Should we treat fever in critically ill patients? A summary of the current evidence from three randomized controlled trials

Ary Serpa Neto Victor Galvão Moura Pereira Giancarlo Colombo Farah Christina de la Cruz Scarin Camila Menezes Souza Pessoa Leonardo Lima Rocha About the authors

Abstracts

A febre é uma resposta não específica a vários tipos de insultos, de origem infecciosa ou não, e sua importância em doenças continua a ser um enigma. Nosso objetivo foi resumir a evidência atual para o uso de antipiréticos em pacientes graves. Foram realizadas revisão sistemática e meta-análise de publicações entre 1966 e 2013. As bases de dados MEDLINE e CENTRAL foram pesquisadas para estudos sobre antipirese em pacientes graves. A meta-análise restringiu-se a ensaios clínicos randomizados em humanos adultos; pacientes graves; tratamento com antipiréticos em um braço contra placebo ou não tratamento no outro; e dados sobre mortalidade. Os desfechos avaliados foram: mortalidade geral na unidade de terapia intensiva, mudança de temperatura e tempo de internação na unidade de terapia intensiva e no hospital. Três ensaios clínicos randomizados com 320 participantes foram incluídos. Os pacientes tratados com antipiréticos tiveram mortalidade na unidade de terapia intensiva semelhante aos controles (razão de risco de 0,91, com intervalo de confiança de 95% de 0,65-1,28). A única diferença observada foi uma diminuição na temperatura após 24 horas em pacientes tratados com antipiréticos (-1,70±0,40 x - 0,56±0,25ºC; p=0,014). Não houve diferença entre tratar ou não a febre em pacientes graves.

Febre/quimioterapia; Doença grave; Cuidados críticos; Antipiréticos/uso terapêutico; Unidades de terapia intensiva


Fever is a nonspecific response to various types of infectious or non-infectious insult and its significance in disease remains an enigma. Our aim was to summarize the current evidence for the use of antipyretic therapy in critically ill patients. We performed systematic review and meta-analysis of publications from 1966 to 2013. The MEDLINE and CENTRAL databases were searched for studies on antipyresis in critically ill patients. The meta-analysis was limited to: randomized controlled trials; adult human critically ill patients; treatment with antipyretics in one arm versus placebo or non-treatment in another arm; and report of mortality data. The outcomes assessed were overall intensive care unit mortality, changes in temperature, intensive care unit length of stay, and hospital length of stay. Three randomized controlled trials, covering 320 participants, were included. Patients treated with antipyretic agents showed similar intensive care unit mortality (risk ratio 0.91, with 95% confidence interval 0.65-1.28) when compared with controls. The only difference observed was a greater decrease in temperature after 24 hours in patients treated with antipyretics (-1.70±0.40 versus - 0.56±0.25ºC; p=0.014). There is no difference in treating or not the fever in critically ill patients.

Fever/drug therapy; Critical illness; Critical care; Antipyretics/therapeutic use; Intensive care units


INTRODUCTION

Fever is a nonspecific response to various types of infectious or non-infectious insults and its significance in diseases remains an enigma. Although fever is primarily a symptom of infection, it is unclear whether the fever is harmful or beneficial to the host.(1. Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajim Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajimi K, Morita K, Matsuo K, Hoshiro K, Hosokawa K, Lee KH, Lee KM, Takatori M, Nishimura M, Sanui M, Ito M, Egi M, Honda N, Okayama N, Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani S, Koh SO, Takeda S, Saito S, Hong SJ, Yamamoto T, Yokoyama T, Yamaguchi T, Nishiyama T, Igarashi T, Kakihana Y, Koh Y; Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group. Correction: Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16(5):450.) In a classical study, Kluger et al. showed that an elevation in temperature in lizards following experimental bacterial infection results in a significant increase in host survival.(2. Kluger MJ, Ringler DH, Anver M. Fever and survival. Science. 1975;188(4184):166-8.) In a recent multi-centered prospective observational study, Lee et al. showed that the association between fever and mortality and of type of antipyretic treatment and mortality was different between septic and non-septic patients. In non-septic patients, temperature ≥39.5°C was associated with 28-day mortality. However, in septic patients, administration of antipyretic therapy was independently associated with increased mortality.(1. Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajim Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajimi K, Morita K, Matsuo K, Hoshiro K, Hosokawa K, Lee KH, Lee KM, Takatori M, Nishimura M, Sanui M, Ito M, Egi M, Honda N, Okayama N, Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani S, Koh SO, Takeda S, Saito S, Hong SJ, Yamamoto T, Yokoyama T, Yamaguchi T, Nishiyama T, Igarashi T, Kakihana Y, Koh Y; Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group. Correction: Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16(5):450.)

