Matt Harmon

205 Summary TTM-treatment could be monitored in real-time based on the brains response and titrated according to specific patient needs. 31 In sepsis, body temperature and the road towards TTM as a treatment is more complex, mostly due to the fact that we have yet to determine whether body temperature alterations in sepsis are beneficial or detrimental to the host. Towards this goal RCTs have been proposed to determine the etiology of the hypothermic response, in which patients are either rewarmed to a certain target temperature or left hypothermic. 2 If patients that are left hypothermic have better outcomes than those that are rewarmed, this would point to hypothermia being an adaptive response. Although the results of such a study would be intriguing, this type of study may suffer from the same pitfall as in previous clinical hypothermia and induced normothermia studies in sepsis. Treating sepsis with active cooling aims to attenuate the excessive immune response in sepsis. However, to what extent this “excessive” immune response still modulates vital physiologic processes in patients is not clear. Treating every septic patient with an identical temperature strategy will therefore likely result in benefit for some but detrimental effects for others. Moreover, previous studies have used clinical parameters such as the occurrence of shock, to categorize patients prior to TTM treatment. But these clinical parameters do not necessarily reflect underlying pathologic processes 34 .This could explain the fact that promising preclinical results on the application of therapeutic hypothermia in sepsis resulted in mixed clinical results. 12 Before initiating more TTM trials in sepsis we need a better understanding of the underlying pathophysiology of body temperature during sepsis. We should focus also on identifying biomarkers that can be used to monitor the adverse or beneficial effects of body temperature. Using these biomarkers, we may be able to determine whether a patient’s body temperature is appropriate or warrants intervening. A starting point for future studies could be cellular hypoxia, which may drive body temperature alterations in sepsis. In both animals and humans, hypoxia regulates body temperature 35 and animal studies have found that spontaneous hypothermic response may a be preemptive attempt by the body to prevent hypoxia. 6 Interestingly, in the unmatched microarray analysis in chapter four, we found that hypothermic patients have a downregulation of cellular hypoxia signaling pathways despite these patients having a higher incidence of shock compared to patients with fever. Hypothetically, hypoxia signaling could be functional until a certain hypoxic threshold is reached. Once tolerable cellular hypoxic levels are exceeded, cellular hypoxia signaling pathways are downregulated and the bodies temperature setpoint is lowered to mitigate further hypoxic damage. Continuous observation of cellular hypoxia markers during spontaneous temperature alterations in septic patients would aid in better understanding the interplay between body temperature and hypoxia. Cutaneous