ORIGINAL ARTICLE

KUMPULAN ARTIKEL

KEPERAWATAN GAWAT DARURAT

Dosen Pembimbing: Nugroho Ari., S.Kep., Ns., M.Kep

Oleh:
Fira Yuniar Laraswati 20171660021

PROGRAM STUDI S1 KEPERAWATAN

FAKULTAS ILMU KESEHATAN
UNIVERSITAS MUHAMMADIYAH SURABAYA
TAHUN AKADEMIK 2020
 ORIGINAL ARTICLE
Indonesian Journal of Neurosurgery (IJN) 2019, Volume 2, Number 1: 5-
11
P-ISSN.2089-1180, E-ISSN.2302-2914

Induced hypothermia for traumatic brain

injury: A systematic review

Rizki Meizikri1*, Galuh Indiradini2

ABSTRACT

Introduction: Traumatic Brain Injury (TBI) is one of major

were included. Relevant journals were then reviewed using
causes of morbidity and mortality, which requires efficacious
Study Appraisal Tool from CEBM.
treatment strategy. Hypothermia has long been used for TBI,
Results: There were no statistically significant differences
but evidences regarding this treatment remain inconclusive.
between hypothermia group and normothermia group in the two
This study aims to review the existing evidence of induced
included studies in terms of functional outcome, mortality, and
hypothermia on functional outcome, mortality, and the rate of
pneumonia. Concerning functional outcome, one of the studies
pneumonia acquired during hospitalization among TBI
yield relative risk reduction (RRR) of -0.4, while the other
patients.
one had an alarming number needed to treat (NNT) of 92.62
Methods: This study is a systematic review. Major online despite positive RRR. Both studies had negative RRR for
databases (Cochrane Library, PubMed, Science Direct, and mortality and pneumonia, indicating the harm of
EBSCO host) was searched using the following keywords: hypothermia for TBI patients.
Traumatic Brain Injury AND Hypothermia OR Normothermia,
Conclusions: There is no evidence that TBI patients would
and narrowed down further to journals published within the
benefit from hypothermia in terms of functional outcome,
last 5 years. Only Randomized Controlled Trials (RCTs) which
mortality, and pneumonia incident.
met the predefined inclusion criteria

Keywords: Hypothermia, systematic review, traumatic brain

injury
Cite This Article: Meizikri, R., Indiradini, G. 2019. Induced hypothermia for traumatic brain injury: A systematic review. Indonesian
Journal of Neurosurgery 2(1): 5-11. DOI:10.15562/ijn.v2i1.57

1
Neurosurgery Department,
Faculty of Medicine,
Universitas Airlangga/ Dr.
Soetomo General Hospital
Surabaya, Indonesia 2Faculty
of Medicine, Brawijaya
University, Malang, Indonesia
* Correspondence to:
Rizki Meizikri;
Neurosurgery Department, Faculty Hypothermia is thought to exert neuroprotective
of Medicine, Universitas Airlangga/
Dr. Soetomo General Hospital
Surabaya, Indonesia;
rizkimz@gmail.com
Received: 2019-03-18
Introduction
Traumatic brain injury (TBI) is one of major
causes of morbidity and mortality among
predominantly younger population.1,2 In Europe,
TBI is responsible for one million hospital
admission.3,4 The deleterious impacts of TBI are
mainly the aftermath of secondary brain injury, a
complex pathophysiological process which
perpetuates the initial insult, triggers intracranial
pressure to raise
and, ultimately, causes mortality and morbidity.5,6,23
Hypothermia has long been used for TBI to
lower intracranial pressure (ICP), but the
evidence for this treatment are inconsistent.7,23
effect through several mechanisms, including
lowering cerebral metabolic rate, inflammation,
excitotoxicity, and preventing blood brain
barrier disruption.1,8,9,10,11
Several studies revealed that hypothermia yield
better neurological outcome among post-cardiac
arrest patients.12,13 Earlier studies reported that
Accepted: 2019-03-22
decrease in ICP.14 In contrast, some RCTs on
hypothermia for TBI patients failed to demonstrate
significant difference in GOS at six months after
injury nor in mortality.2,15
Hypothermia is also known to elicit
complications, namely cardiac arrhytmias,
hypokalemia, and infections, particularly
pneumonia. While it is said that complications
rarely occur as long as temperature does not
trespass
32oC, a meta-analysis found that therapeutic
hypothermia increases the incidence of pneumonia
among post-cardiac arrest patients.16,17,18
Because of the uncertainty surrounding this
topic, we feel encouraged to look at the current
evidence and find out whether or not
hypothermia is beneficial for TBI.
METHODS
Criteria of included studies
Typeofstudiesincludedwas Randomized Controlled
Published: 2019-04-01
 ORIGINAL ARTICLE
hypothermia outcome. One of them reported better Glasgow Trials (RCTs) comparing the outcome between
for TBI did Outcome Score (GOS), while the other reported hypothermia (32o - 35oC) and normothermia.
result in better significant The method to achieve the aforementioned

Published
Open access:
by DiscoverSys
https://ina-jns.org/
| IJN 2019; 2(1): 5-11 | doi: 10.15562/ijn.v2i1.57 5
Table 1. Search keywords and search results
and rewarming before 48 hours or after 72 hours
Selected of hypothermia were excluded.
Database Search Strategy Hits
Articles
(traumatic brain injury) AND Outcome measures
Pubmed 20 1 The primary outcome of this study was outcome
(hypothermia OR normothemia)
at three or six months after injury, measured with
(traumatic brain injury) AND either Glasgow Outcome Score (GOS), Extended
Science Direct 122 0
(hypothermia OR normothemia)
Glasgow Outcome Score (GOS-E), or any other
(traumatic brain injury) AND methods or scoring system which can clearly
Cochrane 156 1 define functional outcome. Secondary outcome
(hypothermia OR normothemia)
were mortality of all-cause up to six months after
(traumatic brain injury) AND TBI and pneumonia acquired during
Ebsco Host 63 0
(hypothermia OR normothemia) hospitalization.

Search method for identification of studies

Literatures were searched on 14 and 17 April 2017
in Pubmed, Science Direct, Cochrane, and Ebsco
Host using keywords combination of Boolean
technique, as seen on Table 1.

