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Brain Injury, July 2012; 26(7–8): 899–908

REVIEW

Therapeutic hypothermia for the management of intracranialhypertension in severe traumatic brain injury: A systematic review

FARID SADAKA1 & CHRISTOPHER VEREMAKIS2

1St. John’s Mercy Medical Center, St Louis University, St Louis, MO, USA, and 2Center for Innovative Care at

Sisters of Mercy Health System, Critical Care Medicine/NeuroCritical Care, Mercy Hospital St Louis/St Louis

University Hospital, St Louis, MO, USA

(Received 5 September 2011; revised 27 December 2011; accepted 23 January 2012)

AbstractBackground: Traumatic brain injury (TBI) is a major source of death and severe disability worldwide. Raised Intracranialpressure (ICP) is an important predictor of mortality in patients with severe TBI and aggressive treatment of elevated ICPhas been shown to reduce mortality and improve outcome. The acute post-injury period in TBI is characterized by severalpathophysiologic processes that start in the minutes to hours following injury. All of these processes aretemperature-dependent; they are all aggravated by fever and inhibited by hypothermia.Methods: This study reviewed the current clinical evidence in support of the use of therapeutic hypothermia (TH) for thetreatment of intracranial hypertension (ICH) in patients with severe TBI.Results: This study identified a total of 18 studies involving hypothermia for control of ICP; 13 were randomized controlledtrials (RCT) and five were observational studies. TH (32–34�C) was effective in controlling ICH in all studies. In the 13RCT, ICP in the TH group was always significantly lower than ICP in the normothermia group. In the five observationalstudies, ICP during TH was always significantly lower than prior to inducing TH.Conclusions: Pending results from large multi-centre studies evaluating the effect of TH on ICH and outcome, TH should beincluded as a therapeutic option to control ICP in patients with severe TBI.

Keywords: Hypothermia, ICP, intracranial hypertension, TBI, traumatic brain injury

Introduction

Traumatic brain injury (TBI) is a major source ofdeath and severe disability worldwide. In the USalone, this type of injury causes 290 000 hospitaladmissions, 51 000 deaths and 80 000 permanentlydisabled survivors [1, 2]. Intracranial hypertensiondevelops commonly in acute brain injury related totrauma [3, 4]. Raised Intracranial Pressure (ICP) isan important predictor of mortality in patients withsevere TBI and aggressive treatment of elevated ICPhas been shown to reduce mortality and improveoutcome [4–11]. Guidelines for the Management ofSevere TBI, published in the Journal of Neurotrauma

in 2007 [12] make a Level II recommendation that

ICP should be monitored in all salvageable patientswith a severe TBI (Glasgow Coma Scale [GCS]score of 3–8 after resuscitation) and an abnormalcomputed tomography (CT) scan. ICP monitoringis also recommended in patients with severe TBI anda normal CT scan if two or more of the followingfeatures are noted at admission: age over 40 years,unilateral or bilateral motor posturing or systolicblood pressure <90 mm Hg (Level III recommenda-tion). Furthermore, ICP should be maintained atless than 20 mmHg and cerebral perfusion pressure(CPP) between 50–70 mmHg (Level III).

As in ischemia–reperfusion injuries, the acutepost-injury period in TBI is characterized by several

Correspondence: Farid Sadaka, 621 S. New Ballas Rd, suite 4006B, St. Louis, MO, 63141, USA. Tel: 214-251-6486. Fax: 314-251-4155.E-mail: [email protected]

ISSN 0269–9052 print/ISSN 1362–301X online � 2012 Informa UK Ltd.DOI: 10.3109/02699052.2012.661120

pathophysiologic processes that start in theminutes-to-hours following injury and may last forhours-to-days. These result in further neuronalinjury and are termed the secondary injury.Cellular mechanisms of secondary injury include allof the following: apoptosis, mitochondrial dysfunc-tion, excitotoxicity, disruption in ATP metabolism,disruption in calcium homeostasis, increase ininflammatory mediators and cells, free radical for-mation, DNA damage, blood–brain barrier disrup-tion, brain glucose utilization disruption,microcirculatory dysfunction and microvascularthrombosis [13–50]. All of these processes aretemperature-dependent; they are all aggravated byfever and inhibited by hypothermia [13–50].In addition, several studies have shown that devel-opment of fever following TBI is closely linked tointracranial hypertension and worsened out-come [51–53]. This evidence has led many author-ities to recommend that fever (temperature)management (hypothermia or normothermia) beimplemented in the routine therapeutic strategiesto control intracranial hypertension, mitigate sec-ondary injury and possibly improve outcome.

