Fever, hypothermia, and mortality in sepsis

Abstract

A. Fever is associated with reduced, hypothermia with increased mortality in septic patients: a meta-analysis of clinical trials. PLoS One. 2017;12(1):e0170152. Sepsis presents a major challenge for critical care and the society worldwide. Despite the ample research interest in understanding the underlying mechanisms, mortality rate remains considerably high in sepsis even nowadays. In order to assess the prognosis and the severity of the disease, thus to initiate the most optimal treatment, it is necessary to identify vital signs and biomarkers, which can predict the outcome. As a manifestation of systemic inflammation, sepsis is often accompanied by changes in body temperature (T b): fever or hypothermia. Our understanding of the thermoregulatory manifestations of systemic inflammation has advanced in the past decades, but it has remained unanswered whether fever and hypothermia can serve as predictors of the outcome in sepsis. In the highlighted study, we investigated the association between the alterations of T b and the rate of mortality in septic patients [1]. By conducting a meta-analysis of clinical trials, we studied the association between changes in T b and mortality in a big number (> 10,000) of septic patients [1]. We found that in septic patients with fever the estimated mortality rate was ~ 22%, which was higher (~ 31%) in normothermic patients, while it was the highest (~ 47%) in hypothermic patients [1]. When we compared the T b data of all septic patients divided into mortality quartiles, we found that T b was by 1°C higher in patients with the lowest (< 25%) mortality than in patients with the highest rate of death (> 75%). The results of our meta-analyses clearly demonstrate a negative correlation between T b and mortality in sepsis: fever is associated with decreased, whereas hypothermia with increased rate of death. However, this association does not automatically imply that fever is always beneficial and hypothermia is harmful in sepsis (Table 1). The causative relationship between the thermoregulatory manifestations and the outcome in systemic inflammation could not be assessed in our study and it deserves discussion. The beneficial versus harmful effect of fever has been debated since the time of Hippocrates. Despite the advancements in our understanding of the molecular, cellular, and physiological mechanisms of the fever response, the question of whether it is a friend or foe is asked even in recent days. The controversies between the findings on beneficial versus harmful effects of fever can be mitigated by focusing on the question of when instead of whether fever is a friend or a foe as suggested by Romanovsky and Szekely [2]. It was proposed that the thermoregulatory manifestations of systemic inflammation can be regarded as adaptations in constellation of the sickness syndrome. Two sickness patterns can be distinguished as part of the syndrome, which represent sequential stages of the body's response to systemic inflammation and constitute two different adaptive strategies to infection [2]. The two distinguished patterns of the syndrome, the early and the late phase syndrome, correspond to mild and severe forms of systemic inflammation. Romanovsky and Szekely [2] proposed that fever, as part of the early phase syndrome, should be regarded as an adaptive strategy of the organism, which occurs at the onset of the infection and constitutes a response of the healthy organism to the forthcoming disease. In this regard, the biological purpose of the early phase syndrome is to engage active defense mechanisms (fever), notify the host about the pathogenic insult (hyperalgesia), and secure the means (vigilance, hyperactivity, hypertension, and anorexia), which can empower the active search for optimal environment (warmth seeking, adequate water supply, protection from external stressors) for fighting the disease. This type of adaptation to