Figure 1. Flow diagram of literature search and
retrieved results
temperature range is not limited to certain physical
or pharmacologic intervention, but should begin
within six hours of injury and last for 48 – 72
hours before initiation of rewarming. Participants
of the included studies are patients admitted to
hospital due to traumatic brain injury, regardless of
the severity. Studies should be published within
the last five years and are written in English. Non-
english publication, non-RCT studies,
inavailability of full- text, hypothermia
commenced after six hours from TBI onset,
hypothermia outside the requisite range,
6 10.15562/ijn.v2i1.57
RESULTS
The literature search result is illustrated in Figure
1. After exclusion process based on the predefined
criteria and eligibility check, two randomized
controlled trials by John Beca et al. and P David
Adelson et al. were critically appraised. The
summary is on Table 2. and the risk of biases, as
assessed using Review Manager, version 5.2
software (RevMan; Cochrane Collaboration,
Oxford, UK), can be seen on Table 2.
Literatures were excluded mainly due to either
being published beyond five years, prolonged
hypothermia, or hypothermia interventions done
beyond first six hours of injury’s onset. Inclusion
criteria were set to specify hypothermia range,
hypothermia onset, and hypothermia duration
to diminish heterogeneity among studies. Age
group was not among our inclusion criteria, but
coincidentally the two included RCTs were both
on children and adolescents, with slight
differences in age range (Beca et al. 1-16 years
old, Adelson et al 0-17 years old). The
hypothermia range applied were identical: 32 –
33oC. Both studies set functional outcome,
mortality, and pneumonia – among others – as
their studies’ outcomes.
Qualities of RCTs were weighed using GRADE
criteria (The Grades of Recommendation,
Assessment, Development and Evaluation
Working Group 2004) and deemed to be of high
quality, as agreed upon by both authors.
Randomization of patients in Beca et al. trial
used variable block sizes and was conveyed by
telephone to the coordinating center where
sequentially numbered opaque envelopes were
used. It is therefore safe to say that the random
sequence generation and allocation concealment
in this trial were unlikely to be biased. Through

10.15562/ijn.v2i1.57 7
ORIGINAL ARTICLE

Table 2. Comparison of baseline characteristic of both studies

Beca et al. Adelson et al.
Domain Normothermia Hypothermia Normothermia (N Hypothermia Note
(N = 26) (N = 24) = 38) (N = 39)

Age (years) 9.5 (5.2–13.8) 11.0 (6.9–14.2) 12.5 (3.3–14.8) 9.7 (4.2–14.5) Median (IQR)
Boys 16 (62) 16 (62) 27 (71) 21 (54) N (%)
Weight (kg) 30 (20–50) 31.5 (24–53) 38 (16–60) 30 (15.4–62) Median (IQR)

Median (IQR)
for Beca et al;
Time to randomization (hrs) 5.0 (4.2–5.8) 5.3 (4.4–6.0) n/a 5h 8min (55 min)
Mean (SD)
for Adelson et
al
GCS in ED 4.5 (3–7) 5.5 (3.5–7) 6 (5–7) 6 (5–7) Median (IQR)

apnea 4(11) apnea 2(5)

aspiration 5(14) aspiration 7(19)
hypotension 3(12) hypotension 0(0) cardiac arrest 1(3) cardiac arrest 1(3)
Identified clinical condition N (%)
hypoxia 0(0) hypoxia 1(4) hypotension 2(6) hypotension 4(11)
hypoxia 3(8) hypoxia 7(18)
seizure 8(21) seizure 4(10)
IQR: Interquartile range
ED: Emergency Department

email correspondence with John Beca, we

Figure 2. Risk of bias assessment of the included studies.
Green indicates low risk of bias, red indicates high
risk, and blank indicates unclear risk
confirmed that the outcomes of study were gauged
by assessors blinded to the treatment. The authors
of this RCT reported five violations of protocols,
leaving 50 patients in the trial and in analysis out
of 55 randomized. The final stats of allocation
after exclusion of those five were 26 patients in
normothermia (16 male and 10 female) and 24 (11
male and 14 female) in normothermia.
Adelson et al. utilized computer-generated
randomization sequence to randomly allocate 77
patients in 1:1 ratio. The system yield 39 patients
(21 boys and 18 girls) in hypothermia group
and 38 (27 boys and 11 girls) in normothermia.
Personel involved in randomization were masked
to allocation, but, as is the case in Beca et al. it is
indeed impossible to blind them from knowing
what interventions were being done, since there
is no odds of a procedure as frank and visible
as surface cooling executed for normothermia
group. That being said, this trial did mask outcome
assessors from group allocation to minimize bias.
Regarding completeness of data, this study lost
three data for functional outcome, but data for
mortality and complications remained complete.
It is also important to note that this study started
hypothermia beyond the predefined six hours
within injury onset in three patients of
hypothermia group and therefore raise suspicion of
bias.
Table 2. summarizes some of baseline
characteristics mentioned in those two studies, but
Table 3. Result of all studies

Quality of Hypothermia
Author Population Outcome Mortality Pneumonia Conclusion
Trial range

John Beca, High 1 - 16 yo 32 - 33oC Poor outcome based Normo: 1 (4%) Normo: 6 (25%) No statistically
et al. (n = 55) on PCPC at 12 Hypo: 3 (13%) Hypo: 7 (27%) significant
months: differences
Normo: 3 (12%) P = 0.34; CI 95% P = 1.0
Hypo: 4 (17%)
P = 0.70; CI 95%

Adelson, High 0 - 17 yo 32 - 33oC GOS and GOS-E- After 3 months: < 120 h No statistically
et al. (n = 77) Peds inconclusive Normo: 2 (5%) Normo: 9 (19%) significant
due to lost to follow- Hypo: 6 (18%) Hypo: 7 (9%) differences
up and missing data. >120h
Favorable outcome: P = 0.15 Normo: 5 (11%)
58% each Hypo: 6 (14%)
Poor outcome: 42%
each P value: not
provided

only Beca et al. provided p value and explained randomly assigned to

that the two groups were not significantly different either
in all baseline characteristics. Adelson et al.
reported more clinical-events while Beca et al.
only reported hypotension and hypoxia.
Both studies share similar result of study:
no statistically significant difference between
hypothermia and normothermia in terms of
functional outcome, mortality, and pneumonia.
Functional outcome were assessed with GOS and
GOS-E Peds in Adelson et al. while Beca et al.,
instead of 6 months, evaluated functional outcome
at 12 months using Pediatric Cerebral Performance
Category (PCPC).

Discussion
We reviewed two RCTs in which patients were
treated with either hypothermia or
normothermia. Those RCTs conform with
PICO, inclusion criteria, and exclusion criteria.
Both studies fulfill validity criteria and were
deemed to be of high quality.

