Invloed van acute en verlengde kritieke ziekte op cholesterol beschikbaarheid in relatie tot de klinische uitkomst

Critical illness is any life-threatening condition for which the patient requires intensive mechanical or pharmacological support to prevent imminent death. Although innovative technologies and pharmacotherapy in modern healthcare tremendously increased a patient's chance to outlive the acute phase of illness, morbidity and mortality is still high in these patients and >10% of the patients remain dependent on life support for a prolonged period of time. Prolonged critically ill patients are at risk for the development of multiple organ failure, superinfections, ICU-acquired weakness and a suppressed adrenal function, which all hamper convalescence. A better understanding of the underlying mechanisms behind this complex disease state might lead to major clinical improvement. A hallmark of critical illness is an immediate and sustained decrease in circulating cholesterol. Plasma levels of total cholesterol and of HDL- and LDL-cholesterol are uniformly decreased in critically ill patients in relation to the severity of their illness and to the risk of death. Although considered to be part of the acute phase response, the metabolic fate of circulating cholesterol during critical illness remains insufficiently understood and the impact of hypocholesterolemia on both muscle and adrenal function has not yet been thoroughly investigated. In this project, we aim to investigate the underlying mechanisms behind this critical illness-induced hypocholesterolemia during the course of critical illness, as we postulate that, during the acute phase, cholesterol availability is reduced because of an increased scavenging of micro-organisms, increased conversion of cholesterol to cortisol and an increased peripheral uptake. Moreover, we postulate that, in the protracted phase of illness, an increased cholesterol metabolism to bile acids contributes to a peripheral shortage of cholesterol availability, which might lead to detrimental consequences on skeletal muscle function and adrenocortical function. Our hypotheses will be tested in a validated mouse model of cecal-ligation and puncture (CLP) -induced, antibiotics-treated polymicrobial abdominal sepsis by means of tracer technologies and pharmacological treatment, and in 3 human studies. With this project we aim to gain more insight in the altered cholesterol availability during the time course of critical illness and aim to develop novel strategies to prevent, or treat, ICU-acquired weakness and/or a suppressed adrenal function, two important debilitating complications of critical illness.