Clinical trials of hypothermia and temperaturemanagement for severe traumatic brain injury aredivided into trials in which hypothermia is used totreat elevated intracranial pressure and those inwhich hypothermia is intended as a neuroprotectant,irrespective of intracranial pressure. Results havebeen disappointing regarding the use of hypothermiaas a neuroprotectant for severe TBI patients[54–56]. These studies have been criticized for thesmall number of patients, multiple methodologicalproblems and the complexities (control of variables,heterogenous populations) of such trials [57]. Theuse of hypothermia as a neuroprotectant for TBIpatients is not the focus of this review. This articlewill review the current clinical evidence in support ofthe use of therapeutic hypothermia and temperaturemanagement for the treatment of intracranial hyper-tension (ICH) in patients with severe TBI.

Methods

This study queried the Medline database with theMeSH terms ‘Hypothermia, induced’, ‘Fever’,‘Intracranial Hypertension’ and ‘Traumatic BrainInjury’ from 1993–2010. It utilized both PubMedand OVID to maximize database penetration. TheCochrane Database of Systematic Reviews wassearched. The authors also hand-searched bibliog-raphies of relevant citations and reviews. Inclusioncriteria were double-blind, placebo-controlled, ran-domized controlled trials (RCTs), observationalstudies or meta-analyses of therapeutic hypothermia

for TBI patients in which ICPs are monitored. Thesearch was limited to human literature; language wasnot limited, but studies were extracted that involvedonly adult subjects excluding studies on the paedi-atric population. Information extracted includednumber of patients, ICP, length of cooling, lengthof re-warming, outcome, complications, methodsused to control ICP and the quality of each study.This study reviewed the literature pertaining topathophysiology of TBI. The literature pertainingto major published guidelines in this area were alsoreviewed.

Results

This review identified a total of 18 studies involvinghypothermia for control of ICP; 13 were randomizedclinical trials and five were observational studies, asshown in Tables I and II, respectively [54, 58–74].In all studies, the patient populations were com-prised of TBI patients with GCS<9 and an abnor-mal CT scan. ICP monitors were inserted in allpatients to measure ICP. Individual study sizesranged from 9–396 patients; a total of 1773 patientswere included in this review. Only three studies weremulti-centre [54, 72, 74]. The goals of therapy werestabilization or improvement of the patient’s neuro-logical condition and maintenance of an ICP of20 mm Hg or less (normal value in healthy subjects:�15 mm Hg) and a cerebral perfusion pressure(CPP¼MAP–ICP) of 60 mm Hg or more or70 mm Hg or more. In patients with ICP higherthan 20 mm Hg, initial (standard) treatmentincluded appropriate sedatives, narcotics, treatmentwith neuromuscular blockers (for ICP control and/orshivering) and administration of hyperosmolar ther-apy. Neurosurgical interventions were undertakenwhen necessary to evacuate subdural lesions or largeintracerebral lesions [58, 61, 63, 64, 66–74]. In ninestudies, there was no mention at all of the use of bar-biturates for ICP control [60, 62, 64, 68, 69, 71–74].In five of the studies, therapeutic hypothermia wasapplied after elevated ICP failed to respond toadequate sedation, hyperosmolar therapy and barbi-turates [58, 63, 65–67]. In the other four studies[54, 59, 61, 70], patients were randomized tohypothermia or normothermia irrespective of ICP,with the goal of studying hypothermia’s role as aneuroprotectant. ICP control was looked at as asecondary outcome in these four studies.

Target temperature (32–34�C) was achieved veryquickly in most studies. Therapeutic hypothermiawas maintained from 24 hours up to 14 daysdepending on the study protocols. Some studiesachieved re-warming passively over 10–24 hours[67, 70, 71, 73], but most studies achieved slow

900 F. Sadaka & C. Veremakis

active rewarming over 12–24 hours, as shown inTables I and II. In one study, hypothermia mainte-nance for 5 days was associated with less reboundICH than hypothermia for 2 days [72]. Therapeutichypothermia was effective in controlling ICH in allstudies, as shown in Tables I and II and Figure 1. Inthe 13 RCT, ICP in the therapeutic hypothermiagroup was always lower than ICP in the normother-mia group, and this difference always reachedstatistical significance, as evidenced in Table I andFigure 1. In the five observational studies, ICPduring hypothermia was always lower then prior toinducing hypothermia; this difference also alwaysreached statistical significance, as shown in Table II.Therapeutic hypothermia also improved neurologicoutcome and survival in 11 of the studies, as can beseen in Table I.

