Fabio Silvio TacconeManoj SaxenaFrederique Schortgen

What’s new with fever control in the ICU

Received: 17 March 2014Accepted: 20 March 2014Published online: 2 April 2014� Springer-Verlag Berlin Heidelberg and ESICM 2014

F. S. TacconeDepartment of Intensive Care, Hopital Erasme Universite Libre deBruxelles, Bruxelles, Belgium

M. SaxenaDepartment of Intensive Care Medicine, St. George HospitalClinical School, University of New South Wales, Sydney, Australia

F. Schortgen ())AP-HP, Groupe Hospitalier Henri Mondor, Service de ReanimationMedicale, CHU Henri Mondor, 51 avenue de Tassigny,94000 Creteil, Francee-mail: frederique.schortgen@hmn.aphp.frTel.: ?33-14-9812389Fax: ?33-14-2079943

F. SchortgenINSERM, U955, Faculte de Medecine, Creteil, France

Introduction

The high prevalence of an elevated body temperature incritically ill patients (sepsis, systemic inflammation andneurological presentations) contrasts with the reliability ofthe evidence that is available to inform the clinical questionof ‘‘should we treat fever?’’ [1]. Recently available highquality studies have enhanced our understanding of thepotential role of fever control in critically ill patients (Fig. 1)and several clinical trials are currently ongoing.

Evidence from observational clinical studies

In studies of the observational relationship between ele-vated temperature during critical illness and outcome, the

nature of the reported relationship depends on the patientpopulation, the nature of the temperature measurement,the assessed outcome and the model used for adjustment.Despite the limitations in interpretation of these data, theyremain useful primarily for the purpose of hypothesisgeneration for clinical trials, rather than for directlyinfluencing clinical practice.

For patients with infections, there may be a relation-ship between early fever and a decrease in mortalityassessed at 28 days [2, 3] or hospital discharge [4].Although this potential protective effect of fever does notappear to persist at higher temperatures ([38.4 �C [2]or [39.4 �C [4]), there does not appear to be a statisti-cally significant association with increased mortality athigh temperatures. The use of pharmacological agents(paracetamol or non-steroidal anti-inflammatory drugs),but not physical cooling, does appear to be associatedwith increased 28-day mortality in this patient population[2].

In contrast, in a cohort study of patients with acutelung injury (ALI), 70 % related to sepsis, each additionalday of fever during the first week resulted in a 33 %reduction in the likelihood of successful ventilator liber-ation (95 % confidence interval for adjusted hazard ratio,0.57 to 0.78; P \ 0.001) [5]. Additionally for patientswith ALI, fever control may reduce oxygen requirement,CO2 production, cardiac output and intrapulmonary shunt[6]. The reduction in cardiac output may be mediatedthrough a reduction in heart rate as a consequence of achange in body temperature and a reduction in vaso-pressor dose [6, 7]. Temperature manipulation is also veryeffective during veno-venous extracorporeal membraneoxygenation (ECMO) as it may improve the ratio betweenblood flow in the ECMO circuit and the patient, thusenhancing arterial oxygenation [6].

During systemic inflammatory pathology, there is anassociation between the presence of early fever ([38.5 �C[2] and [39 �C [4]) and increased 28-day [2] and hospital

Intensive Care Med (2014) 40:1147–1150DOI 10.1007/s00134-014-3277-9 WHAT’S NEW IN INTENSIVE CARE

mortality [4] respectively. The use of pharmacologicalagents or physical cooling was not associated with harmin this patient population [2]. For patients with acute braininjury, elevated early peak temperature ([38 �C) andfever burden in the first 72 h were associated with anincrease in hospital mortality [8]. However, this rela-tionship is not consistently observed [9].

Evidence from randomised controlled trials (RCTs)

In a multi-centre French RCT, physical cooling to nor-mothermia compared to no fever control, in febrile

patients with septic shock (predominantly pneumonia),reduced vasopressor dose and organ failures [7]. Thiseffect was more pronounced in the most severely illpatient subgroup. There was, however, an increasedincidence of secondary infection with the physical coolinggroup compared to no fever control. The 14-day mortal-ity, assessed as a secondary end point, was lower in thecooling group (19 vs. 34 %; P = 0.021) but did notremain significantly different at hospital discharge.

In a multi-centre French study, comatose adults withcommunity-acquired bacterial meningitis were random-ised to induced hypothermia for 48 h or standard of careincluding steroids (induced normothermia) [10]. After theenrolment of 98 patients, the data monitoring and safety

Fig. 1 Potential risks of feverindicating therapeutictemperature modulation.*Induced hypothermia mayincrease the risk of secondaryinfection and inducecardiovascular disturbances.For patients with bacterialmeningitis, it is associated withincreased mortality.**Shivering is a common andpotentially damaging adverseeffect of physical cooling thatneeds to be prevented andcontrolled. TH therapeutichypothermia, CNS centralnervous system

1148

board stopped the study because of an increased mortalityin the hypothermia group (51 vs. 31 %, P = 0.04). Therewas no difference in nosocomial infection, haemorrhage,cardiovascular effects or hyperglycaemia to explain themortality difference between the treatment groups.

