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

Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group, Byung Ho Lee1, Daisuke Inui2, Gee Young Suh3, Jae Yeol Kim4, Jae Young Kwon5, Jisook Park6, Keiichi Tada7, Keiji Tanaka8, Kenichi Ietsugu9, Kenji Uehara7, Kentaro Dote10, Kimitaka Tajimi11, Kiyoshi Morita12, Koichi Matsuo13, Koji Hoshino14, Koji Hosokawa15, Kook Hyun Lee16, Kyoung Min Lee17, Makoto Takatori7, Masaji Nishimura2, Masamitsu Sanui18, Masanori Ito9, Moritoki Egi12*, Naofumi Honda14, Naoko Okayama19, Nobuaki Shime15, Ryosuke Tsuruta20, Satoshi Nogami7, Seok-Hwa Yoon21, Shigeki Fujitani22, Shin Ok Koh23, Shinhiro Takeda8, Shinsuke Saito9, Sung Jin Hong24, Takeshi Yamamoto8, Takeshi Yokoyama14, Takuhiro Yamaguchi25, Tomoki Nishiyama26, Toshiko Igarashi11, Yasuyuki Kakihana19 and Younsuck Koh27

Author Affiliations

1 Department of Anesthesiology, St. Paul's Hospital, Catholic University of Korea, Seoul, Republic of Korea

2 Department of Emergency and Critical Care Medicine, Tokushima University Hospital, Tokushima, Japan

3 Division of Pulmonary and Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

4 Department of Pulmonary and Critical Care Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea

5 Department of Anesthesiology and Pain Medicine, Pusan National University School of Medicine, Busan, Republic of Korea

6 School of Media, Seoul Women's University, Seoul, Republic of Korea

7 Department of Anesthesiology and Intensive Care Medicine, Hiroshima City Hospital, Hiroshima, Japan

8 Division of Intensive and Coronary Care Unit, Nippon Medical School Hospital, Tokyo, Japan

9 Tonami General Hospital, Toyama, Japan

10 Intensive Care Division, Ehime University Hospital, Ehime, Japan

11 Emergency & Critical Care Medicine, Akita University Graduate School of Medicine, Akita, Japan

12 Department of Intensive Care, Okayama University Hospital, Okayama, Japan

13 Department of Internal Medicine, Misato Kenwa Hospital, Saitama, Japan

14 Intensive Care Unit, Department of Anesthesiology, Teine Keijinkai Hospital, Sapporo, Japan

15 Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan

16 Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea

17 Anesthesiology and Critical Cate Medicine, Konkuk University Hospital, Seoul, Republic of Korea

18 Department of Anesthesiology and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan

19 Division of Intensive Care Medicine, Kagoshima University Hospital, Kagoshima, Japan

20 Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, Yamaguchi, Japan

21 Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea

22 Department of Emergency and Critical Care Medicine, St. Marianna University, Kanagawa, Japan

23 Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

24 Department of Anesthesiology and Pain Medicine, Incheon St Mary's Hospital, Catholic University of Korea, Medical College, Incheon, Republic of Korea

25 Innovation of New Biomedical Engineering Center, Tohoku University, Sendai, Japan

26 Department of Anesthesiology and Critical Care, Kamagaya General Hospital, Kamagaya, Japan

27 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, republic of Korea

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Critical Care 2012, 16:R33  doi:10.1186/cc11211


See related commentary by Cavaillon, http://ccforum.com/content/16/2/119

Published: 28 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

Keywords:
body temperature; antipyretic; fever; critical illness; mortality