Discussion

TBI and ICP

In comatose patients with TBIwith an abnormal CTscan, the incidence of ICH was 53–63% [75].Patients with a normal CT scan at admission, onthe other hand, had a relatively low incidence of ICH(13%). However, within the normal CT group, ifpatients demonstrated at least two of three adversefeatures (age over 40 years, unilateral or bilateralmotor posturing, or systolic BP <90 mm Hg); theirrisk of ICH was similar to that of patients withabnormal CT scans [75]. ICP is a strong predictor ofoutcome from severe TBI [5, 6, 9, 76–78]. Becauseof this, ethically a randomized trial of ICP monitor-ing with and without treatment is unlikely to becarried out. Similarly, a trial for treating or nottreating systemic hypotension is not likely. Bothhypotension and raised ICP are the leading causes ofdeath in severe TBI. Furthermore, several studieshave shown that patients who do not have ICH orwho respond to ICP-lowering therapies have a lowermortality than those whose ICH does not respond totherapy [4–11, 79–82]. As a result, Guidelines forthe Management of Severe TBI recommend thattreatment should be initiated with ICP thresholdsabove 20 mm Hg (level II) as well as target a cerebralperfusion pressure (CPP) within the range of 50–70(level III) [12]. Prevention and/or treatment of ICHis commonly accomplished by employing a progres-sion of therapeutic approaches that are efficacious incontrolling ICP and uniformly believed to be easilyapplied with minimal or rare negative side-effects.These measures include elevation of the head of thebed, avoiding hypotension, hypoxia and hypercap-nea or prolonged hypocapnea, intravenous sedationand analgesia, episodic administration of hyperos-molar agents (mannitol, hypertonic saline) and CSF

drainage [12]. Reviewing the evidence behind allthese aforementioned therapies is beyond the scopeof this review, but the evidence of efficacy for all ofthese treatments is variable at best. They arerecommended not so much because there is clear-cut proof of morbidity or mortality benefit butbecause they are deemed treatments without asignificant downside.

Barbiturates for ICP control

High-dose barbiturate administration is recom-mended to control elevated ICP refractory to max-imum standard medical and surgical treatment(level II) [12]. High-dose barbiturates have beenscarcely studied for this indication. In 2004, theCochrane Injuries Group performed a systematicreview of the barbiturate RCTs. In the only twostudies examining the effect on ICP, the relative riskfor refractory ICP with barbiturate therapy was 0.81(95% CI 0.62–1.06). Concerning this indication, theCochrane group concluded:

There is no evidence that barbiturate therapy inpatients with acute severe head injury improvesoutcome. Barbiturate therapy results in a fall inblood pressure in one of four treated patients. Thehypotensive effect of barbiturate therapy will offsetany ICP lowering effect on cerebral perfusionpressure [83].

Significant side-effects of barbiturates include hypo-tension, arrhythmias, immunosuppression, hepato-toxicity, fever and injection site reactions. TheGuidelines for the Management of Severe TBIrecommend that more studies are needed to identifyalternative agents for this indication—‘elevated ICPrefractory to standard therapy’ [12]. Albeit small,there are more RCT evaluating the effect of thera-peutic hypothermia on ICH in severe TBI(13 studies) than for barbiturates, as presented inTable I; all consistently demonstrating that hypo-thermia is effective in controlling ICP. Yet theGuidelines for the Management of Severe TBI [12]make a Level II recommendation that high-dosebarbiturate administration is recommended to con-trol elevated ICP refractory to maximum standardmedical and surgical treatment.

Therapeutic hypothermia for ICP control

Multiple trials, albeit observational or small singlecentre randomized controlled studies, show thatmild-to-moderate hypothermia consistently lowershigh ICP in patients with severe TBI, as shown inFigure 1. It is an accepted premise in the care ofpatients with severe TBI that control of ICPimproves survival and possibly neurologic outcome.

