JOURNAL OF NEUROTRAUMA 32:422–429 (April 1, 2015)

ª Mary Ann Liebert, Inc. Original Articles

DOI: 10.1089/neu.2013.3197

Prolonged Mild Therapeutic Hypothermia versus Fever

Control with Tight Hemodynamic Monitoring and Slow
Rewarming in Patients with Severe Traumatic Brain Injury:
A Randomized Controlled Trial

Tsuyoshi Maekawa,1,2,* Susumu Yamashita,2,* Seigo Nagao,3 Nariyuki Hayashi,4

and Yasuo Ohashi 5 on behalf of the Brain-Hypothermia (B-HYPO) Study Group {

Abstract
Although mild therapeutic hypothermia is an effective neuroprotective strategy for cardiac arrest/resuscitated patients, and
asphyxic newborns, recent randomized controlled trials (RCTs) have equally shown good neurological outcome between
targeted temperature management at 33C versus 36C, and have not shown consistent benefits in patients with traumatic
brain injury (TBI). We aimed to determine the effect of therapeutic hypothermia, while avoiding some limitations of
earlier studies, which included patient selection based on Glasgow coma scale (GCS), delayed initiation of cooling, short
duration of cooling, inter-center variation in patient care, and relatively rapid rewarming. We conducted a multicenter
RCT in patients with severe TBI (GCS 4–8). Patients were randomly assigned (2:1 allocation ratio) to either therapeutic
hypothermia (32–34C, n = 98) or fever control (35.5–37C, n = 50). Patients with therapeutic hypothermia were cooled as
soon as possible for ‡ 72 h and rewarmed at a rate of < 1C/day. All patients received tight hemodynamic monitoring
under intensive neurological care. The Glasgow Outcome Scale was assessed at 6 months by physicians who were blinded
to the treatment allocation. The overall rates of poor neurological outcomes were 53% and 48% in the therapeutic
hypothermia and fever control groups, respectively. There were no significant differences in the likelihood of poor
neurological outcome (relative risk [RR] 1.24, 95% confidence interval [CI] 0.62–2.48, p = 0.597) or mortality (RR 1.82,
95% CI 0.82–4.03, p = 0.180) between the two groups. We concluded that tight hemodynamic management and slow
rewarming, together with prolonged therapeutic hypothermia (32–34C) for severe TBI, did not improve the neurological
outcomes or risk of mortality compared with strict temperature control (35.5–37C).

Key words: cardiac output; cerebral perfusion; intracranial pressure; therapeutic hypothermia.

Introduction in patients with severe traumatic brain injury (TBI).8–12 However,

the outcomes of these RCTs were conflicting, possibly because of

M ild therapeutic hypothermia (MTH) improves neuro-

logical outcomes and can prevent severe brain damage after
cardiac arrest.1,2 Beneficial effects of MTH have also been dem-
the significant pathophysiological complexity and variability of
this disease. Additionally, two well-designed RCTs in adults and
children did not show favorable outcomes with the use of MTH in
onstrated in several randomized controlled trials (RCTs) in new- patients with severe TBI.13,14 Although the overall results of the
born infants with perinatal asphyxia,3–6 whereas a recent RCT National Acute Brain Injury Study: Hypothermia (NABISH) study
could not show significant effects of hypothermia between targeted were negative,13 subsequent analyses identified several factors that
temperature management (36C) and TH (33C) with overall good might improve the effects of MTH for treating patients with TBI in
neurological outcome.7 The efficacy of MTH has also been studied clinical settings. These factors included the time to reach the target

1
Department of Stress and Bio-response Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
2
Advanced Medical Emergency and Critical Care Centre, Yamaguchi University Hospital, Yamaguchi, Japan
3
Department of Neurological Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan.
4
Division of Emergency and Critical Care Medicine, Department of Acute Medicine, Nihon University School of Medicine, Tokyo, Japan.
5
School of Integrated Health Sciences, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
*The first two authors contributed equally.
{
The members of the BHYPO study group are listed at the end of the article.

