Fever therapy in febrile adults: systematic review with meta-analyses and trial sequential analyses

Abstract

ObjectiveTo investigate the effects of fever therapy compared with no fever therapy in a wide population of febrile adults.DesignSystematic review with meta-analyses and trial sequential analyses of randomised clinical trials.Data sourcesCENTRAL, BIOSIS, CINAHL, MEDLINE, Embase, LILACS, Scopus, and Web of Science Core Collection, searched from their inception to 2 July 2021.Eligibility criteriaRandomised clinical trials in adults diagnosed as having fever of any origin. Included experimental interventions were any fever therapy, and the control intervention had to be no fever therapy (with or without placebo/sham).Data extraction and synthesisTwo authors independently selected studies, extracted data, and assessed the risk of bias. Primary outcomes were all cause mortality and serious adverse events. Secondary outcomes were quality of life and non-serious adverse events. Aggregate data were synthesised with meta-analyses, subgroup analyses, and trial sequential analyses, and the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.ResultsForty two trials assessing 5140 participants were included. Twenty three trials assessed 11 different antipyretic drugs, 11 trials assessed physical cooling, and eight trials assessed a combination of antipyretic drugs and physical cooling. Of the participants, 3007 were critically ill, 1892 were non-critically ill, 3277 had infectious fever, and 1139 had non-infectious fever. All trials were assessed as being at high risk of bias. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of death (risk ratio 1.04, 95% confidence interval 0.90 to 1.19; I2=0%; P=0.62; 16 trials; high certainty evidence) and the risk of serious adverse events (risk ratio 1.02, 0.89 to 1.17; I2=0%; P=0.78; 16 trials; high certainty evidence) could be rejected. One trial assessing quality of life was included, showing no difference between fever therapy and control. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of non-serious adverse events could be neither confirmed nor rejected (risk ratio 0.92, 0.67 to 1.25; I2=66.5%; P=0.58; four trials; very low certainty evidence).ConclusionsFever therapy does not seem to affect the risk of death and serious adverse events.Systematic review registrationPROSPERO CRD42019134006

Comparative before-after study of fever prevention versus targeted temperature management following out-of-hospital cardiac arrest

“… 21 More broadly, a recent systematic review of fever therapy in febrile adults found insufficient evidence to confirm or refute any benefit in quality of life. 22 These results do not, however, exclude the potential benefit of hypothermia in subgroups such as patients with non-shockable rhythms and those with cardiogenic shock. 8 , 23 …”

Factors associated with fever after cardiac arrest: A post‐hoc analysis of the FINNRESUSCI study

“…31,32,34,35 A recent meta-analysis by Holgersson and colleagues concluded that fever therapy does not seem to affect mortality, and does not have serious adverse events. 36 The effects of commonly used antipyretics, such as nonsteroidal anti-inflammatories (NSAID) and paracetamol, on fever and functional outcome seem to be modest or non-existent, whereas NSAIDs are associated with increased bleeding risks and renal toxicity, and paracetamol in high doses can cause liver toxicity. 25,37,38 Furthermore, a recent study by Hassager and colleagues showed that prolonged device-based prevention of fever for 72 h did not improve the functional outcome compared to 36-h treatment.…”

“…Fever as a protective mechanism in sepsis has been indicated, and it appears that spontaneous normothermia or mild hypothermia may be an ominous sign 31,32,34,35 . A recent meta‐analysis by Holgersson and colleagues concluded that fever therapy does not seem to affect mortality, and does not have serious adverse events 36 . The effects of commonly used antipyretics, such as nonsteroidal anti‐inflammatories (NSAID) and paracetamol, on fever and functional outcome seem to be modest or non‐existent, whereas NSAIDs are associated with increased bleeding risks and renal toxicity, and paracetamol in high doses can cause liver toxicity 25,37,38 .…”

Das Immunsystem des kritisch Kranken

“…Mehr als die Hälfte der untersuchten Patienten unterlag dabei einer kritischen Erkrankung. Die Studie untersuchte sowohl eine medikamentöse als auch eine physikalische Kühlung und schloss ebenfalls infektiöse sowie nicht infektiöse Ursachen für das Fieber mit ein [40].…”