General comparison
John Beca et al. involved 55 patients who satisfied
the following criteria: aged 1 – 16 years old, were
mechanically ventilated, had GCS lower than 9,
and had abnormal findings on head CT scan.
Patients with penetrating head injury, dilated pupil,
GCS of 3, spinal cord injury, evacuated acute
EDH, post- traumatic seizure with normal CT
scan, refractory shock despite adequate
resuscitation and suspected non-accidental trauma,
were all excluded from the study. They were
hypothermia group or normothermia group, yielding 28 patients and 27
patients in each group, respectively. Four patients from the hypothermia
group and one from the normothermia group were then excluded due to
substandard initial care, leaving 50 patients in the trial and analysis.
P David Adelson et al. did an RCT on 77 children selected out of a
staggering 2140 total candidates based on the following criteria: aged 0 –
17 years old, non-penetrating traumatic brain injury, GCS 3 – 8 with
motoric response less than 6 despite resuscitation, and available for
randomization within 6 hours of injury. Candidates were ruled out based
on the following criteria: normal CT Scan, GCS of 3, unreactive pupils,
systolic blood pressure below 5th percentile for age for more than ten
minutes, coagulopathy (prothrombin time/ partial thromboplastin time >
16/40 s, international normalised ratio > 1.7), hypoxia (oxygen saturation
below 90% lasting for more than 30 minutes after resuscitation),
abbreviated injury severity score of four or greater for organs other than
the brain, suspected to be pregnant, or did not consent for the trial. There
were 39 patients in hypothermia group and 38 in normothermia, although
as the trial went by, three patients from hypothermia group met exclusion
criteria.
Concerning the methods used to achieve the desired temperature, John
Beca et al. utilized a servocontrolled cooling blanket to maintain
temperature among normothermia patients, whereas patients of
hypothermia group received both surface cooling, using ice packs and
cooling
Table 4. Critical appraisal based on validity, importance, and
applicability blanket, and intravenous iced solution. There was
Domain Article not much difference seen in RCT by Adelson et
Beca, et al. 2015 Adelson, et al. 2013 al., but unlike John Beca et al., they specifically
Level of evidence 2 2
Poor functional outcome mentioned that they did the intravenous iced
Validity
Randomization + + saline prior to surface cooling. Adelson et al.
Intention-to-treat + + maintained hypothermia for 48 hours while Beca
Blinding + +
Comparable treatment + + et al. preserved it as long as 72 hours. The two
Similarity + + studies differ over rewarming rate, but they were
Importance
CER 0.115 0.578 all below 1oC per three hours (Beca et al. 0.5oC per
EER 0.167 0.564 3 hours; Adelson et al. 0.5 - 1.0oC per 12 - 24
RRR - 0.4 0.025
ARR - 0.05 0.014 hours). In addition, Adelson et al. had a procedure
NNT - 19.5 67.36 to keep target temperature (32 - 33oC) for another
Applicability
Applicable - - 24 hours if ICP remained above 20 mmHg after 48
Patient’s value Restricted to age group and time after injury hours of hypothermia.
Mortality rate
Validity Both studies share identical result. Functional
Randomization + +
Intention-to-treat + + outcome - assessed with PCPC at 12 months, in
Blinding + + Beca et al. - seems to be slightly worse in
Comparable treatment + +
Similarity + + hypothermia group (three [12%] from
Importance normothermia and four [17%] from hypothermia
CER 0.0384 0.058
EER 0.125 0.153 had poor outcome), but statistical analysis failed to
RRR - 2.25 - 1.61 reveal any significant differences (p = 0.70; CI
ARR - 0.086 - 0.095
NNT - 11.5 - 10.52 95%). Adelson et al. had missing GOS and GOS-E
Applicability
Applicable - - Peds data and one case of lost-to-follow-up,
Patient’s value Restricted to age group rendering the global function outcome assessment
Pneumonia with GOS and GOS-E-Peds inconclusive.
Validity
Randomization + However, both groups had equal percentage of
Intention-to-treat +
Blinding + patients who had good outcome (58% each) and
Comparable treatment + poor outcome (42% each).
Similarity +
Importance Beca et al. found one (4%) mortality from
CER 0.23 normothermia group and three (13%) from
EER 0.29
RRR - 0.06 hypothermia group, while Adelson et al. reported
ARR - 0.06
NNT - 16.4 two of 38 (5%) mortality from normothermia
Applicability group and six of 39 (15%) from hypothermia at
Applicable -
Patient’s value Restricted to age group three months after injury. None of these findings
Pneumonia < 120 hours was statistically significant (p = 0.34; p = 0.15
Validity +
Randomization + respectively). Pneumonia rate in Beca et al. was
Intention-to-treat + seven (27%) and six (25%) from normothermia
Blinding +
Comparable treatment + and hypothermia group (p = 1.0). Adelson
Similarity + reported pneumonia rate in two different time
Importance
CER 0.236 lapses: nine (19%) case of pneumonia in
EER 0.179
RRR 0.242 normothermia group and seven (9%) in
ARR 0.057 hypothermia within the first 120 hours of injury;
NNT 17.4
Applicability five (11%) in normothermia and six (14%) in
Applicable - hypothermia after the first 120 hours. The authors
Patient’s value Restricted to age group
Pneumonia > 120 hours did not provide p value for these findings.
Validity +
Randomization +
Intention-to-treat + Functional outcome
Blinding +
Comparable treatment + Table 4. summed up our critical appraisal on
Similarity + these two studies and further chunked the
Importance
CER 0.131 number based on outcomes being looked on.
EER 0.153 Relative risk reduction (RRR) of -0.4 seen in
RRR - 0.169
ARR - 0.02 John Beca et al. signify that hypothermia
NNT - 44.9 heighten the risk of poor outcome by 40%
Applicability
Applicable - relative to that occuring in the normothermia
Patient’s value Restricted to age group group. Absolute risk reduction (ARR) of this
CER: Control event rate; EER: Experimental event rate; RRR: Relative risk reduction; study generated negative value of 0.05, which
ARR: Absolute risk reduction; NNT: Number needed to treat. indicate that the absolute harm of hypothermia
is a 5% increase in poor outcome. The negative value of Number Needed
to Treat (NNT) in this study indicates that the intervention
is indeed harmful.
this treatment contradict each other. Despite the
Although the ARR of Adelson et al. suggest
controversies, TBI has been used for decades as
that hypothermia reduced poor outcomes by 1%
TBI treatment.5,14,20
and by 2.5% relative to normothermia, it is
Positive results of hypothermia were mainly
important to note that there were missing GOS and
observed in small size study or single center
GOS-E Peds data from this study. The existing
study. Marion et al. in 1997 reported survival
GOS and GOS-E Peds data yield exactly the same
and functional outcome improvement among
percentage of patients who had good outcome and
TBI patients treated with hypothermia.19 Earlier
poor outcome, and therefore the trial was
study by Clifton GL et al. in 1993 reported a trend
considered futile and was eventually discontinued.
toward better GOS among patients treated with
The NNT of 92.62 in this study also reflect how
hypothermia at 32 – 33oC for 48 hours.14
scant hypothermia could result in one good
In 2011, Clifton GL et al. conducted a
outcome.
multicenter RCT, known as National Acute Brain
Although both studies reported poor functional
Injury Study: Hypothermia II (NABISH II), in
outcome, Beca et al. did not report functional
which they assigned 232 patients to either
outcome at six months after injury as this review
hypothermia group - as early as 2.5 hours after
expected. Therefore, it is probably too careless to
injury for 48 hours at 33oC
conclude that they share same results in terms of
- or normothermia group. This large-scale RCT
functional outcome, as they did not report at the
failed to demonstrate any significant differences
same post-injury time.
between the two groups in terms of functional
outcome and mortality (relative risk [RR] 1.08,
Mortality
95% CI 0.76–1.53; p=0.67).15
Calculation of RRR for both groups result in
A systematic review5 by Sydenham et al.
negative value (-2.25 for Beca et al. and -1.61 for
concluded that there was no evidence which
Adelson et al.), meaning that hypothermia in
support the benefit of hypothermia for TBI. This
both studies augment risk of mortality by 22.5%
study reported that there were fewer deaths in
and 16.1% respectively. Absolute Risk Reduction
hypothermia group, although not statistically
of -0.086 in Beca et al. implied that this treatment
significant, and a slight increase in the odds
had an absolute harm of 8.6% increase in
of pneumonia. Hypothermia is indeed more
mortality. Both studies had negative value of NNT,
commonly used in the management of neonatal
which attest further to the harm of hypothermia.
hypoxia and cardiac arrest, but surely they can not
automatically translate to TBI, as neuronal insults
Pneumonia occurring in those conditions and in TBI are
Pneumonia was reported in a different manner in clearly pathophysiologically distinct entities.14,20,21
Adelson et al., in which the incident was reported A large multicenter RCT by Andrews et al.
in two different time segments: before 120 hours enrolled 387 patients spread in 47 centers in
and after 120 hours after injury. We assessed the 18 countries reported that while hypothermia
numbers accordingly and revealed an otherwise
successfully reduce intracranial pressure, it did not
positive result in pneumonia of < 120 hours. While improve functional recovery.2 Systematic review
statistical analysis of pneumonia incident during
by Crossley et al. indicated that there might be
the first 120 hours did not demonstrate significant a benefiticial effect of hypothermia for TBI in
difference, the RRR and ARR was rather positive
terms of mortality and morbidity, but the authors
(0.242 and 0.057). This means that Hypothermia declared that they found the majority of included
for the first 120 hours lower the risk of pneumonia
studies is of low quality. In addition, when they
by 24.2% and an absolute benefit of 5.7% put out studies with high risk of bias , statistical
reduction in pneumonia, although the NNT of 17.4
analysis yield higher Relative Risk (RR) for death
is certainly not a promising number. Pneumonia of (1.62 from 1.31), and poor outcome (1.67 from
more than 120 hours in Adelson et al. and
1.41).10
Pneumonia in Beca et al. yield negative RRR,
A meta-analysis by Ma et al. concluded that
ARR, and NNT, indicating yet another harm of
hypothermia significantly increases risk of
hypothermia.
mortality (RR 1.73, 95 % CI 1.06 to 2.84) among
pediatric TBI patients. Risk of pneumonia was
Agreements and disagreements with past reported to be slightly lower in hypothermia
studies although not statistically significant (RR 0.90, 95
The findings of this systematic review had pros % CI 0.73 to 1.12).22 Systematic review by
and cons from previously done studies. It is Georgiou and Manara did two separate relative
probably due to the pathophysiologically complex risk calculations of mortality and functional
and variable nature of this disease that evidence of
outcome. They got
0.84 [95% confidence interval (CI) [0.72–0.98] for
mortality and 0.81 (95% CI [0.73–0.89]) for poor
functional outcome. The number leaped to 1.28
(95% CI [0.89–1.83]) and 1.07 (95% CI [0.92–
1.24]), respectively, when only high quality trials
were analyzed.4
Conflict of Interest
The authors report no conflict of interest
concerning the materials or methods used in this
study.
Funding
This article received no specific grant from any
funding agency.
Authors’ Contributions
RM and GI designed the study and did literature
review. GI drafted the manuscript. RM made
critical revisions to the manuscript. All authors
read and approved the final manuscript.
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10.1186/s13049-015-0121-3.
17. Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S,
Smith KR Jr, et al. Lack of effect of induction of
hypothermia after acute brain injury. N Engl J Med. 2001;
344(8): 556 – 63. DOI: 10.1056/NEJM200102223440803.
18. Bhattacharjee S, Baidya DK, Maitra S. Therapeutic
hypothermia after cardiac arrest is not associated
with favorable neurological outcome: a meta-analysis.
J Clin Anesth. 2016; 33: 225 – 32. DOI: 10.1016/j.
jclinane.2016.03.001.
19. Marion DW, Penrod LE, Kelsey SF, Obrist WD,
Kochanek PM, Palmer AM, et al. Treatment of traumatic
brain injury with moderate hypothermia. N Engl J Med.
1997; 336(8): 540 – 6. DOI:
10.1056/NEJM199702203360803.
20. Smith M. Therapeutic hypothermia and acute brain injury.
Anaesth Intensive Care Med. 2016; 17(12): 602 – 606.
DOI: 10.1016/j.mpaic.2016.09.014.
21. Saxena M, Andrews PJD, Cheng A, Deol K, Hammond
N. Modest cooling therapies (35ºC to 37.5ºC) for
traumatic brain injury. Cochrane Database of Systematic
Reviews. 2014, Issue 8. Art. No.: CD006811. DOI:
10.1002/14651858. CD006811.pub3.
22. Ma C, He X, Wang L, Wang B, Li Q, Jiang F, Ma J. Is
therapeutic hypothermia beneficial for pediatric patients
with traumatic brain injury? A meta-analysis. Childs Nerv
Syst. 2013; 29(6): 979 – 84. DOI: 10.1007/s00381-013-
2076-x.
23. Pardamean DT, Prasetyo E, Oley M. Therapeutic Mild
Hypothermia Toward Blood Lactate Levels and Glasgow
Coma Score in Severe Traumatic Brain Injury. Bali Med J.
2015;4(2): 82-85.
Sound Health Research Journal Forikes----------------------------------------Volume 10 Number 3, July 2019 p ISSN 2086-3098 E-ISSN
2502-7778

