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REVIEW

CURRENT
OPINION Is there still a role for hypothermia in neurocritical
care?
Florian Frank and Gregor Broessner

Purpose of review
Therapeutic hypothermia (i.e. induced body core temperature  33358C) in neurological patients with
cerebrovascular disease and traumatic brain injury is a controversially discussed issue in the literature. In
this review, we have included the most recently published research covering the use of therapeutic
hypothermia and targeted temperature management in neurologic diseases and translated the results into a
clinical decision support for the professional healthcare community.
Recent findings
Recent findings from large multicenter studies investigating therapeutic hypothermia in patients with various
acute neurologic diseases have revealed that although short-term and long-term temperature modulation on
different temperature levels is feasible with the latest device technology, the effect on outcome is
controversial.
Summary
There is overwhelming evidence that fever is an independent predictor of morbidity and mortality in
patients with acute severe neurologic diseases. Although therapeutic hypothermia has been proven to be a
potent neuroprotective measure acting on various levels in animal models, many questions such as optimal
depth of target temperature, speed of rewarming, duration of cooling and management of side-effects
accompanying therapeutic hypothermia are unresolved in human. Therefore, the application of therapeutic
hypothermia outside of strictly supervised clinical trials must be carefully considered.
Keywords
cerebrovascular disease, controlled normothermia, targeted temperature management, therapeutic
hypothermia

INTRODUCTION hypoxia post resuscitation, neonatal asphyxia, elev-

Although active temperature modulation is widely ated intracranial pressure (ICP), stroke, hepatic
&&

used in different fields of medicine today, there is
still no final definition of the temperature ranges
but therapeutic hypothermia is mainly referred as
an actively induced and controlled body core
temperature between 33 and 358C. The potential
benefits of therapeutic hypothermia have been
tested in many experimental models of acute
neuronal injury as well as in patients with various
disease entities over the last few decades. Although
much has been learned regarding the potentially
beneficial effects of cooling and targeted tempera-
ture management (TTM), ongoing clinical investi-
gations continue to test whether therapeutic
hypothermia is beneficial in patients with cere-
bro-vascular disease and traumatic brain injury
(TBI).
Within the last 20 years, TTM has been inves-
tigated for its neuroprotective properties in a variety
of acute neurological disorders comprising cerebral
encephalopathy, TBI and others [13,4 ]. The
beneficial effect of TTM observed in experimental
models of acute brain injury is the result of a wide
range of neurobiological effects, rather than a single
mechanism of action (Fig. 1) [5]. On the one hand,
this renders TTM one of the most promising tools for
neuroprotection in almost any kind of acute
neuronal damage. On the other hand, this multi-
modal approach makes the effects of TTM difficult
to predict and a beneficial effect might be
Department of Neurology, Medical University of Innsbruck, Innsbruck,
Austria
Correspondence to Gregor Broessner, MD, Associated Professor of
Neurology, Department of Neurology, Medical University of Innsbruck,
Anichstr. 35, 6020 Innsbruck, Austria. Tel: +43 512 504 0; fax: +43 512
504 24288; e-mail: gregor.broessner@i-med.ac.at
Curr Opin Crit Care 2017, 23:000000
DOI:10.1097/MCC.0000000000000398

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KEY POINTS
 Continuous recording of body core temperature is
absolutely pivotal in all patients with acute severe
neurologic disease, and fever should be regarded as
an independent predictor of morbidity and mortality.
 Hyperthermic conditions and fever should be treated in
all patients with acute severe cerebrovascular disease
or TBI following a predefined standardized protocol.
 Animal studies investigating therapeutic hypothermia
have consequently shown a significant benefit in
various disease models, but results could not be
reproduced in larger randomized controlled human
trials; therefore, the application of therapeutic
hypothermia outside of strictly supervised clinical trials
has to be considered absolutely carefully.
 If the concept of strictly avoiding fever in the acute
phase of a disease, by maintaining normothermia (i.e.
body core temperature 36.58378C) using feedback
driven devices, is a seminal concept, has to be further
evaluated in well-designed RCTs.
outweighed by limitations, side-effects or compli-
cations.