The use of antipyretic therapy in febrile critically ill patients is inconsistent, and there are strong arguments both for and against it. Although pyrexia can be an adaptive response to stress, it can increase the oxygen consumption and cause discomfort to patients. Previous randomized controlled trials assessing antipyretic therapy in critically ill patients have been small, underpowered and provided divergent results. In front of these conflicting results, meta-analysis provides an useful tool to pool and analyze the data from these studies.

OBJECTIVE

The widespread use of antipyretic methods in intensive care units’ patients is not supported by clinical data, and fever control may be harmful, particularly when an infectious disease is progressing. Since this is a controversial topic we conducted a brief systematic review and meta-analysis of the literature to summarize the current evidence for the use o antipyretic therapy in critically ill patients.

METHODS

Literature search and data extraction

The online database of MedLine (1966-2013) and Cochrane Register of Controlled Trials (CENTRAL) were searched for studies that fulfill the following inclusion criteria: randomized controlled trials; adult human critically ill patients; treatment with antipyretics in one armversus placebo or non-treatment in other arm; and report of mortality data.

The following terms were combined in the search strategy: (acetaminophen [MeSH Terms] OR NSAID [MeSH Terms] OR aspirin [MeSH Terms] OR antipyrine [MeSH Terms] OR cooling) AND (critical illness [MeSH Terms] OR critical care [MeSH Terms] OR Intensive care [MeSH Terms]). All review articles and cross-referenced studies from retrieved articles were screened for pertinent information. When we found duplicate reports of the same study in preliminary abstracts and articles, we analyzed data from the most complete data set.

Outcomes and data analysis

The primary outcome was overall ICU mortality in patients treated with antipyretics versus patients not treated. The secondary outcomes included change in temperature, ICU length of stay, and hospital length of stay. According to PICOS statement, we evaluated:P, critically ill patients; I, antipyresis; C, no antipyresis; O, ICU mortality; S, intensive care unit.

We extracted data regarding the study design, patient characteristics, overall survival, and mean change in body temperature. For the analysis of survival, we calculated a pooled estimate of risk ratio (RR) in the individual studies using a random effect model according to Mantel and Haenszel and graphically represented these results using forest plot graphs. For continuous variables, we used the standardized mean difference (SMD), which is the difference in means divided by a standard deviation (SD). The homogeneity assumption was checked by a χ2 test with adf equal to the number of analyzed studies minus 1. Also, the heterogeneity was measured by the I2, which describes the percentage of total variation across studies, that is due to heterogeneity rather than chance. I2 was calculated from basic results obtained from a typical meta-analysis as I2 = 100% x (Q – df)/Q, where Qis Cochran’s heterogeneity statistic and df is the degrees of freedom. A percentage of zero indicates no observed heterogeneity, and larger values show increasing heterogeneity. When heterogeneity was found we tried to identify and describe the reason.

Parametric variables were presented as the mean±SD and non-parametric variables were presented as the median (interquartile range). All analyses were conducted with Review Manager v.5.1.1 and Statistical Package for Social Sciences (SPSS) v.16.0.1. For all analyses, p values <0.05 were considered significant.

RESULTS

A comprehensive literature search yielded 351 references, of which 339 articles were excluded during the first screening, which was based on abstracts or titles, leaving 12 articles for full text review. During this review, nine articles were excluded for the following reasons: non-randomized trial (n=6); both groups treated (n=2); and no data about mortality (n=1). Finally, three articles (320 participants) were included in the final analysis(3. Gozzoli V, Schöttker P, Suter PM, Ricou B. Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the effect of external cooling. Arch Intern Med. 2001;161(1):121-3.

. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005;6(4):369-75.
-5. Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012;185(1):1088-95.) (Figure 1 and Table 1).

Figure 1
Literature search strategy

Table 1
Scientific quality of included studies

All three studies analyzed were randomized controlled trials and in two the treatment of fever was with an external cooling device(3. Gozzoli V, Schöttker P, Suter PM, Ricou B. Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the effect of external cooling. Arch Intern Med. 2001;161(1):121-3.,5. Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012;185(1):1088-95.) and in the last with acetaminophen.(4. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005;6(4):369-75.) In one study the patients in the control group could be treated if the temperature reached a determined value(4. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005;6(4):369-75.) and in the other two no intervention was made in the control group. Two studies evaluated surgical patients(3. Gozzoli V, Schöttker P, Suter PM, Ricou B. Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the effect of external cooling. Arch Intern Med. 2001;161(1):121-3.,4. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005;6(4):369-75.) and one assessed patients with septic shock at ICU stay.(5. Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012;185(1):1088-95.) Characteristics and outcomes of the studies analyzed are exposed in table 2.

