Matt Harmon

119 Chapter six Background The dysregulated host-immune response in sepsis involves activation of a procoagulant response and impairment of anticoagulant mechanisms, resulting in consumption coagulopathy with low platelet count, prolonged prothrombin time (PT) and increased D-dimer levels. The most severe septic patients develop overt disseminated intravascular coagulation (DIC). These coagulation changes are associated with multiple organ failure. 1 Sepsis often presents with fever, defined as a core body temperature of > 38.3°C. 2 Fever is commonly thought to be a functional response to infection as it improves pathogen clearance and immune cell mobility. 3 However, fever may also have harmful effects. The increased metabolic cost of fever may exacerbate oxygen deficits at a cellular level, resulting in increased tissue injury, such as cardiac distress and encephalopathy. 3 Also, fever may contribute to an exaggerated pro-inflammatory response, with increased cytokine production and vasodilatory shock. In line with this, induced normothermia in patients with septic shock presenting with fever was found to decrease vasopressor need compared to the febrile control arm 4 , although not all studies have reported beneficial effects. 5 Data are scant on how cooling affects the procoagulant host response. Whereas profound hypothermia decreases platelet function and impairs the synthesis and kinetics of clotting factors 6 , cooling to normothermia is not likely to illicit these processes. Conversely, as induced normothermia has been shown to limit inflammation 5 , this could actually reduce the activation of coagulation. Experimental human endotoxemia provides for a controlled setting to study the effects of fever control on the host immune response. The model of endotoxemia induced by lipopolysaccharide (LPS) is characterized by a procoagulant response, with increased levels of von Willebrand factor (vWf) and tissue factor, together with a (transient) profound decrease in platelet count and prolonged prothrombin time (PT), thereby closely resembling sepsis-associated coagulopathy. 7-9 In this study, we aimed to investigate the effect of induced normothermia on the coagulation processes during LPS-induced endotoxemia in healthy volunteers. We hypothesized that cooling to normothermia limits the activation of coagulation.