422
PROLONGED HYPOTHERMIA FOR TRAUMATIC BRAIN INJURY 423

temperature,13 fluid management,15 intercenter variations in the and tympanic membrane. In addition to critical neurological care,23
management of MTH,16 and the rewarming process.17 Several an arterial catheter, a pulmonary arterial catheter, and an intracra-
systematic reviews suggested that MTH should be maintained nial pressure (ICP) monitoring probe were inserted to maintain
for > 48 h, and that the rate of rewarming should be very slow.18,19 hemodynamic status and ICP at the following levels: mean arterial
The present study, the Brain-Hypothermia (B-HYPO) Study, pressure (MAP) > 80 mmHg, cardiac index (CI) > 2.5 L/min/m2,
systemic vascular resistance index (SVRI) 800–1200 dynes/sec/
was designed to take into account these earlier discussions and
cm5, ICP < 20 mm Hg, and cerebral perfusion pressure (CPP) > 60
recommendations. Although several trials were published after mm Hg. The partial pressures of arterial oxygen (PaO2) and carbon
starting our study,20–22 the effects of MTH in patients with severe dioxide (PaCO2) were maintained at > 100 mm Hg and 30–40 mm
TBI remained controversial in terms of neurological outcomes. Hg, respectively. If ICP was > 20 mm Hg, any treatment re-
We performed this study in emergency and critical care centers commended by the Japanese guidelines could be applied, including
in Japan to compare the neurological outcomes between TH (32– mannitol/glycerol and/or a bolus infusion of barbiturates,23 but not
34C) and fever control (35.5–37C) for patients with TBI, and to continuous infusion of barbiturates, because of the enormous sup-
clarify the clinical efficacy of MTH. pressive effects on cardiac function. Hyperventilation was allowed,
but excessive hypocapnia < 30 mm Hg was prohibited. ICP could
also be reduced by decompressive craniectomy. Anticonvulsants
Methods were allowed as deemed necessary.
Patients, randomization, and blinding Cooling blankets, rapid cold fluid infusion (up to 1000 mL sa-
line, human plasma products, or dextrose-free plasma expanders),
The study covered the period from December 2002 to September and/or cold gastric lavage could be used during the induction phase
2008. It was designed as a multicenter RCT with prospective an- in both groups. The aim was to achieve the target temperature
alyses and blinded assessment of neurological outcomes. The within 6 h after the onset of TBI. The desired temperature was to be
protocol and consent procedures were approved by the Institutional maintained for ‡ 72 h, mainly using surface cooling blankets, in
Review Board of each participating hospital. The study was reg- each group. The patient was rewarmed at a rate of < 1C/day and
istered with the University Hospital Medical Information Network core body temperature was maintained at < 38C for 7 days after
(UMIN-CTR, No. C000000231) in Japan and the National In- the onset of TBI.
stitutes of Health (Clinical Trials.gov Identifier NCT00134472) in Our sedation protocol specified either midazolam (0.2–0.4 mg/
the United States of America. The randomization list was auto- kg/h) and non-narcotic analgesics for patients treated between
matically generated by the UMIN computer system to allocate December 2002 and April 2005, or neuroleptic analgesia (NLA)
patients in a 2:1 ratio to receive TH (32–34C) or fever control (25 lg/kg/h droperidol and 1 lg/kg/h fentanyl) for patients treated
(35.5–37C). The temperature of the control group was set to 35.5– between May 2005 and May 2008. Vecronium (0.05 mg/kg/h) or
37C for ethical reasons, because MTH was reported to be effective pancuronium (0.05 mg/kg/h) could be used in each sedation pro-
in adult cardiac arrest/resuscitated patients at that time.1,2 We also tocol during the induction and maintenance phases as deemed
attempted to try quick initiation of temperature managements in necessary. In terms of hemodynamic outcomes, NLA may be su-
which cooling was allowed to be 35.5C before the randomization perior to midazolam, because NLA can dilate peripheral blood
in both groups, to prolong duration of hypothermia ( > 72 h), to vessels, increase cardiac output, and facilitate quicker cooling.24
reduce rewarming speed ( < 1.0C/day) and to randomize for two Sedatives and analgesics were usually tapered off, once the patients
parameters (Glasgow Coma Scale [GCS] scores 4–5 and 6–8; ages had been rewarmed to 36C. The muscle relaxant was stopped
15–45 years and 46–69 years) in each participating hospital. when shivering had disappeared, which usually occurred during the
Inclusion criteria were age 15–69 years for both sexes, GCS maintenance phase. Muscle relaxants were restarted as deemed
score of 4–8, and ability to initiate cooling within 2 h after the onset necessary.
of TBI. Patients with any of the following were excluded: good
motor response (GCS motor response = 6), systolic blood pressure
Data collection and study outcomes
< 90 mm Hg after fluid and vasopressor resuscitation, platelet count
< 50,000 /mm3, severe pre-existing medical conditions (e.g., liver, All data, except head CT data, were transmitted to the UMIN
kidney, or heart failure, or severe arrhythmia), acute myocardial center via an Internet-based system. Injury severity score (ISS) and
infarction, pregnancy, severe alcohol intoxication that prevented head CT classification were also assessed. In this study, ISS was
assessment of consciousness, penetrating brain injury, epidural also calculated as an abbreviated injury score (AIS).25 Head CT
hematoma without brain parenchymal injury, or core body tem- was classified as follows: diffuse injury grade I, all diffuse injuries
perature < 30C. Eligible patients were enrolled and their core without CT findings; diffuse injury grade II, high or mixed density
temperature was lowered to the desired temperature as quickly as lesions with a volume of < 25 mL; diffuse injury grade III, high or
possible. Head computed tomography (CT) scans were performed mixed density lesions with a volume of < 25 mL and compressed or
and evaluated on admission and after rewarming in all patients. absent basal cisterns; diffuse injury grade IV, high or mixed density
After obtaining written informed consent from the patient’s le- lesions with a volume of < 25 mL and a midline shift of > 5 mm;
gally authorized representative, the patient was randomized to ei- and evacuated/nonevacuated mass, high or mixed density lesions
ther TH or fever control based on the randomization list. An with a volume of > 25 mL with or without surgical evacuation.26
Internet-based enrolment system managed by the UMIN enabled Hemodynamic and laboratory data were recorded on Days 0, 1, and
instant randomization for the patient upon admission at each par- 3, as well as 1 day after rewarming (defined as the day on which the
ticipating site. Patient private information was secured. If informed core body temperature reached 36C). Representative values were
consent could not be obtained within 2 h of admission, the consent recorded for each day.
policy was waived. The primary outcome, Glasgow Outcome Scale (GOS) at 6
months, was assessed by a neurosurgeon, a neurologist, or an
Treatments emergency physician who was unaware of the patient’s treatment
method.27 After discharge from the original hospital, the patients
Core body temperature was measured by a thermistor coupled to were evaluated by telephone. Severe disability (SD), persistent
an internal jugular venous catheter. If the catheter could not be vegetative state (PVS), or death (D) were defined as poor neuro-
inserted, body temperature was measured in another site that was logical outcomes, whereas moderate disability (MD) or good re-
selected in the following order: pulmonary artery, bladder, rectum, covery (GR) were defined as good neurological outcomes. The
424 MAEKAWA ET AL.

