Matt Harmon

127 Chapter six thrombocytopenia is transient. More likely, induced normothermia reduced endothelial cell activation with less activation of the ensuing coagulation cascade. The effect on the APTT may also be explained by less endothelial cell activation with less vWF release. As vWf is the carrier of factor VIII in plasma, decrease in vWf in the normothermia group compared to controls may in part explain normalization of aPTT levels in the normothermia group. In line with the decrease in APTT, INTEM CT in the fever group was prolonged compared to the normothermia group. Of note though, the differences in INTEM CT between groups were already apparent at T=1, so the differences between groups may not have been a result of normothermia. Other LPS- induced coagulation derangements were not detected by ROTEM results. As ROTEM values are influenced by platelet function and counts 20 and we previously showed that ROTEM has diagnostic value in detecting DIC, this finding was unexpected. 20-22 Also, ROTEM values were previously shown to be altered in LPS induced endotoxemia. 20 However, the impact of LPS on ROTEM values seems subtle and there was a large spread compared to conventional coagulation tests. Therefore, the number of subjects in this trial may have been too small to detect any subtle coagulation changes. There are limitations to this study. To reduce shivering, medication including magnesium sulphate was used. Thereby, we cannot dissect whether the external cooling or the medications have contributed to observed effects. High magnesium levels inhibit blood coagulation and thrombus formation 23 and potentially limit inflammation in experimental studies. 24-26 An α 2-adrenoreceptor agonist such as clonidine does not induce platelet aggregation 27,28 or affect coagulation 29 but may have anti-inflammatory effects. 27,28,30 . We attempted to include a third control group receiving only medication but without induced normothermia. Due to hypotension, we prematurely stopped inclusion in this group. However, as external cooling requires some form of sedation or analgesia to combat shivering, this study reflects pragmatic clinical practice. Conclusion In conclusion, induced normothermia reverses LPS-induced derangements of the coagulation system resembling those noted in sepsis-induced consumption coagulopathy and DIC, suggesting a decrease in endothelial driven coagulation. Induced normothermia should be further studied as a potential treatment in hyperinflammatory states such as sepsis.