Hypothermia for ICP control in severe TBI 901

Tab

leI.

Eff

ects

of

hyp

oth

erm

iaon

intr

acra

nia

lp

ress

ure

and

ou

tcom

ein

pat

ien

tsw

ith

seve

retr

aum

atic

bra

inin

jury

:R

and

om

ized

con

trolled

tria

ls.

Ref

eren

ceN

o.

of

pat

ien

tsIC

P(n

orm

)IC

P(H

ypo)

Len

gth

of

coolin

gL

engt

hof

rew

arm

ing

Com

plica

tion

sof

hyp

oth

erm

iaO

utc

om

e

Sh

ioza

kiet

al.

[58]

33

35.4

25

(p<

0.0

1)

48

hou

rs24

hou

rsN

od

iffe

ren

ce6

mon

thsu

rviv

al(5

0%

vs18%

,p<

0.0

5)

Dea

thfr

om

un

con

-tr

olled

ICH

(31%

vs71%

,p<

0.0

5)

Mar

ion

etal

.[5

9]

40

ICP>

20

(25%

)IC

P>

20

(13%

)(p<

0.0

01)

24

hou

rs12

hou

rsN

od

iffe

ren

ce3

mon

thgo

od

GO

S(6

0%

vs40%

,p<

0.2

4)

Mar

ion

etal

.[6

1]

82

19.7

15.4

(p¼

0.0

1)

24

hou

rs12

hou

rsE

leva

ted

PT

T,

dec

reas

edp

ota

ssiu

m

12

mon

thgo

od

neu

ro-

logi

cou

tcom

e(6

2%

vs38%

,p¼

0.0

5)

Jian

get

al.

[64]

87

29.6

18.9

(p<

0.0

1)

3–1

4d

ays

1�C

h�

1—

1ye

argo

od

GO

S(4

6.5

%vs

27.3

%,

p<

0.0

5)

1ye

arm

ort

alit

y(2

5.6

%vs

45.5

%,

p<

0.0

5)

Clift

on

etal

.[5

4]

392

ICP>

30

(59%

)IC

P>

30

(41%

)(p¼

0.0

2)

47

hou

rs18

hou

rs(0

.�C

h�

1)

Hyp

ote

nsi

on

,b

rad

ycar

dia

No

dif

fere

nce

Pold

erm

anet

al.

[65]

41

36

15

(p<

0.0

1)

n/a

n/a

Hyp

om

agn

esem

-ia

,h

ypoca

lcem

ia,

hyp

oka

lem

ia,

hyp

op

hosp

hat

emia

No

dif

fere

nce

Pold

erm

anet

al.

[66]

136

37

<20

(p<

0.0

1)

4.8

day

s1�C

/12

hou

rsar

ryth

mia

s6

mon

thgo

od

GO

S(1

5.7

%vs

9.7

%,

p<

0.0

2)

Mort

alit

y(6

2%

vs72%

,p<

0.0

5)

Gal

etal

.[6

7]

30

18

12

(p¼

0.0

007)

72

hou

rsp

assi

ve—

6m

on

thgo

od

GO

S(8

7%

vs47%

)Z

hi

etal

.[6

8]

396

26.9

14.8

(p<

0.0

5)

1–7

day

s(M¼

62

hou

rs)

16–2

0h

ou

rs(1�C

/4h

ou

rs)

hyp

oka

lem

ia6

mon

thG

ood

GO

S(3

8.8

%vs

19.7

%,

p<

0.0

5)

Mort

alit

y(2

5.7

%vs

36.4

%,

p<

0.0

5)


Sm

rcka

etal

.[7

0]

72

Pri

mar

y(1

8.9

)E

xtra

cere

bra

l(1

6.6

)

Pri

mar

y(1

0.8

)(p<

0.0

001)

Ext

race

reb

ral

(13.2

)(p¼

0.1

)

72

hou

rsp

assi

veb

rad

ycar

dia

Pri

mar

y(6

mon

thG

OS

:p¼

0.4

4)

Ext

race

reb

ral

(6m

on

thG

OS

:3–5

,p¼

0.0

006)

Tota

l6

mon

thgo

od

GO

S(8

5%

vs48.5

%)

Qiu

etal

.[7

1]

86

24

hou

rs:

32.6

48

hou

rs:

34.8

72

hou

rs:

31.8

27.3

(p<

0.0

5)

29.4

(p<

0.0

5)

26.4

(p<

0.0

5)

3–5

day

sP

assi

ve(u

pto

24

hou

rs)

Pn

eum

on

ia,

thro

mb

ocy

top

enia

2ye

argo

od

GO

S(6

5%

vs37%

,p<

0.0

5)

Mort

alit

y(2

5.6

%vs

51.2

%,

p<

0.0

5)

Jian

get

al.

