfavourable outcome. Longitudinal assessment of these parameters has the potential to be used for risk stratification in patients with early sepsis.