DOI: http://dx.doi.org/10.33846/sf10308

Hypothermia Management in Patients with Head Injury: A Literature Review

Ismail Fahmi
Students of Master of Medical Surgical Nursing, Faculty of Nursing, University of Indonesia;
fahmi270684@gmail.com (correspondent)
Amelia Ganefianty
Students of Master of Medical Surgical Nursing, Faculty of Nursing, University of Indonesia
Ely Nurachmah
Department of Medical Surgical Nursing, Faculty of Nursing, University of Indonesia

ABSTRACT

Head injury is a crucial public health problem and causes social and economic problems throughout the world. Increased blood brain volume associated
with Increased body temperature will increase of intracranial pressure (ICP) and cause the brain at risk of other injuries. This paper aims to identify the
effect of hypothermia on head injury management Patients. This article was a review of the literature from Several of data bases, Pubmed, EBSCO Host,
Google scholar, and Web of Science. Article search was restricted from 2007 to 2018 using the keyword "head injury", "hypothermia management",
"hypothermia in head injury". The search results of the article were that
management of hypothermia in head injury Patients can reduce the metabolic requirements, cerebral metabolic rate for oxygen (CMRO 2), excitotoxicity, reduce
glutamate release, reduce free radical formation, reduce edema formation, Stabilize membranes, maintain adenosine triphosphate
(ATP), reduce influx of Ca, and intracranial pressure so that it can reduce the risk of brain damage and death.

Keywords: head injury; hypothermia in head injury; hypothermia management

ABSTRACT

Head injury is a crucial public health problem and cause social problems as well as economies around the world. Increased cerebral blood volume
associated with a rise in body temperature will increase intracranial pressure ( intracranial pressure / ICP) and causes the brain at risk of another injury.
This paper aims to identify the effect of hypothermia in the management of head injured patients. This paper is a literature review of some of the data
base that is Pubmed, EBSCO Host, Google scholar, and Web of Science. Search articles is limited to 2007 to 2018 using the keyword "head injury",
"management hypothermia", "hypothermia in head injury". Search result article is management hypothermia in patients with head injuries can have an
effect reducing metabolic demand, cerebral metabolic
rate for oxygen ( CMRO 2), eksitotoksisitas, decreases the release of glutamate, reduce the formation of free radicals, reduce edema
formation, membrane stabilization, maintaining adenosine triphosphate ( ATP), decrease the influx of Ca, and intracranial pressure so as to reduce
the risk of brain damage and death.

