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Mouse sepsis models: don't forget ambient temperature!
Intensive Care Medicine Experimental volume 10, Article number: 29 (2022)
The recently published contribution by Bauer et al.  in this journal deciphers the heuristic value of a biological definition of sepsis as a failing stress response. Rightly, the authors proposed to expand the concept of sepsis by incorporating infectious stress within the general organismic stress response to define sepsis as an illness state characterized by allostatic overload and failing adaptive responses along with biotic (pathogen) and abiotic environmental (e.g., ambient temperature, Ta) stress factors.
We want to take the opportunity to ventilate a serious shortcoming of experimental sepsis research, which compromises its translational value: the systematic disregard of Ta on sepsis progression and outcome (Table 1). Textbook knowledge says that thermoregulation is a fundamental homeostatic function of all mammals. It includes afferent thermal sensing, central regulation, and an efferent response with the consequence of tightly controlled body temperature within a narrow species-specific range . Variations of core body temperature (Tc) outside this range trigger autonomic thermoregulatory responses, mainly via a gradually increased sympathetic activity . Clinical data clearly indicate that spontaneous Tc lowering (hypothermia indicating energy exhaustion) is directly correlated with poor outcome of sepsis [4,5,6]. Hence, in clinical settings, recommendations clearly define optimal ambient temperature ranges for appropriate care of septic patients to prevent cold stress. Therefore, Ta is controlled within a narrow range of thermoneutral temperatures at which energy expenditure to maintain body temperature is lowest to save metabolic demands and prevent additional cold stress and its negative consequences on critically ill patients .
Surprisingly, this fundamental prerequisite to warrant best possible care for patients is widely unregarded in experimental sepsis research. Mice exhibit a rather unfavorable surface area to body mass ratio as well as an unfavorable whole body thermal conductance (> one order of magnitude difference between mouse and human): therefore, already under healthy and thermoneutral conditions (similar for mouse and human at ~ 30 °C), mice have to compensate it by an enhanced basal metabolic rate.
Incredibly, almost all sepsis experiments with mice are done at “room temperature”! However, these standard housing temperatures for laboratory mice, e.g., Ta of 20 °C and 24 °C [8,9,10] induce chronic cold stress for mice. Healthy mice are capable of controlling such a challenge and maintain their core temperature through an appropriate increase of their metabolism. Indeed, energy demand is increased by about 50% at Ta of 22 °C compared with thermoneutral conditions . However, sick mice are compromised by severe infection or systemic inflammation and additional cold stress markedly altered their response to sepsis by recruiting different defense mechanisms. Recently, two seminal publications appeared on experimental sepsis research and mild cold stress. Ganeshan et al.  exemplified that activation of immunity (by LPS and bacterial sepsis) causes an energetic trade-off with homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. Among other measures, the primary outcome parameter was survival. Sepsis caused by induced bacteremia led to an increased mortality rate in mice kept at Ta = 30 °C (~ 40%) compared with mice kept at Ta = 22 °C (~ 5%). A similar result in terms of mortality rate was reported in response to LPS at the dosages used there (LPS 1–1.5 mg/kg): in mice kept at Ta = 30 °C (~ 75%) compared with mice kept at Ta = 22 °C (~ 50%). In contrast, Carpenter et al.  reported that the survival rate of male C57BL/6 mice housed at 30 °C (78%) after abdominal sepsis was significantly increased compared with mice housed at 22 °C (40%). This is in line with findings after LPS administration . These findings highlight the pronounced impact of housing temperature on established sepsis models and the importance of reporting housing temperature.
All in all, these studies substantiate the importance of tightly controlling Ta to prevent significant bias in results from preclinical animal research on infection and inflammation. Hence, a decisive difference is whether cold-adapted (stressed) mice or mice housed under thermoneutral (unstressed) conditions were characterized to be “well-designated mouse models”, particularly when translational implications are addressed. Accounting for Ta will likely improve the predictive power and value of preclinical sepsis research and may aid in overcoming the “replication crisis” .
We strongly recommend considering thermoneutral conditions as “standard housing conditions for mice in translational approaches” to improve animal modeling in sepsis .
