Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study

Abstract

Introduction: Fever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness.

Methods: We designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring >48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality.

Results: We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P=0.028, acetaminophen: 2.05, P=0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P=0.15, acetaminophen: 0.58, P=0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU ≥ 39.5°C increased risk of 28-day mortality in non-septic patients (adjusted odds ratio 8.14, P=0.01), but not in septic patients (adjusted odds ratio 0.47, P=0.11) [corrected].

Conclusions: In non-septic patients, high fever (≥39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis.

Trial registration: ClinicalTrials.gov: NCT00940654.

Figures

Figure 1

Flow chart showing current study. ICU, intensive care units.

Figure 2

Mean peak daily temperature of patients with and without sepsis. The white circles indicate the mean peak daily temperature in patients with sepsis. The black circles indicate the mean peak daily temperature in patients without sepsis. For the first seven days after admission, peak body temperature of patients with sepsis was significantly higher than of patients without sepsis. CI, confidential interval; ICU, intensive care unit.

Figure 3

Maximum body temperature during ICU stay and survival of patients with and without sepsis. This figure shows Kaplan-Meier estimates for the probability of survival, which at 28 days was greater in non-septic patients with MAXICU 38.5°C to 39.4°C and ≥ 39.5°C than those with 36.5°C to 37.4°C. In septic patients, there were no significant differences of provability of survival in each category compared with patients of MAXICU with 36.5°C to 37.4°C. *, significantly different probability of survival at 28 days after ICU admission than patients with 36.5°C to 37.4°C.

Figure 4

Administration of pharmacological antipyretic treatments (NSAIDs and/or acetaminophen) in each MAXICU category. Data show patients categorized in subgroups according to MAXICU value range: 37.5°C to 38.4°C, 38.5°C to 39.4°C and ≥ 39.5°C. White bar, patients given NSAIDs; black bar, patients given acetaminophen; gray bar, patients given both NSAIDs and acetaminophen. For the subgroup with MAXICU of 37.5°C to 38.4°C, the proportion of patients received pharmacological antipyretic treatments was significantly higher in non-septic patients (P = 0.007). For the rest of the subgroups, it was not significantly different between patients with and without sepsis (38.5°C to 39.4°C, P = 0.62; ≥ 39.5°C, P = 0.25). Acetaminophen was used more frequently for patients with sepsis, and NSAIDs for patients without sepsis in each MAXCAT subgroup (P < 0.001). MAXICU, maximum body temperature recorded during ICU stay; NSAIDs: non-steroid anti-inflammatory drugs.

Figure 5

Use of physical cooling in each MAXICU category of patients with and without sepsis. Data show patients categorized in subgroups according to MAXICU value range: 37.5°C to 38.4°C, 38.5°C to 39.4°C, and ≥ 39.5°C. *statistically significant difference between patients with and without sepsis. MAXICU, maximum body temperature recorded during ICU stay.