In order to keep this review brief and ready to
use for practicing clinicians, the reader is referred
FIGURE 1. Possible mechanisms of therapeutic hypothermia and hyperthermia and their proposed neurobiological effects,
data from [5].
2 www.co-criticalcare.com
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elsewhere for details of the use of TTM in non-
neurologic diseases such as post resuscitation care
&
or neonatal intensive care medicine [6 ].
INTRACEREBRAL HEMORRHAGE
Spontaneous, nontraumatic intracerebral hemor-
rhage (ICH) accounts for almost 30% of all strokes
worldwide with a devastating mortality rate at
1 month reported to be up to 40%, increasing to
54% at 1 year [7,8]. Despite high incidence and high
burden of ICH, no specific treatment is currently
available and optimal management of patients with
ICH still remains controversial.
In spontaneous ICH, TTM/hypothermia is con-
sidered to act primarily on tissue at risk in the
perihematomal penumbra by modulating different
processes that lead to neuronal injury and death.
Including experimental and clinical studies on the
use of TTM in spontaneous ICH in a recent system-
atic review by our working group, we found consist-
ent improvement of structural outcome, such as a
reduction of edema, inflammatory response and
reduced bloodbrain barrier (BBB) breakdown
through induced hypothermia in almost all animal
&&
studies [9 ]. Although most of the experimental
studies showed promising results on preserving
cell-structure through TTM, only 36% could also
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Role for hypothermia in neurocritical care Frank and Broessner
translate these positive effects on functional out-
come, that is the majority remaining neutral (64%)
&&
[9 ].
Clinical trials: in a small pilot study enrolling 12
patients with spontaneous ICH (>25 ml), thera-
peutic hypothermia reduced both perihematomal
edema increase over time and mortality [10].
Patients were treated with mild therapeutic hypo-
thermia of 358C (body core temperature) for a period
of 10 consecutive days, followed by controlled
rewarming (0.58C per 24 h). Importantly, all inves-
tigated patients survived until day 90 and endovas-
cular cooling was well tolerated with the exception
of increased pneumonia rate in the therapeutic
hypothermia group [10]. The same group confirmed
the results of their pilot study showing a beneficial
effect of mild prolonged hypothermia on perihema-
tomal edema in a cohort of 25 patients with spon-
taneous ICH [11]. Moreover, the authors reported
improved functional outcome after 3 months and
after 1 year in patients receiving hypothermia treat-
ment compared with historical controls.
A Chinese research group reported results of a
controlled study enrolling ICH patients treated with
local brain hypothermia (n 20, 68C for 48 h) in
addition to standard of care treatment with osmotic
and antihypertensive agents (n 20) [12]. The vol-
umes of edema 1 and 2 weeks after therapy were
significantly lower in the therapeutic hypothermia
group compared with the standard care group (only
English abstract available) [12].
At present, there are two randomized-controlled
trials investigating TTM in patients with ICH
[13,14]. Although the Cooling In Intracerebral Hem-
orrhage (CINCH) trial is on hold, the Targeted
Temperature Management after Intracerebral Hem-
orrhage (TTM-ICH) trial is currently enrolling
patients with ICH who will be randomized within
18 h of symptom onset to either 72 h of TTM to
moderate hypothermia (32348C) followed by a
controlled rewarming at 0.050.18C per hour or
72 h of TTM to normothermia (36378C) using
endovascular or surface cooling [13,14]. Neverthe-
less, based on the current evidence available,
therapeutic hypothermia and prophylactic normo-
thermia after spontaneous ICH cannot be recom-
mended outside the confines of clinical trials.
Although the American Heart Association rates
treatment of fever after ICH may be reasonable
(Class IIb; Level of Evidence C), the European Stroke
Organization states that there is insufficient evi-
dence whether, when and for whom preventive or
early fever treatment should be given after acute
ICH (quality of evidence: low; strength of recom-
mendation: weak) again calling for high-quality
randomized controlled trials (RCTs) [7,8].
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Questions regarding the optimal target tempera-
ture, onset, duration, method of cooling and speed
of rewarming for patients with ICH need to be
addressed in future randomized studies.