Bauer M, Shankar-Hari M, Thomas-Ruddel DO, Wetzker R (2021) Towards an ecological definition of sepsis: a viewpoint. Intensive Care Med Exp 9:63
Nakamura K (2011) Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol 301:R1207-1228
Tan CL, Knight ZA (2018) Regulation of body temperature by the nervous system. Neuron 98:31–48
Schortgen F (2012) Fever in sepsis. Minerva Anestesiol 78:1254–1264
Thomas-Ruddel DO, Hoffmann P, Schwarzkopf D, Scheer C, Bach F, Komann M, Gerlach H, Weiss M, Lindner M, Ruddel H, Simon P, Kuhn SO, Wetzker R, Bauer M, Reinhart K, Bloos F, Group Ms (2021) Fever and hypothermia represent two populations of sepsis patients and are associated with outside temperature. Crit Care 25:368
Young PJ, Saxena M, Beasley R, Bellomo R, Bailey M, Pilcher D, Finfer S, Harrison D, Myburgh J, Rowan K (2012) Early peak temperature and mortality in critically ill patients with or without infection. Intensive Care Med 38:437–444
Laupland KB, Zahar JR, Adrie C, Minet C, Vesin A, Goldgran-Toledano D, Azoulay E, Garrouste-Orgeas M, Cohen Y, Schwebel C, Jamali S, Darmon M, Dumenil AS, Kallel H, Souweine B, Timsit JF (2012) Severe hypothermia increases the risk for intensive care unit-acquired infection. Clin Infect Dis 54:1064–1070
CotEU-EP (2010) Directive 2010/63/EU of the European Parliament and of the council on the protection of animals used for scientific purposes. Off J Eur Union L 276:33–79
GV-SOLAS (2014) Tiergerechte Haltung von Labormäusen. https://wwwgv-solasde/wp-content/uploads/2021/08/hal_201408Tiergerechte-Haltung-Maus.pdf
NRC (2011) Guide for the care and use of laboratory animals. The National Academy Press, Washington, DC
Gordon CJ (2017) The mouse thermoregulatory system: its impact on translating biomedical data to humans. Physiol Behav 179:55–66
Ganeshan K, Nikkanen J, Man K, Leong YA, Sogawa Y, Maschek JA, Van Ry T, Chagwedera DN, Cox JE, Chawla A (2019) Energetic trade-offs and hypometabolic states promote disease tolerance. Cell 177(399–413):e312
Carpenter KC, Zhou Y, Hakenjos JM, Fry CD, Nemzek JA (2020) Thermoneutral housing temperature improves survival in a murine model of polymicrobial peritonitis. Shock 54:688–696
Ndongson-Dongmo B, Lang GP, Mece O, Hechaichi N, Lajqi T, Hoyer D, Brodhun M, Heller R, Wetzker R, Franz M, Levy FO, Bauer R (2019) Reduced ambient temperature exacerbates SIRS-induced cardiac autonomic dysregulation and myocardial dysfunction in mice. Basic Res Cardiol 114:26
Dirnagl U, Duda GN, Grainger DW, Reinke P, Roubenoff R (2022) Reproducibility, relevance and reliability as barriers to efficient and credible biomedical technology translation. Adv Drug Deliv Rev 182:114118
Osuchowski MF, Ayala A, Bahrami S, Bauer M, Boros M, Cavaillon JM, Chaudry IH, Coopersmith CM, Deutschman C, Drechsler S, Efron P, Frostell C, Fritsch G, Gozdzik W, Hellman J, Huber-Lang M, Inoue S, Knapp S, Kozlov AV, Libert C, Marshall JC, Moldawer LL, Radermacher P, Redl H, Remick DG, Singer M, Thiemermann C, Wang P, Wiersinga WJ, Xiao X, Zingarelli B (2018) Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis. Intensive Care Med Exp 6:26
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Helbing, D.L., Stabenow, L.K. & Bauer, R. Mouse sepsis models: don't forget ambient temperature!. ICMx 10, 29 (2022). https://doi.org/10.1186/s40635-022-00457-4