Table 2
Characteristics and outcomes of the studies included in the meta-analysis

Of 163 patients, 44 (27%) assigned to fever treatment and 47 out of 157 patients (30%) assigned as controls died during ICU stay (RR: 0.91; 95% of confidence interval – 95%CI: 0.65-1.28). There was no difference in stratified analysis between surgical patients and septic shock patients (RR: 2.19; 95%CI: 0.68-7.06; and RR: 0.80; 95%CI: 0.56-1.13, respectively). There is mild heterogeneity among the results (Table 3 and Figure 2). The visual inspection of survival analysis funnel plot revealed symmetry and the Begg test was not statistically significant (p=0.54).

Table 3
Characteristics and outcome of the patients analyzed in the meta-analysis

Figure 2
Meta-analysis of overall survival for antipyresis or no antipyresis in critically ill patients

There is no difference in ICU and hospital length of stay between patients treated and controls (Table 2 andFigure 3). As expected, the patients treated with antipyretic agents had greater decrease in temperature during 24 hours and lower body temperature at the end of the follow-up (Table 2 and Figures 4 and 5).

Figure 3
Meta-analysis of intensive care unit and hospital length of stay for antipyresis or no antipyresis in critically ill patients

Figure 4
Meta-analysis of temperature at the beginning and at the end of 24 hours for antipyresis or no antipyresis in critically ill patients

Figure 5
Change in temperature after 24 hours in patients treated with antipyretics (black circle and continuous line) and controls (black square and dashed line)

DISCUSSION

We founded evidence that the use of antipyretics for fever control in critically ill patients was not associated with better outcomes when compared to patients that were not treated. Notably, the decrease in the temperature during the first 24 hours and the temperature after 24 hours were significantly lower in the group treated with antipyresis.

Fever has been recognized as a hallmark of diseases for 4,500 to 5,000 years.(6. Cavaillon JM. Good and bad fever. Crit Care. 2012;16(2):119) It is due to a number of endogenous molecules able to modify the regular temperature. While the activity of pyrexin was possibly due to an endotoxin contamination, the fever-producing substance from polymorphonuclear leukocytes, and the endogenous pyrogen were candidates, now recognized as pyrogenic cytokines.(6. Cavaillon JM. Good and bad fever. Crit Care. 2012;16(2):119

. Menkin V. Chemical basis of fever. Science. 1944;100(2598):337-8.

. Bennett Il Jr, Beeson PB. Studies on the pathogenesis of fever. II. Characterization of fever-producing substances from polymorphonuclear leukocytes and from the fluid of sterile exudates. J Exp Med. 1953;98(5):493-508.
-9. Atkins E, Wood WB Jr. Studies on the pathogenesis of fever. II. Identification of an endogenous pyrogen in the blood stream following the injection of typhoid vaccine. J Exp Med. 1955;102(5):499-516.)

In the decade of 1970, Kluger et al.(2. Kluger MJ, Ringler DH, Anver M. Fever and survival. Science. 1975;188(4184):166-8.) showed that housing lizards infected with a bacteria at 42°C allowed them to survive, while all died when kept at 34°C. Thirty years after, Jiang et al.(1010 . Jiang Q, Cross AS, Singh IS, Chen TT, Viscardi RM, Hasday JD. Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect Immun. 2000;68(3):1265-70.) conducted a similar experiment in mice. Peritonitis infection was inoculated in mice housed in an ambient to allow a core temperature of 37.5 or 39.7°C. The bacterial load was exponential in the peritoneal cavity of mice with no fever and was under control in mice with fever. All mice with no fever died while 50% of those with fever survived.

Fever was found to be associated with better outcome in humans in several observational studies. In patients with Gram-negative bacteremia, fever was among the factors related to a decreased mortality.(1111 . Bryant RE, Hood AF, Hood CE, Koenig MG. Factors affecting mortality of gram-negative rod bacteremia. Arch Intern Med. 1971;127(1):120-8.) In elderly patients with community-acquired pneumonia, fever and leukocytosis were also associated with decreased mortality.(1212 . Ahkee S, Srinath L, Ramirez J. Community-acquired pneumonia in the elderly: association of mortality with lack of fever and leukocytosis. South Med J. 1997;90(3):296-8.) Due to numerous experimental animal models of severe infection which antipyresis was shown to increase mortality, physician were warned about the use of antipyresis in septic patients.(1313 . Shann F. Antipyretics in severe sepsis. Lancet. 1995;345(8946):338.)

