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

Abstract

Objective: To investigate the effects of fever therapy compared with no fever therapy in a wide population of febrile adults.

Design: Systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.

Data sources: CENTRAL, BIOSIS, CINAHL, MEDLINE, Embase, LILACS, Scopus, and Web of Science Core Collection, searched from their inception to 2 July 2021.

Eligibility criteria: Randomised 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 synthesis: Two 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.

Results: Forty 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).

Conclusions: Fever therapy does not seem to affect the risk of death and serious adverse events.

Systematic review registration: PROSPERO CRD42019134006.

Fig 1

Risk of bias summary for randomised controlled trials included in evidence synthesis. Risk of bias assessment used Cochrane risk of bias tool 2 (RoB2). D1=bias arising from randomisation process; D2=bias due to deviations from intended intervention; D3=bias due to missing outcome data; D4=bias in measurement of outcome; D5=bias in selection of reported result

Fig 2

Random effects meta-analysis comparing fever therapy versus control interventions for all cause mortality (risk ratio 1.04, 95% confidence interval 0.90 to 1.19; P=0.62; I²=0%; 16 trials)

Fig 3

Trial sequential analysis of fever therapy versus control interventions for all cause mortality. Two sided trial sequential analysis graph of fever therapy versus control interventions for all cause mortality in 16 trials. Diversity adjusted required information size (DARIS) was calculated on basis of all cause mortality proportion in control group of 22.6%, relative risk reduction of 22% in experimental group, type I error (α) of 2%, and type II error (β) of 10% (90% power). Diversity was 10%. Required information size was calculated to be 3760 participants. Cumulative z curve (purple line) did not cross trial sequential monitoring boundaries for either benefit or harm. Cumulative z curve did cross inner wedge futility line (yellow outward sloping lines). Black dashed lines show conventional boundary (α=5%)

Fig 4

Random effects meta-analysis comparing fever therapy versus control interventions for serious adverse events (risk ratio 1.02, 95% confidence interval 0.89 to 1.17; P=0.78; I²=0%; 16 trials)

Fig 5

Trial sequential analysis of fever therapy versus control interventions for serious adverse events. Two sided trial sequential analysis graph of fever control interventions versus control interventions for serious adverse events in 16 trials. Diversity adjusted required information size (DARIS) was calculated on basis of all cause mortality proportion in control group of 22.6%, relative risk reduction of 23% in experimental group, type I error (α) of 2%, and type II error (β) of 10% (90% power). Diversity was 21%. Required information size was calculated to be 3916 participants. Cumulative Z curve (purple line) did not cross trial sequential monitoring boundaries for either benefit or harm. Cumulative Z curve did cross inner wedge futility line (yellow outward sloping lines). Black dashed lines show conventional boundary (α=5%).