FIG. 1. Patient dispositions. Overall, 99 patients were enrolled in the therapeutic hypothermia group and 51 patients were enrolled in
the fever control group. Hemodynamic status, laboratory parameters, and the primary outcome were assessed in 148 patients.

RCT stopped at the interim because of a shortage of TBI patients

and the trial’s futility. Table 1. Patient Characteristics

Hypothermia Fever control

Statistical analysis (32.0–34.0C) (35.5–37.0C)
The planned sample size of 300 patients allocated in a 2:1 ratio to Variable n = 98 n = 50 p value
receive TH or fever control would detect a 20% difference (90%
power) in the percentage of patients with a good neurological Age (years) 39 – 19 39 – 18 0.940
outcome because the percentage of good neurological outcomes in Male 69 (70) 34 (68) 0.763
severe TBI patients without MTH was 31% by an inquiry taken Systolic blood pressure 144 – 34 151 – 39 0.222
from the participating hospital in Japan before our RCT and there (mmHg)
was a 20% difference between TH and control groups in the cardiac Diastric blood pressure 81 – 20 83 – 20 0.464
arrest /resuscitated patients.1,2 From these facts, the sample sizes (mmHg)
were planned to be 200 and 100 for TH and fever control groups, Heart rate (beats/min) 92 – 28 88 – 24 0.431
respectively. Glasgow Coma Scale 5.8 – 1.4 5.9 – 1.3 0.513
Poor neurological outcomes and mortality were compared be- 4–5 41 (42) 16 (32) 0.245
tween the two groups. Patients were stratified into predefined 6–8 57 (58) 34 (68)
subgroups according to initial GCS (4–5 or 6–8) and age ( £ 45 or Unreactive pupil or pupils 47 (48) 23 (46) 0.821
> 45 years old) based on the results of the first NABISH study.13 Scores on head CT scans
Continuous variables were statistically analyzed using Student’s Diffuse injury grade I 1 (1) 1 (2) 0.600
t test and the Mann–Whitney U test, as appropriate. Categorical Diffuse injury grade II 30 (31) 16 (32)
variables were statistically analyzed using v2 tests and Fisher’s Diffuse injury grade III 15 (15) 9 (18)
exact probability test, where appropriate. The threshold of signifi- Diffuse injury grade IV 3 (3) 1 (2)
cance was set at p < 0.05. Evacuated mass 43 (44) 21 (42)
Nonevacuated mass 5 (5) 0 (0)
Unknown 1 (1) 2 (4)
Results
Surgical operation 61 (62) 31 (62) 0.977
The RCT enrollment began in 2002 and was stopped in 2008 for TBI
before completion of sample size (300 cases) goals, because of Injury severity score 27 – 9 24 – 7 0.037
concern about shortage of TBI patients (95 cases) and very small AIS score for head 4.3 – 0.7 4.2 – 0.7 0.560
differences in neurological outcome between the two groups at the AIS score ‡ 4 10 (10) 3 (6) 0.393
for other organs
interim analysis in 2005. After this analysis, the sedative protocol
was changed from midazolam to NLA as the initial plan. Figure 1 Values are n (%) or mean – standard deviation.
shows the disposition of the 150 patients enrolled and randomized TBI, traumatic brain injury; AIS, Abreviated Injury Score.
PROLONGED HYPOTHERMIA FOR TRAUMATIC BRAIN INJURY 425

Table 2. Patient Characteristics assessed at 6 months in four patients in the TH group and in two
patients in the fever control group, respectively. Four patients in the
Median fever control group received hypothermic treatment during their
(interquartile
Variable Group n range) p value clinical course because of uncontrollable ICP. In these patients,
hypothermic treatment was only performed after several attempts
Time from the onset of TBI to reduce ICP, including decompressive craniectomy.
To admission (h) Hypothermia 98 0.7 (0.5–1.0) 0.780 Table 1 shows the patients’ characteristics. There were no sig-
Fever control 50 0.8 (0.5–0.9) nificant differences between the two groups for age, sex, blood
To randomization (h) Hypothermia 91 3.8 (2.7–5.1) 0.906
pressure, heart rate, GCS on admission, nonreactive pupil or pupils,
Fever control 46 3.3 (2.3–4.5)
To the start Hypothermia 94 3.0 (2.3–4.5) head CT scan scores, neurosurgical operation rate, ISS, AIS score
of cooling (h) for the head, or AIS score ‡ 4 for other organs, except for ISS which
to 35.5C (h) Hypothermia 91 5.2 (3.5–7.5) was significantly higher in the TH group. Decompressive cra-
to 34.0C (h) Hypothermia 92 8.1 (5.3–11.8) niectomy applied to six patients in the TH group and to five in the
Duration of cooling (h) Hypothermia 82 75.5 (68.9–84.0) fever control group. Table 2 shows the times from the onset of TBI
Duration of Hypothermia 80 76.0 (51.5–113.5) to admission, randomization, initiation of cooling, and reaching the
rewarming (h)
desired core body temperature (35.5C or 34C) in the TH group.
TBI, traumatic brain injury. The durations of the maintenance and rewarming periods in the TH
group are also shown. The median times from the onset of TBI to
the desired core body temperatures of 35.5C and 34C in the TH
in this study. Ninety-nine patients were randomized to the TH group were 5.2 h and 8.1 h, respectively. The durations of the
group and 51 to the fever control group. After enrolment, informed cooling and rewarming periods for the hypothermia group were
consent could not be obtained from two patients (one patient per 75.5 h and 76.0 h, respectively. Figure 2 shows temperature curves
group). Therefore, intention-to-treat analyses were performed in in both groups.
148 patients. One patient in the fever control group was found to be Table 3 shows the hemodynamic parameters measured on days
> 70 years old after randomization. Six patients in the TH group and 0, 1, and 3 of treatment, and 1 day after rewarming. Most of the
one patient in the fever control group had unstable vital signs before patients had an arterial catheter (100%), a pulmonary arterial
temperature management. Neurological outcomes could not be catheter (89%), a jugular venous catheter (85%), and an ICP

