Matt Harmon

202 Chapter ten preclinical studies to clinical patients was underlined by the cooling and surviving septic shock (CASS) trial, an randomized controlled trial (RCT) in which patients with septic shock were treated with therapeutic hypothermia (32°C - 34°C). This study was stopped early due to futility, but cooling actually adversely effected several markers of organ failure. 12 Induced normothermia however, may be an alternative intervention in sepsis. Treatment with induced normothermia in patients with fever and septic shock showed promising results with improved hemodynamic status and 14-day mortality compared to controls. More recently however, results of two clinical trials showing potentially adverse effects of induced normothermia, specifically regarding tissue perfusion. 13,14 The reason for these conflicting results is unclear. Therefore, we investigated the effects of induced normothermia in a highly reproducible healthy volunteer model of endotoxemia. In chapter eight, induced normothermia lowered heart rate while maintaining perfusion compared to healthy volunteers who only received LPS. Induced normothermia decreased interleukin-10 levels, but did not lower pro-inflammatory cytokine levels or CRP. In chapter nine, induced normothermia decreased disseminated intravascular coagulation (DIC) scores and plasma von Willebrand factor (vWf) levels and maintained platelet levels compared to volunteers that only received LPS, possibly indicating decreased endothelial activation. The results indicate that treatment with induced normothermia could be targeted to specific patient subpopulations, for example, patients with deranged coagulation or excessive endothelial activation. Targeted temperature management in patients with cardiac arrest In non-infectious etiologies such as hypoxic-ischemic brain injury after cardiac arrest, the effects of fever are well-defined; fever harms the injured brain. 15 Targeted temperature management (TTM), in which patients with cardiac arrest are actively cooled to 32°C-36°C, has improved survival and neurologic outcome since its implementation. 16 But TTM treatment can still be improved, to tailor the treatment to the specific needs of cardiac arrest patients. Towards this goal, we studied mechanical ventilation practices in patients following cardiac arrest in chapter five . We found that in the majority of the cardiac arrest patients, protective ventilation settings are applied, including low tidal volumes and driving pressures. TTM at 33°C resulted in lower end-tidal CO2 levels and a higher alveolar dead space fraction compared to TTM at 36°C, but did not result in a lower minute volume ventilation. The higher dead space in patients treated with TTM at 33°C could be a result of lower pulmonary perfusion due to increased vasoconstriction and this may be an unwanted side effect of cooling to 33°C. In