ISCHEMIC STROKE
Acute ischemic stroke is a devastating neurologic
disease, leaving more than half of patients with a
&
poor functional outcome [15,16 ]. Elevated body
temperatures either in the early stage after the insult
or during the hospital phase have consistently been
associated with mortality and poor functional out-
come [17,18]. On the basis of these results, current
guidelines recommend the use of antipyretics for
febrile patients with stroke, but do not provide a
time window [19]. A recent study enrolling more
than 400 patients showed that higher body tem-
peratures in the first 3 days after ischemic stroke,
rather than on admission, are associated with larger
infarct size and poor functional outcome, further
suggesting that prevention of higher temperatures
in this stage of the disease is of utmost importance
&
and should be investigated in greater detail [16 ].
The use of therapeutic hypothermia in ischemic
stroke is supported by robust data from experimen-
tal models that have been validated impressively by
a recent meta-analysis using rigorous statistical
approaches warranting consideration of therapeutic
hypothermia in larger clinical trials of acute ische-
&&
mic stroke [20 ,21]. In their recent meta-analysis,
&&
Dumitrascu et al. [20 ] found across a wide variety
of models, species and protocols, that therapeutic
hypothermia overall was associated, with an esti-
mated normalized median treatment effect size of
1080% depending on the outcome measure
(infarct/edema volume and functional outcome)
used.
CLINICAL TRIALS USING THERAPEUTIC
HYPOTHERMIA IN ISCHEMIC STROKE
The ICTuS 2/3 Trial (Intravascular Cooling in the
Treatment of Stroke 2) was originally designed as a
prospective, randomized, multicenter phase 2/3
study to include 1600 ischemic stroke patients
treated within 3 h of symptom onset with intrave-
nous recombinant tissue plasminogen activator and
then being randomized either to endovascular
maintained hypothermia targeted to 338C (over
&
24 h) or normothermia [22 ]. Intraarterial recanali-
zation procedures were disallowed by protocol. The
trial was stopped early after enrolling 120 patients
because of the approval of intraarterial neurothrom-
bectomy and the expiration of the initial funding
period. Therefore, the published results have to be
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Neuroscience
interpreted with great caution, as the statistical
analysis plan was calculated based on the enroll-
ment of 1600 patients. However, although the cool-
ing rates and adherence to target temperature were
in accordance to protocol, no significant difference
was found in the respective outcome parameters
(modified Rankin Score, mortality, pneumonia rate
and serious adverse event rate) between the treat-
&
ment groups [22 ]. Importantly, although not being
statistically significant, there was an almost two-fold
nominal increase in pneumonia rate and mortality
in the therapeutic hypothermia group, a problem
that was also seen in the previous ICTuS-L trial
&
[22 ,23]. This could indicate a systematical bias that
might be inherent to the implementation of thera-
peutic hypothermia to awake stroke patients:
multiple studies showed that therapeutic hypother-
mia in awake patients requires aggressive shivering
control and these measures include prolonged infu-
sions of multiple drugs, which are likely to increase
susceptibility to complications, such as aspiration,
drop of blood pressure and impairment of con-
&
sciousness [22 ,24].
If this observation is also true for nonstroke
patients, has to be investigated, but theoretically
we have to speculate if therapeutic hypothermia
or even strict normothermia, which might also co-
me along with shivering and sedation, may only be
feasible and safe in properly sedated and intubated
patients in an intensive care medicine setting [1,25].
Along with implementing endovascular recan-
alization therapy by intraarterial thrombolysis,
stenting or mechanical clot extraction in patients
with large proximal vessel occlusion into guidelines,
some research groups also developed the idea of
combining endovascular therapy with local brain
cooling [26,27]. This approach should help to min-
imize harmful effects of systemic hypothermia by
only focusing therapeutic hypothermia to the target
tissue the brain. In a small pilot study, 26 patients
with large-vessel occlusion received intraarterial
recanalization combined with infusion of cold phys-
iological saline (48C) into the ischemic territory via
the angiographic catheter within 8 h after symptom
onset [27]. The temperature of ischemic cerebral
tissue was decreased by at least 28C during infusion
of the cold solution, whereas systemic temperature
was only mildly reduced (maximum 0.38C). Further-
more, no obvious complications related to intra-
arterial hypothermia were reported [27]. Of
course, these results can only be regarded as hypoth-
esis generating and have to be reproduced in bigger
randomized trials.