Keywords: head injury; hypothermia in a head injury; management of hypothermia

PRELIMINARY

Head injury is a crucial public health problem and cause social and economic problems around the world ( 1). In 2013, there were
approximately 2.8 million patients with head injuries admitted to hospital in the United States, approximately 500,000 people died, 282,000
hospitalized, and
2.5 million patients admitted to the Emergency Room (ER). Year 2007-2013, the rate of head injury incoming visit to the ER increased by 47% (
2).

A head injury can increase the mortality rate in the period and the gathering is also lower life expectancy ( 3). This is due to a head injury
may increase the incidence of seizures, sleep disorders, neurodegenerative diseases, endocrine disrefulasi, psikoatrik disorders, sexual
dysfunction, urinary incontinence and bowel blader, and systemic metabolic dysregulation that may persist despite several months or even several
years after a head injury ( 3).

Management of head injury patients must be comprehensive, starting from the site of the accident, during transport, operating rooms, and
post-surgical management (management of perioperative) ( 4). Patients with intracranial hypertension risk, such as patients with head injury, was
significantly affected by changes in body temperature due to cerebral blood flow ( Cerebral blood flow / CBF) will increase along with the increase
in body temperature. Increased cerebral blood volume associated with a rise in body temperature will increase intracranial pressure ( intracranial
pressure / ICP) and causes the brain at risk of another injury. Therefore,

Sound Health Research Journal Forikes------------http://forikes-ejournal.com/index.php/SF

199
Hyperthermia increases the risk of damage to neural cells and putting the patient at risk of secondary brain injury through an increase in ICP ( 5).
Postiskemik hyperthermia is associated with increased infarct size and outcome worse. Although strict control towards a
normal body temperature was noted as an important therapeutic strategy in Guideline for Management of Severe Head Injury, however, management
strategies hypothermia as a clinical therapy for practitioners often considered ineffective and possibly is contraindicated
in patients with head injury ( 6). This paper will discuss how the effects of hypothermia on the management of head injured patients.

METHOD

This paper is a literature review of some of the data base that is Pubmed, EBSCO Host, Google scholar, and Web of Science. Search articles is limited to
2007 to 2018 using the keyword "head injury", "management hypothermia", "hypothermia in head injury". Literature
search process can be seen in carrying Figure 1.

256 articles through search the database ( EBSCO,

PubMed, Google Scholar, Web of Science)

115 article after the removal of duplication

28 relevant studies were not issued after filtering

53 acquisition of potential article out all the titles and abstracts

14 articles issued the following reasons: It is

25 full-text articles were assessed for eligibility not a full-text article

11 studies included in the review of the literature

Figure 1. Results of the search in a database associated with the management of hypothermia in patients with head injury

RESULTS

Patients with intracranial hypertension, such as patients with head injury, was significantly affected by changes in body temperature due to
cerebral blood flow ( Cerebral blood flow / CBF) will increase along with the increase in body temperature.
Increased cerebral blood volume associated with a rise in body temperature will increase intracranial pressure ( intracranial pressure / ICP) and causes
the brain at risk of another injury. Therefore, hyperthermia increases the risk of damage to neural cells and putting the
patient at risk of secondary brain injury through an increase in ICP ( 7). Hypothermia brain protection mechanism is to reduce metabolic demands,
cerebral metabolic rate for oxygen ( CMRO2), eksitotoksisitas, decreases the release of glutamate, reduce the formation of free radicals, reduce
edema formation, membrane stabilization, maintaining adenosine triphosphate ( ATP), decrease the influx of Ca, and intracranial pressure. While
severe hypothermia complications are pneumonia, sepsis, cardiac dysrhythmias, hypotension, bleeding problems and chills. The ideal temperature
for therapeutic hypothermia is 35 0 C ( 8). In addition, post-ischemic hyperthermia is associated with increased infarct size and outcome worse ( 5).

Studies systematic review explains that patients who do early hypothermia in less than 24 hours, can affect the lower the risk of death due to
head injury ( 8). Furthermore, the underlying pathophysiological mechanism is where hypothermia lowers the metabolic and functional activity of the
brain. Temperature coefficient (Q10) shows the factor by which cerebral metabolic rate for oxygen

(CMRO2) changes every 10 degrees of temperature difference. For most biological reactions, Q10 value is approximately 2 (a 50% reduction
for each temperature decrease CMRO2 10 0 C). So brain normal body temperature (37 ℃) can tolerate complete ischemia that lasted 5 minutes,
at a temperature of 27 ℃ brain can tolerate ischemia that lasted for 10 minutes ( 5). In another study also mentioned that the treatment of head
injury with hypothermia therapy at a temperature of 32-34 0 C for more than 48 hours effective
lowering brain damage and death ( 6). The mechanism of hypothermia therapy in preventing brain damage described in Figure 2.

Figure 2. Mechanism of hypothermia therapy in preventing brain damage ( 9)

Surface cooling is one of the interventions that can be performed on patients with head injury, one study randomized controlled trial
aimed at assessing the effectiveness s urface cooling with a cold compress to reduce head injury patient's body temperature. The study was
conducted on the 47 head injury patients with ventilator installed, do a cold compress for 3 hours, research shows
Surface cooling with a cold compress to effectively lower the patient's temperature ( 4). Another study explained that cooling surface with a target
temperature of 32-34 0 C effectively prevents damage to the brain ( 9).
Process rewarming important after hypothermia therapy, patients with intracranial hypertension are known to have a reflex
increase ICP during rewarming fast. shivering during
rewarming will increase oxygen consumption and must be stopped with sedation and muscle relaxants. Tool is a heating fluid warmers, circuits
humidifier, hot water blanket, forced air warming blankets
(Fastest), infrared heating lamp. Rewarming is done when the ICP <20 mmHg (stable for 48 hours). recommended rewarming slow more than 12
hours at a speed of 0.1 0C / hour, someone suggested
rewarming with a speed of 1 0C every 3-4 hours, 1 0C / day, 0.5 0C in 2 hours. rewarming slow
0.25 0 C / hr provide maximum protection ( 8). From exposure to some studies, the authors conclude that therapeutic hypothermia intrkranial
effective in lowering pressure in patients with head injury.

DISCUSSION

Normotermia control (prevention of intravascular heat with cooling) is effective in reducing the severity of heat and secondary brain
injury after a severe head injury as a result of a decrease in intracranial pressure and heat , It has long been known from a few experimental
studies that hypothermia is neuroprotective after brain ischemia. The mechanism by which hypothermia has the effect of brain protection, unclear.
Probably due to lower brain metabolism, preventing apoptosis, reducing the dysfunction of mitochondria
reduces the production of free radicals and reduce oxidative damage to DNA, decreasing the influx of Ca2 +, decreases the release exitatory amino acids (
EAA) glutamate, preventing lipid peroxidation, reduces formation of edema ( 5).