FIG. 2. Blood temperature. Core temperature was defined as a bladder temperature or blood temperature in the study. Pulmonary
blood temperature of therapeutic hypothermia group and fever control group are plotted. A pulmonary arterial catheter was used for
tight hemodynamic monitoring in 133 patients and automatically recorded blood temperature was available in 84 patients. The
temperature curves display the means, and the I bars indicate – standard deviation.
426 MAEKAWA ET AL.

MAP, mean arterial pressure; ICP, intracranial pressure; CPP, cerebral perfusion pressure; CVP, central venus pressure; CI, cardiac index; SvO2, mixed venous oxygen saturation; SVRI, systemic vascular
Hypothermia Fever control p value Hypothermia Fever control p value Hypothermia Fever control p value Hypothermia Fever control p value
monitor (90%). Consequently, hemodynamic status was well

0.113
0.832
0.188
0.226

0.413
0.669

0.278
0.380
0.736
0.849
controlled (Table 3), and none of these parameters differed between
1 day after rewarming the two groups on any measurement day, except for systemic
vascular resistance index which was significantly higher in the TH

(111–130)

634 – 384
36.7 – 0.8

7.4 – 4.9
4.2 – 1.8
group on day 1. The white blood cell count at 1 day after rewarming

99 – 14
22 – 16

77 – 23
29 (81)

33 (92)
7 (19)

78 – 8
3 (8)
121
and aspartate aminotransferase (AST) on day 3 of treatment were
significantly higher in the TH group than in the fever control group,
whereas the other laboratory parameters did not differ significantly
between the two groups.
(147–219)

622 – 214
Table 4 shows the proportions of patients with poor neurological
36.5 – 0.8

6.5 – 3.4
4.4 – 1.1
8 (11%)
98 – 15
18 – 15

80 – 23
65 (89)

65 (89)
8 (11)

78 – 9
178

outcomes (i.e., SD, PVS, or D) and the mortality rates at 6 months

after the onset of TBI in both groups. Data are shown for all patients
and for subgroups of patients stratified by GCS and age. The overall
rate of poor neurological outcomes in the TH and fever control
< 0.001
0.458
0.602
0.289

0.817
0.642

0.688
0.426
0.936
0.390
groups were 53% and 48%, respectively. We found no significant
difference in the likelihood of poor neurological outcomes, eval-
uated by GOS (relative risk [RR] 1.24, 95% confidence interval
[CI] 0.62–2.48, p = 0.597) and mortality (RR 1.82, 95% CI 0.82–
666 – 242
35.6 – 1.0

7.3 – 3.5
3.8 – 1.1
(67–76)

94 – 18
20 – 15

71 – 28
35 (90)

33 (85)
4 (10)

6 (15)

4.03, p = 0.180), between the patients treated with hypothermia or

79 – 7
72
Day 3

strict fever control groups. There was no significant difference in

the outcome between the two subgroups.
Table 5 shows the incidence of protocol deviation and compli-
cation rates. The time to the target temperature of 34C exceeded
712 – 284
33.6 – 1.0

7.6 – 4.8
3.6 – 1.0
(65–78)

92 – 16
22 – 24

69 – 33
70 (82)
15 (18)

16 (19)
69 (81)

6 h in 62% of patients in the TH group. The overall rates of com-

79 – 9
71

plications were 17% in the TH group and 2% in the fever control

Table 3. Hemodynamic Parameters

group, which were statistically significant.

< 0.001
0.960
0.969
0.612

0.611
0.326

0.338
0.057
0.251
0.038

Discussion
We found no significant difference in the likelihood of poor
neurological outcomes, evaluated by GOS and mortality, between
709 – 256
35.7 – 1.0

5.9 – 3.7
3.5 – 1.0

the patients treated with TH (32–34C) or strict temperature control

(19–31)

89 – 15
22 – 17

64 – 27
37 (84)

35 (80)
7 (16)

9 (20)

78 – 6

(35.5–37C). Background characteristics and the severity of injury

26
Day 1

were similar, except for ISS in both groups, indicating appropriate

randomization of patients (Table 1). In addition, patient care de-
livered in the intensive care units of the participating hospitals was
822 – 298

comparable, as only one hemodynamic parameter (Table 3) and

33.4 – 0.8

6.6 – 4.0
3.1 – 0.9
(20–29)

89 – 15
22 – 24

67 – 27

76 – 11
70 (80)
17 (20)

12 (14)
75 (86)

only a few laboratory parameters differed between the two groups

24

on any of the measurement days. These results might be attributable

to our treatment protocol, hemodynamic management, and nursing
care, among other factors.
0.002
0.135
0.088
0.795

0.296
0.946

0.059
0.824
0.401
0.578

Compared with the NABISH and NABISH II RCTs that also

used TH for severe TBI,13,22 the rates of poor neurological out-
comes and mortality rate were generally similar in the present study
(Table 4).
750 – 458
(2.2–8.3)

36.1 – 0.9

7.0 – 3.7
3.3 – 1.1
95 – 23
29 – 23

76 – 31
25 (71)
10 (29)

27 (82)
6 (18)

We also compared outcomes in subgroups of patients stratified

76 – 7
5.9
Day 0

by GCS (4–5 and 6–8) and age ( £ 45 years old or > 45 years old)
Values are n (%) or mean – standard deviation.

