Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study
Authors:   Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group, Lee Byung Ho , Inui Daisuke , Suh Gee Young , Kim Jae Yeol , Kwon Jae Young , Park Jisook , Tada Keiichi , Tanaka Keiji , Ietsugu Kenichi , Uehara Kenji , Dote Kentaro , Tajimi Kimitaka , Morita Kiyoshi , Matsuo Koichi , Hoshino Koji , Hosokawa Koji , Lee Kook Hyun , Lee Kyoung Min , Takatori Makoto , Nishimura Masaji , Sanui Masamitsu , Ito Masanori , Egi Moritoki , Honda Naofumi , Okayama Naoko , Shime Nobuaki , Tsuruta Ryosuke , Nogami Satoshi , Yoon Seok-Hwa , Fujitani Shigeki , Koh Shin Ok , Takeda Shinhiro , Saito Shinsuke , Hong Sung Jin , Yamamoto Takeshi , Yokoyama Takeshi , Yamaguchi Takuhiro , Nishiyama Tomoki , Igarashi Toshiko , Kakihana Yasuyuki , Koh Younsuck 
Published: February 2012

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 36.5°C to 37.4°C), MAXICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11).

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