Recently, Lee et al.(1. Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajim Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajimi K, Morita K, Matsuo K, Hoshiro K, Hosokawa K, Lee KH, Lee KM, Takatori M, Nishimura M, Sanui M, Ito M, Egi M, Honda N, Okayama N, Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani S, Koh SO, Takeda S, Saito S, Hong SJ, Yamamoto T, Yokoyama T, Yamaguchi T, Nishiyama T, Igarashi T, Kakihana Y, Koh Y; Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group. Correction: Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16(5):450.) showed that, in critically ill patients, the association of fever and mortality varied according to the level of fever and it was independently associated with mortality only in subgroup ≥39.5°C of patients without sepsis. In this group of patients, it can be assumed that high fever is likely to be caused by infection and this may account for mortality. High fever is associated with cardiac arrhythmias, increased oxygen demand, brain damage, and convulsions.(1414 . Manthous CA, Hall JB, Olson D, Singh M, Chatila W, Pohlman A, et al. Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit Care Med. 1995;151(1):10-4.,1515 . Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-63.) In patients with non-infective fever, these deleterious effects will occur without the potential benefit of fever-related protection.(1. Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajim Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajimi K, Morita K, Matsuo K, Hoshiro K, Hosokawa K, Lee KH, Lee KM, Takatori M, Nishimura M, Sanui M, Ito M, Egi M, Honda N, Okayama N, Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani S, Koh SO, Takeda S, Saito S, Hong SJ, Yamamoto T, Yokoyama T, Yamaguchi T, Nishiyama T, Igarashi T, Kakihana Y, Koh Y; Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group. Correction: Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16(5):450.)

Fever is thought to inhibit the activity of viruses and bacteria and antipyretic treatment can decrease this action.(1. Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajim Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajimi K, Morita K, Matsuo K, Hoshiro K, Hosokawa K, Lee KH, Lee KM, Takatori M, Nishimura M, Sanui M, Ito M, Egi M, Honda N, Okayama N, Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani S, Koh SO, Takeda S, Saito S, Hong SJ, Yamamoto T, Yokoyama T, Yamaguchi T, Nishiyama T, Igarashi T, Kakihana Y, Koh Y; Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group. Correction: Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16(5):450.,1616 . Ryan AJ, Flanagan SW, Moseley PL, Gisolfi CV. Acute heat stress protects rats against endotoxin shock. J Appl Physiol. 1992;73(4):1517-22.) Also, antipyresis in septic patients with non-steroidal anti-inflammatory drugs and acetaminophen may be toxic, as they might be associated with hypotension and renal dysfunction.(1717 . Hersch M, Raveh D, Izbicki G. Effect of intravenous propacetamol on blood pressure in febrile critically ill patients. Pharmacotherapy. 2008;28(10):1205-10.) Again, Lee et al.(1. Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajim Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajimi K, Morita K, Matsuo K, Hoshiro K, Hosokawa K, Lee KH, Lee KM, Takatori M, Nishimura M, Sanui M, Ito M, Egi M, Honda N, Okayama N, Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani S, Koh SO, Takeda S, Saito S, Hong SJ, Yamamoto T, Yokoyama T, Yamaguchi T, Nishiyama T, Igarashi T, Kakihana Y, Koh Y; Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group. Correction: Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16(5):450.) showed that mortality is higher for septic patients who fail to develop fever, supporting the argument that fever might be naturally protective. One study of trauma patients was prematurely stopped due trend toward increase in risk of infection and death in patients treated aggressively with acetaminophen and physical cooling.(4. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005;6(4):369-75.) Also, two studies reported that therapy with ibuprofen in patients with sepsis did not influence mortality.(1818 . Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, et al. 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(13):912-8.,1919 . 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(11):1339-47.)

Limitations of our study include the risk of bias which may exaggerate the study’s conclusion if publication is related to the strength of the results. Also, there are only three trials included, which increases the bias of these studies. We searched the references in few databases and used a simple search strategy, which could lead to loss of some studies. The analysis of physical cooling together with drugs could be another source of bias.

