Crit Care. 2012; 16(1): R33.
©2012 FACE study group et al.; licensee BioMed Central Ltd.
Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study
1Department of Anesthesiology, St. Paul's Hospital, Catholic University of Korea, Seoul, Republic of Korea
2Department of Emergency and Critical Care Medicine, Tokushima University Hospital, Tokushima, Japan
3Division of Pulmonary and Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
4Department of Pulmonary and Critical Care Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea
5Department of Anesthesiology and Pain Medicine, Pusan National University School of Medicine, Busan, Republic of Korea
6School of Media, Seoul Women's University, Seoul, Republic of Korea
7Department of Anesthesiology and Intensive Care Medicine, Hiroshima City Hospital, Hiroshima, Japan
8Division of Intensive and Coronary Care Unit, Nippon Medical School Hospital, Tokyo, Japan
9Tonami General Hospital, Toyama, Japan
10Intensive Care Division, Ehime University Hospital, Ehime, Japan
11Emergency & Critical Care Medicine, Akita University Graduate School of Medicine, Akita, Japan
12Department of Intensive Care, Okayama University Hospital, Okayama, Japan
13Department of Internal Medicine, Misato Kenwa Hospital, Saitama, Japan
14Intensive Care Unit, Department of Anesthesiology, Teine Keijinkai Hospital, Sapporo, Japan
15Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
16Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
17Anesthesiology and Critical Cate Medicine, Konkuk University Hospital, Seoul, Republic of Korea
18Department of Anesthesiology and Critical Care Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
19Division of Intensive Care Medicine, Kagoshima University Hospital, Kagoshima, Japan
20Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, Yamaguchi, Japan
21Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
22Department of Emergency and Critical Care Medicine, St. Marianna University, Kanagawa, Japan
23Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
24Department of Anesthesiology and Pain Medicine, Incheon St Mary's Hospital, Catholic University of Korea, Medical College, Incheon, Republic of Korea
25Innovation of New Biomedical Engineering Center, Tohoku University, Sendai, Japan
26Department of Anesthesiology and Critical Care, Kamagaya General Hospital, Kamagaya, Japan
27Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, republic of Korea
Received October 14, 2011; Revised February 21, 2012; Accepted February 28, 2012.
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We studied 1,429 consecutive patients. We excluded four patients for whom data were incomplete (4/1,429, 0.3%), leaving a total of 1,425 patients with 63,441 body temperature measurements eligible for inclusion in the study. Seventy-two percent of body temperature was measured by axillary thermometers, 16% by bladder catheter thermistors, 9% by tympanic membrane thermometers and 3% by pulmonary artery catheter thermistors. The median APACHE II score was 17, and 28-day mortality was 12.0%. The median length of stay in ICU was 7 days and in hospital 26 days. Among the 1,425 patients, 606 patients met the criteria for sepsis during the first 24 h. The remaining 819 patients were without sepsis (Figure ).
Flow chart showing current study. ICU, intensive care units.
Table provides clinical characteristics, MAXICU and antipyretic treatments for septic and non-septic patients and for the total cohort. Septic patients tended to be more severely ill, older and were less likely to be post-operative patients or to have required mechanical ventilation during ICU stay. The 28-day mortality in septic patients was significantly higher than in non-septic patients.
Comparison of baseline characteristics of patients with and without sepsis
Septic patients exhibited significantly higher MAXICU than non-septic patients (38.3°C vs. 37.8°C, P < 0.001). MAXICU in septic patients was more frequently in the higher range (≥ 38.5°C) (Table ). This difference was present for the first seven days of ICU stay (Figure ).
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 (more ...)
Table shows 28-day mortality and odds ratio for each range of MAXICU relative to the reference range of 36.5°C to 37.4°C in septic and non-septic patients, respectively. Mortality did not relate to MAXICU in septic patients. By contrast, for non-septic patients, 28-day mortality increased according to MAXICU, and was significantly greater when MAXICU was ≥ 38.5°C (odds ratio; 5.13 (P < 0.007) and 13.4 (P < 0.001), 38.5°C to 39.4°C and ≥ 39.5°C, respectively). There was no significant difference in 28-day mortality between patients with single and multiple episodes of MAXICU ≥ 39.5°C. Mortality for septic patients with MAXICU < 36.5°C was as high as 50%, but no significant difference was detected owing to the small number of patients in this category (n = 4) (odds 3.08, P = 0.57).
