Research Article: Fever Is Associated with Reduced, Hypothermia with Increased Mortality in Septic Patients: A Meta-Analysis of Clinical Trials

Date Published: January 12, 2017

Publisher: Public Library of Science

Author(s): Zoltan Rumbus, Robert Matics, Peter Hegyi, Csaba Zsiboras, Imre Szabo, Anita Illes, Erika Petervari, Marta Balasko, Katalin Marta, Alexandra Miko, Andrea Parniczky, Judit Tenk, Ildiko Rostas, Margit Solymar, Andras Garami, Chiara Lazzeri.


Sepsis is usually accompanied by changes of body temperature (Tb), but whether fever and hypothermia predict mortality equally or differently is not fully clarified. We aimed to find an association between Tb and mortality in septic patients with meta-analysis of clinical trials.

We searched the PubMed, EMBASE, and Cochrane Controlled Trials Registry databases (from inception to February 2016). Human studies reporting Tb and mortality of patients with sepsis were included in the analyses. Average Tb with SEM and mortality rate of septic patient groups were extracted by two authors independently.

Forty-two studies reported Tb and mortality ratios in septic patients (n = 10,834). Pearson correlation analysis revealed weak negative linear correlation (R2 = 0.2794) between Tb and mortality. With forest plot analysis, we found a 22.2% (CI, 19.2–25.5) mortality rate in septic patients with fever (Tb > 38.0°C), which was higher, 31.2% (CI, 25.7–37.3), in normothermic patients, and it was the highest, 47.3% (CI, 38.9–55.7), in hypothermic patients (Tb < 36.0°C). Meta-regression analysis showed strong negative linear correlation between Tb and mortality rate (regression coefficient: -0.4318; P < 0.001). Mean Tb of the patients was higher in the lowest mortality quartile than in the highest: 38.1°C (CI, 37.9–38.4) vs 37.1°C (CI, 36.7–37.4). Deep Tb shows negative correlation with the clinical outcome in sepsis. Fever predicts lower, while hypothermia higher mortality rates compared with normal Tb. Septic patients with the lowest (< 25%) chance of mortality have higher Tb than those with the highest chance (> 75%).

Partial Text

Sepsis constitutes a global burden for medical care with an estimated 31 million cases per year worldwide [1]. The incidence of sepsis has remained considerable [2–4] and it is associated with high mortality rates even nowadays [3]. It also underlies the importance and actuality of the topic for clinical praxis that the definitions of sepsis and associated illnesses have been updated recently [5].

Our meta-analysis was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols [25] (S1 Table). The analysis was based on the Participants, Intervention (prognostic factor), Comparison, Outcome (PICO) model: in septic population, we aimed to assess the predictive role of Tb deviations on the mortality ratio. No review protocol has been registered for the current meta-analysis.

In the current analysis we revealed a clear association between Tb and mortality in septic patients by using a detailed statistical approach which was based on an extensive literature search of previous human studies. We found that the presence of fever reduces, while that of hypothermia promotes mortality in septic patients as compared to normothermic subjects.

The abnormalities of deep Tb are strongly associated with the clinical outcome in sepsis. The mortality ratio of febrile patients is lower, while in patients with hypothermia it is markedly higher than that of patients with normal Tb. In cases of sepsis, there is a strong negative correlation between the mortality ratio and deep Tb in a wide temperature range. Septic patients with the lowest (< 25%) chance of mortality have significantly higher deep Tb than those who belong to the highest mortality quartile (> 75%).

Our meta-analysis included data from a total of 10,834 septic patients with overall 2,724 mortality events. We believe that our search strategy was adequately broad and included the three main databases of human studies. As result, 42 full-text articles could be indentified and used in our analyses. Although the sample size and the overall event rate can be considered large enough to draw solid conclusions about the association of Tb and mortality rate in sepsis, our study has certain limitations.




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