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

Critical Care

Younsuck Koh³  Yasuyuki Kakihana^1,15  Toshiko Igarashi⁴  Tomoki Nishiyama^2,27  Takuhiro Yamaguchi^1,10  Takeshi Yokoyama⁸  Takeshi Yamamoto^1,19  Sung Jin Hong⁷  Shinsuke Saito²  Shinhiro Takeda^1,19  Shin Ok Koh¹  Shigeki Fujitani⁹  Seok-Hwa Yoon^1,18  Satoshi Nogami^2,20  Ryosuke Tsuruta^1,16  Nobuaki Shime^2,25  Naoko Okayama^1,15  Naofumi Honda⁸  Moritoki Egi^1,11  Masanori Ito²  Masamitsu Sanui⁵  Masaji Nishimura^1,14  Makoto Takatori^2,20  Kyoung Min Lee^1,17  Kook Hyun Lee^1,12  Koji Hosokawa^2,25  Koji Hoshino⁸  Koichi Matsuo^1,13  Kiyoshi Morita^1,11  Kimitaka Tajimi⁴  Kentaro Dote^2,26  Kenji Uehara^2,20  Kenichi Ietsugu²  Keiji Tanaka^1,19  Keiichi Tada^2,20  Jisook Park^2,24  Jae Young Kwon^2,21  Jae Yeol Kim⁶  Gee Young Suh^2,22  Daisuke Inui^1,14  Byung Ho Lee^2,23 

[1] Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea;Tonami General Hospital, Toyama, Japan;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, republic of Korea;Emergency & Critical Care Medicine, Akita University Graduate School of Medicine, Akita, Japan;Department of Anesthesiology and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan;Department of Pulmonary and Critical Care Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea;Department of Anesthesiology and Pain Medicine, Incheon St Mary's Hospital, Catholic University of Korea, Medical College, Incheon, Republic of Korea;Intensive Care Unit, Department of Anesthesiology, Teine Keijinkai Hospital, Sapporo, Japan;Department of Emergency and Critical Care Medicine, St. Marianna University, Kanagawa, Japan;Innovation of New Biomedical Engineering Center, Tohoku University, Sendai, Japan;Department of Intensive Care, Okayama University Hospital, Okayama, Japan;Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea;Department of Internal Medicine, Misato Kenwa Hospital, Saitama, Japan;Department of Emergency and Critical Care Medicine, Tokushima University Hospital, Tokushima, Japan;Division of Intensive Care Medicine, Kagoshima University Hospital, Kagoshima, Japan;Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, Yamaguchi, Japan;Anesthesiology and Critical Cate Medicine, Konkuk University Hospital, Seoul, Republic of Korea;Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea;Division of Intensive and Coronary Care Unit, Nippon Medical School Hospital, Tokyo, Japan;Department of Anesthesiology and Intensive Care Medicine, Hiroshima City Hospital, Hiroshima, Japan;Department of Anesthesiology and Pain Medicine, Pusan National University School of Medicine, Busan, Republic of Korea;Division of Pulmonary and Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;Department of Anesthesiology, St. Paul's Hospital, Catholic University of Korea, Seoul, Republic of Korea;School of Media, Seoul Women's University, Seoul, Republic of Korea;Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan;Intensive Care Division, Ehime University Hospital, Ehime, Japan;Department of Anesthesiology and Critical Care, Kamagaya General Hospital, Kamagaya, Japan

关键词: mortality;    critical illness;    fever;    antipyretic;    body temperature;   

Others  :  1093083
DOI  :  10.1186/cc11211

 received in 2011-10-14, accepted in 2012-02-28,  发布年份 2012

【 摘 要 】

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 (MAX_ICU) 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 (MAX_ICU 36.5°C to 37.4°C), MAX_ICU ≥ 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

