Matt Harmon

201 Summary other hand, if hypothermia during sepsis is a deleterious response, rewarming to normothermia may benefit patients. Some authors have even hypothesized that patients should be rewarmed to febrile temperatures to invoke the beneficial immune response attributed to fever. 4 In order to gain insight in the etiology of the hypothermic response in sepsis, we studied risk factors, host immune markers and endothelial markers in the hypothermic septic population in chapters three and four . In chapter three we found that patients with cardiovascular risk factors and low BMI were at risk for developing hypothermia. We also found signs that hypothermic patients may suffer from increased endothelial dysfunction. We subsequently proposed a mechanism to reconcile results from experimental studies and our clinical findings. 5 Animal studies show that spontaneous hypothermia in endotoxemia may be a pre-emptive strategy to prevent hypoxia. 6 Patients with sepsis and preexisting circulatory dysfunction (i.e. chronic cardiovascular dysfunction) or a metabolic deficit (i.e. lower body mass index) may reach a cellular hypoxic threshold sooner than other patients. Cellular hypoxia may be further exacerbated in these patients as we found signals of increased endothelial dysfunction in hypothermic septic patients. 5 Moreover, in chapter four we found that the tryptophan degradation X pathway was upregulated in patients with hypothermia compared to fever. Tryptophan has the potential, through serotonin mediated pathways, to lower body temperature. 7,8 But tryptophan metabolites are also toxic for some immune cells, potentially explaining the observation of prolonged lymphopenia in hypothermic septic patients. 9 Hypothetically, the hypothermic response could be a short-term strategy by the body to (temporarily) ward off hypoxia or extend metabolic reserves by lowering body temperature and decreasing oxygen consumption. This strategy may leave patients immunocompromised, ultimately resulting in increased mortality later on. Perhaps patients with hypothermic sepsis should be allowed to stay hypothermic. However, they may need some form of immune stimulation to potentially compensate for the immunosuppressive effects of hypothermia. Induced hypothermia and induced normothermia in sepsis patients Induced hypothermia and induced normothermia (also called fever control), in which patients with fever are cooled to hypothermia or normothermia, are experimental treatment strategies aimed at limiting metabolism and decreasing inflammation in sepsis. Animals studies have overwhelmingly shown that therapeutic hypothermia, in which animals with sepsis or endotoxemia are actively cooled to below 36°C, is associated with decreased inflammation and improved outcome. 10,11 However, the difficulty in translating results from these controlled