Matt Harmon

49 Chapter three Background Sepsis is the consequence of a dysregulated immune response to infection, involving both proinflammatory and anti-inflammatory components, as well as a highly activated endothelium, resulting in increased vascular permeability, organ failure and shock. 1 Fever and hypothermia are both hallmark characteristics of sepsis. 2 Hypothermia is observed in 9%-35% of septic patients. 3,4 Whereas fever is generally considered beneficial for patients, hypothermia is independently associated with increased mortality. 4 However the etiology of hypothermia during sepsis is poorly understood. Studies attempting to elucidate the hypothermic response in sepsis focused on a hypothesized lack of proinflammatory cytokines, in particular interleukin (IL)-6 and tumor necrosis factor (TNF)- α , which are the main mediators of fever. However, these studies could not demonstrate that a depression of the proinflammatory response is associated with hypothermia in sepsis. 5,6 Anti- inflammatory cytokines such as IL-10, which possess antipyretic properties in humans 7 and animals 8 , have not been studied before in hypothermic septic patients. An excessive anti-inflammatory response could potentially explain hypothermia 9 and associated lymphopenia which was recently found in hypothermic patients with sepsis. 10 Other mechanisms have yet to be explored in hypothermic patients with sepsis. Endothelial dysfunction could also play a role in the development of hypothermia, as generalized peripheral vasodilation and loss of endothelial integrity during sepsis may result in heat loss by hampering the body’s ability to regulate its core temperature. 11,12 The aim of this current prospective observational study was to determine if hypothermia is independently associated with 90-day mortality. We subsequently characterized the host immune response in patients with hypothermic sepsis, by determining both proinflammatory and anti-inflammatory cytokines, and whole blood ex vivo responsiveness to lipopolysaccharide (LPS). We also measured markers of endothelial activation and integrity. Finally, we studied risk factors for hypothermic sepsis in an attempt to find potential new insights into the etiology of hypothermia in sepsis. Understanding the etiology of hypothermic sepsis may contribute to the identification of potential targets for future interventions.