Fabio Silvio Taccone

Manoj Saxena
Frederique Schortgen
Whats new with fever control in the ICU
Received: 17 March 2014
Accepted: 20 March 2014
Published online: 2 April 2014
Springer-Verlag Berlin Heidelberg and ESICM 2014
F. S. Taccone
Department of Intensive Care, Hopital Erasme Universite Libre de
Bruxelles, Bruxelles, Belgium
M. Saxena
Department of Intensive Care Medicine, St. George Hospital
Clinical School, University of New South Wales, Sydney, Australia
F. Schortgen (
)
)
AP-HP, Groupe Hospitalier Henri Mondor, Service de Reanimation
Medicale, CHU Henri Mondor, 51 avenue de Tassigny,
94000 Creteil, France
e-mail: frederique.schortgen@hmn.aphp.fr
Tel.: ?33-14-9812389
Fax: ?33-14-2079943
F. Schortgen
INSERM, U955, Faculte de Medecine, Creteil, France
Introduction
The high prevalence of an elevated body temperature in
critically ill patients (sepsis, systemic inammation and
neurological presentations) contrasts with the reliability of
the evidence that is available to informthe clinical question
of should we treat fever? [1]. Recently available high
quality studies have enhanced our understanding of the
potential role of fever control incriticallyill 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 patient
population, the nature of the temperature measurement,
the assessed outcome and the model used for adjustment.
Despite the limitations in interpretation of these data, they
remain useful primarily for the purpose of hypothesis
generation for clinical trials, rather than for directly
inuencing clinical practice.
For patients with infections, there may be a relation-
ship between early fever and a decrease in mortality
assessed at 28 days [2, 3] or hospital discharge [4].
Although this potential protective effect of fever does not
appear to persist at higher temperatures ([38.4 C [2]
or [39.4 C [4]), there does not appear to be a statisti-
cally signicant association with increased mortality at
high temperatures. The use of pharmacological agents
(paracetamol or non-steroidal anti-inammatory drugs),
but not physical cooling, does appear to be associated
with increased 28-day mortality in this patient population
[2].
In contrast, in a cohort study of patients with acute
lung injury (ALI), 70 % related to sepsis, each additional
day of fever during the rst week resulted in a 33 %
reduction in the likelihood of successful ventilator liber-
ation (95 % condence interval for adjusted hazard ratio,
0.57 to 0.78; P\0.001) [5]. Additionally for patients
with ALI, fever control may reduce oxygen requirement,
CO
2
production, cardiac output and intrapulmonary shunt
[6]. The reduction in cardiac output may be mediated
through a reduction in heart rate as a consequence of a
change in body temperature and a reduction in vaso-
pressor dose [6, 7]. Temperature manipulation is also very
effective during veno-venous extracorporeal membrane
oxygenation (ECMO) as it may improve the ratio between
blood ow in the ECMO circuit and the patient, thus
enhancing arterial oxygenation [6].
During systemic inammatory pathology, there is an
association 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) 40:11471150
DOI 10.1007/s00134-014-3277-9
WHATS NEW IN INTENSIVE CARE
mortality [4] respectively. The use of pharmacological
agents or physical cooling was not associated with harm
in this patient population [2]. For patients with acute brain
injury, elevated early peak temperature ([38 C) and
fever burden in the rst 72 h were associated with an
increase 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]. This
effect was more pronounced in the most severely ill
patient subgroup. There was, however, an increased
incidence of secondary infection with the physical cooling
group compared to no fever control. The 14-day mortal-
ity, assessed as a secondary end point, was lower in the
cooling group (19 vs. 34 %; P = 0.021) but did not
remain signicantly different at hospital discharge.
In a multi-centre French study, comatose adults with
community-acquired bacterial meningitis were random-
ised to induced hypothermia for 48 h or standard of care
including steroids (induced normothermia) [10]. After the
enrolment of 98 patients, the data monitoring and safety
Fig. 1 Potential risks of fever
indicating therapeutic
temperature modulation.
*Induced hypothermia may
increase the risk of secondary
infection and induce
cardiovascular disturbances.
For patients with bacterial
meningitis, it is associated with
increased mortality.
**Shivering is a common and
potentially damaging adverse
effect of physical cooling that
needs to be prevented and
controlled. TH therapeutic
hypothermia, CNS central
nervous system
1148
board stopped the study because of an increased mortality
in the hypothermia group (51 vs. 31 %, P = 0.04). There
was no difference in nosocomial infection, haemorrhage,
cardiovascular effects or hyperglycaemia to explain the
mortality difference between the treatment groups.
Therapeutic hypothermia had become a standard of
care for out of hospital cardiac arrest until the recent
publication of the Targeted Temperature Management
Trial [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 or
36 C for 24 h (ensuring minimisation of temperature
elevation above 37.5 C in the control arm) [11]. No
difference in mortality was observed between the two
groups (50 % in the 33 C and 48 % in the 36 C group,
P = 0.51) or in the composite outcome of death or poor
neurologic function. Hypothermia was associated with a
trend towards more complications and an increase in
cardiovascular instability. Among these complications,
acquired infections have been frequently reported [11
13]. A systematic review has recently shown that induced
hypothermia increases the risk of pneumonia and sepsis,
but not the overall rate of infections [14]. However,
dening acquired infection and sepsis in the context of
blunted fever response remains a challenging task.
Current and recently completed RCTs
There are two ongoing multi-centred, phase 2b RCTs
investigating the effect of temperature reduction in febrile
critically ill patients that both exclude patients with acute
neurological presentations. Firstly, the HEAT study
(Australia and New Zealand) is designed to determine if a
permissive temperature strategy, compared with a usual
care strategy of administration of paracetamol, increases
the number of alive ICU-free days at day 28, for 700
febrile critically ill patients with known or suspected
infection [15]. HEAT has recruited 504 patients. Sec-
ondly, the FACE II study (Japan and Korea) compares the
safety and efcacy of two temperature targets (physical
cooling or pharmacological agents to achieve targets
of \38 C vs. \39.6 C) on ICU-free survival at 28 days
in 360 febrile critically ill patients; one quarter of the
patients have been enrolled [16]. Additionally, the CASS
study (Denmark) is a phase 3 randomised trial to deter-
mine whether induced hypothermia (3234 C) for 24 h
[followed by 48 h of fever control (3638 C)], compared
to usual care (fever-respect), can reduce mortality in 560
adult patients with septic shock (NCT01455116); 182
patients have been recruited. Lastly, in patients with
traumatic brain injury, the PARITY study which was
designed to investigate the safety and efcacy of intra-
venous paracetamol in reducing core temperature has
recently stopped recruitment at 40 patients [17]. The
Eurotherm3235 is an ongoing international RCT,
designed to examine the effects of therapeutic hypother-
mia (3235 C) compared to the standard care in 600
patients; 318 have been recruited [18].
Conclusion
For febrile critically ill patients with sepsis, physical
cooling to normothermia, compared to no fever control,
may improve short-term outcomes. However, for patients
with sepsis due to bacterial meningitis, induced hypo-
thermia is associated with increased long-term mortality
when compared to normothermia. For patients following
cardiac arrest, targeted temperature management to a
temperature of 36 C is recommended, and induced
hypothermia is not associated with any discernible
benet.
Further high quality clinical trials are being currently
conducted that will help further understand whether fever
in specic patient populations is a marker of illness
severity, part of a protective response by the host to
critical illness, or a risk factor that through therapeutic
modication (fever control) may improve patient-cen-
tred outcomes.
Conicts of interest The authors declare that there are no conicts
of interest.
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