Matt Harmon

Chapter four 88 Impaired phenylalanine metabolism can interfere with the production of catecholamine and augment shock. Interestingly, tetrahydrobiopterin (BH4) is a co-factor for the degradation of both phenylalanine and tryptophan 45 , providing a link between the two pathways found in this study. Taken together, the presence of pathways that are upregulated irrespective of disease severity, suggests that hypothermic sepsis is associated with a distinct genomic profile. Our results suggest an important relation to the modulation of body temperature and immunosuppression. The genes and pathways found in this study could serve as potential therapeutic targets and warrant more investigation. The importance of these findings is not only limited to understanding the pathophysiology hypothermic response. Although not the primary aim of our study, the pathways identified in this study could also be used to identify at risk septic patients and monitor illness severity and efficacy of treatment. 44 In general, the etiology and pathophysiology of the hypothermic response remains unclear. Our study suggests that patients with hypothermia distinct differences in gene expression profiles. Although several pathways were only altered in the unmatched analysis, these pathways may also hold valuable insights in the pathophysiology of hypothermic sepsis. By matching for disease severity, important pathways relating hypothermia and sepsis may be overlooked as hypothermia may represent a symptom of disease severity. 46 How the genes and pathways found in this study relate to the hypothermic response and increased mortality remains to be seen. While our study was not designed to address the relationship between transcriptomes of hypothermic adult and pediatric sepsis patients, generalizability of our findings to pediatric sepsis patients would represent an important extension. Based on previous reports on endotype classification of adult and pediatric sepsis patients 47 , we envisage that transcriptional profiles in hypothermic/normothermic/febrile pediatric sepsis patients will reflect, at least in part, those observed in adult sepsis patients. This study has several strengths. In this prospective cohort we looked at the extremes of temperatures in sepsis (hypothermia vs. fever). By doing this we reason we had the highest likelihood of finding pathways that relate to the hypothermic septic response. Of note, our study is based on a prospective observational cohort that was not designed to address the scope of our study. Future studies in larger cohorts of sepsis with or without hypothermia are certainly warranted . Secondly, instead of using conventional biomarkers, we used microarray in blood leukocytes to identify potential clues to the etiology of the hypothermic response in sepsis. Blood leukocytes represent a clinically relevant and easily accessible body compartment that has been extensively employed in clinical studies to identify fundamental features of the immune response during sepsis. 11 Results