Matt Harmon

70 Chapter three That study revealed that, similarly to animal models of endotoxemia, hypothermia in human sepsis is usually self-limiting and transient. Perhaps most importantly, hypothermia was rarely observed in the moments that preceded death, when multiple organ failure is presumably at its peak. Hence, it is possible that an early, regulated form of hypothermia exists in human sepsis. By the same token, the reported association between hypothermia and higher mortality should not be taken as evidence that hypothermia is a dysfunction that worsens sepsis. This association could merely reflect the fact that hypothermia replaces fever in the most severe cases of sepsis, both in rats and humans. In our opinion, the impact of septic hypothermia on clinical outcomes can only be adequately addressed by an interventional study in which spontaneous hypothermia is allowed or prevented within the hypothermic subset of septic patients. We are planning such a study and invite those interested to join us. References 1 Wiewel, M. A. et al. Risk factors, host response and outcome of hypothermic sepsis. Critical care 20 , 328, doi:10.1186/s13054-016-1510-3 (2016). 2 Corrigan, J. J., Fonseca, M. T., Flatow, E. A., Lewis, K. & Steiner, A. A. Hypometabolism and hypothermia in the rat model of endotoxic shock: independence of circulatory hypoxia. J Physiol 592 , 3901-3916, doi:10.1113/jphysiol.2014.277277 (2014). 3 Romanovsky, A. A., Shido, O., Sakurada, S., Sugimoto, N. & Nagasaka, T. Endotoxin shock: thermoregulatory mechanisms. The American journal of physiolog y 270 , R693-703 (1996). 4 Liu, E. et al. Naturally occurring hypothermia is more advantageous than fever in severe forms of lipopolysaccharide- and Escherichia coli-induced systemic inflammation. American journal of physiolog y. Regulatory, integrative and comparative physiolog y 302 , R1372-1383, doi:10.1152/ajpregu.00023.2012 (2012). 5 Fonseca, M. T. et al. Spontaneous hypothermia in human sepsis is a transient, self-limiting and non- terminal response. Journal of applied physiolog y , jap 00004 02016, doi:10.1152/japplphysiol.00004.2016 (2016).