(Table 4). There were no significant differences in the rates of poor

neurological outcomes or mortality between the two groups.
Among patients with a GCS of 6–8, the mortality rate was higher in
807 – 390
(1.5–9.3)

35.3 – 1.6

5.2 – 3.8
3.3 – 1.4
89 – 19
21 – 19

69 – 27

73 – 14
48 (74)
17 (26)

12 (19)
52 (81)

the TH group (33%) than in the fever control group (16%,

5.8

p = 0.084), although this difference was not statistically significant.

Similar observations were reported in a study of children with se-
vere TBI.14 A probable explanation is that hypothermia itself is a
risk factor for mortality in trauma patients.28 Actually, accumulated
Interval from onset (h)

Core temperature (C)

SVRI (dynes/s/cm–5)

complications were significantly higher (Table 5) in the TH group

Interquatile range

(17%) than in the fever control group (2%). Our results may indi-
resistance index.
MAP (mmHg)

CI (L/min/m2)
CVP (mmHg)

cate that TH may be harmful or should be applied more carefully in

CPP (mmHg)
ICP (mmHg)

patients with TBI and a GCS of 6–8.

SvO2 (%)
Variable

In the present study, the fever control group (strict temperature

Median

£ 30
> 30

£ 50
> 50

control to 35.5–37C) had 48% unfavorable outcomes and 23%

mortality (Table 4). Consequently, approximately half of the
PROLONGED HYPOTHERMIA FOR TRAUMATIC BRAIN INJURY 427

Table 4. Rates of Poor Neurological Outcomes and Mortality

Total Poor outcomes Relative risk Total Relative risk

Treatment group n n (%) (95% CI) p value n Mortality (95% CI) p value

All patients 142 1.24 (0.62–2.48) 0.597 142 1.82 (0.82–4.03) 0.180
Hypothermia 94 50 (53) 94 33 (35)
Fever control 48 23 (48) 48 11 (23)
Patients with GCS 4–5 56 0.50 (0.14–1.83) 0.365 56 1.00 (0.30–3.31) 1.000
Hypothermia 40 24 (60) 40 15 (38)
Fever control 16 12 (75) 16 6 (38)
Patients with GCS 6–8 86 1.77 (0.72–4.38) 0.263 86 2.70 (0.89–8.19) 0.084
Hypothermia 54 26 (48) 54 18 (33)
Fever control 32 11 (34) 32 5 (16)
Patients > 45 years old 63 0.89 (0.28–2.82) 1.000 63 1.82 (0.61–5.41) 0.418
Hypothermia 42 29 (69) 42 20 (48)
Fever control 21 15 (71) 21 7 (33)
Patients £ 45 years old 79 1.61 (0.60–4.35) 0.462 79 1.92 (0.56–6.58) 0.392
Hypothermia 52 21 (40) 52 13 (25)
Fever control 27 8 (30) 27 4 (15)

CI, confidence interval; GCS, Glasgow coma scale.

patients with severe TBI could return to their daily life with good As a result, it was proved that the status of statistical non-
outcomes or only moderate disability, a result that may have been significance of TH was not affected at all even after adjusted for
attributable to suppression of reactive hyperthermia. other factors including GCS and ISS.
We admitted that GCS and ISS differed slightly between the two One limitation of our study may be that 62% of patients in the
groups despite the randomization. Therefore, we conducted a post- TH group could not be cooled to the target temperature within 6 h
hoc multivariate logistic analysis to confirm that the differences in (Table 5). In the present study (Table 2), cooling started within a
severity of the cases did not have any effect on the outcome. We set median of 3.0 h, and randomization was achieved within a median
the poor outcome (binary) as the object variable, and age, sex, GCS, of 3.8 h after the onset of TBI, respectively. Physicians might take
ISS, evacuated mass lesion, and TH as the explanatory variables. time to perform a trauma survey before cooling, and 62% of pa-
tients in the therapeutic hypothermia group underwent a surgical
Table 5. Deviations from the Study Protocol procedure for TBI (Table 1). Nevertheless, patients should be kept
and Complications cool during the surgical procedures. It took 8.1 h to reach the target
of 34C in the TH group in the present study (Table 2), which was
Variable n (%) similar to the time taken to reach the target temperature in NABISH
Deviations from the study protocol study.13 Although it had become 4.4 h in NABISH II in 2011, the
Therapeutic hypothermia group 98 neurological outcome was similar between the hypothermia and the
Patients who could not be cooled to control groups. 22 However, this was the fastest time possible using
35.5C within 6 h of TBI onset 35 (36) the available surface cooling methods at the time of performing this
34.0C within 6 h of TBI onset 61 (62) study. Most of the patients allocated to the TH group were not
Unexpected hypotension before temperature 5 (5) cooled to the target temperature within 6 h, highlighting the need
management for additional rapid cooling methods, such as intravenous cooling in
Unexpected hypoxia before temperature 1 (1) a clinical setting.29 It is,therefore, notable that much better results
management were reported in a large retrospective observational study in Japan,
Untreatable bleeding after cooling 2 (2)
in which quicker cooling was achieved using a cardiopulmonary
Continuous infusion of barbiturate or propofol 3 (3)
Fever control group 50 supporting device after cardiac arrest.30
Found to be > 70 years old after randomization 1 (2) The second limitation was that we enrolled only 150 of the
Unexpected hypotension after temperature 1 (2) planned 300 patients, and had used a 2:1 randomization strategy.
management Accordingly, this study was underpowered. The prevalence of TBI
Uncontrollable ICP and using hypothermia 4 (8) decreased during the course of the study because of the im-
treatment plementation of educational campaigns and because the Japanese
Complications government introduced severe penalties for drunk drivers and their
Therapeutic hypothermia group 98 passengers with driving licenses.
Thrombocytopaenia 6 (6) The third limitation was that the control temperature range was
Sepsis 5 (5) chosen to be 35.5–37C. When we designed our protocol, MTH was
Severe pneumonia 3 (3) reported to be effective in the cardiac arrest/resuscitated patients.1,2
Coagulopathy 2 (2) Therefore, we set the control temperature to 35.5–37C for ethical
Arrythmia 1 (1)
reasons. If we had selected it to 36.5–37.5C, finding a difference in
Fever control group 50
Severe pneumonia 1 (2) neurological outcome would have had much less significance. In
patients with severe TBI, we found no differences in the rates of poor
TBI, traumatic brain injury; ICP, intracranial pressure neurological outcomes or mortality between patients who received
428 MAEKAWA ET AL.

