Matt Harmon

Chapter four 82 hypothermic and febrile (n=18) are shown in supplemental table 1 for the purpose of interpretation, but these were not included in the microarray analysis). Of the 168 included patients, 67 patients were hypothermic and 101 patients were febrile. Minimum temperature in the hypothermic group was lower compared to the febrile group (35.0°C±0.9 vs. 37.2°C±0.7) as was the maximum temperature (37.1°C±0.9 vs. 39.3°C±0.9). Hypothermic patients were also older compared to febrile patients but BMI and gender distribution were similar between groups. There was also a similar distribution of site of infection between hypothermic and febrile patients. Patients in the hypothermic group compared to febrile patients had higher APACHE IV scores and SOFA scores, increased incidence of shock and higher rates of mortality at 30-days post-ICU admission (29 (43%) vs. 22 (22%)). Alterations in microarray gene expression in hypothermia compared to fever A total of 1930 transcripts were significantly altered in hypothermic patients compared to febrile patients, of which 1425 were reduced and 505 transcripts were elevated (supplemental figure 1A). Supplemental figure 1B shows the significant canonical pathways associated with these genes. Subsequently, we matched patients for APACHE IV scores and presence of shock. In total, 55 patients in each group remained for further analysis (characteristics of whom are shown in supplemental table 1). After matching there was no difference between groups in terms of APACHE IV scores and SOFA scores as well as incidence of shock. The 30-day mortality remained significantly increased in hypothermic patients (21 (38%) vs. 10 (18%), p = 0.041). Despite matching for APACHE IV scores, which includes age, patients in the hypothermic group were significantly older (67.3 years±11.6 vs. 61.8 years±16.3, p = 0.044). In total, 205 transcripts were significantly altered in hypothermic patients compared to febrile patients, of which 136 were reduced and 69 were elevated (figure 2A and B). The top-most significant gene was CIRBP , encoding cold-induced RNA binding protein, which plays a role in cold-induced suppression of cell proliferation. Among the genes with decreased expression in hypothermic patients we found members of the heat shock protein 70 complex (HSP70), namely HSPH1 and HSPA6 , encoding chaperone proteins that play essential roles in stress-induced misfolded protein responses (figure 2A). Pathway analysis of significantly altered, high expression genes resulted in significant associations with tryptophan degradation X, phenylalanine degradation IV and putrescine degradation III canonical signaling pathways (figure 2C). These signaling pathways relate to immunometabolic reactions that function in the degradation of amino acids and (poly)amines.