Hyperthermia in patients with head injury occurs because brain tissue hypoxia resulting from a significant decrease in CBF and the
occurrence of edema formation, this led to an increase in the temperature is higher than the core temperature, another hypothesis reveals the potential
role of heme degradation products. Heme molecule is degraded by heme oxygenase into biliverdin, iron, and carbon monoxide (CO), carbon
monoxide which increases the body temperature more than 1 ° C ( 7). Another study reported that 50% of patients
with subarachnoid hemorrhage suffered hyperthermia. Then the patients were found occurrence of leukocytosis, leukocytosis is one of the
complications of brain injury. Epinephrine and Cortisol is considered one role in the occurrence of leukocytosis. In addition, there are other
mechanisms mediated by inflammatory mediators ( 10). The increase in the number of leukocytes is associated with poor outcomes in patients with
brain injury ( 11). The accumulation of leukocytes to areas of the brain injury is very important for the level of inflammation and secondary brain
damage ( 12).

Inflammation, as well as other organs, is also an important part of patomekanisme traumatic brain injury. On one occasion a brain
injury need a balance between the cytokines that cause an inflammatory reaction, with the aim to limit the damage and restore, as well as anti-
inflammatory cytokines
Interleukin 10 ( IL-10) which limit the work of the inflammatory cytokine that is not an exaggeration, that when it happens it will cause
adverse effects ( 13).
Hypothermia brain protection mechanism is to reduce metabolic demands, cerebral metabolic rate for oxygen ( CMRO2), eksitotoksisitas,
decreases the release of glutamate, reduce the formation of free radicals, reduce edema formation, membrane stabilization, maintaining adenosine
triphosphate ( ATP), decrease the influx of Ca, and intracranial pressure. Patients who do early hypothermia in less than 24 hours, can affect the lower
the risk of death due to head injury ( 8). In addition, management of hypothermia with a target temperature of 32-34 0 C effectively prevents damage to
the brain ( 9).

CONCLUSION

Management of hypothermia in patients with head injuries can have an effect reducing metabolic demand,
cerebral metabolic rate for oxygen ( CMRO2), eksitotoksisitas, decreases the release of glutamate, reduce the formation of free radicals, reduce
edema formation, membrane stabilization, maintaining adenosine triphosphate ( ATP), decrease the influx of Ca, and intracranial pressure. So as to
reduce the risk of brain damage and death.

REFERENCES

1. Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury.
Nature Reviews Neurology. 2013 Jul; 9 (4): 231.
2. Faul M, Coronado V. Epidemiology of traumatic brain injury. InHandbook of clinical neurology 2015 Jan. 1 (Vol. 127, pp. 3-13). Elsevier.
3. Masel BE, DeWitt DS. Traumatic brain injury: a disease process, not an event. Journal of Neurotrauma.
2010 Aug 1; 27 (8): 1529-40.
4. Mayer SA, Kowalski RG, Presciutti M, Ostapkovich ND, McGann E Fitzsimmons BF, Yavagal DR, Du
YE, Naidech AM, Janjua NA, Claassen J. Clinical trial of a novel surface cooling system for fever control in neurocritical care Patients. Critical care
medicine. 2004 Dec 1; 32 (12): 2508-15.
5. Bisri DY, Bisri T. Therapeutic Hypothermia after Traumatic Brain Injury.
6. Andresen M, Gazmuri JT, Marín A, Regueira T, Rovegno M. Therapeutic hypothermia for acute brain
injuries. Scandinavian Journal of trauma, resuscitation and emergency medicine. 2015 Dec; 23 (1): 42.
7. Mrozek S, Vardon F, Geeraerts T. Brain temperature: physiology and pathophysiology after brain injury.
Anesthesiology research and practice. 2012; 2012.
8. Watson HI, Shepherd AA, Rhodes JK, Andrews PJ. Revisited: a systematic review of therapeutic
Adult Patients Following hypothermia for traumatic brain injury. Critical care medicine. 2018 Jun 1; 46 (6): 972-9.

9. Yokobori S, Yokota H. Targeted temperature management in traumatic brain injury. Journal of intensive
care. 2016 Dec; 4 (1): 28.
10. VE Johnson, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W. Inflammation and white
matter degeneration persist for years after a single traumatic brain injury. Brain. 2013 Jan. 1; 136 (1): 28-42.
11. Subramanian A, Agrawal D, Pandey RM, Nimiya M, Albert V. The leukocyte count, immature
granulocyte count and immediate outcome in head injury Patients. InBrain Injury-Pathogenesis, Monitoring, Recovery and Management
2012 March 23. IntechOpen.
12. Dardiotis E, Fountas KN, Dardioti M, Xiromerisiou G, Kapsalaki E, Tasiou A, Hadjigeorgiou GM.
Genetic association studies in Patients with traumatic brain injury. Neurosurgical Focus. 2010; 28 (1): E9.
13. Sriyanto S. The relationship between the increase in the volume of epidural hematoma (EDH) with increased levels
Glial Fibrilary Acidic Protein (GFAP) plasma (The correlation between epidural hematoma (EDH) and GFAP's plasma volume consentration).
Doctoral dissertation. Semarang: Diponegoro University Postgraduate Program.
 DOI: 10.5137/1019-5149.JTN.19696-16.2
Received: 17.12.2016 / Accepted:
29.10.2017
Published Online: 21.11.2017

Review

Hypothermia Therapy after Traumatic Brain Injury:

A Systematic Review and Meta-Analysis
Lige LENG
Medical College, Xiamen University, Xiamen, Fujian Province, China

ABSTRACT

The purpose of this article was mainly to focus on whether hypothermia improves mortality and/or the chance of a good
neurological outcome compared with the standard of care alone in patients with traumatic brain injury (TBI). We used a
comprehensive search strategy. Articles were eliminated in a stepwise fashion. Data from each study was entered in the Review
Manager (RevMan) software version 5.0 when reported. Seven studies including 1331 patients met all selection criteria. This meta-
analysis merged all data of the 7 articles to come to a conclusion. It also conducted a detailed analysis of the different
classifications, trying to outline the possible mechanisms. We included two Chinese articles and tried to find out the effects of
hypothermia on the Asian race. Regarding the poor outcome of hypothermia on diffuse lesions, we also analyzed the mechanism
and provided our speculation. Children with traumatic brain injury were also analyzed regarding the effect of hypothermia treatment
and the possible cause of the poor outcome. The results of these clinical trials were heterogeneous. Hypothermia treatment in TBI
seems to provide good outcomes on focal lesions, adult patients, Asian patients and at a relatively higher temperature (33-36°C).
KEywORDS: Hypothermia, Intracranial pressure, Traumatic brain injury

