Risk factors, host response and outcome of hypothermic sepsis

Maryse A Wiewel, Matthew B Harmon, Lonneke A van Vught, Brendon P Scicluna, Arie J Hoogendijk, Janneke Horn, Aeilko H Zwinderman, Olaf L Cremer, Marc J Bonten, Marcus J Schultz, Tom van der Poll, Nicole P Juffermans, W Joost Wiersinga, Maryse A Wiewel, Matthew B Harmon, Lonneke A van Vught, Brendon P Scicluna, Arie J Hoogendijk, Janneke Horn, Aeilko H Zwinderman, Olaf L Cremer, Marc J Bonten, Marcus J Schultz, Tom van der Poll, Nicole P Juffermans, W Joost Wiersinga

Abstract

Background: Hypothermia is associated with adverse outcome in patients with sepsis. The objective of this study was to characterize the host immune response in patients with hypothermic sepsis in order to determine if an excessive anti-inflammatory response could explain immunosuppression and adverse outcome. Markers of endothelial activation and integrity were also measured to explore potential alternative mechanisms of hypothermia. Finally we studied risk factors for hypothermia in an attempt to find new clues to the etiology of hypothermia in sepsis.

Methods: Consecutive patients diagnosed with sepsis within 24 hours after admission to ICUs in two tertiary hospitals in the Netherlands were included in the study (n = 525). Hypothermia was defined as body temperature below 36 °C in the first 24 h of ICU admission.

Results: Hypothermia was identified in 186 patients and was independently associated with mortality. Levels of proinflammatory and anti-inflammatory cytokines were not different between groups. Hypothermia was also not associated with an altered response to ex vivo stimulation with lipopolysaccharide in a subset of 15 patients. Risk factors for hypothermia included low body mass index, hypertension and chronic cardiovascular insufficiency. Levels of the endothelial activation marker fractalkine were increased during the first 4 days of ICU stay.

Conclusions: Hypothermia during sepsis is independently associated with mortality, which cannot be attributed to alterations in the host immune responses that were measured in this study. Given that risk factors for hypothermic sepsis are mainly cardiovascular and that the endothelial activation marker fractalkine increased in hypothermia, these findings may suggest that vascular dysfunction plays a role in hypothermic sepsis.

Trial registration: ClinicalTrials.gov NCT01905033.

Keywords: Fractalkine; Host response; Hypothermia; Mortality; Risk factors; Sepsis.

Figures

Fig. 1
Fig. 1
Survival curve in patients with and without hypothermia during the first 24 h of ICU admission. Kaplan–Meier plot of survival time up to 90 days after ICU admission. ***P < 0.001
Fig. 2
Fig. 2
Plasma cytokine levels in patients with sepsis, stratified according to the presence of hypothermia. Box and whisker diagrams depict the median and lower quartile, upper quartile and respective 1.5 IQR as whiskers. Dashed lines represent median levels in healthy volunteers. Differences between patient groups were not significant
Fig. 3
Fig. 3
Whole blood leukocyte responsiveness to lipopolysaccharide (LPS) stratified according to the presence of hypothermia. Responsiveness of whole blood leukocytes to LPS was reduced compared to healthy subjects (n = 18), but was not different between hypothermic (n = 5) and nonhypothermic (n = 10) patients with sepsis. Box and whisker diagrams depict the median and lower quartile, upper quartile, and their respective 1.5 IQR as whiskers. *P < 0.05, **P <0.01
Fig. 4
Fig. 4
Endothelial cell activation in patients with sepsis, stratified according to the presence of hypothermia. Box-and-whisker diagrams depict the median and lower quartile, upper quartile and their respective 1.5 IQR as whiskers. Dashed lines represent the median in 27 healthy volunteers. ICAM-1 intercellular adhesion molecule-1. Note: soluble ICAM-1 is also derived from leukocytes. ***P < 0.001, *P < 0.05

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