Therapeutic hypothermia had become a standard ofcare for out of hospital cardiac arrest until the recentpublication of the Targeted Temperature ManagementTrial [11]. In this Scandinavian-led international RCT,939 patients with cardiac arrest of presumed cardiac ori-gin were randomised to a temperature target of 33 or36 �C for 24 h (ensuring minimisation of temperatureelevation above 37.5 �C in the control arm) [11]. Nodifference in mortality was observed between the twogroups (50 % in the 33 �C and 48 % in the 36 �C group,P = 0.51) or in the composite outcome of death or poorneurologic function. Hypothermia was associated with atrend towards more complications and an increase incardiovascular instability. Among these complications,acquired infections have been frequently reported [11–13]. A systematic review has recently shown that inducedhypothermia increases the risk of pneumonia and sepsis,but not the overall rate of infections [14]. However,defining acquired infection and sepsis in the context ofblunted fever response remains a challenging task.

Current and recently completed RCTs

There are two ongoing multi-centred, phase 2b RCTsinvestigating the effect of temperature reduction in febrilecritically ill patients that both exclude patients with acuteneurological presentations. Firstly, the HEAT study(Australia and New Zealand) is designed to determine if apermissive temperature strategy, compared with a usualcare strategy of administration of paracetamol, increasesthe number of ‘‘alive ICU-free days’’ at day 28, for 700febrile critically ill patients with known or suspectedinfection [15]. HEAT has recruited 504 patients. Sec-ondly, the FACE II study (Japan and Korea) compares thesafety and efficacy of two temperature targets (physicalcooling or pharmacological agents to achieve targets

of \38 �C vs. \39.6 �C) on ICU-free survival at 28 daysin 360 febrile critically ill patients; one quarter of thepatients have been enrolled [16]. Additionally, the CASSstudy (Denmark) is a phase 3 randomised trial to deter-mine whether induced hypothermia (32–34 �C) for 24 h[followed by 48 h of fever control (36–38 �C)], comparedto usual care (fever-respect), can reduce mortality in 560adult patients with septic shock (NCT01455116); 182patients have been recruited. Lastly, in patients withtraumatic brain injury, the PARITY study which wasdesigned to investigate the safety and efficacy of intra-venous paracetamol in reducing core temperature hasrecently stopped recruitment at 40 patients [17]. TheEurotherm3235 is an ongoing international RCT,designed to examine the effects of therapeutic hypother-mia (32–35 �C) compared to the standard care in 600patients; 318 have been recruited [18].

Conclusion

For febrile critically ill patients with sepsis, physicalcooling to normothermia, compared to no fever control,may improve short-term outcomes. However, for patientswith sepsis due to bacterial meningitis, induced hypo-thermia is associated with increased long-term mortalitywhen compared to normothermia. For patients followingcardiac arrest, targeted temperature management to atemperature of 36 �C is recommended, and inducedhypothermia is not associated with any discerniblebenefit.

Further high quality clinical trials are being currentlyconducted that will help further understand whether feverin specific patient populations is a marker of illnessseverity, part of a protective response by the host tocritical illness, or a risk factor that through therapeuticmodification (‘‘fever control’’) may improve patient-cen-tred outcomes.

Conflicts of interest The authors declare that there are no conflictsof interest.

1149

References

1. Niven DJ, Stelfox HT, Shahpori R,Laupland KB (2013) Fever in adultICUs: an interrupted time seriesanalysis. Crit Care Med 41:1863–1869

2. Fever and Antipyretic in Critically illpatients Evaluation (FACE) StudyGroup, Lee BH, Inui D, Suh GY, KimJY, Kwon JY, Park J, Tada K, TanakaK, Ietsugu K, Uehara K, Dote K, TajimiK, Morita K, Matsuo K, Hoshino K,Hosokawa K, Lee KH, Lee KM,Takatori M, Nishimura M, Sanui M, ItoM, Egi M, Honda N, Okayama N,Shime N, Tsuruta R, Nogami S, YoonSH, Fujitani S, Koh SO, Takeda S, SaitoS, Hong SJ, Yamamoto T, YokoyamaT, Yamaguchi T, Nishiyama T, IgarashiT, Kakihana Y, Koh Y (2012)Association of body temperature andantipyretic treatments with mortality ofcritically ill patients with and withoutsepsis: multi-centered prospectiveobservational study. Crit Care 16:R33