prolonged MTH ( ‡ 72 h), slow rewarming, and neurological in- Treatment of traumatic brain injury with moderate hypothermia. N.
tensive care, and those who received strict fever control only. For Engl. J. Med. 336, 540–546.
10. Aibiki, M., Maekawa, S., and Yokono, S. (2000). Moderate hypo-
these reasons, we recommend that further studies be performed to
thermia improves imbalances of thromboxane A2 and prostaglandin I2
assess the clinical outcomes of very rapid cooling and fever control. production after traumatic brain injury in humans. Crit. Care Med. 28,
3902–3906.
Conclusion 11. Jiang, J., Yu, M., and Zhu, C. (2000). Effect of long-term mild hy-
pothermia therapy in patients with severe traumatic brain injury: 1-
Prolonged TH ( ‡ 72 h) for patients with severe TBI together with year follow-up review of 87 cases. J. Neurosurg. 93, 546–549.
tight hemodynamic management and slow rewarming ( < 1.0C/day) 12. Shiozaki, T., Hayakata, T., Taneda, M., Nakajima, Y., Hashiguchi, N.,
did not improve neurological outcomes or mortality compared with Fujimi, S., Nakamori, Y., Tanaka, H., Shimazu, T., and Sugimoto, H.
(2001). A multicenter prospective randomized controlled trial of the
strict fever control. However, the CIs for the primary outcome efficacy of mild hypothermia for severely head injured patients with
were wide, and do not exclude either benefit or harm for MTH. low intracranial pressure. Mild Hypothermia Study Group in Japan. J.
Neurosurg. 94, 50–54.
Acknowledgments 13. Clifton, G.L., Miller, E.R., Choi, S.C., Levin, H.S., McCauley, S.,
Smith, K.R. Jr., Muizelaar, J.P., Wagner, F.C. Jr., Marion, D.W.,
This study was supported by grants from Japanese Ministry of Luerssen, T.G., Chesnut, R.M., and Schwartz, M. (2001). Lack of
Health, Labour and Welfare (H-14-shinkin-005, H-15-shinkin-001, effect of induction of hypothermia after acute brain injury. N. Engl. J.
and H-16-shinkin-001), and the Japanese Human Science Asso- Med. 344, 556–563.
14. Hutchison, J.S., Ward, R.E., Lacroix, J., Hébert, P.C., Barnes, M.A.,
ciation 2002–2004. We thank Takahiro Kiuchi (Director of the Bohn, D.J., Dirks, P.B., Doucette, S., Fergusson, D., Gottesman, R.,
UMIN Centre) and Kiyoshi Ichihara (Yamaguchi University Joffe, A.R., Kirpalani, H.M., Meyer, P.G., Morris, K.P., Moher, D.,
Graduate School of Medicine) for their support. We also thank Singh, R.N., Skippen, P.W., and Hypothermia Pediatric Head Injury
Kees H Polderman (University of Pittsburgh Medical Center) for Trial Investigators and the Canadian Critical Care Trials Group.
(2008). Hypothermia therapy after traumatic brain injury in children.
reviewing our manuscript and for his valuable suggestions.
N. Engl. J. Med. 358, 2447–2456.
15. Clifton, G.L., Miller, E.R., Choi, S.C., and Levin, H.S. (2002). Fluid
Author Disclosure Statement thresholds and outcome from severe brain injury. Crit. Care Med. 30,
739–745.
No competing financial interests exist. 16. Clifton, G.L., Choi, S.C., Miller, E.R., Levin, H.S., Smith, K.R. Jr.,
Muizelaar, J.P., Wagner, F.C. Jr., Marion, D.W., and Luerssen, T.G.
References (2001). Intercenter variance in clinical trials of head trauma–experi-
ence of the National Acute Brain Injury Study: Hypothermia. J.
1. The Hypothermia After Cardiac Arrest Study Group (2002). Mild Neurosurg. 95, 751–755.
therapeutic hypothermia to improve the neurologic outcome after 17. Clifton, G.L., Miller, E.R., Choi, S.C., Levin, H.S., McCauley, S.,
cardiac arrest. N. Engl. J. Med. 346, 549–556. Smith, K.R. Jr., Muizelaar, J.P., Marion, D.W., and Luerssen, T.G.
2. Bernard, S.A., Gray, T.W., Buist, M.D., Jones, B.M., Silvester, W., (2002). Hypothermia on admission in patients with severe brain injury.
Gutteridge, G., and Smith, K. (2002). Treatment of comatose survivors J. Neurotrauma 19, 293–301.
of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J. 18. McIntyre, L.A., Fergusson, D.A., Hébert, P.C., Moher, D., and Hutch-
Med. 346, 557–563. ison, J.S. (2003). Prolonged therapeutic hypothermia after traumatic
3. Shankaran S., Laptook A.R., Ehrenkranz R.A., Tyson J.E., McDonald brain injury in adults: a systematic review. JAMA 289, 2992–2999.
S.A., Donovan E.F., Fanaroff, A.A., Poole, W.K., Wright, L.L., 19. Peterson, K., Carson, S., and Carney, N. (2008). Hypothermia treat-
Higgins, R.D., Finer, N.N., Carlo, W.A., Duara, S., Oh, W., Cotton, ment for traumatic brain injury: a systematic review and meta-anal-
C.M., Stevenson, D.K., Stoll, B.J., Lemons, J.A., Guillet, R., and Jobe, ysis. J. Neurotrauma 25, 62–71.
A.H. (2005). Whole-body hypothermia for neonates with hypoxic- 20. Jiang, J.Y., Xu, W., Li, W.P., Gao, G.Y., Bao, Y.H., Liang, Y.M., and
ischemic encephalopathy. N. Engl. J. Med. 353, 1574–1584. Luo, Q.Z. (2006). Effect of long-term mild hypothermia or short-term
4. Gluckman, P.D., Wyatt, J.S., Azzopardi, D., Ballard, R., Edwards, mild hypothermia on outcome of patients with severe traumatic brain
A.D., Ferriero, D.M., Polin, R.A., Robertson, C.M., Thoresen, M., injury. J. Cereb. Blood Flow Metab. 26, 771–776.
Whitelaw, A., and Gunn, A.J. (2005). Selective head cooling with 21. Qiu, W., Zhang, Y., Sheng, H., Zhang, J., Wang, W., Liu, W., Chen,
mild systemic hypothermia after neonatal encephalopathy: multicenter K., Zhou, J., and Xu, Z. (2007). Effects of therapeutic mild hypo-
radomised trial. Lancet 365, 663–670. thermia on patients with severe traumatic brain injury after craniot-
5. Eicher, D.J., Wagner, C.L., Katikaneni, L.P., Hulsey, T.C., Bass, W.T., omy. J. Crit. Care 22, 229–235.
Kaufman, D.A., Horgan, M.J., Languani, S., Bhatia, J.J., Givelichian, 22. Clifton, G.L., Valadka, A., Zygun, D., Coffey, C.S., Drever, P.,
L.M., Sankaran, K., and Yager, J.Y. (2005). Moderate hypothermia in Fourwinds, S., Janis, L.S., Wilde, E., Taylor, P., Harshman, K.,
neonatal encephalopathy: efficacy outcomes. Pediatr. Neurol. 32, 11–17. Conley, A., Puccio, A., Levin, H.S., McCauley, S.R., Bucholz, R.D.,
6. Azzopardi, D.V., Strohm, B., Edwards, A.D., Dyet, L., Halliday, H.L., Smith, K.R., Schmidt, J.H., Scott, J.N., Yonas, H., and Okonkwo, D.O.
Juszczak, E., Kapellou, O., Levene, M., Marlow, N., Porter, E., (2011). Very early hypothermia induction in patients with severe brain
Thoresen, M., Whitelaw, A., Brocklehurst, P., and TOBY Study injury (the National Acute Brain Injury Study: Hypothermia II): a
Group. (2009). Moderate hypothermia to treat perinatal asphyxial randomized trial. Lancet Neurol. 10, 131–139.
encephalopathy. N. Engl. J. Med. 361, 1349–1358. 23. The Japan Society of Neurotraumatology (2001). Guidelines for the
7. Nielsen N., Wetterslev J., Cronberg T., Erlinge D., Gasche Y., Has- Management of Severe Head Injury. Igaku-Shoin: Tokyo.
sager C., Horn J., Hovdenes J., Kjaergaard J., Kuiper M., Pellis T., 24. Kasaoka, S., Oda, Y., Yamashita, S., Tsuruta, R., Fujisawa, H., Okabayashi,
Stammet P., Wanscher M., Wise M. P., Åneman A., Al-Subaie N., K., and Maekawa, T. (2006). Hemodynamic efficacy of neurolepta-
Boesgaard S., Bro-Jeppesen J., Brunetti I., Bugge J. F., Hingston C. nesthesia for therapeutic hypothermia in acute brain injury, in: Minimally
D., Juffermans N. P., Koopmans M., Køber L., Langørgen J., Lilja G., Invasive Neurosurgery and Multidisciplinary Neurotraumatology. T.
Møller J. E., Rundgren M., Rylander C., Smid O., Werer C., Winkel Kanno, Y. Kato (eds.). Springer-Verlag: Tokyo, pps. 335–338.
P., and Friberg H., for the TTM Trial Investigators (2013). Targeted 25. Civil, I.D., and Schwab, C.W. (1988).The Abbreviated Injury Scale,
temperature management at 33C versus 36C after cardiac arrest. N 1985 revision: a condensed chart for clinical use. J. Trauma 28, 87–90.
Engl. J. Med. 369, 2197–2206. 26. Marshall, L.F., Marshall, S.B., Klauber, M.R., van Berkum Clark, M.,
8. Clifton, G.L., Allen, S., Barrodale, P., Plenger, P., Berry, J., Koch, S., Eisenberg, H.M., Jane, J.A., Luerssen, T.G., Marmarou, A., and
Fletcher, J., Hayes, R.L., and Choi, S.C. (1993). A phase II study of Foulkes, M.A. (1991). A new classification of head injury based on
moderate hypothermia in severe brain injury. J. Neurotrauma 10, 263–271. computerized tomography. J. Neurosurg. 75, S14–S20.
9. Marion, D.W., Penrod, L.E., Kelsey, S.F., Obrist, W.D., Kochanek, 27. Jennett, B., and Bond, M. (1975). Assessment of outcome after severe
P.M., Palmer, A.M., Wisniewski, S.R., and DeKosky, S.T. (1997). brain damage. Lancet 1, 480–484.
PROLONGED HYPOTHERMIA FOR TRAUMATIC BRAIN INJURY 429