Hong et al. [28] published another promising
trial of therapeutic hypothermia in ischemic stroke.
They investigated the effects of mild systemic
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(endovascular or surface device) hypothermia
(34.58C) in intubated patients with adequate
sedation during a period of 48 h of cooling and
48 h of rewarming versus normothermia after suc-
cessful recanalization therapy. The hypothermia
group (n 39) had less cerebral edema (P 0.001),
hemorrhagic transformation (P 0.016) and better
outcome (P 0.017) compared with the normother-
mia group (n 36) [28]. What especially highlights
their results is: the implementation of therapeutic
hypothermia only in angiographically proven
recanalization; controlled and slow rate of rewarm-
ing (over 48 h); and intubation and deep sedation in
all patients to prevent pneumonia and shivering
[28].
In the light of the results from the pilot studies
mentioned above, the investigation of therapeutic
hypothermia in stroke patients after successful recan-
alization therapy/thrombectomy in adequately pow-
ered and well-performed studies would be necessary
in the future.
TRAUMATIC BRAIN INJURY
TBI represents a significant challenge in healthcare
all over the world, being the leading cause of death
and permanent disability in young adults with
&&
increasing incidence worldwide [29 ,30].
Over more than 30 years, positive results have
been reported in experimental models of TBI dem-
onstrating that modest levels of therapeutic hypo-
thermia induced after the traumatic insult
significantly improve behavioral and histological
outcomes in a number of laboratory settings [31].
Based on these robust laboratory data, clinical
studies were implemented and while some small
pilot trials could show promising findings consecu-
tive randomized larger studies raised questions and
uncertainties regarding the use of therapeutic hypo-
thermia in the head-injured patient [32,33]. In 2001
and 2011, Clifton et al. [33] published two large
multicenter studies that found either no difference
or worse outcome in the hypothermia groups [34].
Noteworthy, a subgroup analysis of the 2011 pub-
lished NABIS H-II study revealed an improved out-
come in patients with evacuated hematomas, which
did not occur in patients with diffuse brain injury
[33]. This subgroup is currently under further explo-
ration in the HOPES trial conducted in multiple US
centers (HypOthermia for Patients requiring Evacu-
ation of Subdural Hematoma: A Multicenter,
Randomized Clinical TrialClinicalTrials.gov Iden-
tifier: NCT02064959).
A factor that is strongly associated with secon-
dary neuronal injury and unfavorable outcome in
TBI patients is elevation of ICP in the course of
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Role for hypothermia in neurocritical care Frank and Broessner
the disease. Theoretically, therapeutic hypothermia
can be administered either early after injury and
prior to ICP elevation (i.e. referred to as prophy-
lactic) or as a consequence for refractory ICP
elevation (i.e. referred to as therapeutic). Especially
after the failure of the NABISH II (the National Acute
Brain Injury Study: Hypothermia II) trial in which
prophylactic therapeutic hypothermia [33358C for
48 h versus normothermia (378C)] could not show
any outcome difference, some authors focused on
the use of therapeutic hypothermia in patients with
&&
TBI and elevated ICP only [4 ,33].
In a recent mainly European-based study, adult
patients with TBI and ICP monitoring devices (and
ICP > 20 mm despite mechanical ventilation and
sedation management) were randomized either
to standard care (control group) or hypothermia
(32358C) and standard care. Despite being ICP
guided, this study was terminated prematurely after
387 patients, because an interim analysis using the
Extended Glasgow Outcome Scale (GOS-E) indi-
cated a worse outcome in the hypothermia group
compared with the control group [1.53 (95% confi-
dence interval, 1.022.30; P 0.04)] [4 ].