Maximum body temperature during ICU stay and 28-day mortality of patients with and without sepsis.
Figure shows Kaplan-Meier estimates for the probability, which at 28 days was greater in non-septic patients with MAXICU ≥ 38.5°C than those with temperatures of 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.
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 (more ...)
Antipyretic treatment was applied 4,863 times to 737 patients (51.7%). NSAIDs were administered 429 times to 130 patients (9.1%), acetaminophen was administered 571 times to 148 patients (10.4%) and physical cooling was applied 3,863 times to 671 patients (47.1%). Delta body temperature from application of antipyretic to next temperature monitoring was -0.3°C (IQR; -0.7, 0.0) and -0.4°C (IQR; -0.9, -0.2), for NSAIDs and acetaminophen respectively, which is significantly greater than -0.1°C for physical cooling (P < 0.001) (Table ).
Figure shows the proportion of patients who received pharmacological antipyretic treatments (NSAIDs, acetaminophen or both) in each subgroup. For the subgroup with MAXICU of 37.5°C to 38.4°C, the proportion of patients who received pharmacological antipyretic treatments was significantly higher than 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 septic patients, and NSAIDs for non-septic patients in each range of MAXICU (P < 0.001) (Figure ). Figure shows the proportion of septic and non-septic patients who received physical cooling. Physical cooling was applied frequently in septic patients, when MAXICU was ≤ 39.4°C (Figure ).
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 (more ...)
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. (more ...)
Table shows univariate comparisons of patient demographic data and antipyretic treatments. In septic patients, the use of NSAIDs and acetaminophen was significantly associated with increased mortality (odds ratio: NSAIDs 2.32, P = 0.02; acetaminophen 2.30, P = 0.002) (Table ). By contrast, for non-septic patients, the pharmacological antipyretic treatments were not associated with mortality (odds ratio: NSAIDs 0.20, P = 0.08; acetaminophen 0.69, P = 0.72). Physical cooling was associated with mortality in neither septic nor non-septic patients (odds ratio: with sepsis 1.00, P = 0.99; without sepsis 1.14, P = 0.74).
Comparison of baseline characteristics and antipyretic treatments of survivors and non-survivors
As shown in Table , the presence of confounders, such as severity of illness, age, reason for ICU admission and mechanical ventilation requirement, necessitated multivariate analysis adjusting for relevant predictors of 28-day mortality.
In septic patients relative to the reference range (36.5°C to 37.4°C), MAXICU 37.5°C to 38.4°C was associated with decreased mortality (adjusted odds ratio 0.45, P = 0.014) and MAXICU ≥ 38.5°C was not (adjusted odds ratio 38.5°C to 39.4°C; 0.52, P = 0.09, ≥ 39.5°C; 0.47, P = 0.11). In non-septic patients, adjusted risk of death was increased as MAXICU increased, and MAXICU ≥ 39.5°C was associated with mortality (adjusted odds ratio 8.14, P = 0.01) (Table ).
Multivariate logistic analysis for 28-day mortality
In septic patients, administration of NSAIDs or acetaminophen was independently associated with mortality (adjusted odds ratio: NSAIDs 2.61, P = 0.028; acetaminophen 2.05, P = 0.01). In non-septic patients, the pharmacological antipyretic treatments were not associated with mortality (adjusted odds ratio: NSAIDs 0.22, P = 0.15; acetaminophen 0.58, P = 0.63) (Table ). The model was a good fit for data from both groups (Hosmer-Lemeshow: with sepsis, P = 0.21, without sepsis, P = 0.89).
To exclude the possible effects of hypothermia, we further performed multivariate logistic analysis excluding data from 106 patients with low body temperature (≤ 35°C) during ICU stay (Table ). Even in this model, administration of NSAIDs and acetaminophen in septic patients was independently associated with mortality (adjusted odds ratio: NSAIDs 2.48, P = 0.04; acetaminophen 1.95, P = 0.03). Meanwhile, for non-septic patients, MAXICU ≥ 38.5°C was associated with mortality (adjusted odds ratio 38.5°C to 39.4°C; 7.49, P = 0.02, ≥ 39.5°C; 11.7, P = 0.02).
Multivariate logistic analysis for 28-day mortality in patients with lowest body temperature > 35°C