28. Eddy, V.A., Morris, J.A., Jr., and Cullinane, D.C. (2000). Hypothermia, Address correspondence to:
coagulopathy, and acidosis. Surg. Clin. North Am. 80, 845–854. Tsuyoshi Maekawa, MD, PhD
29. Holzer, M., Müllner, M., Sterz, F., Robak, O., Kliegel, A., Losert, H.,
Department of Stress and Bio-Response Medicine
Sodeck, G., Uray, T., Zeiner, A., and Laggner, A.N. (2006). Efficacy
and safety of endovascular cooling after cardiac arrest: cohort study Yamaguchi University Graduate School of Medicine
and Bayesian approach. Stroke 37, 1792–1797. 1-1-1 Minami-Kogushi
30. Nagao, K., Kikushima, K., Watanabe, K., Tachibana, E., Tominaga, Y., Ube, Yamaguchi 755-8505
Tada, K., Ishii, M., Chiba, N., Kasai, A., Soga, T., Matsuzaki, M., Nishikawa, Japan
K., Tateda, Y., Ikeda, H., and Yagi, T. (2010). Early induction of hypo-
thermia during cardiac arrest improves neurological outcomes in patients
with out-of-hospital cardiac arrest who undergo emergency cardiopulmo- E-mail: [email protected]
nary bypass and percutaneous coronary intervention. Circ. J. 74, 77–85.