&&
As a consequence of all this, the just updated
Brain Trauma Foundation Guidelines do not recom-
mend early (within 2.5 h) or short-term (48 h post-
injury) prophylactic hypothermia to improve
&&
outcomes in patients with diffuse brain injury [29 ].
Many clinical trials have only focused on a cool-
ing period over 48 h, an interval probably too short
to cover all the deleterious secondary processes post
TBI. Some authors therefore propose therapeutic
hypothermia for up to 5 days post TBI and investi-
gate this in current trials [long-term mild hypother-
&&
mia for severe TBI (the LTH-1 trial)] [35 ,36].
ELEVATED INTRACRANIAL PRESSURE
The mechanisms by which therapeutic hypother-
mia can reduce ICP are thought to be multifactorial,
mainly driven through stabilization of the BBB,
decrease in cerebral blood volume via matched
reduction of cerebral metabolic requirement, vaso-
genic edema limitation, minimization of local
thermo-pooling and anti-inflammatory effects (see
&&
also Fig. 1) [5,37 ].
In 2003, Henderson et al. [38] published the
results of a systematic review analyzing eight studies
comprising 748 patients with severe TBI and TTM.
Pooled analysis revealed that therapeutic hypother-
mia had an effect on elevated ICP; however, no
significant effect on outcome and increased rate
of pneumonia in the therapeutic hypothermia
group was observed.
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In 2009, Schreckinger and Marion [39] pub-
lished a systematic review comprising the literature
from 1975 to 2008 in order to examine the short-
term metabolic or physiologic effects of therapeutic
hypothermia and its beneficial effect on brain swel-
ling and to set the effect of therapeutic hypothermia
in context with other conventional measures to
control ICP. On the basis of results of 11 prospective
RCTs that compared ICP levels with hypothermia
versus normothermia and six prospective cohort
studies that provided ICP data before and during
hypothermia, they found a mean ICP reduction
with therapeutic hypothermia of 10 mmHg; this
effect was lowest with ICP reduction of 6 mmHg
for hyperventilation, 8 mmHg for mannitol and
barbiturates, 15 mmHg for hypertonic saline and
CSF drainage and highest with 19 mmHg for decom-
pressive craniectomy [39]. Furthermore, therapeutic
hypothermia effectively lowered ICP in patients
who were refractory to the sustained application
of all three hyperventilation, mannitol and barbitu-
&&
rate coma [37 ,39].
IS PROPHYLACTIC NORMOTHERMIA THE
FUTURE?
If the concept of strictly avoiding fever in the acute
phase of a disease, by maintaining normothermia
(i.e. body core temperature 36.58378C) using feed-
back driven devices, is a seminal concept, has to be
further evaluated in well-designed RCTs
CONCLUSION
Taken together, there is a large body of evidence
that fever (i.e. body core temperature > 38.38C) is
associated with increased mortality and morbidity
[i.e. long-term outcome (Glasgow Ouctome Scale
and modified Rankin Scale), hospital and ICU
length of stay] in patients with acute severe
neuronal injury [17,18]. Experimental studies,
including strict meta-analyses, investigating thera-
peutic hypothermia have consequently shown a
significant benefit in various models (ischemic
stroke, ICH, TBI and elevated ICP), but the reprodu-
cibility of these more than promising results in
randomized controlled human trials is limited
because of complex reasons; therefore, the appli-
cation of therapeutic hypothermia outside of
strictly supervised clinical trials has to be con-
sidered absolutely carefully.
However, we strongly believe that up-to-date
neurological care should always include continuous
temperature recording and active counteracting of
fever following a predefined standardized protocol.
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Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
G.B. received travel grants for scientific conferences and
honoraria for lectures from Bard Medical and Zoll
Medical Austria. He received honoraria for consulting
from Zoll Medical Austria. F.F. received travel grants for
scientific conferences from Bard Medical and Zoll
Medical Austria.
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been highlighted as:
& of special interest
&& of outstanding interest
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This article includes the current recommendations of the Brain Trauma Foundation
on Traumatic Brain Injury and TTM, released in 2016.
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37. Lazaridis C, Robertson CS. Hypothermia for increased intracranial pressure:
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