Matt Harmon

14 Chapter one Potential defects along fever induction pathways in figure 1 could hypothetically result in hypothermia. These can be divided in pre-hypothalamic, hypothalamic and post-hypothalamic mechanisms. 35 Pre-hypothalamic mechanisms include the ability to induce fever through proinflammatory cytokines as previously discussed. These not only mediate the febrile response but are also essential in mounting an adequate host response to invading pathogens. Observational clinical studies on these pre-hypothalamic mechanisms have yielded some minimal understanding of the hypothermic response. 26,33-35 Hypothermic patients are not deficient of proinflammatory cytokines, the main driver of the febrile response. TNF α, iL1-b and iL-6 levels have been shown be either similar 33,35 or even increased in hypothermic patients. 26 A retrospective study found that hypothermic septic patients are inclined to develop abnormally low levels of lymphocytes, also called lymphopenia. 34 In line with this finding, afebrile septic patients have reduced human leukocyte antigen (HLA)-DR monocyte expression, a measure of sepsis induced immunosuppression. 36 The increased incidence of lymphopenia in hypothermic septic patients indicates that these patients might be prone to sepsis-induced immunosuppression and subsequent nosocomial infections. 34 However, data is conflicting on whether hypothermic septic patients suffer from an increased incidence of nosocomial infections. 36,37 Hypothalamic and post-hypothalamic mechanisms for spontaneous hypothermia have not been studied in septic patients. Mechanisms could include altered thermal setpoint due to sepsis induced CNS-dysfunction or defective post-hypothalamic heat generating mechanisms such as endothelial dysfunction resulting in inadequate heat preservation. 35 Clinical aspects of the hypothermic response in sepsis. Patients presenting with spontaneous hypothermia and sepsis suffer from higher incidences of shock 1,24,38 and organ dysfunction 24,26,35,39 , including increased central nervous system dysfunction. 39 Coincidingly, patients with hypothermic sepsis have a higher mortality rate, almost twice that of patients presenting with fever. 24,40 Despite the high mortality rate in hypothermic sepsis, hypothermia does not appear to be a premortal sign in sepsis. Most patients rewarm to normothermia prior to death indicating that thermoregulatory capacity may still be intact in these patients. 26,28 Interestingly, when exploring the temporal relationship between developing hypothermia and the chances of developing respiratory distress or shock, these events appear to occur independently from hypothermia. 28 Other interesting observations in hypothermic septic patients include a lack of shivering. 26 this could indicate a dysfunction of the bodies heat generating mechanisms, but could also be the result of a downward shift in the body temperature threshold