Appendix: Authors’ Contributions

T.M. designed the study concept with input from other authors. Hospital, Ehime; Ohota Nishinouchi Hospital, Fukushima; Gifu
S.Y. wrote the entire study protocol and built the data input system. University Hospital, Gifu; Sapporo University Hospital, Hokkaido;
Y.O. managed all data and performed statistical analysis. S.N. and The Hospital of Hyogo College of Medicine, Hyogo; Iwate Medical
N.H. greatly contributed to the study concept and writing of the University Hospital, Iwate; Kagawa University Hospital, Kagawa;
report. T.M. wrote the first draft of the report and other study group Kitasato University Hospital, Kanagawa; St. Marianna University
members contributed to subsequent drafts. Hospital, Kanagawa; Aizawa Hospital, Nagano; Shinshu University
Other B-HYPO Study Group members were Mayuki Aibiki, Toru Hosiptal, Nagano; Nara Medical University Hospital, Nara; Oita
Aruga, Yasufumi Asai, Kenji Dohi, Yutaka Eguchi, Motoki Fujita, University Hospital, Oita; Kawasaki Medical School Hospital,
Toshio Fukuoka, Kazumi Ikeda, Tomomi Iwashita, Kotaro Kaneda, Okayama; Kansai Medical University Takii Hospital, Osaka; Mis-
Tadashi Kaneko, Yoko Kato, Kenya Kawakita, Kosaku Kinoshita, hima Emergency Critical Care Center, Osaka; Osaka National Hos-
Takao Kitahara, Kazuo Kitazawa, Hitoshi Kobata, Hiroyasu Koi- pital, Osaka; Saitama Medical Center, Saitama; Shiga University
zumi, Yasuhiro Kuroda, Seishiro Marukawa, Kazuhisa Mori, Hiroshi Hospital, Shiga; Saiseikai Utsunomiya Hospital, Tochigi; Tokushima
Nakamura, Shunsuke Nakamura, Masashi Nakatsukasa, Norifumi University Hospital, Tokushima; Japanese Red Cross Musashino
Ninomiya, Shigeto Oda, Yasutaka Oda, Kazuo Okuchi, Ryoichi Hospital, Tokyo; National Tokyo Medical Center, Tokyo; Nihon
Saito, Atsushi Sugie, Shinichiro Suzaki, Koichiro Suzuki, Michiyasu University Hospital, Tokyo; Nippon Medical School Hospital, Tokyo;
Suzuki, Yasuhiko Taira, Jun Takezawa, Hiroki Tomita, Hiroyuki Nippon Medical School Tama Nagayama Hospital, Tokyo; Showa
Yokota, Shinichi Yoshimura, and Tetsuo Yukioka, These authors University Hospital, Tokyo; Teikyo University Hospital, Tokyo;
contributed to the research and preparation of the report. Toho University Omori Medical Center, Tokyo; Tokyo Medical
Collaborating hospitals were Fujita Health University Hospital, University Hachioji Medical Center, Tokyo; Tokyo Medical Uni-
Aichi; Nagoya Medical Center, Aichi; Chiba Emergency Medical versity Hospital, Tokyo; and Yamaguchi University Hospital, Ya-
Center, Chiba; Chiba University Hospital, Chiba; Ehime University maguchi. All collaborating hospitals are in Japan.