3. Kushimoto S, Gando S, Saitoh D,Mayumi T, Ogura H, Fujishima S,Araki T, Ikeda H, Kotani J, Miki Y,Shiraishi SI, Suzuki K, Suzuki Y,Takeyama N, Takuma K, Tsuruta R,Yamaguchi Y, Yamashita N, Aikawa N(2013) The impact of body temperatureabnormalities on the disease severityand outcome in patients with severesepsis: an analysis from a multicenter,prospective survey of severe sepsis. CritCare 17:R271

4. Young PJ, Saxena M, Beasley R,Bellomo R, Bailey M, Pilcher D, FinferS, Harrison D, Myburgh J, Rowan K(2012) Early peak temperature andmortality in critically ill patients with orwithout infection. Intensive Care Med38:437–444

5. Netzer G, Dowdy DW, Harrington T,Chandolu S, Dinglas VD, Shah NG,Colantuoni E, Mendez-Tellez PA,Shanholtz C, Hasday JD, Needham DM(2013) Fever is associated with delayedventilator liberation in acute lunginjury. Ann Am Thorac Soc10:608–615

6. Kimmoun A, Vanhuyse F, Levy B(2013) Improving blood oxygenationduring venovenous ECMO for ARDS.Intensive Care Med 39:1161–1162

7. Schortgen F, Clabault K, Katsahian S,Devaquet J, Mercat A, Deye N,Dellamonica J, Bouadma L, Cook F,Beji O, Brun-Buisson C, Lemaire F,Brochard L (2012) Fever control usingexternal cooling in septic shock: arandomized controlled trial. Am JRespir Crit Care Med 185:1088–1095

8. Li J, Jiang JY (2012) Chinese headtrauma data bank: effect ofhyperthermia on the outcome of acutehead trauma patients. J Neurotrauma29:96–100

9. Seguin P, Roquilly A, Mimoz O,Maguet PL, Asehnoune K, BiedermanS, Carise E, Malledant Y (2012) Riskfactors and outcomes for prolonged vs.brief fever: a prospective cohort study.Crit Care 16:R150

10. Mourvillier B, Tubach F, van de BeekD, Garot D, Pichon N, Georges H,Lefevre LM, Bollaert PE, Boulain T,Luis D, Cariou A, Girardie P, Chelha R,Megarbane B, Delahaye A, Chalumeau-Lemoine L, Legriel S, Beuret P, BrivetF, Bruel C, Camou F, Chatellier D,Chillet P, Clair B, Constantin JM,Duguet A, Galliot R, Bayle F, HyvernatH, Ouchenir K, Plantefeve G, QuenotJP, Richecoeur J, Schwebel C, SirodotM, Esposito-Farese M, Le Tulzo Y,Wolff M (2013) Induced hypothermiain severe bacterial meningitis: arandomized clinical trial. JAMA310:2174–2183

11. Nielsen N, Wetterslev J, Cronberg T,Erlinge D, Gasche Y, Hassager C, HornJ, Hovdenes J, Kjaergaard J, Kuiper M,Pellis T, Stammet P, Wanscher M, WiseMP, Aneman A, Al-Subaie N,Boesgaard S, Bro-Jeppesen J, BrunettiI, Bugge JF, Hingston CD, JuffermansNP, Koopmans M, Kober L, LangorgenJ, Lilja G, Moller JE, Rundgren M,Rylander C, Smid O, Werer C, WinkelP, Friberg H, Investigators TTMT(2013) Targeted temperaturemanagement at 33 vs. 36 �C aftercardiac arrest. N Engl J Med369:2197–2206

12. Perbet S, Mongardon N, Dumas F,Bruel C, Lemiale V, Mourvillier B,Carli P, Varenne O, Mira JP, Wolff M,Cariou A (2011) Early-onsetpneumonia after cardiac arrest:characteristics, risk factors andinfluence on prognosis. Am J RespirCrit Care Med 184:1048–1054

13. Kurz A, Sessler DI, Lenhardt R (1996)Perioperative normothermia to reducethe incidence of surgical-woundinfection and shorten hospitalization.Study of Wound Infection andTemperature Group. N Engl J Med334:1209–1215

14. Geurts M, Macleod MR, Kollmar R,Kremer PH, van der Worp HB (2014)Therapeutic hypothermia and the risk ofinfection: a systematic review andmeta-analysis. Crit Care Med42:231–242

15. HEAT TrialGroup (2014)https://www.heat-trial.org.nz/PublicPages/WhatIsHeat.aspx.Accessed 31 Mar 2014

16. UMIN (2011) https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000006527&language=J. Accessed 31 Mar 2014

17. ANZCTR (2009) https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12609000444280. Accessed 31 Mar2014

18. Eurotherm3235 Trial Group (2012)http://www.eurotherm3235trial.eu/home/index.phtml. Accessed 31 Mar2014

1150