A large randomized controlled trial is being conducted to confirm the real effect of antipyresis in critically ill patients.(2020 . Young PJ, Saxena MK, Bellomo R, Freebairn RC, Hammond NE, van Haren FM, Henderson SJ, McArthur CJ, McGuinness SP, Mackle D, Myburgh JA, Weatherall M, Webb SA, Beasley RW; ANZICS Clinical Trials Group. The HEAT trial: a protocol for a multicentre randomised placebo-controlled trial of IV paracetamol in ICU patients with fever and infection. Crit Care Resusc. 2012;14(4):290-6.)

CONCLUSION

The results of this review suggest that antipyresis in critically ill patients was not associated with better survival compared with no treatment of the fever. Further larger studies are needed to confirm the effect of fever control on mortality and to determine whether mild hypothermia provides additional benefits in critically ill patients.

References

  • 1
    Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajim Lee BH, Inui D, Suh GY, Kim JY, Kwon JY, Park J, Tada K, Tanaka K, Ietsugu K, Uehara K, Dote K, Tajimi K, Morita K, Matsuo K, Hoshiro K, Hosokawa K, Lee KH, Lee KM, Takatori M, Nishimura M, Sanui M, Ito M, Egi M, Honda N, Okayama N, Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani S, Koh SO, Takeda S, Saito S, Hong SJ, Yamamoto T, Yokoyama T, Yamaguchi T, Nishiyama T, Igarashi T, Kakihana Y, Koh Y; Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group. Correction: Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012;16(5):450.
  • 2
    Kluger MJ, Ringler DH, Anver M. Fever and survival. Science. 1975;188(4184):166-8.
  • 3
    Gozzoli V, Schöttker P, Suter PM, Ricou B. Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the effect of external cooling. Arch Intern Med. 2001;161(1):121-3.
  • 4
    Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt). 2005;6(4):369-75.
  • 5
    Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012;185(1):1088-95.
  • 6
    Cavaillon JM. Good and bad fever. Crit Care. 2012;16(2):119
  • 7
    Menkin V. Chemical basis of fever. Science. 1944;100(2598):337-8.
  • 8
    Bennett Il Jr, Beeson PB. Studies on the pathogenesis of fever. II. Characterization of fever-producing substances from polymorphonuclear leukocytes and from the fluid of sterile exudates. J Exp Med. 1953;98(5):493-508.
  • 9
    Atkins E, Wood WB Jr. Studies on the pathogenesis of fever. II. Identification of an endogenous pyrogen in the blood stream following the injection of typhoid vaccine. J Exp Med. 1955;102(5):499-516.
  • 10
    Jiang Q, Cross AS, Singh IS, Chen TT, Viscardi RM, Hasday JD. Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect Immun. 2000;68(3):1265-70.
  • 11
    Bryant RE, Hood AF, Hood CE, Koenig MG. Factors affecting mortality of gram-negative rod bacteremia. Arch Intern Med. 1971;127(1):120-8.
  • 12
    Ahkee S, Srinath L, Ramirez J. Community-acquired pneumonia in the elderly: association of mortality with lack of fever and leukocytosis. South Med J. 1997;90(3):296-8.
  • 13
    Shann F. Antipyretics in severe sepsis. Lancet. 1995;345(8946):338.
  • 14
    Manthous CA, Hall JB, Olson D, Singh M, Chatila W, Pohlman A, et al. Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit Care Med. 1995;151(1):10-4.
  • 15
    Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-63.
  • 16
    Ryan AJ, Flanagan SW, Moseley PL, Gisolfi CV. Acute heat stress protects rats against endotoxin shock. J Appl Physiol. 1992;73(4):1517-22.
  • 17
    Hersch M, Raveh D, Izbicki G. Effect of intravenous propacetamol on blood pressure in febrile critically ill patients. Pharmacotherapy. 2008;28(10):1205-10.
  • 18
    Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, et al. 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(13):912-8.
  • 19
    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(11):1339-47.
  • 20
    Young PJ, Saxena MK, Bellomo R, Freebairn RC, Hammond NE, van Haren FM, Henderson SJ, McArthur CJ, McGuinness SP, Mackle D, Myburgh JA, Weatherall M, Webb SA, Beasley RW; ANZICS Clinical Trials Group. The HEAT trial: a protocol for a multicentre randomised placebo-controlled trial of IV paracetamol in ICU patients with fever and infection. Crit Care Resusc. 2012;14(4):290-6.

Publication Dates

  • Publication in this collection
    18 Nov 2014
  • Date of issue
    Oct-Dec 2014

History

  • Received
    12 Mar 2013
  • Accepted
    1 Dec 2013
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