[72]

215

28

(2d

ayh

ypoth

erm

ia)

18

(5d

ayh

ypoth

erm

ia)

2d

ays

vs5

day

s1�C

h�

1M

ore

reb

ou

nd

incr

ease

inIC

Pin

2d

aygr

ou

p(p<

0.0

5)

Pn

eum

on

iaan

dar

rhyt

hm

ias

(sim

ilar

)

6m

on

thgo

od

GO

S(4

3.5

%in

5d

aygr

ou

pvs

29%

in2

day

grou

p,

p<

0.0

5)

Qiu

etal

.[7

3]

80

24

hou

rs:

25.8

48

hou

rs:

25.9

72

hou

rs:

24.6

23.5

(p¼

0.0

0)

24.6

(p¼

0.0

0)

22.5

(p¼

0.0

03)

4d

ays

Pas

sive

(10–2

4h

ou

rs)

Pn

eum

on

ia,

thro

mb

ocy

top

enia

1ye

argo

od

neu

rolo

gic

ou

tcom

eG

OS

(70%

vs47.5

%,

p¼

0.0

41)

GO

S,

Gla

sgow

Ou

tcom

eS

core

.


It follows, therefore, that induced hypothermia inpatients with poorly controlled ICP may bea reasonable therapeutic strategy when routinesedation, analgesia and neuromuscular paralysisfail. This benefit would be relevant regardless ofany cellular or metabolic neuroprotective effect.Indeed, the additional potential neuroprotectivebenefits suggest that therapeutic hypothermia ifwithout negative side-effects should be implementedas a part of routine ICP control rather than as rescuetherapy.

Side-effects of therapeutic hypothermia in TBI

Complications from hypothermia included electro-lyte imbalances, increase in incidence of infections,thrombocytopenia, coagulopathy, arrhythmias(especially bradycardia), pancreatitis and reboundICH (during re-warming), as presented in Tables Iand II. In one extensive review, Povlishock et al. [84]showed that post-traumatic hypothermia followedby slow rewarming appeared to provide maximalprotection in terms of traumatically induced axonaldamage, microvascular damage and dysfunction,contusional expansion, intracranial hypertensionand neurocognitive recovery. In contrast, hypother-mia followed by rapid rewarming not only reversedthe protective effects associated with hypothermicintervention, but exacerbated the traumatically-induced pathology and its neurologic consequences.Povlishock and Wei’s review concluded that the rateof post-hypothermic rewarming is an importantvariable in assuring maximal efficacy following theuse of hypothermic intervention. Two meta-analyses[12, 85] also showed that duration >48 hours andslow rewarming were associated with improvedoutcome.

Recommendation

It is puzzling why barbiturates with well-knownnegative side-effects are recommended while hypo-thermia with its known efficacy in controlling ICH isnot. The reasons for this may be the relativeinexperience with TH, complexity of TH imple-mentation, concerns for adverse reactions and theneed for sophisticated technology [86, 87]. In 2002,studies have indicated that TH with a reduction ofbody core temperature (T) to 33�C over 12–24hours has improved survival and neurologic outcomein cardiac arrest patients [88, 89]. A meta-analysisshowed that therapeutic hypothermia for cardiacarrest patients was associated with a risk ratio of 1.68(95% CI, 1.29–2.07) favouring a good neurologicoutcome when compared with normothermia [90].The number needed to treat (NNT) to generate onefavourable neurological recovery was 6.Subsequently, the International Liaison Committee

Tab

leII

.E

ffec

tsof

hyp

oth

erm

iaon

intr

acra

nia

lp

ress

ure

and

ou

tcom

ein

pat

ien

tsw

ith

seve

retr

aum

atic

bra

inin

jury

:N

on

-ran

dom

ized

ob

serv

atio

nal

tria

ls.

