Matt Harmon

101 Chapter five Background Sepsis is characterized by an excessive hyper-inflammatory host response. 1 This response is partially mediated by pro- and anti-inflammatory cytokines, ultimately leading to organ failure and death. 2 Fever, often defined as a temperature ³ 38.3°C, is common in sepsis and augments the inflammatory response during infections and sepsis. This response may be considered beneficial by promoting an adequate host immune response to invading organisms. 3 However, fever also has adverse effects, such as vasodilation, increased metabolic rate and tissue injury. 3 It is unclear to what extent critically ill septic patients can increase their metabolism without exacerbating tissue hypoperfusion. Induced normothermia using external cooling could potentially benefit patients with sepsis. In a randomized controlled trial, cooling to a target temperature of 37°C lowered heart rate, decreased vasopressor use and possibly decreased 14-day mortality. 4,5 The mechanism is not known but may include inhibition of an excessive hyper-inflammatory response. 6,7 Also, induced normothermia could potentially reduce fever induced adrenergic stress by reducing heart rate, similar to beta-adrenergic blockade treatment. 5,8 However, intervening in the febrile response is controversial due to the perceived immune benefits of fever in addition to the potential side effects of cooling to normothermia. Induced normothermia may be associated with increased rates of nosocomial infections. 4 Also, although lowering body temperature decreases oxygen consumption, induced normothermia could potentially exacerbate tissue perfusion by decreasing cardiac output and causing vasoconstriction. 9 Lastly, induced normothermia in awake patients is perceived to cause discomfort. Data are limited on the effects of induced normothermia on physiology and the host immune response in hyperinflammatory states such as sepsis. Human endotoxemia models provide a controlled setting to study the physiologic and host immune effects of induced normothermia. 10 In this study we examined the physiologic response to induced normothermia and studied the effects of induced normothermia on the host immune response during human endotoxemia. We hypothesized that induced normothermia improves hemodynamic parameters and mitigates the lipopolysaccharide (LPS) induced inflammatory cytokine release.