Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis

Abstract

Objective: This meta-analysis aimed to examine the impact of antipyretic therapy on mortality in critically ill septic adults.

Data sources: Literature searches were implemented in Ovid Medline, Embase, Scopus, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, and ClinicalTrials.gov through February 2016.

Study selection: Inclusion criteria were observational or randomized studies of septic patients, evaluation of antipyretic treatment, mortality reported, and English-language version available. Studies were excluded if they enrolled pediatric patients, patients with neurologic injury, or healthy volunteers. Criteria were applied by two independent reviewers.

Data extraction: Two reviewers independently extracted data and evaluated methodologic quality. Outcomes included mortality, frequency of shock reversal, acquisition of nosocomial infections, and changes in body temperature, heart rate, and minute ventilation. Randomized and observational studies were analyzed separately.

Data synthesis: Eight randomized studies (1,507 patients) and eight observational studies (17,432 patients) were analyzed. Antipyretic therapy did not reduce 28-day/hospital mortality in the randomized studies (relative risk, 0.93; 95% CI, 0.77-1.13; I = 0.0%) or observational studies (odds ratio, 0.90; 95% CI, 0.54-1.51; I = 76.1%). Shock reversal (relative risk, 1.13; 95% CI, 0.68-1.90; I = 51.6%) and acquisition of nosocomial infections (relative risk, 1.13; 95% CI, 0.61-2.09; I = 61.0%) were also unchanged. Antipyretic therapy decreased body temperature (mean difference, -0.38°C; 95% CI, -0.63 to -0.13; I = 84.0%), but not heart rate or minute ventilation.

Conclusions: Antipyretic treatment does not significantly improve 28-day/hospital mortality in adult patients with sepsis.

Figure 1.

Flowchart of study selection.

Figure 2.

Results of meta-analysis for 28 days per hospital mortality in (A) randomized studies and (B) observational studies. A relative risk (RR) or odds ratio (OR) less than 1 favors antipyretic therapy. The size of the grey box corresponds to weight in the random effects analysis. NSAID = nonsteroidal anti-inflammatory drug.

Figure 3.

Extended funnel plot demonstrating the effect size and se combinations required of an additional randomized study to change the results of this meta-analysis using a fixed effects model with an alpha level of 0.05. Black dots represent the effect size and ses of the included randomized studies. To change the results of the meta-analysis to favor antipyretics, an additional study would need to have an effect estimate and se combination that falls in the dark grey shaded area. Note that none of the current studies have an effect size-se in the dark grey region; this suggests that the results of the meta-analysis would be robust to an additional study.