Ref

eren

ceN

o.

of

pat

ien

tsIC

P(p

re)

ICP

(Hyp

o)

Len

gth

of

coolin

gL

engt

hof

rew

arm

ing

Com

plica

tion

sof

hyp

oth

erm

iaO

utc

om

e

Met

zet

al.

1996

10

24

14

(p<

0.0

5)

25

hrs

22

hrs

Th

rom

bocy

top

enia

,d

ecre

ased

crea

tin

ine

clea

ran

ce,

pan

crea

titi

s

7p

atie

nts

(good

reco

very

)1

pat

ien

t(s

ever

ed

isab

ilit

y)2

pat

ien

ts(d

ead

)

Nar

aet

al.

[62]

920

12

(p<

0.0

5)

n/a

n/a

n/a

3m

on

thgo

od

GO

S(8

/9¼

88.8

%)

Tat

eish

iet

al.

[63]

924

15

(p<

0.0

5)

20–1

18

hou

rs(M¼

68

hou

rs)

<1�C

/6h

ou

rsIn

fect

ion

,in

crea

seC

RP

,th

rom

bocy

top

enia

Good

GO

S7/9

Toku

tom

iet

al.

[69]

31

24

14

(p<

0.0

001)

48–7

2h

ou

rsn

/ap

neu

mon

ia6

mon

thG

ood

GO

S(1

9%

)M

ort

alit

y(4

8%

)S

ahu

qu

illo

etal

.[7

4]

24

23.8

16.8

(p<

0.0

01)

155

hou

rs1�C

/day

arry

thm

ias

6m

on

thN

euro

logi

cou

tcom

e(G

ood

:29.2

%,

mod

erat

e:8.3

%)


on Resuscitation [91] and the American HeartAssociation [92] recommended the use of TH aftersudden cardiac arrest. As a result, intensivists andneurointensivists have become much more familiarwith the methodology (following cardiac arrest) sothat the process is now familiar. Also, with appro-priate hypothermia protocols, order sets and educa-tion programmes, mild hypothermia can beaccomplished with very few side-effects. It is impor-tant to note, however, that there are importantdifferences between short duration hypothermiafollowing cardiac arrest and long-term hypothermiain patients with TBI and ICH who frequently alsohave extra-cranial injuries and extra attention to theabove-mentioned side-effects should be applied.Hypothermia should no longer be viewed as avantguard or dangerous and the authors believe that itshould take the place of barbiturates as the bestmodality for refractory ICH. Indeed, there is anargument, pending large scale studies, to consider itan extension of standard treatment.

An ongoing trial (The Eurotherm3235trial,www.eurotherm3235trial.eu) will examine the rela-tionship between ICP reduction after TBI usingtherapeutic hypothermia and patient outcome. Thetrial will enrol patients with TBI who have ICP>20 mmHg that is resistant to stage 1 therapy.Pending large multi-centre, randomized, controlledtrials evaluating the effect of hypothermia on ICPcontrol and outcome, the available data suggests thattherapeutic hypothermia deserves at least a level IIevidence recommendation for the treatment ofrefractory ICH.

Conclusion

Preliminary evidence points to the effectiveness ofmild-to-moderate therapeutic hypothermia in

controlling ICH in patients with severe TBI. Theexperience with induced hypothermia in the treat-ment of post-cardiac arrest patients has demon-strated an acceptable safety profile when themodality is applied in specialized units by experi-enced personnel according to a defined protocol. Inaddition, the above-mentioned studies of therapeutichypothermia in patients with TBI show that theadverse effects of hypothermia are reasonable andmanageable when hypothermia is done in specializedand experienced ICUs. Pending results from largemulti-centre studies evaluating the effect of thera-peutic hypothermia on ICH and outcome, thera-peutic hypothermia should be included as atherapeutic option to control ICP in patients withsevere TBI. The most challenging issue appears tobe rebound ICP during re-warming. It is suggestedthat re-warming only be considered if the patient’sICP is stable and <20 mm Hg for at least 48 hoursand thereafter implemented at a rate not faster than0.25�C per hour.

Declaration of Interest: The authors report noconflicts of interest. All authors declare that nocompeting financial interests exist. All authors reportthat no potential conflicts of interest exist with anycompanies/organizations whose products or servicesmay be discussed in this article.

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Figure 1. Effect of hypothermia on intracranial pressure (ICP).


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