█ INTRODUCTION damage (13). Hypothermia may be beneficial for the injured

brain not only by reducing ICP and cerebral metabolic needs

T
raumatic brain injury (TBI) is a primary cause of death
and long-term morbidity. Induced hypothermia is now
an accepted method to improve the outcome following
anoxic brain injury associated with heart failure (2,12), but
its benefits in TBI are unclear. The effect of hypothermia on
high intracranial pressure (ICP) is beneficial, but probably
unrelated to its effect on the outcome. The outcome related
to the intracranial pressure was evident both in patients who
had normothermia on admission and whose outcome did not
improve with induced hypothermia and in patients who had
hypothermia at admission and whose outcome did improve
with lasting hypothermia. Brain ischemia results from impaired
auto-regulation, local and global hypoperfusion, elevated ICP
and increased cerebral metabolic needs (4,8). Reperfusion
injury is due to a complex cellular cascade leading to tissue
(17,19), but also by decreasing damage of the blood–brain
barrier (BBB)(14) and inhibiting the inflammatory cascade that
may lead to reperfusion injury (3,18). There had been some
meta-analysis included in these 7 articles before, but none of
them refined or classified these articles. This meta-analysis
will also get all data of 7 articles together to come to a
conclusion and it will carry out a detailed analysis of the
different classifications, trying to outline the possible
mechanisms. For example, in this meta-analysis, we included
two Chinese articles, trying to find out the effects of
hypothermia on the Asian race. For the poor outcome of
hypothermia of diffuse lesions, we also analyzed the
mechanisms and provided our speculation. Children with TBI
were also analyzed for the effect of hypothermia treatment
and the possible cause of the poor outcome.

Corresponding author: Lige LENG

E-mail: lenglige@xmu.edu.cn

Turk Neurosurg, 2017 | 1


█ QUESTION
The purpose of this review was to answer the following
question: In patients with TBI without major contraindications
(e.g., hypotension, ongoing hemorrhage), does mild-to-
moderate (32º–36ºC) hypothermia, in addition to standard
of care, improve mortality and/or the chance of a good
neurological outcome (Glasgow Outcome Scale [GOS] score)
at a specified time after rehabilitation, compared with the
standard of care alone? The GOS is a widely used 5-point
scale measuring neurological outcome where 1 indicates
death, 2–3 indicates vegetative state or dependent living, and
4–5 indicates independent living or return to work/school.
█ METHOD
Search Strategy and Selection Criteria
We followed the recommendations of the Cochrane
Handbook for Systematic Reviews of Interventions and the
QUOROM (quality of reporting of meta-analyses) statement
in this meta-analysis. We developed a comprehensive search
strategy and using the database with appropriate keywords,
searched the MEDLINE, Pubmed clinical trials, Web of
Science, the Cochrane Central Register of Controlled Trials,
the Cochrane Database of Systematic Reviews, Papers
First and Proceedings First. In addition, we hand-searched
conference proceedings, abstracts and the bibliographies of
other literature reviews and of all short-listed studies.
Leng L: Hypothermia After Traumatic Brain
Injury
Data Extraction and Quality Assessment
Articles were then eliminated in stepwise fashion (Figure 1).
First the duplicates were eliminated and then we eliminated
clearly irrelevant papers that did not meet our inclusion
criteria based on the title or abstract. The remaining papers
were retrieved for full-text review by 1 reviewer and short-
listed for final review if the reviewer could not eliminate the
possibility that the paper was a clinical trial of hypothermia for
TBI. All short-listed papers that had not been eliminated by
this stage were reviewed in their entirety by 2 independent
reviewers according to an a priori protocol. We assessed
agreement on inclusion and exclusion between the 2
reviewers as a simple ratio of studies agreed on to total
studies assessed. Data in the form of mortality and
dichotomized GOS were extracted in duplicate by 2
independent reviewers.
Data Analysis
Data from each study was entered in the Review Manager
(RevMan) software version 5.0 for Windows (The Nordic
Cochrane Centre, The Cochrane Collaboration). As there
was significant clinical heterogeneity among the studies,
we chose to perform a random effects meta-analysis using
RevMan to calculate relative risk (RR) and absolute risk
with 95% confidence intervals (CIs) for mortality. We tested
for the presence of statistical heterogeneity using the χ 2
test and I2 value, using a priori–defined cutoffs of p<0.10 or
I2>50%. In case these cutoffs were surpassed, we planned
Figure 1: Flow chart showing the elimination
of articles.
sensitivity analyses with low-quality studies removed. We
also constructed a funnel plot to assess the likelihood of
publication bias.
█ RESULTS
Seven studies (1,5,6,10,11,15,20) including 1331 patients met
all selection criteria and were identified (Table I). Of these 7
trials, 2 were conducted in China and the remaining five were
conducted as multicenter studies in many countries. Six trials
compared the effect of hypothermia treatment versus regular
treatment. One trial divided the patients into three groups.
One group was induced hypothermia, at 35-36°C; one
group mild hypothermia, at 33-34°C; and one group normal
temperature. In order to make a comprehensive analysis, we
will define the first two groups as one hypothermia group.
All 7 studies included mortality data and also had data
on functional outcome (dichotomized GOS). All 7 studies
evaluated a short-term (24–48 hours) cooling strategy. There
was significant heterogeneity among studies in the following
areas: study quality, outcome assessment blinding described
in 4/6 studies, various depth/duration of hypothermia and
criteria for re-warming in hypothermia protocols, and
variations in the
Figure 2: Forest plot showing relative risk of mortality in trials of hypothermia compared with standard therapy.
Figure 3: Forest plot showing relative risk of good neurologic outcome in trials of hypothermia compared with standard therapy.
control group mortality (Table I). None of the pooled estimates
met the a priori criteria for statistical heterogeneity (Figures 2,
3). When data from 7 included studies were pooled, there
was no statistical difference for patients receiving
hypothermia for mortality (RR 1.21, 95% CI 0.93-1.57) and
also no statistical difference for good neurological outcome
(GOS score of 4 or 5) (RR1.00, 95% CI 0.80-1.21) (Figures 2,
3).
Two Chinese studies (10,20) showed that hypothermia
treatment had better effects on Asian patients, and this seems
related to controlled hypothermia at a little higher temperature
(33-36°C).
Clifton et al.(6) discovered that there was a significant
interaction between treatment and presence of surgically
removed haematoma compared with diffuse brain injury
(p=0.001). We tried to analyze the possible reasons (Figure
4).
Hutchison et al.(11) indicated that in children with severe TBI,
hypothermia therapy that is initiated within 8 hours after injury
and continued for 24 hours does not improve the neurologic
outcome and may increase mortality. We also tried to analyze
the possible mechanism (Figure 5).
Turk Neurosurg, 2017 | 3
 Table I: Summary of Included Studies
(a) Characteristics of included studies
Time to target
Study Population Inclusion criteria Target Rewarming
temperature Duration
temperature time

387 (195 for hypothermia ICP of more than

Andrews not mentioned 32~35°C More than
treatment; 192 at normal 20 mm Hg 48h 0.25°C /h
2015
temperature)
368 (190 for hypothermia Glasgow Coma
Clifton 2001 treatment; 178 at normal Scale [GCS] score 8.4±3.0 h 33°C 47.2±3.0h 18.1±7.0h
temperature) ≤8
97 (52 for hypothermia Glasgow Coma
Clifton 2011 treatment; 45 at normal Scale [GCS] score not mentioned 33°C 48h 8h
temperature) ≤8
225 (108 for hypothermia Glasgow Coma
Hutchison 2008 treatment; 117 at normal Scale [GCS] score not mentioned 32.5±0.5°C 24h 8h
temperature) ≤8
82 (40 for hypothermia Glasgow Coma
Marion 1997 treatment; 42 at normal Scale [GCS] score 10h 32~33°C 24h 4h
temperature) ≤7