【 授权许可】

   
2012 FACE study group et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Laupland KB, Shahpori R, Kirkpatrick AW, Ross T, Gregson DB, Stelfox HT: Occurrence and outcome of fever in critically ill adults. Crit Care Med 2008, 36:1531-1535.
• [2]O'Grady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, Kalil AC, Linden P, Maki DG, Nierman D, Pasculle W, Masur H, American College of Critical Care Medicine, Infectious Diseases Society of America: Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med 2008, 36:1330-1349.
• [3]Hawksworth JS, Leeser D, Jindal RM, Falta E, Tadaki D, Elster EA: New directions for induction immunosuppression strategy in solid organ transplantation. Am J Surg 2009, 197:515-524.
• [4]Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL, International Surviving Sepsis Campaign Guidelines Committee, American Association of Critical-Care Nurses, American College of Chest Physicians, American College of Emergency Physicians, Canadian Critical Care Society, European Society of Clinical Microbiology and Infectious Diseases, European Society of Intensive Care Medicine, European Respiratory Society, International Sepsis Forum, Japanese Association for Acute Medicine, Japanese Society of Intensive Care Medicine, Society of Critical Care Medicine, Society of Hospital Medicine, Surgical Infection Society, World Federation of Societies of Intensive and Critical Care Medicine: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008, 36:296-327. Erratum in: Crit Care Med 2008, 36:1394-1396.
• [5]Manthous CA, Hall JB, Olson D, Singh M, Chatila W, Pohlman A, Kushner R, Schmidt GA, Wood LD: Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit Care Med 1995, 151:10-14.
• [6]Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest N Engl J Med 2002, 346:549-556.
• [7]Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002, 346:557-563.
• [8]Axelrod P: External cooling in the management of fever. Clin Infect Dis 2000, 31(Suppl 5):S224-229.
• [9]Fumagalli R, Bellani G, Perri A: Which drugs for the control of fever in critical patients. Curr Drug Targets 2009, 10:881-886.
• [10]Young P, Saxena M, Eastwood GM, Bellomo R, Beasley R: Fever and fever management among intensive care patients with known or suspected infection: a multicentre prospective cohort study. Crit Care Resusc 2011, 13:97-102.
• [11]Ryan AJ, Flanagan SW, Moseley PL, Gisolfi CV: Acute heat stress protects rats against endotoxin shock. J Appl Physiol 1992, 73:1517-1522.
• [12]Villar J, Ribeiro SP, Mullen JB, Kuliszewski M, Post M, Slutsky AS: Induction of the heat shock response reduces mortality rate and organ damage in a sepsis-induced acute lung injury model. Crit Care Med 1994, 22:914-921.
• [13]Kluger MJ, Kozak W, Conn CA, Leon LR, Soszynski D: The adaptive value of fever. Infect Dis Clin North Am 1996, 10:1-20.
• [14]Eyers S, Weatherall M, Shirtcliffe P, Perrin K, Beasley R: The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. J R Soc Med 2010, 103:403-411.
• [15]Brandts CH, Ndjavé M, Graninger W, Kremsner PG: Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria. Lancet 1997, 350:704-709.
• [16]Muckart DJ, Bhagwanjee S: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions of the systemic inflammatory response syndrome and allied disorders in relation to critically injured patients. Crit Care Med 1997, 25:1789-1795.
• [17]Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. 1992. Chest 2009, 136(5 Suppl):e28.
• [18]Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med 1985, 13:818-829.
• [19]Laupland KB, Zahar JR, Adrie C, Schwebel C, Goldgran-Toledano D, Azoulay E, Garrouste-Orgeas M, Cohen Y, Jamali S, Souweine B, Darmon M, Timsit JF: Determinants of temperature abnormalities and influence on outcome of critical illness. Crit Care Med 2012, 40:145-151.
• [20]von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007, 370:1453-1457.
• [21]Fulbrook P: Core temperature measurement: a comparison of rectal, axillary and pulmonary artery blood temperature. Intensive Crit Care Nurs 1993, 9:217-225.
• [22]Togawa T: Body temperature measurement. Clin Phys Physiol Meas 1985, 6:83-108.
• [23]Azzimondi G, Bassein L, Nonino F, Fiorani L, Vignatelli L, Re G, D'Alessandro R: Fever in acute stroke worsens prognosis. A prospective study. Stroke 1995, 26:2040-2043.
• [24]Rossi S, Zanier ER, Mauri I, Columbo A, Stocchetti N: Brain temperature, body core temperature, and intracranial pressure in acute cerebral damage. J Neurol Neurosurg Psychiatry 2001, 71:448-454.
• [25]Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008, 34:17-60. Erratum in: Intensive Care Med 2008, 34:783-785.
• [26]Pittet D, Thievent B, Wenzel RP, Li N, Auckenthaler R, Suter PM: Bedside prediction of mortality from bacteremic sepsis. A dynamic analysis of ICU patients. Am J Respir Crit Care Med 1996, 153:684-693.
• [27]Leroy O, Gangneux JP, Montravers P, Mira JP, Gouin F, Sollet JP, Carlet J, Reynes J, Rosenheim M, Regnier B, Lortholary O, AmarCand Study Group: Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005-2006). Crit Care Med 2009, 37:1612-1618.
• [28]Hersch M, Raveh D, Izbicki G: Effect of intravenous propacetamol on blood pressure in febrile critically ill patients. Pharmacotherapy 2008, 28:1205-1210.
• [29]Gozzoli V, Treggiari MM, Kleger GR, Roux-Lombard P, Fathi M, Pichard C, Romand JA: Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response. Intensive Care Med 2004, 30:401-407.
• [30]Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Alhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasch L, Baracco G, Cohn SM: The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt) 2005, 6:369-375. Erratum in: Surg Infect (Larchmt) 2010, 11:495. Li, Pam (corrected to Li, Pamela); Alhaddad, Ahmed (corrected to Elhaddad, Ahmed)
• [31]Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB: The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 1997, 336:912-918.
• [32]Haupt MT, Jastremski MS, Clemmer TP, Metz CA, Goris GB: Effect of ibuprofen in patients with severe sepsis: a randomized, double-blind, multicenter study. The Ibuprofen Study Group. Crit Care Med 1991, 19:1339-1347.
• [33]Egi M, Morita K: Fever in non-neurological critically ill patients: a systematic review of observational studies. J Crit Care 2012, in press.