106 (36 at 35~36°C; Glasgow Coma

35~36°C; according to Natural
Zhihong 2007 35 at 33-34°C; 35 at normal Scale [GCS] score 4~6h
33-34°C ICP rewarming
temperature) ≤8

Gengsheng 66 (33 for hypothermia Glasgow Coma according to Natural

2010 treatment; 33 at normal Scale [GCS] score 3h 32-34°C
ICP rewarming
temperature) ≤8

(b) Results of included studies

Follow-up
Study Mortality rate favorable outcomes Complication
time
The risk of death (hazard ratio, 49 of 191 patients (25.7%) in the
Andrews 1.45; 95% CI, 1.01 to 2.10; hypothermia group and in 69 of
not mentioned 6 months
2015 P=0.047), 68 (34.9%) at 32~35°C to 189 patients (36.5%) in the control
51 (26.6%) at normal temperature group (P=0.03)

78±22% at
28(53%) at 33°C; 82 (43%) at 33°C; 76 (43%)
Clifton 2001 33°C;70±29% at 6 months
27(48%) at normal temperature at normal temperature
normal temperature

12(23%) at 33°C;
Clifton 2011 8 (18%) at normal temperature 21 (40%) at 33°C; 20 (44%)
not mentioned 6 months
at normal temperature
Hutchinson
2008 23 (21%) at 33°C; 70 (69%) at 32.5~33.5°C; 80 (78%)
not mentioned 6 months
14 (12%) at normal temperature at normal temperature
9 (23%) at 33°C;
Marion 1997 10 (24%) at normal temperature 15 (38%) at 33°C;11 (26%)
not mentioned 12 months
at normal temperature
28 (77.8%) at 35~36°C;
7 (19.4%) at 35~36°C; 19 (52.8%) at 35~36°C; 18 (51.4%)
Zhihong 2007 56 (160.0%) at 33-
6 (17.1%) at 33-34°C; at 33-34°C; 8 (22.9%) 3 months
34°C; 28 (80.0%) at
13 (37.1%) at normal temperature at normal temperature
normal temperature
Gengsheng 2010 at normal temperature
2 (6.1%) at 32~34°C; 5 (15.2%)
23 (69.7%) 15 (45.4%) not mentioned 12 months
at 32~34°C; at normal temperature

There was much variability in adverse events reported by
studies in this meta-analysis. Clifton et al.(5) found that 10%
of the patients in the hypothermia group and 3% of those in
the normothermia group had critical hypotension (a mean
arterial pressure of less than 70 mm Hg associated with
organ failure) for two or more consecutive hours (p=0.01).
Bradycardia associated with hypotension for two or more
consecutive hours occurred in 16% of the patients in the
hypothermia group and 4% of the patients in the
normothermia group (p=0.04). The percentage of hospital
days on which any complication was recorded was 78±22%
for patients in the hypothermia group and 70±29% for patients
in the normothermia group (p=0.005).
Figure 4: Possible mechanism of poor
outcomes of diffuse brain injury by
hypothermia treatment.
Figure 5: Possible mechanism of
poor outcomes in childhood TBI by
hypothermia treatment.
Zhihong et al.(20) found complication recorded 77.8% (at 35-
36°C) and 160.0% (at 33-34°C) for patients in the
hypothermia group and 80.0% for patients in the
normothermia group. Clifton et al.(7) found that there were no
significant differences in the percentage of patients with any
individual complication or group of complications, whether
critical or non-critical, between groups.
█ DISCUSSION
There was no statistical difference for patients receiving hypo-
thermia and mortality and also for good neurological outcome
(GOS score of 4 or 5) in the 7 clinical trials. We found some
interesting points, analyzed the mechanism and provided our
speculation. Two Chinese studies (10,20) showed that hypo-
thermia treatment had better effects on Asian patients, and
this seems related to controlled hypothermia at a little higher
temperature (33-36°C). There was no significant difference of
prognosis in the induced hypothermia group (35-36°C) and
mild hypothermia group (33-34°C), but these two groups had
a much better prognosis than the control group. Regarding
complications, the induced hypothermia group and the con-
trol group had no significant difference, but were much better
than the mild hypothermia group. The hypothermia treatment
on TBI seems had good outcomes on focal lesions, in adult
patients. We try to explain this finding (Figures 4, 5). First, in
the 2001 Clifton’s trial, there was an average delay of 8.4
hours in attaining the target temperature. The subgroup of
patients in this trial who were initially hypothermic and then
randomized to hypothermia had a significant long-term
neurological advan- tage compared to normothermia (8).
While Clifton’s second randomized trial in 2011 achieved
faster and earlier induction of hypothermia, other limitations
again probably negated any benefit achieved by this study
design improvement. However, any future trial should aim to
achieve hypothermia as early as possible and ideally at the
location of the traumatic event. Second, in severe TBI the
generalized swelling of brain tissue frequently persists for
over 48 hours. It is therefore likely that therapeutic levels of
hypothermia lasting for only 48 hours were insufficient. This
assertion is supported by evidence from several meta-
analyses including the brain trauma foun- dation (BTF) meta-
analysis finding that trials of prophylactic hypothermia longer
than 48 hours were associated with sig- nificantly reduced
mortality (9). The pathophysiology of TBI helps to explain why
there may be benefit to performing hypo- thermia beyond 48
hours. In a recent observational research of ICP after TBI,
only one-third of patients achieved their peak ICP within the
first 2 days after injury, and 20% did not achieve their highest
ICP until after day 5. A number of studies have reported a
rebound increase in ICP associated with the dis- continuation
of cooling, perhaps negating any benefit accrued during the
first 48 hours of cooling. In earlier studies, a 24–48 hour
duration of cooling was chosen because of concerns that
longer periods of hypothermia would be associated with
increased risk of adverse events. However, increased dura-
tion of hypothermia has not been shown to increase risk of
delayed hemorrhage or pneumonia. Future trials investigat-
ing the protective effects of therapeutic hypothermia should
ensure hypothermia is maintained in excess of 48 hours.
Further research may elucidate whether earlier implementa-
tion of hypothermia therapy or more prolonged hypothermia
therapy would improve the outcome with severe TBI. Third,
the Clifton’s trials withdrew hypothermia on a time-based
trigger rather than according to a physiological trigger. Re-
warming of patients despite ongoing increases in ICP is not
considered optimal clinical practice (16). Hypothermia should
ideally be withdrawn using a physiological trigger and over a
gradual period to avoid uncontrolled intracranial hypertension.
The 2 Chinese studies withdrew hypothermia according to a
physiological trigger (ICP) and over a gradual period to avoid
intracranial hypertension. And the results of these 2 studies
showed that the prognosis of hypothermia group was much
better than the control group. Future research may shed new
light on this field.
█ CONCLUSION
The results of these clinical trials suggest that the effects
of hypothermia on TBI were heterogeneous. Hypothermia
treatment for TBI seems to provide good outcomes in focal
lesions in adult patients, Asian patients, and at a relatively
higher temperature (33-36°C).
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